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['PMC8253860'] | ['34215730'] | ['Tab1', 'MOESM1', 'MOESM1', 'Fig1', 'Fig1', 'Fig1', 'Fig1', 'MOESM1', 'MOESM1', 'MOESM1', 'MOESM1', 'MOESM1', 'MOESM1'] | To determine how the TCR repertoire of TIL/Tc influenced PD1 CPB outcome, we analyzed pre-treatment biopsies from 16 metastatic melanoma patients who received anti-PD1 agents in Manchester, Padova, and Meldola (Table1). There were no differences in total TIL/Tc numbers, the number of TIL/Tc clones, or the diversity and clonality of the TCR when comparing lymph-node tumors and tumors from extranodal sites (Supplementary Fig.1a–d), suggesting that the lymph-node microenvironment did not affect tumor infiltration by T cells. We also did not find significant correlation between patient overall survival (OS) and baseline peripheral serum lactic dehydrogenase levels, total number of TIL/Tc, number of TIL/Tc clones, TCR diversity, the number of non-synonymous single-nucleotide variants (SNVs), or PD-L1 staining (Supplementary Table1). However, we did find better OS and reduced death hazard (Cox regressionP= 0.0401, hazard ratio = 4.8 × 10−14, C-index = 0.88) correlated to high TCR clonality in these pre-treatment tumor samples (Fig.1A, B). We validated our findings using published data from 106 metastatic melanoma patients biopsied prior to treatment with PD1 or sequential PD1/CTLA4 blockade6,7. Here again, better OS correlated with higher TIL/Tc TCR clonality (P= 0.0225, external validation C-index = 0.582, 95% confidence interval = 0.501–0.664; Fig.1C, D).Table 1Training cohort clinical characteristics.N(%)Median (range)Age (years)68 (28–83.7)SexMale7 (44)Female9 (56)Drug receivedNivolumab4 (25)Pembrolizumab12 (75)StageUnresectable stage III2 (12)M1a6 (38)M1b1 (6)M1c7 (44)Lactic dehydrogenase (U/L)287 (51–822)The table shows the number of patients with the given characteristic with the percentage in parentheses or the median value for the variable with the range in parentheses.Fig. 1TIL/Tc TCR repertoire in melanoma biopsies is predictive for overall survival and response to PD1 CPB.ASurvival curves for our metastatic melanoma training cohort of patients treated with anti-PD1 drugs with high (green) or low (orange) pre-treatment TIL/Tc clonality (n= 16, cut-off = 0.06, log-rankP= 0.0003),Bpredictive effect of TIL/Tc clonality on the relative hazard for death in the same cohort asA.Y-axis: log of relative hazard; a hazard ratio (HR) of 1 corresponds to 0, upper values correspond to HR > 1, and lower values correspond to HR < 1. The blue curves represent the HR function and “Rug plots” on curves show the density of the predictor (univariate Cox regressionP= 0.0193); pointwise 95% confidence bands (shadowed area) are also shown.CSurvival curves for the metastatic melanoma validation cohort6,7of patients treated with anti-PD1 drugs with high (green) or low (orange) pre-treatment TIL/Tc clonality (n= 106, cut-off = 0.10, log-rankP= 0.0039),Dpredictive effect of TIL/Tc clonality on the relative hazard of death in the same cohort (univariate Cox regressionP= 0.0225).EViolin plots of the pre-treatment TIL/Tc clonality distribution in patients who achieved radiological response (green,n= 12, median = 0.23, SD = 0.09) and progressed (orange,n= 13, median = 0.14, SD = 0.07) to treatment with PD1 CPB in a metastatic melanoma cohort9(simple logistic regression log-likelihood ratio for association with probability of response = 8.6,P= 0.0033,n= 25) andFreceiver operating curve (ROC) of the linear regression response prediction (area under the curve = 0.89).GViolin plots of the pre-treatment TIL/Tc clonality distribution in patients who achieved radiological response (green,n= 6, median = 0.15, SD = 0.09) and progressed (orange,n= 12, median = 0.04, SD = 0.05) to treatment with PD1 CPB in a metastatic melanoma cohort8(simple logistic regression log-likelihood ratio for association with probability of response = 7.2,P= 0.007,n= 18) andHreceiver operating curve (ROC) of the linear regression response prediction (area under the curve = 0.81).IViolin plots of the pre-treatment TIL/Tc clonality distribution in patients who achieved radiological response (green,n= 9, median = 0.14, SD = 0.09) and progressed (orange,n= 9, median = 0.06, SD = 0.05) to treatment with neoadjuvant PD1 CPB in an advanced melanoma cohort10(simple logistic regression log-likelihood ratio for association with probability of response = 4.5,P= 0.0340,n= 18) andJreceiver operating curve (ROC) of the linear regression response prediction (area under the curve = 0.74). Analyses are two-sided; TIL/Tc clonality and diversity are retained as continuous variables in the regression analyses;nis single patient; single green dots represent single patients; horizontal dotted lines in the violin plots represent median and SD; SD = standard deviation. Source data are provided as a Source data file. To ensure that OS was not confounded by subsequent treatments, we also tested the correlation between TIL/Tc TCR clonality and PD1 CPB response. In two independent metastatic melanoma patient cohorts8,9, we found that pre-treatment TIL/Tc TCR clonality was directly associated with the likelihood of response for metastatic palliative and neoadjuvant PD1 CPB10(Fig.1E–H, area under the curve [AUC] of the receiver operating curve [ROC] = 0.89 and 0.81and Fig.1I, J, AUC of the ROC = 0.74, respectively), and although the numbers were too small to draw conclusions, only patients with TIL/Tc TCR clonality above the median have recurred at the time of analysis (Supplementary Fig.2a). Intriguingly, the analysis of TIL/Tc TCR clonality in the on-treatment biopsy did not increase the performance of the prediction for response (Supplementary Fig.2b, c, AUC of ROC = 0.74). Notably, we observed consistency of our findings across the two platforms (TCR reconstruction from RNA sequencing (RNA-Seq) and targeted TCR sequencing) used to reconstruct the TCR in these melanoma cohorts and also with no significant difference in the overall TIL/Tc clonality, although TCR reconstruction from the RNA-Seq data yielded overall fewer unique TCR clonotypes than from the targeted TCR sequencing (Supplementary Fig.3a, b). The cumulative CDR3 length was also comparable in the samples analyzed with the two platforms (Supplementary Fig.3c), and we did not observe significant skewing of V gene representation (Supplementary Fig.4a, b), nor striking differences in the similarity scores across samples, since these were largely unrelated in the two series (Supplementary Fig.5a, b). Thus, high TCR clonality in the pre-treatment TIL/Tc population was predictive for PD1 CPB activity and efficacy across multiple series and using two methods to identify the TCR sequences. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | [] | ASurvival curves for our metastatic melanoma training cohort of patients treated with anti-PD1 drugs with high (green) or low (orange) pre-treatment TIL/Tc clonality (n= 16, cut-off = 0.06, log-rankP= 0.0003),Bpredictive effect of TIL/Tc clonality on the relative hazard for death in the same cohort asA.Y-axis: log of relative hazard; a hazard ratio (HR) of 1 corresponds to 0, upper values correspond to HR > 1, and lower values correspond to HR < 1. The blue curves represent the HR function and “Rug plots” on curves show the density of the predictor (univariate Cox regressionP= 0.0193); pointwise 95% confidence bands (shadowed area) are also shown.CSurvival curves for the metastatic melanoma validation cohort6,7of patients treated with anti-PD1 drugs with high (green) or low (orange) pre-treatment TIL/Tc clonality (n= 106, cut-off = 0.10, log-rankP= 0.0039),Dpredictive effect of TIL/Tc clonality on the relative hazard of death in the same cohort (univariate Cox regressionP= 0.0225).EViolin plots of the pre-treatment TIL/Tc clonality distribution in patients who achieved radiological response (green,n= 12, median = 0.23, SD = 0.09) and progressed (orange,n= 13, median = 0.14, SD = 0.07) to treatment with PD1 CPB in a metastatic melanoma cohort9(simple logistic regression log-likelihood ratio for association with probability of response = 8.6,P= 0.0033,n= 25) andFreceiver operating curve (ROC) of the linear regression response prediction (area under the curve = 0.89).GViolin plots of the pre-treatment TIL/Tc clonality distribution in patients who achieved radiological response (green,n= 6, median = 0.15, SD = 0.09) and progressed (orange,n= 12, median = 0.04, SD = 0.05) to treatment with PD1 CPB in a metastatic melanoma cohort8(simple logistic regression log-likelihood ratio for association with probability of response = 7.2,P= 0.007,n= 18) andHreceiver operating curve (ROC) of the linear regression response prediction (area under the curve = 0.81).IViolin plots of the pre-treatment TIL/Tc clonality distribution in patients who achieved radiological response (green,n= 9, median = 0.14, SD = 0.09) and progressed (orange,n= 9, median = 0.06, SD = 0.05) to treatment with neoadjuvant PD1 CPB in an advanced melanoma cohort10(simple logistic regression log-likelihood ratio for association with probability of response = 4.5,P= 0.0340,n= 18) andJreceiver operating curve (ROC) of the linear regression response prediction (area under the curve = 0.74). Analyses are two-sided; TIL/Tc clonality and diversity are retained as continuous variables in the regression analyses;nis single patient; single green dots represent single patients; horizontal dotted lines in the violin plots represent median and SD; SD = standard deviation. Source data are provided as a Source data file. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | ['Fig2', 'MOESM1', 'MOESM1', 'Fig2', 'Fig2', 'MOESM1'] | To test whether high TIL/Tc TCR clonality also correlated to prognosis in melanoma patients who did not receive PD1 CPB, we analyzed the TIL/Tc TCR repertoire in The Cancer Genome Atlas (TCGA) melanoma cohort11, because the data-lock for these samples predated approval of anti-PD1 inhibitors. As expected, in multivariate analysis, age, clinical stage, and prevalence of single base substitution signature 7 (SBS7v2)12,13were prognostic for OS (P< 0.001; Fig.2Aand Supplementary Table2). Notably, whereas TIL/Tc TCR clonality was not prognostic for survival in this cohort (Supplementary Table2), high TIL/Tc TCR diversity was associated with better OS (Fig.2B). Thus, high TCR diversity in pre-treatment TIL/Tc was prognostic for OS in melanoma patients who did not receive anti-PD1 treatments, and the addition of TCR diversity to the standard clinical covariates significantly increased the prognostic C-index (from 0.646 to 0.693, analysis of varianceP< 0.001). To quantify cumulative melanoma risk based on these findings, we developed a nomogram to assist clinical decisions (Fig.2C) and provide an example of the use of this tool (Supplementary Fig.6).Fig. 2TIL/Tc TCR repertoire in melanoma biopsies is prognostic for overall survival in absence of PD1 CPB.Analyses of TCGA skin melanoma cohort (n= 412):Aforest plot showing HR and 95% CI for significant covariates retained in the multivariate Cox regression prognostic model calculated using the fast-backward method and the Akaike Information Criterion as a stopping rule (events = 147, model for OS globalP< 0.001, concordance index = 0.71);Bsurvival curves for patients with high (blue) or low (pink) TIL/Tc diversity (cut-off = 3.49, log-rankP< 0.0001);Cnomogram tailored on the final model with the significant prognostic factors fromA; the sum of the prognostic factor values corresponds to the survival probability at 24 and 60 months, an example of the nomogram use is shown in Supplementary Fig.6. Analyses are two-sided; TIL/Tc clonality and diversity are retained as continuous variables in the regression analyses;nis single patient, OS is overall survival, HR is hazard ratio, CI is confidence interval; signature 7 is single base substitution signature 7 version 212,13. Source data are provided as a Source data file. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | ['MOESM1'] | Analyses of TCGA skin melanoma cohort (n= 412):Aforest plot showing HR and 95% CI for significant covariates retained in the multivariate Cox regression prognostic model calculated using the fast-backward method and the Akaike Information Criterion as a stopping rule (events = 147, model for OS globalP< 0.001, concordance index = 0.71);Bsurvival curves for patients with high (blue) or low (pink) TIL/Tc diversity (cut-off = 3.49, log-rankP< 0.0001);Cnomogram tailored on the final model with the significant prognostic factors fromA; the sum of the prognostic factor values corresponds to the survival probability at 24 and 60 months, an example of the nomogram use is shown in Supplementary Fig.6. Analyses are two-sided; TIL/Tc clonality and diversity are retained as continuous variables in the regression analyses;nis single patient, OS is overall survival, HR is hazard ratio, CI is confidence interval; signature 7 is single base substitution signature 7 version 212,13. Source data are provided as a Source data file. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | ['Fig3', 'MOESM1', 'MOESM1', 'Fig3', 'MOESM1'] | Since PD1 CPB is now standard of care for melanoma in the adjuvant and metastatic settings, prospective analysis of anti-PD1 naive melanoma patients who will not receive CPB in their clinical history is no longer feasible, so we examined TIL/Tc TCR diversity and clonality in other TCGA cancer cohorts. This also allowed us to assess whether the prognostic value of pre-treatment TIL/Tc is unique to melanoma or is shared by other cancers. We focused on the cancers with an average TIL/Tc count in the highest quartile (>317.5), which includes breast cancer (BRCA), melanoma (SKCM), squamous lung carcinoma (LUSC), lung adenoma (LUAD), thymoma (THYM), clear cell renal cancer (KIRC), and testicular cancer (TGCT) (Fig.3Aand Supplementary Tables3–7). As in previous studies14, we restricted our LUSC analysis to patients with low cigarette use, and due to insufficient OS events15, we used progression-free interval as the TGCT endpoint. Also, due to the small number of events for patients with TCR data, we could not perform regression analysis for THYM15. Despite these restrictions, we found that high TCR diversity in the TIL/Tc was associated with improved survival in all of these cancers (Fig.3B–L) while clonality was not, although it had borderline significance for OS in KIRC (Supplementary Table7).Fig. 3TIL/Tc TCR diversity is prognostic across several cancer histotypes.A–LAnalyses of the TCGA cancer cohorts.AEstimated total number of tumor-infiltrating T cells (TIL/Tc) in the cancer cohorts; the cohorts above the upper quartile of TIL/Tc are highlighted in blue;B–Gsurvival curves for the cancer cohorts with abundant TIL/Tc fromAof patients with high (blue) or low (pink) TIL diversity:BBRCA (n= 908, cut-off = 3.34, OS log-rankP= 0.0029),CLUSC patients with cigarette use < median (n= 238, cut-off = 3.17, OS log-rankP= 0.2849),DLUAD (n= 481, cut-off = 3.53, OS log-rankP= 0.0204),ETGCT (n= 148, cut-off = 3.29, DFI log-rankP= 0.0124),FKIRK (n= 322, cut-off = 3.26, OS log-rankP= 0.0088),GTHYM (n= 92, cut-off = 5.93, OS log-rankP= 0.0306);H–Lforest plots showing the HR and 95% CI for the significant covariates retained in the multivariate Cox regression prognostic model calculated using the fast-backward method and the Akaike Information Criterion as a stopping rule for the cancer cohorts with abundant TIL/Tc from A; TIL/Tc metrics were analyzed as continuous variables:HBRCA (events = 113, model for OS globalP< 0.001, concordance index = 0.66),ILUSC patients with cigarette use < median (events = 31, model for OS global P = 0.0096, concordance index = 0.69),JLUAD (events = 166, model for OS globalP< 0.001, concordance index = 0.63),KTGCT (events = 31, model for PFSP= 0.0637, concordance index = 0.63),LKIRK (events = 53, model for OS globalP< 0.001, concordance index = 0.74). Analyses are two-sided and TIL/Tc diversity is retained as continuous variable in the regression analyses;nis single patient, OS is overall survival, DFI is disease-free-interval, PFS is progression-free survival, HR is hazard ratio, CI is confidence interval. (BLLG brain lower grade glioma,n= 289; PCPG pheochromocytoma and paraganglioma,n= 142; ADCC adrenocortical carcinoma,n= 40; GBMF glioblastoma multiforme,n= 140; UTSC uterine carcinosarcoma,n= 45; UVML uveal melanoma,n= 47; KICH kidney chromophobe,n= 82; SARC sarcoma,n= 218; LIHC liver hepatocellular carcinoma,n= 383; CHOL cholangiocarcinoma,n= 42; BLCA bladder urothelial carcinoma,n= 380; KIRP kidney renal papillary cell carcinoma,n= 295; UCEC uterine corpus endometrial carcinoma,n= 184; THCA thyroid carcinoma,n= 518; HNSC head and neck squamous cell carcinoma,n= 524; COAD colon adenocarcinoma,n= 325; PRAD prostate adenocarcinoma,n= 536; MESO mesothelioma,n= 83; READ rectum adenocarcinoma,n= 100; PAAD pancreatic adenocarcinoma,n= 145; DLBC diffuse large B cell lymphoma,n= 331; CESC cervical squamous cell carcinoma and endocervical adenocarcinoma,n= 296; BRCA breast carcinoma,n= 1160; SKCM skin cutaneous melanoma,n= 426; LUSC lung squamous carcinoma,n= 528; LUAD lung adenocarcinoma,n= 585; TGCT testicular germinal cell tumors,n= 153; KIRC kidney renal clear cell carcinoma,n= 597; THYM thymoma,n= 93). Source data are provided as a Source data file. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | [] | A–LAnalyses of the TCGA cancer cohorts.AEstimated total number of tumor-infiltrating T cells (TIL/Tc) in the cancer cohorts; the cohorts above the upper quartile of TIL/Tc are highlighted in blue;B–Gsurvival curves for the cancer cohorts with abundant TIL/Tc fromAof patients with high (blue) or low (pink) TIL diversity:BBRCA (n= 908, cut-off = 3.34, OS log-rankP= 0.0029),CLUSC patients with cigarette use < median (n= 238, cut-off = 3.17, OS log-rankP= 0.2849),DLUAD (n= 481, cut-off = 3.53, OS log-rankP= 0.0204),ETGCT (n= 148, cut-off = 3.29, DFI log-rankP= 0.0124),FKIRK (n= 322, cut-off = 3.26, OS log-rankP= 0.0088),GTHYM (n= 92, cut-off = 5.93, OS log-rankP= 0.0306);H–Lforest plots showing the HR and 95% CI for the significant covariates retained in the multivariate Cox regression prognostic model calculated using the fast-backward method and the Akaike Information Criterion as a stopping rule for the cancer cohorts with abundant TIL/Tc from A; TIL/Tc metrics were analyzed as continuous variables:HBRCA (events = 113, model for OS globalP< 0.001, concordance index = 0.66),ILUSC patients with cigarette use < median (events = 31, model for OS global P = 0.0096, concordance index = 0.69),JLUAD (events = 166, model for OS globalP< 0.001, concordance index = 0.63),KTGCT (events = 31, model for PFSP= 0.0637, concordance index = 0.63),LKIRK (events = 53, model for OS globalP< 0.001, concordance index = 0.74). Analyses are two-sided and TIL/Tc diversity is retained as continuous variable in the regression analyses;nis single patient, OS is overall survival, DFI is disease-free-interval, PFS is progression-free survival, HR is hazard ratio, CI is confidence interval. (BLLG brain lower grade glioma,n= 289; PCPG pheochromocytoma and paraganglioma,n= 142; ADCC adrenocortical carcinoma,n= 40; GBMF glioblastoma multiforme,n= 140; UTSC uterine carcinosarcoma,n= 45; UVML uveal melanoma,n= 47; KICH kidney chromophobe,n= 82; SARC sarcoma,n= 218; LIHC liver hepatocellular carcinoma,n= 383; CHOL cholangiocarcinoma,n= 42; BLCA bladder urothelial carcinoma,n= 380; KIRP kidney renal papillary cell carcinoma,n= 295; UCEC uterine corpus endometrial carcinoma,n= 184; THCA thyroid carcinoma,n= 518; HNSC head and neck squamous cell carcinoma,n= 524; COAD colon adenocarcinoma,n= 325; PRAD prostate adenocarcinoma,n= 536; MESO mesothelioma,n= 83; READ rectum adenocarcinoma,n= 100; PAAD pancreatic adenocarcinoma,n= 145; DLBC diffuse large B cell lymphoma,n= 331; CESC cervical squamous cell carcinoma and endocervical adenocarcinoma,n= 296; BRCA breast carcinoma,n= 1160; SKCM skin cutaneous melanoma,n= 426; LUSC lung squamous carcinoma,n= 528; LUAD lung adenocarcinoma,n= 585; TGCT testicular germinal cell tumors,n= 153; KIRC kidney renal clear cell carcinoma,n= 597; THYM thymoma,n= 93). Source data are provided as a Source data file. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | [] | Our data shows that, as in melanoma, in various other cancers TIL/Tc diversity is prognostic for OS in the absence of PD1 blockade, whereas pre-treatment TIL/Tc clonality is predictive of response to anti-PD1 treatment. This is consistent with observations that on-treatment TIL/Tc clonality anticipates radiological response to immunotherapy in melanoma8,16. Our results suggest that high TCR diversity in TIL/Tc identifies patients whose immune system achieves durable tumor control without anti-PD1 therapy, whereas high TIL/Tc clonality identifies which patients will mount an effective anti-PD1-induced immune response. The reconstruction of the TCR using cancer transcriptomic datasets is a powerful approach in defining the T cell repertoire in solid tumors, but here we show that targeted TCR sequencing approaches identify more unique TCR clonotypes than reconstruction from RNA-Seq data and consequently targeted sequencing could provide a more robust resolution when analyzing samples presenting limited numbers of TIL/Tc. Despite this, we showed consistent results with the two platforms, supporting our hypothesis that TIL/Tc repertoire analysis provides new ways to explore delivery of personalized immunotherapy, although we expect more sensitive and accurate approaches to eventually replace existing state-of-the-art solutions. With adjuvant PD1 CPB already approved in stage III melanoma and currently being trialed in stage II melanoma (NCT03553836), the need for predictive and prognostic stratification tools for CPB is becoming more pressing. This is particularly important for patients with intermediate-risk disease where the odds of toxicity could outweigh the benefit of adjuvant immunotherapy and where the TIL/Tc repertoire could provide a much-needed reliable biomarker for patient selection. More studies are needed to determine why high TIL/Tc clonality is predictive of CPB benefit, whereas TIL/Tc diversity is prognostic in the absence of CPB, but our findings nevertheless have important clinical implications because of their potential to contribute to the development of personalized therapeutic strategies through the identification of the patients who could better benefit from treatments. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | [] | The training cohort patient samples do not involve clinical trials/clinical trial-associated data, as patient samples were collected prior to standard-of-care treatment. Biopsy pre-treatment samples from Manchester patients were prospectively collected under the Manchester Cancer Research Centre (MCRC) Biobank ethics application #18/NW/0092; the study was approved by MCRC Biobank Access Committee application 13_RIMA_01. Biopsy pre-treatment samples and clinical information from Padova patients were collected under the University of Padova Department of Surgery, Oncology and Gastroenterology ethics application 04/03/2002 protocol #448 and Veneto Oncology Institute ethics approval 09/04/2018 protocol #006264. Biopsy pre-treatment samples from Meldola patients were collected under ethics application #5483/2018 of Comitato Etico della Romagna. All patients gave written informed consent to the use of the samples for research purposes. Clinical endpoints: date of death was obtained from clinical records (pre-CPB training cohort), the original publications (pre-CPB validation cohorts), and TCGA clinical information files. Radiological response information was obtained from the original publications. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | [] | RNA was extracted from pre-treatment human fresh frozen tumor samples using the AllPrep DNA/RNA Kit (Qiagen, Manchester, UK) according to the manufacturer’s instructions: briefly, tissue samples were first lysed and homogenized in a highly denaturing guanidineisothiocyanate-containing buffer to inactivate DNases and RNases and ensure isolation of intact DNA and RNA; the lysates were then passed through an AllPrep DNA membrane that, in combination with the high-salt buffer, binded the genomic DNA that was then eluted; ethanol was added to the flow-throughs from the AllPrep DNA membrane to provide appropriate binding conditions for RNA, and the samples were then applied to an RNeasy membrane; total RNA binded to the membranes and contaminants were washed away; high-quality RNA was then eluted in 45–70 μl water. Indexed PolyA libraries were prepared using 200 ng of total RNA and 14 cycles of amplification with the Agilent SureSelect Strand Specific RNA Library Prep Kit for Illumina Sequencing (Agilent, G9691B, Santa Clara, CA, US). Libraries were quantified by quantitative PCR (qPCR) using the KAPA Library Quantification Kit for Illumina platforms (Kapa Biosystems Inc., KK4873, Wilmington, MA, US). Paired-end 100 bp sequencing was carried out by clustering 15 pM of pooled libraries on the cBot and sequenced on the Illumina HiSeq 2500 in high output mode using TruSeq SBS V3 chemistry (Illumina Inc., San Diego, CA, US); average of all samples was 68 million pass-filter (PF) reads (each end). The primers were all supplied as part of the kits that are listed. After removing adapters using Cutadapt (v1.14) and trimming poor quality base calls using Trimmomatic (v0.36)17, the human reads were aligned to GRCh37 (release 75) using STAR (v2.5.1) aligner18. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | [] | CDR3 TCR sequence data generated by Bo Li et al.11for the 29 TCGA cohorts were kindly made available by the authors; the clinical data for the cohorts were downloaded from cBioportal in February 2018. CDR3 TCR sequences were inferred from RNA Seq data from pre-treatment biopsies for the training cohort samples using ImReP19; inclusion criterion for downstream analyses was minimum four TCR sequences identified. Clonality was calculated with the functionclonalityfromLymphoSeqR package; heatmaps were generated usingLymphoSeq,pheatmap, andggplot2R packages. The diversity was calculated using Renyi index (α= 1) as per Spreafico et al.20. Whole-exome sequencing snap-frozen tumor tissue was manually dissected by sectioning (25-μm thick), and DNA was extracted from sections with an estimated tumor cell percentage of at least 80% using the AllPrep DNA/RNA Kit (Qiagen) according to the manufacturer’s instructions, as per description above. Germline DNA was isolated from patients’ blood. DNA quantity was assessed using a Qubit® 2.0 Fluorometer (Life Technologies). One microgram of genomic DNA was sheared using a Covaris S2 ultrasonicator (Covaris, Inc.). Multiplexed libraries were prepared using the SureSelectXT Target Enrichment System for Illumina Paired-End Sequencing and the SureSelect Human All Exon V6 Capture Library (Agilent, G9641B/5190-8864). Libraries were quantified by qPCR using the KAPA Library Quantification Kit for Illumina platforms (Kapa Biosystems, Inc., KK4873). Paired-end 100 bp sequencing was carried out by clustering 14 pM of pooled libraries on the cBot and sequenced on the Illumina HiSeq 2500 in high output mode using TruSeq SBS V3 chemistry (Illumina, Inc.); average PF reads (each end) was 126 million for tumor samples and 67 million for germline samples. The primers were all supplied as part of the kits that are listed. After removing adapters using Cutadapt (v1.14) and trimming poor quality base calls using Trimmomatic (v0.36), the reads were aligned to the GRCh37 (release 75) human genome using BWA aligner (v0.7.7). The PCR duplicate reads were filtered using Picard (v1.96), and the base quality score recalibration and local INDEL realignments were performed using GATKtools (v3.1). Using tumor–normal pairs, SNVs were identified using MuTect21(v1.1.7). Variant Effect Predictor (Ensembl version 73/84) was used to annotate the mutations. Known variants present in dbSNP were excluded. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | [] | Mutational signatures for TCGA SKCM cohort were determined by fitting somatic SNVs with tri-nucleotide context to the 30 COSMIC mutational signatures using deconstructSigs12package using default parameters. Signatures with contribution weights <6% were excluded. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | [] | Pre-treatment biopsy samples were fixed in 10% neutral buffered formalin (Sigma-Aldrich), processed, and embedded in paraffin wax. Samples were sectioned (4 μm) and stained with hematoxylin and eosin using standard protocols. Formalin-fixed paraffin-embedded sections were deparaffinized using xylene and rehydrated passing through a series of graded ethanol to distilled water steps. Heat-induced epitope retrieval (125 °C, 60 s; 90 °C, 10 s) was performed using a Pascal pressure chamber (Dako) with Dako target retrieval solution pH 6 (S203130, Agilent Technologies, Santa Clara, California, US). Sections were then processed and stained with anti-PD-L1 22C3 PharmDx (Agilent Technologies, Santa Clara, CA, US) as per the manufacturer’s instructions: briefly, after peroxidase block for 5 min, the sections were incubated with the 22C3 antibody using a concentration of 1:50 for 60 min at room temperature and then incubated for 30 min at room temperature with the linker antibody provided with the kit and specific to the host species of the primary antibody; finally, the sections were incubated with a ready-to-use visualization reagent provided with the kit and consisting of secondary antibody molecules and horseradish peroxidase molecules coupled to a dextran polymer backbone. Sections were then quantified by a clinical pathologist according to good clinical practice guidelines for approved diagnostic PD-L1 quantification. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | ['Fig3', 'Fig2', 'Fig3'] | All tests were two-sided andPvalues < 0.05 were retained as significant. Unless otherwise specified, multivariate Cox regression was used to calculate the hazard of death; fast-backward method was applied to select the covariates retained in the multivariate models (fastbwfunction inrmsR package,type=“individual”). The Akaike Information Criterion [AIC] as a stopping rule was used to select the covariates in the final model in order to weight the probability of both significance and prediction strength. The model performance was quantified with C-indexes, calculated after validation with 200 bootstraps (validatein rms R package, rule = “aic”) and compared with analysis of variance. A nomogram (rms R package) was tailored on the final regression model for the melanoma TCGA cohort; the total number of points derived by specifying the covariate values was used to calculate the expected survival probabilities at 24 and 60 months; to proceed with the nomogram design, the missing values in the final regression model were estimated with multiple imputations using additive regression, bootstrapping, and predictive matching; a correction on the estimation procedure was based on 200 multiple imputations. Cox–Snell residuals were used to verify the proportional hazard hypothesis (with aPvalue >0.05 confirming the hypothesis for all covariates retained in the multivariate models with the exception of melanoma stage and breast cancer estrogen receptor status, which were time dependent). Kaplan–Meier method with log-rank test was used to plot survival data and patients’ allocation to groups were based on the biomarker cut-off determined withOptimalCutpointsR package, with the exception that the TCR metrics were retained as continuous variables for all the regression analyses to avoid cut-off artifacts and selection bias. Simple logistic regression was applied to calculate the log-likelihood ratio of radiological response to anti-PD1 therapy according to the clonality of baseline biopsy TIL/Tc; the AUC of the ROC was calculated for the parameters sensitivity and 1 − specificity. We used the “rule of the thumb” to determine the maximum number of covariates to use in the regression models22. Samples with less than four TCR sequences were outbound for the algorithm to calculate Renyi index and were excluded from the analysis. TCGA samples with incomplete clinical annotation and no survival information were included in the TCR analysis shown in Fig.3Abut were excluded from the survival and Cox regression analyses in Fig.2and Fig.3B–L. The investigators were blinded during experiments; outcome assessment was performed after experiments. Analyses were performed with GraphPad Prism version 7 (GraphPad Software, La Jolla, CA, USA) or R (v. 3.6.3, The R Foundation for Statistical Computing, Vienna, Austria). Data reporting follows REMARK guidelines (REporting recommendations for tumor MARKer prognostic studies). | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC8253860'] | ['34215730'] | ['MOESM3'] | Further information on research design is available in theNature Research Reporting Summarylinked to this article. | PMC8253860 | Article | null | 34,215,730 | The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival | Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N, Marais R. | Nat Commun. 2021 Jul 2;12(1):4098. doi: 10.1038/s41467-021-24343-x. | Valpione S | Nat Commun | 2,021 | 2021/07/03 | PMC8253860 | null | 10.1038/s41467-021-24343-x | oa_comm/txt/all/PMC8253860.txt | e274a0dfd85bc286f7cf65b296798129 | Nat Commun. 2021 Jul 2; 12:4098 | 2021-09-04 06:53:28 | CC BY | no |
['PMC10954323'] | ['37882611'] | ['ciad656-B15', 'ciad656-B15', 'ciad656-B15', 'ciad656-B16'] | This was a 2-arm, open-label, nonrandomized, multicenter pharmacokinetic substudy with descriptive safety and efficacy analysis of the EMPIRICAL randomized, controlled trial (NCT03915366) that aims to determine whether empirical treatment for cytomegalovirus and TB improves the survival of infants with HIV who are admitted with severe pneumonia [15]. The main trial includes infants aged 28–365 days with HIV and pneumonia who met the criteria for hospitalization and parenteral antibiotics following WHO guidelines [15]. Eligible infants in the main trial were first randomized to rifampicin-based TB treatment plus the standard of care (SOC; intravenous antibiotics, therapeutic cotrimoxazole, and prednisolone for the treatment ofPneumocystis jiroveciipneumonia) or to SOC alone. The second randomization was to valganciclovir for 15 days plus SOC versus SOC alone. If a clinical or laboratory diagnosis of TB was made in an infant not randomized to TB treatment, rifampicin-based TB treatment was initiated [15]. Consequently, we anticipated enrolling a larger number of infants on rifampicin compared with infants without rifampicin for this study. This pharmacokinetic substudy recruited infants who weighed more than 3 kg at the time of pharmacokinetic sampling and were receiving dolutegravir BID with rifampicin compared with OD without rifampicin-based TB treatment from hospitals in Mozambique, Uganda, Zambia, and Zimbabwe. All infants needed to be on dolutegravir treatment for at least 14 days and rifampicin for at least 30 days. Exclusion criteria for this substudy included the use of concomitant medications known to have DDIs with dolutegravir, grade 4 anemia or likelihood of progressing to grade 4 anemia at the day of sampling, and vomiting within 4 hours of drug administration [16]. The EMPIRICAL trial protocol, including the pharmacokinetic substudies, was approved by local ethics committees and national ethical and regulatory authorities. Written informed consent was obtained from the caregivers of the infants, with the consent documents translated into local languages. | PMC10954323 | Major Article; HIV/AIDs; AcademicSubjects/MED00290 | null | 37,882,611 | Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial | Jacobs TG, Mumbiro V, Cassia U, Zimba K, Nalwanga D, Ballesteros A, Domínguez-Rodríguez S, Tagarro A, Madrid L, Mutata C, Chitsamatanga M, Bwakura-Dangarembizi M, Passanduca A, Buck WC, Nduna B, Chabala C, Najjingo E, Musiime V, Moraleda C, Colbers A, Mujuru HA, Rojo P, Burger DM; EMPIRICAL Clinical Trial Group. | Clin Infect Dis. 2024 Mar 20;78(3):702-710. doi: 10.1093/cid/ciad656. | Jacobs TG | Clin Infect Dis | 2,024 | 2023/10/26 | PMC10954323 | null | 10.1093/cid/ciad656 | oa_comm/txt/all/PMC10954323.txt | 7b161aded446bfee04adef90e2bb4fe3 | Clin Infect Dis. 2023 Oct 26; 78(3):702-710 | 2024-07-20 23:20:26 | CC BY | no |
['PMC10954323'] | ['37882611'] | ['ciad656-B6', 'ciad656-B17', 'ciad656-B18', 'ciad656-B19', 'ciad656-B14'] | All infants received dolutegravir 10 mg scored DTs with abacavir/lamivudine, following national guidelines. Dosing of dolutegravir followed the WHO weight bands; children weighing 3 to <6 kg and 6 to <10 kg were administered 0.5 and 1.5 dolutegravir 10 mg DTs, respectively, with the dose frequency increased from OD to BID while on rifampicin [6]. Furthermore, rifampicin was given as part of a fixed-dose DT (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) with ethambutol 100 mg DTs and dosed in accordance with the WHO pediatric dosing guidance; infants weighing 4 to 7 kg and 8 to 11 kg received 75 mg and 150 mg rifampicin, respectively [17]. Six blood samples were collected from each participant over 12 (BID) or 24 (OD) hours at predetermined intervals (predose and at 2, 4, 6, 8, and 12/24 hours after drug administration) within 30–60 days after enrollment in the main trial. The volume of blood collected from each participant did not exceed the maximum limit of 2.5% of the total blood volume for sick children [18]. Infants were considered fed if they received food or breastmilk within 2 hours before or 1 hour after taking dolutegravir. Treatment adherence to both ART and TB treatment of each infant was recorded by their caretaker over 3 days prior to the pharmacokinetic sampling. HIV viral load (VL) and safety data were obtained as part of the EMPIRICAL trial. All adverse events (AEs) and severe AEs (SAEs) reported within the first 180 days after enrollment in the trial were descriptively reported for all pharmacokinetic participants. Furthermore, virological outcomes, expressed as the proportion of infants with an undetectable VL and those with >1000 copies/mL on study visit day 180 (upon completion of the TB treatment course), were described for infants in both study groups who had received at least 120 days of dolutegravir-based ART. Dolutegravir and dolutegravir-glucuronide plasma concentrations were quantified at the Pharmacy Department of the Radboud University Medical Centre in Nijmegen, the Netherlands, a laboratory that participates in an international quality control program for monitoring antiretroviral drugs, including dolutegravir [19]. The liquid chromatography-tandem mass spectrometry assay had a lower limit of quantification (LLOQ) of 0.05 mg/L for dolutegravir and 0.005 mg/L for dolutegravir-glucuronide [14]. The precision of the assay, expressed as coefficient of variation, showed a range of 1.9% to 7.7% within runs and 3.2% to 7.6% between runs. The accuracy of the assay was within 90.0% to 106.0%. | PMC10954323 | Major Article; HIV/AIDs; AcademicSubjects/MED00290 | null | 37,882,611 | Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial | Jacobs TG, Mumbiro V, Cassia U, Zimba K, Nalwanga D, Ballesteros A, Domínguez-Rodríguez S, Tagarro A, Madrid L, Mutata C, Chitsamatanga M, Bwakura-Dangarembizi M, Passanduca A, Buck WC, Nduna B, Chabala C, Najjingo E, Musiime V, Moraleda C, Colbers A, Mujuru HA, Rojo P, Burger DM; EMPIRICAL Clinical Trial Group. | Clin Infect Dis. 2024 Mar 20;78(3):702-710. doi: 10.1093/cid/ciad656. | Jacobs TG | Clin Infect Dis | 2,024 | 2023/10/26 | PMC10954323 | null | 10.1093/cid/ciad656 | oa_comm/txt/all/PMC10954323.txt | 7b161aded446bfee04adef90e2bb4fe3 | Clin Infect Dis. 2023 Oct 26; 78(3):702-710 | 2024-07-20 23:20:26 | CC BY | no |
['PMC10954323'] | ['37882611'] | ['ciad656-B11', 'ciad656-B20', 'ciad656-B21', 'ciad656-B22', 'ciad656-B23'] | Dolutegravir and dolutegravir-glucuronide pharmacokinetic parameters were determined with noncompartmental pharmacokinetic analysis using WinNonlin (Phoenix 64 v8.3, Certara) and were described as geometric mean with an associated coefficient of variance. Similar to previous studies, pharmacokinetic profiles were considered nonevaluable if the predose minimum concentration of dolutegravir was more than 15 times lower than the end-of-dose interval Ctrough, suggesting potential nonadherence [11,20,21]. The first concentration below the LLOQ at the end of the curve was set to half the LLOQ. Subsequent concentrations below the LLOQ were recorded as undetectable. The Cmaxand time to reach maximum concentration (Tmax) were directly derived from the plasma concentration-time curve. The AUC was calculated using the linear up-log down trapezoidal rule and oral clearance (CL/F) by dividing the dose by AUC. The AUC0–24hfor BID dosing was estimated by multiplying the AUC0–12hby 2 to enable comparison with the AUC0–24hfor OD dosing. The apparent elimination half-life (T1/2) was calculated as 0.693 divided by the apparent terminal-phase elimination rate constant (λz), which was estimated through linear regression using logarithmic data for the last 3 data points of concentration versus time. Geometric mean ratios (GMRs) comparing dolutegravir AUC0–24h, Cmax, and Ctroughfor infants receiving rifampicin versus those without rifampicin were calculated using an unpairedttest on log-transformed data. The proportion of infants with a dolutegravir Ctroughbelow the 90% effective concentration (EC90; 0.32 mg/L), the dolutegravir concentration at which 90% of the maximal VL reduction was achieved in a 10-day monotherapy study in adults, as well as below the in vitro protein-adjusted 90% maximal inhibitory concentration (IC90; 0.064 mg/L) was reported per study arm [22,23]. The individual dolutegravir metabolic ratio was calculated by dividing the AUC0–24hof dolutegravir-glucuronide by the AUC0–24hof dolutegravir, after adjusting for the molar mass. Correlation between dolutegravir AUC0–24hand dolutegravir metabolic ratio with age and weight-for-height was evaluated using Spearman’s rank correlation method, separately for the 2 study groups. The statistical analyses were performed using IBM SPSS Statistics software (v27). | PMC10954323 | Major Article; HIV/AIDs; AcademicSubjects/MED00290 | null | 37,882,611 | Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial | Jacobs TG, Mumbiro V, Cassia U, Zimba K, Nalwanga D, Ballesteros A, Domínguez-Rodríguez S, Tagarro A, Madrid L, Mutata C, Chitsamatanga M, Bwakura-Dangarembizi M, Passanduca A, Buck WC, Nduna B, Chabala C, Najjingo E, Musiime V, Moraleda C, Colbers A, Mujuru HA, Rojo P, Burger DM; EMPIRICAL Clinical Trial Group. | Clin Infect Dis. 2024 Mar 20;78(3):702-710. doi: 10.1093/cid/ciad656. | Jacobs TG | Clin Infect Dis | 2,024 | 2023/10/26 | PMC10954323 | null | 10.1093/cid/ciad656 | oa_comm/txt/all/PMC10954323.txt | 7b161aded446bfee04adef90e2bb4fe3 | Clin Infect Dis. 2023 Oct 26; 78(3):702-710 | 2024-07-20 23:20:26 | CC BY | no |
['PMC10954323'] | ['37882611'] | ['ciad656-F1', 'ciad656-T1'] | A total of 30 infants were recruited between August 2021 and August 2022 (seeFigure 1for the study profile). Of these, 27 had evaluable pharmacokinetic profiles with a median (interquartile range) age of 7.1 months (6.1–9.9), weighing 6.3 kg (5.6–7.2), and 11 of 27 (41%) were female. Nonevaluable pharmacokinetic profiles were the result of nonadherence (n = 2) and comedication interaction with valproic acid (n = 1). Twenty-five of the 27 infants were considered to have been fed during the administration of dolutegravir at the pharmacokinetic visit. Demographic characteristics of the included infants are displayed inTable 1. One child was lost to follow-up; all other children completed study visit day 180 of the main trial. | PMC10954323 | Major Article; HIV/AIDs; AcademicSubjects/MED00290 | null | 37,882,611 | Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial | Jacobs TG, Mumbiro V, Cassia U, Zimba K, Nalwanga D, Ballesteros A, Domínguez-Rodríguez S, Tagarro A, Madrid L, Mutata C, Chitsamatanga M, Bwakura-Dangarembizi M, Passanduca A, Buck WC, Nduna B, Chabala C, Najjingo E, Musiime V, Moraleda C, Colbers A, Mujuru HA, Rojo P, Burger DM; EMPIRICAL Clinical Trial Group. | Clin Infect Dis. 2024 Mar 20;78(3):702-710. doi: 10.1093/cid/ciad656. | Jacobs TG | Clin Infect Dis | 2,024 | 2023/10/26 | PMC10954323 | null | 10.1093/cid/ciad656 | oa_comm/txt/all/PMC10954323.txt | 7b161aded446bfee04adef90e2bb4fe3 | Clin Infect Dis. 2023 Oct 26; 78(3):702-710 | 2024-07-20 23:20:26 | CC BY | no |
['PMC10954323'] | ['37882611'] | ['ciad656-F2', 'ciad656-F3', 'ciad656-T2', 'ciad656-T2', 'sup1'] | The dolutegravir plasma concentration-time curves for the 2 study groups are displayed inFigure 2. One of 21 infants receiving rifampicin and none of 6 infants without rifampicin had a dolutegravir Ctroughbelow the EC90target (dolutegravir, 0.32 mg/L), and none of the participants had a Ctroughbelow the IC90target (dolutegravir, 0.064 mg/L), as shown inFigure 3andTable 2. The dolutegravir GMRs comparing dolutegravir BID with rifampicin with dolutegravir OD without rifampicin were 0.91 (95% confidence interval [CI], .59–1.42) for AUC0–24h, 0.95 (95% CI, .57–1.59) for Ctrough, and 0.87 (95% CI, .57–1.33) for Cmax. The apparent oral clearance of dolutegravir was 2.1 times higher in infants receiving rifampicin compared with those not receiving rifampicin, and the metabolic ratio (dolutegravir-glucuronide/dolutegravir ratio) was 2.3 times higher (as shown inTable 2). No significant correlation was found between dolutegravir AUC0–24hand dolutegravir metabolic ratio with age (P= .124 andP= .183, respectively) or weight-for-height (P= .747 andP= .297, respectively) (seeSupplementary Figure 1). | PMC10954323 | Major Article; HIV/AIDs; AcademicSubjects/MED00290 | null | 37,882,611 | Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial | Jacobs TG, Mumbiro V, Cassia U, Zimba K, Nalwanga D, Ballesteros A, Domínguez-Rodríguez S, Tagarro A, Madrid L, Mutata C, Chitsamatanga M, Bwakura-Dangarembizi M, Passanduca A, Buck WC, Nduna B, Chabala C, Najjingo E, Musiime V, Moraleda C, Colbers A, Mujuru HA, Rojo P, Burger DM; EMPIRICAL Clinical Trial Group. | Clin Infect Dis. 2024 Mar 20;78(3):702-710. doi: 10.1093/cid/ciad656. | Jacobs TG | Clin Infect Dis | 2,024 | 2023/10/26 | PMC10954323 | null | 10.1093/cid/ciad656 | oa_comm/txt/all/PMC10954323.txt | 7b161aded446bfee04adef90e2bb4fe3 | Clin Infect Dis. 2023 Oct 26; 78(3):702-710 | 2024-07-20 23:20:26 | CC BY | no |
['PMC10954323'] | ['37882611'] | ['ciad656-T3', 'sup1', 'ciad656-F4'] | During the 180-day follow-up period, 82 AEs were reported (summarized inTable 3). Four of 21 infants (19%) experienced an AE, of which 2 were SAEs (liver abnormalities) that were potentially related to rifampicin, and 1 of 27 infants (4%) experienced an AE that was possibly related to dolutegravir. All 5 successfully resolved without treatment discontinuation. VL was below 1000 copies/mL in 76% and 100% of infants and undetectable in 35% and 20% of infants with and without rifampicin, respectively. Development of VL during the study is presented inSupplementary Figure 2. Dolutegravir Ctroughwas comparable for infants who had a VL ≥1000 copies/mL versus those with <1000 copies/mL, as shown inFigure 4. | PMC10954323 | Major Article; HIV/AIDs; AcademicSubjects/MED00290 | null | 37,882,611 | Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial | Jacobs TG, Mumbiro V, Cassia U, Zimba K, Nalwanga D, Ballesteros A, Domínguez-Rodríguez S, Tagarro A, Madrid L, Mutata C, Chitsamatanga M, Bwakura-Dangarembizi M, Passanduca A, Buck WC, Nduna B, Chabala C, Najjingo E, Musiime V, Moraleda C, Colbers A, Mujuru HA, Rojo P, Burger DM; EMPIRICAL Clinical Trial Group. | Clin Infect Dis. 2024 Mar 20;78(3):702-710. doi: 10.1093/cid/ciad656. | Jacobs TG | Clin Infect Dis | 2,024 | 2023/10/26 | PMC10954323 | null | 10.1093/cid/ciad656 | oa_comm/txt/all/PMC10954323.txt | 7b161aded446bfee04adef90e2bb4fe3 | Clin Infect Dis. 2023 Oct 26; 78(3):702-710 | 2024-07-20 23:20:26 | CC BY | no |
['PMC10954323'] | ['37882611'] | ['ciad656-B24', 'ciad656-B25', 'ciad656-B6', 'ciad656-B26', 'ciad656-B4', 'ciad656-B27', 'ciad656-B28', 'ciad656-B4', 'ciad656-B6', 'ciad656-B22', 'ciad656-B29', 'ciad656-B23', 'ciad656-B7', 'ciad656-B30', 'ciad656-B33', 'ciad656-B34', 'ciad656-B35', 'ciad656-B36', 'ciad656-B37', 'ciad656-B38', 'ciad656-B39', 'ciad656-B14', 'ciad656-B9', 'ciad656-B10', 'sup1', 'ciad656-B40', 'ciad656-B21', 'ciad656-B25'] | To our knowledge, we are the first to report dolutegravir pharmacokinetic data and descriptive safety and efficacy for infants receiving concomitant rifampicin. Our findings showed that BID dosing of dolutegravir in the presence of rifampicin resulted in adequate dolutegravir exposure. The geometric mean Ctroughwas similar in infants receiving dolutegravir OD without rifampicin (1.11 mg/L) and infants receiving dolutegravir BID with rifampicin (1.06 mg/L). Furthermore, the Ctroughlevels in our study population were comparable to Ctroughlevels in adults after administration of 50 mg dolutegravir OD without rifampicin (1.20 mg/L) and in infants receiving dolutegravir OD without rifampicin following WHO weight-band dosing (Ctrough, 1.18 to 1.45 mg/L) [24,25]. Dolutegravir and rifampicin are widely recognized as the preferred components for treating HIV and TB, respectively, with well-established pharmacokinetics, efficacy, and safety in infants when given in the absence of the other drug [6,26]. Furthermore, the options for appropriate alternative ART for infants receiving rifampicin-based TB treatment are limited due to suboptimal pharmacokinetic outcomes or limited drug availability [4,27,28]. Hence, cotreatment with rifampicin and dolutegravir is preferred for treatment of infants with HIV-associated TB [4,6]. Moreover, providing dolutegravir-based ART to infants receiving rifampicin also allows for harmonization of preferred ART regimens across all ages. The appropriate minimum effective concentration of dolutegravir is currently the subject of ongoing debate. The EC90, or the concentration of dolutegravir at which 90% of the maximum reduction in VL was observed in a 10-day adult monotherapy study [22], may represent an overestimation of the actual target as various studies have shown adequate treatment outcomes despite Ctroughthat was below the EC90[29]. On the other hand, the IC90(0.064 mg/L) may be an underestimation of the target as it is solely based on in vitro data [23]. The one dolutegravir Ctroughbelow EC90in our study was 0.21 mg/L, which is well above the IC90, leading to confidence in the conclusion that BID dosing of dolutegravir is sufficient to overcome its interaction with rifampicin in infants with HIV. While our study showed similar pharmacokinetic profiles in infants compared with older children and adults, the proportion of infants with an undetectable VL after 6 months of follow-up was relatively modest with 35% and 20% of infants with and without rifampicin, respectively. Furthermore, 24% of infants receiving rifampicin and none of the infants without rifampicin had a VL of >1000 copies/mL on day 180 of the study. These findings warrant cautious interpretation given the small sample sizes and the reliance on self-reported dolutegravir treatment adherence by caregivers. It is important to note that time to viral suppression is generally longer in infants and young children on dolutegravir and alternative ART [7]. In different cohorts following CWH who were not acutely ill, similar results were reported, with only 37%, 45%, and 60% of infants achieving virological control after 6, 12, and 24 months of early ART, respectively [30–32]. Response on treatment was deemed unrelated to the pharmacokinetics of dolutegravir in our study as Ctroughlevels were comparable between infants with VL above or below 1000 copies/mL at study visit day 180. The large number of reported AEs and SAEs in this study was deemed related to severe underlying illness that initially led to hospitalization or other treatments. Only 5 AEs, including 2 SAEs (both liver function alterations), were possibly related to rifampicin or dolutegravir. As liver function alterations are not uncommon during first-line TB treatment and all resolved without treatment discontinuation, dolutegravir and rifampicin cotreatment appeared safe in our study population [33]. There is growing interest in continuing OD dosing of dolutegravir in the presence of rifampicin instead of increasing the dolutegravir dose frequency to BID. A recent prospective clinical trial showed promising results for this strategy in adults with HIV–TB coinfection, despite a substantial number of patients (35%) in the OD arm having dolutegravir Ctroughbelow the IC90target [34]. Considering that young children generally require a longer time for virological suppression after ART initiation, we advise caution when studying OD dosing of dolutegravir in infants on rifampicin-based TB treatment. On top of that, currently recommended dosages of rifampicin have been reported to result in low exposure (AUC) in infants, and higher dosages may therefore be introduced in the near future [35]. Additionally, studies are exploring the potential use of high-dose rifampicin (up to 35 mg/kg) for children [36,37]. These developments may result in higher exposure to rifampicin and, as a consequence, a larger decrease in dolutegravir levels, as observed in adults [38]. Dolutegravir’s metabolic ratio was 2.3-fold higher in infants on rifampicin compared with those without rifampicin. This ratio is consistent with an ex vivo study that showed that rifampicin at therapeutic concentrations increases the expression of UGT1A1 in human hepatocytes by 2-fold [39]. Notably, the dolutegravir metabolic ratio was substantially lower in our control arm (0.0292) compared with adult reference values (0.08) [14]. Low activity of UGT could theoretically result in less inducibility of UGT and result in a less pronounced magnitude of the DDI. However, the magnitude of the DDI observed in our study population seems comparable to findings from adult studies that also reported comparable AUC and Ctroughvalues between the 2 arms [9,10]. While the dolutegravir metabolic ratio did not show a significant correlation with age, infants aged <6 months in the rifampicin group appeared to have lower dolutegravir metabolic ratios (seeSupplementary Figure 1). This may be because maturation of UGT1A1 primarily occurs within the initial 3 to 6 months of life. Data from a single neonate suggest a very low dolutegravir metabolic ratio in neonates, which is in line with low activity of UGT1A1 in this population [40]. Our study has several limitations including dolutegravir not being administered as an investigational product of the EMPIRICAL trial. Therefore, assessing the relationship between AEs and dolutegravir was not part of the main study aim, and adherence to dolutegravir treatment was self-reported. Nevertheless, dolutegravir being administered as part of standard-of-care practice increases the generalizability of the results to real-world conditions. Furthermore, most infants in our study were considered fed and part of the group that did not have confirmed HIV-TB coinfection, which could have impacted dolutegravir rifampicin exposure, making comparisons with similar DDI studies more complex. However, we believe that this situation reflects real-world practice where infants are fed regularly. Additionally, the sample size in our control arm was small because a large number of infants in the non-TB treatment arms of the main trial received TB treatment following post-randomization clinical or laboratory TB diagnosis. Hence, these infants were ineligible for inclusion in the control arm of our substudy, which complicated the comparative analyses. Despite this, the pharmacokinetic parameters found in our study were comparable to those reported in previous studies evaluating dolutegravir pharmacokinetics in children not receiving rifampicin [21,25]. In conclusion, consistent with data from older children and adults, BID dosing of dolutegravir in infants receiving rifampicin, following WHO weight-band dosing, resulted in adequate exposure to dolutegravir. These pharmacokinetic data support the use of this dosing regimen in infants with HIV and receiving concomitant rifampicin therapy. Larger studies, including the main EMPIRICAL trial, are expected to assess virological response in infants receiving dolutegravir BID with rifampicin compared with dolutegravir OD without rifampicin. | PMC10954323 | Major Article; HIV/AIDs; AcademicSubjects/MED00290 | null | 37,882,611 | Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial | Jacobs TG, Mumbiro V, Cassia U, Zimba K, Nalwanga D, Ballesteros A, Domínguez-Rodríguez S, Tagarro A, Madrid L, Mutata C, Chitsamatanga M, Bwakura-Dangarembizi M, Passanduca A, Buck WC, Nduna B, Chabala C, Najjingo E, Musiime V, Moraleda C, Colbers A, Mujuru HA, Rojo P, Burger DM; EMPIRICAL Clinical Trial Group. | Clin Infect Dis. 2024 Mar 20;78(3):702-710. doi: 10.1093/cid/ciad656. | Jacobs TG | Clin Infect Dis | 2,024 | 2023/10/26 | PMC10954323 | null | 10.1093/cid/ciad656 | oa_comm/txt/all/PMC10954323.txt | 7b161aded446bfee04adef90e2bb4fe3 | Clin Infect Dis. 2023 Oct 26; 78(3):702-710 | 2024-07-20 23:20:26 | CC BY | no |
['PMC10954323'] | ['37882611'] | ['sup1'] | Supplementary materialsare available atClinical Infectious Diseasesonline. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. | PMC10954323 | Major Article; HIV/AIDs; AcademicSubjects/MED00290 | null | 37,882,611 | Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial | Jacobs TG, Mumbiro V, Cassia U, Zimba K, Nalwanga D, Ballesteros A, Domínguez-Rodríguez S, Tagarro A, Madrid L, Mutata C, Chitsamatanga M, Bwakura-Dangarembizi M, Passanduca A, Buck WC, Nduna B, Chabala C, Najjingo E, Musiime V, Moraleda C, Colbers A, Mujuru HA, Rojo P, Burger DM; EMPIRICAL Clinical Trial Group. | Clin Infect Dis. 2024 Mar 20;78(3):702-710. doi: 10.1093/cid/ciad656. | Jacobs TG | Clin Infect Dis | 2,024 | 2023/10/26 | PMC10954323 | null | 10.1093/cid/ciad656 | oa_comm/txt/all/PMC10954323.txt | 7b161aded446bfee04adef90e2bb4fe3 | Clin Infect Dis. 2023 Oct 26; 78(3):702-710 | 2024-07-20 23:20:26 | CC BY | no |
['PMC7212579'] | ['32393349'] | ['CR1', 'CR2', 'CR3', 'CR4', 'CR5', 'CR6', 'CR7', 'CR8', 'CR9', 'CR11', 'CR12', 'CR13', 'CR16'] | Oral diseases constitute a major burden of chronic disease, collectively impacting half of the global population [1]. Leading causes of oral disease include dental caries, which affect a third of the population; gingivitis, a highly prevalent condition in children and adults; and severe periodontitis, a major cause of tooth loss, found in 10 to 15% of adults [2]. Disadvantaged communities, in both high- and low-income countries, have higher rates of oral disease and more limited access to oral health care, especially preventative services [3]. Critical knowledge gaps about the inequities in oral health care exist, including those related to the implementation of effective community-based intervention programs for oral diseases [4,5]. In Nepal, like many low-income countries, oral health facilities, equipment, and qualified personnel, are in short supply [6]. Nepal has only two dentists per 100,000 people, one of the lowest ratios among South Asian countries [7]. In such contexts, shifting clinical tasks to less specialized health care workers may help alleviate the human resource demand for research or programmatic purposes [8]. Community health workers (CHWs) have demonstrated the ability to safely and effectively conduct clinical diagnostic tasks, and deliver essential care, for a variety of diseases in low resource settings [9–11]. Yet fewer studies have evaluated the ability of CHWs to adopt oral health services, with most previous investigations focused on oral health promotion; diagnostic screening, typically for childhood caries; or, in limited cases, providing simple preventative services. Shifting other aspects of preventative or therapeutic clinical oral health care to CHWs, such as screening for periodontal diseases, have not been evaluated [12]. Periodontal assessment is an important component of routine oral health care for diagnosis and management of common conditions in adults like gingivitis and periodontitis. Periodontal disease has also been implicated as a risk factor for chronic diseases, including adverse pregnancy outcomes and cardiovascular disease [13–16]. Shifting responsibility for periodontal assessment to CHWs would require assessment of the validity of procedures prior to wider implementation, which is especially important considering the precise techniques involved in various clinical periodontal measurements. Given the potential benefit of extending access to periodontal examination in community settings in low-resource areas, we estimated the validity of periodontal measurements collected by auxiliary nurse midwives relative to an experienced dentist in rural Sarlahi, Nepal. | PMC7212579 | Research Article | null | 32,393,349 | Feasibility of training community health workers to conduct periodontal examinations: a validation study in rural Nepal | Erchick DJ, Agrawal NK, Khatry SK, Katz J, LeClerq SC, Rai B, Reynolds MA, Mullany LC. | BMC Health Serv Res. 2020 May 11;20(1):412. doi: 10.1186/s12913-020-05276-5. | Erchick DJ | BMC Health Serv Res | 2,020 | 2020/05/13 | PMC7212579 | null | 10.1186/s12913-020-05276-5 | oa_comm/txt/all/PMC7212579.txt | 5f1f18b5ab62b9fed67d8ea3cd98e07f | BMC Health Serv Res. 2020 May 11; 20:412 | 2021-06-19 05:27:54 | CC BY | no |
['PMC7212579'] | ['32393349'] | ['Fig1'] | We recruited twenty-one pregnant women < 26 weeks gestation in a sub-area of Sarlahi District, Nepal, between January and November 2016. These women were enrolled in a community-based, prospective cohort study of maternal gingival inflammation and adverse pregnancy outcomes. Participants in this study were identified and determined eligible using the infrastructure of a large community-based randomized trial, the Nepal Oil Massage Study (NOMS) (NCT01177111), which was actively enrolling a population-based sample of pregnant women in Sarlahi District. Five female auxiliary nurse midwives, all of whom had completed an 18-month government certified midwifery program and resided in the study area, were selected as data collectors for the study. The auxiliary nurse midwives had no previous training or professional experience in dentistry or clinical research. A training course for the auxiliary nurse midwives was designed and conducted by an experienced dentist (NA) from the Department of Dentistry, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal. The training course covered basic dental anatomy, oral pathology, and the procedures for periodontal examination. Practical training included identification of plaque and calculus, signs of gingivitis, and measurement of probing depth (PD), bleeding on probing (BOP), and distance from the cemento-enamel junction to the free gingival margin (CEJ-GM). Auxiliary nurse midwives were also trained in clinical research methods and ethics for human subjects research. Training lasted 3–4 weeks and covered both classroom instruction and practice of periodontal techniques under the guidance of the dentist. All study visits were conducted at participant’s homes (Fig.1) because of the wide dispersion of households and villages across this rural community and the impracticality of bringing participants to a central location. Auxiliary nurse midwives and an assistant traveled to participants’ homes by motorbike, carrying with them all of the equipment required to conduct the exam. After the consent process, auxiliary nurse midwives asked the participant where in the home they felt most comfortable having the examination. A location was selected by the auxiliary nurse midwives to conduct the examination that maximized the available natural light and participant privacy. Often examinations were conducted inside the house on a bed or the floor in dim lighting. Ideal conditions were found in households with an enclosed courtyard, allowing for the exam to be conducted outdoors on the porch or ground, providing the most natural light. Electric lighting was present in very few households, and whether examinations were conducted inside or outside, auxiliary nurse midwives relied on battery-powered headlamps to illuminate the mouth.Fig. 1Auxiliary nurse midwives conduct periodontal examinations on study participants at their homes in a rural area of Sarlahi District in the Terai region of Nepal Auxiliary nurse midwives conducted a full mouth examination on each of the participants in the household. After the examination, participants rinsed their mouth with water and rested for fifteen minutes. Finally, the dentist, who was masked to the results of the auxiliary nurse midwives, conducted a second examination in the household under the same conditions. Data were recorded on paper forms by a trained assistant and electronically entered by experienced data entry operators. Periodontal measurements were made using a color Williams probe (Hu-Friedy, Chicago, IL, USA). PD was measured on six sites per tooth (disto-, mid-, and mesial- aspects of buccal and lingual surfaces) and the CEJ-GM distance on two sites per tooth (mid- buccal and lingual aspects), excluding third molars. After probing each quadrant, the presence or absence of BOP was recorded for buccal and lingual surfaces of each tooth. PD values were recorded in millimeters from 1 to 10, rounded to the next higher whole number. CEJ-GM distances were recorded similarly, with values of 0 to 10 mm. If the free gingiva was coronal to the CEJ, the CEJ-GM measurement was recorded as 0. Clinical attachment loss (CAL) was calculated by summing PD and the CEJ-GM distance; the CEJ-GM distance was assigned a value of 0 for distal and mesial sites, where this measure was not collected. After the examination, auxiliary nurse midwives had a conversation with participants to provide basic information on oral health, covering messages about oral self-care, cessation from smoking, chewing tobacco, and use of betel nut, and care-seeking for preventative and therapeutic services. Messages on care seeking included sharing a list of the nearest government-run dental health care facilities. Participants with signs of periodontal disease, or other potential conditions identified by the auxiliary nurse midwives during the examination, were encouraged to improve their oral hygiene and seek care from one of these facilities. Basic participant characteristics were reported as percentages. Differences between periodontal characteristics, as measured by the auxiliary nurse midwives and the dentist, were evaluated using paired t-tests or McNemar’s chi-squared tests. Percent agreement was calculated between the pooled auxiliary nurse midwives and each individual worker compared to the dentist for perfect agreement and considering values of PD ±1 mm as agreement. Confidence intervals (95%) for percent agreement were adjusted for clustering associated with the measurement of multiple teeth per participant using a generalized estimating equation (GEE) model. Kappa and weighted kappa (considering PD ±1 mm as agreement) statistics for PD were calculated, using tooth site as the unit of analysis, for pooled and individual auxiliary nurse midwives relative to the dentist. Confidence intervals (95%) for weighted and unweighted kappa statistics were also adjusted for clustering by participant using a bootstrap approach (1000 replications). Similarly, intraclass correlation coefficients (ICC) and associated cluster-adjusted, bootstrapped 95% confidence intervals were calculated for PD, using absolute agreement and tooth site as the unit of analysis, comparing the auxiliary nurse midwives to the dentist for perfect agreement and PD ±1 mm agreement. Sensitivity and specificity for the classification of tooth sites as PD > 2 mm were calculated for pooled and individual auxiliary nurse midwives vs. the dentist. A GEE model was used to estimate the effect of periodontal characteristics on agreement between the pooled auxiliary nurse midwives and dentist. This study received ethical approval from the Institutional Review Board at Johns Hopkins Bloomberg School of Public Health (Baltimore, USA) and the Ethical Review Board of the Nepal Health Research Council (Kathmandu, Nepal). Our study adheres to the Standards for Reporting Diagnostic accuracy studies (STARD) 2015 guidelines. | PMC7212579 | Research Article | null | 32,393,349 | Feasibility of training community health workers to conduct periodontal examinations: a validation study in rural Nepal | Erchick DJ, Agrawal NK, Khatry SK, Katz J, LeClerq SC, Rai B, Reynolds MA, Mullany LC. | BMC Health Serv Res. 2020 May 11;20(1):412. doi: 10.1186/s12913-020-05276-5. | Erchick DJ | BMC Health Serv Res | 2,020 | 2020/05/13 | PMC7212579 | null | 10.1186/s12913-020-05276-5 | oa_comm/txt/all/PMC7212579.txt | 5f1f18b5ab62b9fed67d8ea3cd98e07f | BMC Health Serv Res. 2020 May 11; 20:412 | 2021-06-19 05:27:54 | CC BY | no |
['PMC7212579'] | ['32393349'] | ['Tab1', 'Tab2', 'Fig2', 'Tab3', 'MOESM1', 'Tab4', 'Tab5'] | Twenty-one pregnant women < 26 weeks gestation were enrolled in this study. The mean age of participants was 22 (SD: ±3) years (Table1). A majority of women (62%) were literate, 38% had no education, 38% 1–9 years of schooling, and 24% 10 or more years. Nearly three-quarters (71%) of participants lived in a house constructed from thatch, sticks, or bamboo, with the other 29% in a house of wood, brick, or stone, and half (48%) had no access to a latrine.Table 1Demographic characteristicsCharacteristicFrequencyPercentAge (years)< 20733.320–241152.425–29314.3LiteracyNo838.1Yes1361.9Education (years)0838.11–9838.1≥ 10523.8House construction materialNone, thatch, sticks, or bamboo1571.4Wood planks, brick, or stones with mortar628.6LatrineNo latrine1047.6Brick, concrete, or pit latrine1152.4Demographic characteristics of study participants All participants had 28 teeth (excluding third molars), except for three women who were missing a single tooth (Table2). Mean probing depth (PD) was 1.6 mm (SD: 0.3) with a range of 1 to 4 mm as measured by the auxiliary nurse midwives, and 1.4 mm (SD: 0.2) ranging 1 to 3 mm according to the dentist, a mean difference of 0.2 mm (p= 0.02) (Fig.2). When non-congruent, these absolute differences in PD were nearly universally 1 mm, and roughly equally distributed in either direction. Collectively, the auxiliary nurse midwives identified one woman from the total twenty-one participants with at least one site with PD ≥4 mm, although the dentist measured these sites as < 4 mm and identified no other women as having any sites with PD ≥4 mm.Table 2Periodontal characteristicsCharacteristicAuxiliary nurse midwivesDentistP-valueNumber of teethaMean number of teeth27.9 ± 0.3627.9 ± 0.36–Bleeding on probing (BOP)Proportion of sites BOP13.6 ± 11.311.4 ± 12.00.22≥ 1 site BOP (No. (%))18 (85.7)17 (81.0)0.56≥ 1 site & < 10% of sites BOP (No (%))5 (23.8)8 (38.1)–≥ 10% & < 25% of sites BOP (No (%))8 (38.1)5 (23.8)–≥ 25% of sites BOP (No (%))5 (23.8)4 (19.1)0.56Probing depth (PD)Mean PD (mm)1.6 ± 0.31.4 ± 0.20.02Proportion of sites with PD ≥3 mm9.3 ± 11.54.2 ± 6.00.05≥ 1 site PD ≥4 mm (No (%))1 (4.8)0 (0.0)–Clinical attachment loss (CAL)bMean CAL (mm)1.6 ± 0.31.4 ± 0.20.02≥ 1 site CAL ≥4 mm (No (%))2 (9.5)1 (4.8)0.56Data presented as mean ± SD unless otherwise notedaExcluding third molarsbDirect site onlyPeriodontal characteristics of study participants as measured by the auxiliary nurse midwives and dentistFig. 2Mean probing depth (PD) measured by individual auxiliary nurse midwives and dentist for each participant. Comparison of mean probing depth (PD) by participant as measured by individual auxiliary nurse midwives and dentist The mean number of sites with bleeding on probing (BOP) was 13.6 (SD: ±11.3) and 11.4 (SD: ±12.0) for the auxiliary nurse midwives and the dentist, respectively (p= 0.22). Most women, 86% according to the auxiliary nurse midwives, and 81% according to the dentist, had at least some bleeding (p= 0.56). The auxiliary nurse midwives identified two, and the dentist three, of 21 total participants as having ≥1 mm recession of the gingival margin from the CEJ. Therefore, mean clinical attachment loss (CAL) did not differ substantially from the measures of PD. Overall percent agreement of PD for the auxiliary nurse midwives relative to the dentist was 63% (95% CI: 58, 69%) for perfect agreement and 99% (95% CI: 99, 100%), for ±1 mm agreement (Table3). Percent agreement differed significantly (p< 0.001) when stratified by PD, ranging from 62% agreement for PD = 1 mm to 48% for PD = 3 mm. For the individual auxiliary nurse midwives vs. the dentist, percent agreement ranged from 58% (95% CI: 44, 72%) to 69% (95% CI: 54, 83%) (Additional File1) and percent agreement ±1 mm ranged from 99% (95% CI: 97, 100%) to 100% (Table4). We calculated a design effect of 13.2 for the perfect agreement among the pooled auxiliary nurse midwives, indicating a high level of variation in PD between subjects. By individual participant, percent agreement and agreement ±1 mm ranged from 40 to 90% and 96 to 100%, respectively. Design effects for perfect percent agreement among the individual auxiliary nurse midwives ranged from 3.7 to 25.9.Table 3Intraclass correlation coefficients and kappa statistics for pooled auxiliary nurse midwives vs. dentistMeasurePoint estimate95% CIPercent agreement63.357.5, 69.1Percent agreement ±1 mm99.398.8, 99.8ICC0.430.35, 0.51ICC ±1 mm0.940.91, 0.98Kappa0.320.24, 0.41Kappa ±1 mm0.850.76, 0.93Validity measures comparing pooled auxiliary nurse midwives to the dentistTable 4Measures of probing depth agreement and sensitivity and specificity of probing depth (PD) > 2 mm and bleeding on probing (BOP) classification for individual auxiliary nurse midwives vs. dentistPD agreementPD > 2 mmbBOPbANMNaTooth sitesPercent agreement ± 1 mmICC ± 1 mmKappa ± 1 mmNo. sitesSensitivitySpecificityNo. sitesSensitivitySpecificity14669100.0 (99.5, 100.0)11955.60%95.30%12671.40%89.00%2466698.8 (97.7, 99.9)0.92 (0.83, 1.00)0.85 (0.65, 1.00)2483.30%91.50%7830.80%95.90%3466698.8 (97.4, 100.0)0.90 (0.80, 1.00)0.74 (0.67, 0.78)2738.10%94.70%5466.70%87.80%4583499.3 (98.3, 100.0)0.93 (0.85, 1.00)0.79 (0.69, 0.95)3318.50%98.60%10841.70%91.30%5467299.7 (99.4, 100.0)0.97 (0.95, 1.00)0.92 (0.79, 1.00)1384.60%97.00%3060.00%93.50%Data presented as point estimate (95% CI)aNumber of participants assessed by both the auxiliary nurse midwives and dentistbNumber of sites with PD > 2 mm and BOP according to dentist’s measurementValidity measures comparing individual auxiliary nurse midwives to the dentist for probing depth ± 1 mm agreement and sensitivity and specificity of probing depth (PD) > 2 mm and bleeding on probing (BOP) classification The kappa score for PD agreement between the pooled auxiliary nurse midwives and the dentist was 0.32 (95% CI: 0.24, 0.41) for perfect agreement, and 0.85 (95% CI: 0.76, 0.93) for agreement within ±1 mm. Kappa scores for the five individual auxiliary nurse midwives compared to the dentist ranged from 0.24 (95% CI: 0.06, 0.42) to 0.40 (0.22, 0.59) for perfect agreement, and 0.74 (95% CI: 0.67, 0.78) to 1.0 for agreement within ±1 mm. The intraclass correlation coefficient (ICC) between the pooled auxiliary nurse midwives and the dentist was 0.43 (95% CI: 0.35, 0.51) for perfect agreement, and 0.94 (95% CI: 0.91, 0.98) for agreement within ±1 mm. ICC values for the five individual auxiliary nurse midwives compared to the dentist ranged from 0.34 (95% CI: 0.16, 0.55) to 0.49 (95% CI: 0.31, 0.66) for perfect agreement, and 0.90 (95% CI: 0.80, 1.00) to 1.0 for agreement within ±1 mm. Relative to the dentist, the pooled auxiliary nurse midwives classified individual tooth sites as PD ≤2 mm or PD > 2 mm with 50% sensitivity and 96% specificity. For the five individual auxiliary nurse midwives, each relative to the dentist, sensitivity ranged from 19 to 85%, and specificity from 92 to 99%. However, auxiliary nurse midwives classified more sites as PD > 2 mm than the dentist, an average of 5.6% sites per participant vs. 2.5%. Sensitivity and specificity of BOP were 53.8 and 91.5%, respectively, for the pooled auxiliary nurse midwives relative to the dentist, with sensitivity ranging from 31 to 71%, and specificity from 88 to 96%, for individual auxiliary nurse midwives. We modeled the relative risk (RR) of percent agreement for PD of the auxiliary nurse midwives relative to the dentist using a generalized estimating equation (GEE) regression model, including covariates for periodontal characteristics (Table5). Covariates for jaw (maxilla, mandible), side (left, right), and probing depth (≤2 mm, > 2 mm) were not significantly related to percent agreement. PD measurements on posterior teeth and lingual surfaces were associated with an average reduction in percent agreement of 15% (RR 0.85, 95% CI: 0.81, 0.90) and 10% (RR 0.90, 95% CI: 0.86, 0.95), respectively. Measurements on direct tooth site, relative to the proximal site, were associated with a 21% increase in agreement.Table 5Relationships between probing depth (PD) agreement and periodontal characteristics using a multivariable GEE modelVariablesRR95% CIJawMandible0.960.92, 1.00MaxillaRef–SideRight1.010.97, 1.06LeftRef–PositionPosterior0.850.81, 0.90AnteriorRef–SurfaceLingual0.900.86, 0.95FacialRef–SiteDirect1.211.15, 1.28ProximalRef–Probing depth> 2 mm0.850.70, 1.05≤ 2 mmRef–Multivariable GEE model reporting relative risk (RR) of PD agreement between auxiliary nurse midwives relative to the dentist by periodontal characteristics | PMC7212579 | Research Article | null | 32,393,349 | Feasibility of training community health workers to conduct periodontal examinations: a validation study in rural Nepal | Erchick DJ, Agrawal NK, Khatry SK, Katz J, LeClerq SC, Rai B, Reynolds MA, Mullany LC. | BMC Health Serv Res. 2020 May 11;20(1):412. doi: 10.1186/s12913-020-05276-5. | Erchick DJ | BMC Health Serv Res | 2,020 | 2020/05/13 | PMC7212579 | null | 10.1186/s12913-020-05276-5 | oa_comm/txt/all/PMC7212579.txt | 5f1f18b5ab62b9fed67d8ea3cd98e07f | BMC Health Serv Res. 2020 May 11; 20:412 | 2021-06-19 05:27:54 | CC BY | no |
['PMC7212579'] | ['32393349'] | ['CR9', 'CR10', 'CR17', 'CR12', 'CR18', 'CR19', 'CR20', 'CR21', 'CR22', 'CR23', 'CR24', 'CR25', 'CR26', 'CR27', 'CR28', 'CR29', 'CR30', 'CR31', 'CR27', 'CR32', 'CR33', 'CR36', 'CR37', 'CR38', 'CR37', 'CR39'] | Our results demonstrate that auxiliary nurse midwives with minimal training can satisfactorily conduct periodontal examinations at patient homes in rural Nepal. Percent agreement, weighted kappa scores, and intraclass correlation coefficients, with an allowance of ±1 mm, exceeded 99%, 0.7, and 0.9, respectively, indicating an acceptable level of agreement. While the auxiliary nurse midwives tended to overestimate probing depth (PD) scores relative to the dentist, the magnitude of over-estimation was small (0.2 mm) and unlikely to impact population-based estimates of critical indicators. Relative to the dentist, the capacity of the auxiliary nurse midwives to distinguish sites with PD > 2 mm was less than ideal (sensitivity of 50%); however, auxiliary nurse midwives demonstrated an excellent ability to discern sites with PD ≤2 mm (specificity 96%). Sensitivity and specificity for bleeding on probing (BOP) data exhibited a similar pattern to PD, but should be interpreted with caution, due to the possible influence of the first examination on the subsequent one, given the short recovery interval (15 min) for each participant. Globally, studies have shown that CHWs can safely and effectively deliver a range of health promotion services, diagnostic screenings, and therapeutic interventions in community-based, low-resource settings. These include, for example, ultrasound examination for diagnosis of obstetric risk factors, sign-based algorithms for assessment of omphalitis, and pneumonia case management [9,10,17]. However, the literature on training of CHWs to provide oral health care services is less well-developed relative to other areas, and is primarily limited to health promotion and use of simple diagnostic screening tools [12]. Available evidence from LMICs supports the ability of CHWs to conduct oral health promotion activities to teach proper oral hygiene behaviors, commonly brushing and flossing, and encourage care seeking. In the city of Rio Grande da Serra in southeastern Brazil, a pre-post intervention study showed that a training program and regular supervision for CHWs from a family health program led to improved oral health knowledge, oral hygiene behaviors, and care seeking and utilization of oral health services of women in the community [18]. Another pre-post intervention study, conducted in north Indian city of Chandigarh, reported that an oral hygiene education package delivered by local community-based Anganwadi workers, who are responsible for maternal and child health education, led to a decrease in plaque and caries activity among children and an increase in self-reported oral hygiene behaviors [19]. A few studies have shown that CHWs in LMICs can utilize oral health diagnostic screening tools in community-based settings, including to identify childhood caries or oral disease in the elderly. A study in Brazil found use of the Revised Oral Assessment Guide by community health workers, relative to a dentist, to have acceptable validity and reliability for the identification of oral health problems in elderly individuals in a clinic setting [20,21]. In Thailand, CHWs, who had a secondary school level education, were successfully trained to provide oral health education, conduct root scaling and planing, sterilize instruments, control infection, and make referrals [22]. In Australia, several studies evaluated efforts to train Aboriginal Health Workers to expand oral health promotion, diagnostic screening, and delivery of basic interventions to remote and rural areas of the country [23]. A cluster randomized trial in Australia’s Northern Territory reported that health promotion and application of fluoride varnish by Aboriginal Health Workers reduced dental caries in young children [24]. Findings from this study suggest that auxiliary nurse midwives, who far outnumber dentists and other oral health workers in Nepal, have the potential to expand access to oral health services in the community. Auxiliary nurse midwives and other similar CHWs live nearby and work in health facilities at all levels of government across Nepal, including in rural areas where access to oral health care is generally lower. In 2018, there were 31,764 auxiliary nurse midwives registered with the Nepal Nursing Council, although staffing shortages for auxiliary nurse midwives exist across the health system [25]. For example, in 2015, the percent of sanctioned health posts for auxiliary nurse midwives that were filled ranged between 71 to 79% for different types of facilities from the zonal to the health post levels, with the exception of urban health centers, which were staffed at 36% capacity [26]. Beyond availability of auxiliary nurse midwives and similar CHWs, other issues would need to be considered by any effort to shift responsibility for delivery of oral health services to this cadre of CHWs. A few such questions include how effective oral health information provided by CHWs is at changing oral hygiene behaviors and reducing oral disease in this community; whether CHWs can safely and effectively provide basic oral health treatments in a community setting; how CHWs would refer patients requiring more skilled care to nearby dental health facilities; and whether delivery of oral health services by CHWs in rural communities provides cost savings to the health system. Periodontal examination in a community-setting presents various challenges not found in a typical clinical setting, including difficult field conditions, such as the absence of a high-quality light source [27]. Some variability observed in the measures of validity in this study may be attributable to the field conditions. We identified lower agreement on posterior teeth, lingual surfaces, and proximal sites, areas that may be more difficult to measure accurately in low light. Alternatively, this variability could have resulted from the limited training of the auxiliary nurse midwives, or even normal inter-rater variability, as lower agreement for posterior, lingual, and proximal sites has also been seen in reliability studies utilizing highly trained periodontal examiners [28,29]. A majority of women in our study had signs of gingival inflammation, but few had significant probing depths or attachment loss. This could be a result of the young age of the study population, which, at a mean of 22, is low even for studies of the periodontal disease and adverse pregnancy outcome association [30]. Alternatively, the small sample size of this study may have played a role; data from the parent cohort study indicate a prevalence of ≥1 site with PD ≥4 mm of over 8% [31]. As a result of the absence of moderate and severe disease, the bulk of our analyses focused on discriminating between low probing depth scores (i.e., 1–2 mm), which are indicative of periodontal health. This limited our ability to fully explore the capacity of the auxiliary nurse midwives to accurately measure the full range of clinical periodontal parameters and distinguish between states of disease from health. Our assessment of the amount of measurement error associated with the study’s auxiliary nurse midwives may be underestimated if higher probing depths are measured with lower reliability in this setting as has been documented elsewhere [27,32]. In recent years, periodontal researchers have sought to improve data quality by designing a standardized process to assess periodontal examiners [33–36]. Validity and reliability studies have been used to determine if periodontal measurements conducted by periodontal examiners are consistent with a gold standard or within and between examiners [37,38]. Yet a review of the periodontal literature, conducted by Hefti and Preshaw (2012), showed that only 30% of publications using the Gingival Index or Modified Gingival Index reported on examiner assessment, and almost none discussed the possible consequences of examiner validity or reliability on the outcome of the study [37]. Studies of the periodontal disease and adverse pregnancy outcomes association often do not report on examiner assessment, and those that do typically include a limited mention in methods section without estimates of uncertainty or information on study design used to collect these data. Our estimates of validity were generally comparable to those documented by similar studies of the periodontal disease and adverse pregnancy outcome association, although some achieved both weighted kappas and ICCs of over 0.9 [39]. A limitation of this study was its small sample size, which was restricted for logistical reasons. With additional participants we could have estimated reliability measures of intra-rater agreement for the repeated measurements of each auxiliary nurse midwife and inter-rater agreement between the study’s five auxiliary nurse midwives. We prioritized validity over reliability because the auxiliary nurse midwives in this study had no previous experience in dentistry or clinical research. We could have also measured agreement using the subject as the unit of analysis, for example by classifying participants has having gingivitis or periodontitis, an approach that might have yielded more practical information for our parent study, which will take the subject as the primary unit of analysis in examining the relationship between periodontal disease and adverse pregnancy outcomes. | PMC7212579 | Research Article | null | 32,393,349 | Feasibility of training community health workers to conduct periodontal examinations: a validation study in rural Nepal | Erchick DJ, Agrawal NK, Khatry SK, Katz J, LeClerq SC, Rai B, Reynolds MA, Mullany LC. | BMC Health Serv Res. 2020 May 11;20(1):412. doi: 10.1186/s12913-020-05276-5. | Erchick DJ | BMC Health Serv Res | 2,020 | 2020/05/13 | PMC7212579 | null | 10.1186/s12913-020-05276-5 | oa_comm/txt/all/PMC7212579.txt | 5f1f18b5ab62b9fed67d8ea3cd98e07f | BMC Health Serv Res. 2020 May 11; 20:412 | 2021-06-19 05:27:54 | CC BY | no |
['PMC7212579'] | ['32393349'] | ['CR11'] | Our results suggest the potential to shift delivery of certain basic oral health services from dentists and other highly trained professionals to auxiliary nurse midwives or similar CHWs. Policy and programmatic decisions to task CHWs with provision of oral health care should be taken in the context of the multiple factors that affect the success of community health worker programs, including health systems factors (e.g., human resource structures, management and supervision policies), community factors (e.g., health beliefs, community mobilization), and national socioeconomic and political factors (e.g., political will, poverty) [11]. Increased efforts are needed to consider how CHWs could expand access to essential oral health knowledge and services in low-resource settings. | PMC7212579 | Research Article | null | 32,393,349 | Feasibility of training community health workers to conduct periodontal examinations: a validation study in rural Nepal | Erchick DJ, Agrawal NK, Khatry SK, Katz J, LeClerq SC, Rai B, Reynolds MA, Mullany LC. | BMC Health Serv Res. 2020 May 11;20(1):412. doi: 10.1186/s12913-020-05276-5. | Erchick DJ | BMC Health Serv Res | 2,020 | 2020/05/13 | PMC7212579 | null | 10.1186/s12913-020-05276-5 | oa_comm/txt/all/PMC7212579.txt | 5f1f18b5ab62b9fed67d8ea3cd98e07f | BMC Health Serv Res. 2020 May 11; 20:412 | 2021-06-19 05:27:54 | CC BY | no |
['PMC8292936'] | ['34255680'] | ['ref1', 'ref2', 'ref3', 'ref4', 'figure1', 'ref5', 'ref6', 'figure2', 'ref6', 'ref6', 'ref8', 'ref6', 'ref3', 'ref6', 'ref9', 'ref10', 'ref11', 'ref12', 'ref13', 'ref14'] | Arthrogryposis multiplex congenita (AMC) is an umbrella term used to describe more than 400 conditions characterized by congenital joint contractures present in at least two body areas and affecting 1 in 4300-5100 live births [1,2]. Amyoplasia and distal arthrogryposis are the most common types of AMC, representing approximately 50%-65% of all AMC diagnoses [3,4]. Amyoplasia is characterized by decreases muscle mass and the typical positioning of the limbs (Figure 1) [5,6]. Distal arthrogryposis is characterized by contractures that mainly affect the distal limbs (ie, feet and hands;Figure 2) [6]. Individuals with AMC may have poor muscle mass in addition to limitations in range of motion (ROM), resulting in difficulties in transfers, mobility, and independent activities of daily living [6-8]. One aspect contributing to the limited ROM in individuals with AMC is the lack of movement of limbs, which may be overcome by physical exercise [6]. Some studies speculated that exercise in youth with AMC may maintain ROM, increase muscle strength, and decrease pain, but the direct effects of an exercise program remain to be tested in this population [3,6,9,10]. A positive association was also reported between knee and hip muscle strength and motor function (eg, rolling, sitting, standing, and climbing) in individuals with AMC, suggesting the importance of preserving sufficient muscle strength for daily activities [11]. Currently, most interventions in individuals with AMC, specifically rehabilitation, occur in early childhood, and the frequency decreases during school-age and adolescent years despite new challenges arising during these transition periods [12,13]. Rehabilitation for school-aged children with AMC focuses mostly on body functions (eg, mobility of joints and muscle endurance) and structure (eg, joint contracture of the elbow or knee), which does not always correspond to the individual’s specific needs such as participating in activities and increasing independence for attending school and employment [14]. | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC8292936'] | ['34255680'] | ['ref15', 'ref16', 'ref17', 'ref18'] | Given the rarity, youths with AMC often require specialized care, but many of these individuals live far from subspecialized health care centers. Therefore, clinicians and researchers face challenges in developing adjunct therapies with frequent follow-ups, such as an exercise program. To overcome such challenges, novel intervention approaches and technologies are needed to increase access to subspecialized care for individuals with AMC living in remote areas. Telerehabilitation, an innovative way to deliver rehabilitation services remotely using telecommunication technologies, may offer a solution for delivering intervention programs with frequent follow-ups [15]. This new approach may contribute to reduced costs and decreased in-person visits to the hospital [16]. Telerehabilitation is not only useful for people with AMC living in remote areas but also useful for those living close by when they need consultations during a pandemic (such as the COVID-19 pandemic) in which social distancing is needed [17]. Despite its benefits, telerehabilitation has been understudied in children with physical disabilities [18]. Therefore, the primary aim of this pilot study is to evaluate the feasibility of using telerehabilitation to provide a home exercise program (HEP) for youth with AMC. As part of the feasibility objective, the interrater reliability of using a virtual goniometer for ROM measurements is explored. The secondary aim is to explore the effectiveness of this type of intervention. | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC8292936'] | ['34255680'] | [] | This prospective interventional single-cohort pilot study was conducted between January 2019 and March 2020 at the Shriners Hospitals for Children (SHC)–Canada. The study was approved by the department of medical research at the SHC (CAN1806) in July 2018, and ethics approval was received from the institutional review board of the McGill University Faculty of Medicine (#A08-B38-18B) in October 2018. Patients were included if they were aged between 8 and 21 years, understood written and spoken English or French, and had multiple congenital contractures as documented in their electronic medical records. Individuals were excluded if they had undergone a recent surgery (ie, 3 months prior for soft tissue and 6 months prior for bony surgery), lived outside Canada, or had cognitive deficits. Potential participants were identified by reviewing onsite medical records, and all eligible youths were approached during their clinic visit or by postal mail or phone if they did not have an upcoming appointment. Recruitment was also sought by posting an advertisement on a Canadian AMC support group on social media. Informed consent forms were filled by all parents and youths aged ≥14 years. Assent was provided for those aged 8-13 years. | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC8292936'] | ['34255680'] | ['ref19'] | To establish the 12-week HEP, an initial assessment was conducted by an occupational therapist and a physical therapist using a videoconferencing platform. This assessment included active ROM measurements of the upper and lower limb joints, an evaluation of overall function (mobility, transfers, and activities of daily living), and a pain assessment using the Adolescent and Pediatric Pain Tool (APPT). For the ROM assessment, the participants were asked to hold different positions, and screen captures were collected for subsequent measurements. The therapists guided the participants and the caregiver, when present, to ensure that the movements were performed properly and in the right plane of the camera (eg, the therapists asked for the camera to be tilted when needed). Based on the assessment and needs of the participants, the therapists and participants determined individualized goals using the Goal Attainment Scale (GAS). The scoring of the goals was defined according to the type of goal set, such as the percentage of perceived strength, a 0-10 satisfaction scale, or walking endurance measured in minutes. The information obtained through this initial assessment was used by the rehabilitation team to develop an individualized 12-week HEP. In addition, the participants were asked to complete web-based questionnaires, including the Physical Activity Questionnaire for Adolescents (PAQ-A) and the Pediatrics Outcomes Data Collection Instrument (PODCI), and to provide baseline disorder and sociodemographic information (ie, type of AMC, location of joint contractures, services care received, schooling, employment, volunteering, and leisure). All telerehabilitation meetings were conducted remotely using Zoom Pro (Zoom Video Communications Inc), a videoconferencing platform that allowed an encrypted connection and synchronous exchange between the participants and therapists. When needed, a parent was present to help position the camera and position or assist the participant or aid in the exercise material setup. In 1 case, the telerehabilitation meetings took place at the participant’s school with the assistance of the school therapist. The methods used for the pilot study are described in detail in Gagnon et al [19]. At the end of the 12-week HEP, the participants underwent a final assessment, with the occupational therapist and physical therapist using the same outcome measures as those used during the initial assessment, and they completed the same web-based questionnaires with the addition of 19 closed-ended and 4 open-ended questions on their satisfaction with the HEP. | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC8292936'] | ['34255680'] | ['app1', 'figure3'] | All information gathered during the initial assessment was used to build an individualized HEP for each participant based on their goals and abilities. The therapists used Physiotec (Physiotec Québec Inc), a software program that easily creates an HEP and provides participants with access to detailed instructions and videos of the exercises. Examples of these HEPs can be found in theMultimedia Appendix 1. A week after the initial assessment, a physical rehabilitation therapist (PRT), a professional whose role is to develop treatment plans and provide appropriate intervention in collaboration with a physical therapist, explained the HEP to each participant during a remote session. When needed, the PRT demonstrated the exercises. During this session, the PRT ensured that the participant understood and performed the exercises safely. The participants were asked to perform their HEP 3 times a week for approximately 15 to 30 minutes at a time. Follow-ups were provided every 3 weeks (ie, at weeks 3, 6, and 9) by the PRT to ensure that the exercises were properly performed and to assess the level of difficulty of the HEP. Exercises were adjusted for progression or regression as needed (eg, number of repetitions and type of exercise). When necessary, for optimal loading, materials such as elastic resistance bands or theraputty (a silicone-based exercise material used for hand therapy) were sent to participants by postal mail. To record the compliance to the HEP, the participants were asked to wear a Polar A370 activity monitor (Polar Electro, Inc), which was sent to them by postal mail, to capture their exercise sessions and to complete a data log sheet. The activity monitor was worn on the wrist during the HEP session and was used to capture the number of exercise sessions. The participants were asked to charge their activity monitor every 3 to 4 days and, at the same time, to download their data to the Polar Flow platform through Bluetooth or direct connection. The downloaded data became available to the research team throughout the Polar Flow for Coach web platform. The research assistant (MG) manually scrutinized all recorded sessions on the Polar Flow for Coach web platform to remove those that were too short to be considered exercise sessions (≤15 min) or were recorded as another sport and made a note on the data log sheet (eg, hockey or skiing).Figure 3shows a summary of the intervention. | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC8292936'] | ['34255680'] | [] | Given that this was a pilot study with a small sample size and a heterogeneous population, nonparametric and descriptive statistics were used.Pvalue corrections for multiple comparisons were not used because of the exploratory purpose of this study. Statistical analyses were performed using IBM SPSS Statistics version 24 for Windows (IBM Corp). | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC8292936'] | ['34255680'] | ['box1', 'ref19', 'app2', 'table1', 'ref29', 'ref30'] | The feasibility was evaluated using different operationalization criteria. These operationalization criteria are listed inTextbox 1and defined in detail in the published protocol for this study [19]. Compliance to the HEP and the telerehabilitation meetings were described using summary statistics and compared with pre-established feasibility criteria using a 1-sample Wilcoxon signed-rank test. For the remaining operationalization criteria, a comparison with pre-established criteria was performed using the same method. The technical issues (major technical issues being issues that resulted in the cancellation of the meeting and minor issues being something that could be resolved during the meeting) experienced during the program were also descriptively assessed using summary statistics. As part of evaluating feasibility, this pilot study also aimed to determine the most suitable outcome measures for this type of intervention. The recruitment rate among eligible participants followed at the SHC who were reachable was 38% (10/26), which was lower than the target set at ≥50%. The withdrawal rate before the start of the intervention was 18% (2/11) and after the start of the intervention, it was 18% (2/11), which met the established criteria of ≤20% and ≤30%, respectively. The HEP completion rate was 64% (7/11), which corresponded to the criterion of ≥50%. The number of meetings that needed to be rescheduled in ≤24 hours was 11% (5/47), which reached the target set at ≤15%. The median HEP compliance was 2.04 times per week (95% CI 1.25-4.08), which when compared with the 3 weekly sessions set in the HEP, corresponded to 68.1% (95% CI 41.7%-136.1%) and was higher than the target set at ≥50% (P=.046). Different technical issues arose during the telerehabilitation meetings. No major technical issue necessitating canceling a meeting occurred, but minor technical problems occurred in 11% (5/47) of meetings. Echo voices were present with 1 participant, and this was resolved with the muting option: when the therapists or the participant spoke, the others muted themselves. The therapist lost the connection in one meeting for a few seconds and had to reconnect. On one occasion, a participant had difficulty with the sound output on their computer and had to join the meeting with their phone as an alternative. Regarding issues with the activity monitor, 5 participants had difficulties syncing the device, and the project coordinator resolved this problem by sharing the screen during the telerehabilitation meetings to review the required steps for setting it up. All participants completed the pre- and postintervention questionnaires, except for 1 participant who did not return the data log sheet and never synced their activity monitor; therefore, they were excluded from the HEP compliance calculation despite reporting having performed their HEP regularly. For the ROM measurements, the missing values for each joint can be found inMultimedia Appendix 2. All 7 participants reported being comfortable communicating through the telerehabilitation platform, and the clarity of the video and audio of the platform was acceptable. The participants felt supported during the 12-week program, reported reduced travel time compared with if they had to visit the SHC in person, and expressed interest in using telerehabilitation in the future. All were satisfied or very satisfied with the remote evaluation, delivery of the HEP, follow-ups, and the overall organization of the 12-week program. The participants suggested increasing the span of the program (n=1), to include an in-person follow-up visit halfway through the program (n=1), and to include outcome measures targeting the adolescent age group (n=1). A summary of the improvements reported by the participants in the open-ended questions can be found inTable 1. Feasibility was demonstrated with the achievement of all operationalization criteria, except for the recruitment rates. The observed completion rate of 63.6% corresponded to the criteria set at ≥50%. One withdrawal was due to the need for more support from the caregiver to perform the HEP. Support from families or the entourage of the participant was important for most of the participants, specifically for the youngest participants and those with more severe joint involvement. The intervention in this study was semisupervised, with follow-ups provided every 3 weeks. The compliance of 68.1% (2.04/3 times per week) to the HEP measured in this study is closer to the compliance rate of 76% observed in supervised interventions [29] than to that of nonsupervised interventions (11%-37%) [30]. A total of 11% (5/47) of the telerehabilitation meetings were canceled on the same day, which is similar to the 12% (997/8306) observed for in-person appointments in the rehabilitation department at the SHC–Canada (unpublished data, 2019). Extreme weather in Canada often results in cancellation of appointments, but none were canceled for this reason in this study owing to its web-based care delivery. A few technical issues occurred during this study, but all were resolved promptly, and none affected the safety of the participants. Therefore, technical issues should not be a reason to preclude the use of telerehabilitation in future studies or in clinical practice. Although the reproducibility of using a virtual goniometer varied across joints, this method of measuring ROM was nevertheless useful for setting individualized goals, developing the HEP, and performing the initial and final assessments. Some challenges with web-based ROM measurements included different movement planes for measurement, varying positions in which ROM measurements were taken according to the participants’ contractures (eg, elbow flexion in sitting or standing position), space restrictions in the home, or poor or high luminosity. In future studies using web-based ROM measurements, we recommend the use of guidelines for proper positioning, therapist training, contrasting clothing for the participants, proper luminosity, and laptop or tablet use to allow adjustment of the camera as needed. | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC8292936'] | ['34255680'] | ['ref20', 'ref21', 'ref23', 'table2'] | The interrater reliability of using a virtual goniometer to measure active ROM has been shown to be feasible when compared with an in-person assessment with a goniometer on 10 healthy adults [20]. However, its reliability has not been assessed in children and adolescents with a musculoskeletal disorder such as AMC. The interrater reliability was established by having 2 raters (MG and GMM) use a virtual goniometer (Kinovea version 0.8.15) to measure the ROM of 4 participants selected at random. ROM measurements taken in the appropriate plane of movement were included in the analysis. The intraclass correlation coefficient (ICC) and associated 95% CI for each joint and overall were calculated based on a single-measurement, absolute-agreement, two-way random-effects model [21-23]. The interrater reliability varied among different joints, with an ICC of 0.985 (95% CI 0.980-0.989) for all joints combined. The lowest ICC was in forearm pronation with a median ICC of 0.252 (95% CI −0.477 to 0.75), and the highest was in shoulder extension with a median ICC of 0.998 (95% CI 0.983-1.00). The specific ICC for each joint is presented inTable 2. | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC8292936'] | ['34255680'] | ['ref24', 'ref25', 'ref26', 'ref27', 'ref28', 'table3', 'app3', 'app4', 'table4', 'ref31', 'ref32', 'ref33', 'ref34'] | Summary statistics, including the median and 95% CI for continuous variables and counts and proportions for categorical variables, were produced for all variables. As this was a pilot study on a rare disorder, statistical comparisons were produced only for exploratory purposes using a significance (α) level set a priori to 10% as has been proposed for research on rare disorders [24]. The effectiveness of the HEP was explored using the GAS. Raw GAS scores were converted to GAStscores for each participant and the global HEP [25]. Within-participant pre- and postintervention scores of the PODCI, PAQ-A, APPT, and ROM were compared using the related-samples Wilcoxon signed-rank test. Individual changes were also compared to evaluate clinically important differences as defined by Oeffinger et al [26] in the following domains of the PODCI (changes in points associated with a minimum clinically important difference): upper extremity (4.8 points), transfers and mobility (5.2 points), sports and physical function (10.3 points), pain and comfort (26.3 points), happiness (11.2 points), and global function (8.2 points). Changes in the APPT for the 10-point pain intensity scale were considered clinically meaningful when there was a change of more than two points [27,28]. For the PODCI and PAQ-A questionnaires, a sensitivity analysis was conducted because a participant had an ankle injury, unrelated to the HEP execution, before the final assessment. An imputation technique was used to replace the final results of the participant who was directly affected by the injury by using the median of the group for the PAQ-A and in the following domains of the PODCI: transfer and mobility, sport and physical function, pain and comfort, and global function. For the GAS, the objectives varied among the participants and were related to pain management (n=2); endurance in manual labor (n=1), writing (n=1), standing (n=1), or walking (n=2); sports (sledge hockey: n=1; karate: n=1); and daily activities (buttoning up shirt: n=1; transfer ability: n=2; controlling stair descent: n=1; self-propelling a wheelchair: n=1; self-feeding with utensils: n=1). The median number of goals established with the participants was 2 (range 1-3). A total of 15 goals were established, and 12 goals were achieved. The 3 goals that were not achieved included pain management (n=2) and walking endurance (n=1). The overall programtscore was 74.85, whereas the mediantscore among participants was 56.21 (95% CI 30-72.82); both scores are higher than the threshold of 50 points, meaning that overall, the participants achieved their goals. The pre- and postintervention results from the different questionnaires are shown inTable 3. A statistically significant change was observed in the pain and comfort domain of the PODCI (P=.08). The number of participants with clinically important changes was as follows: upper extremity (improvement: n=2; decrease: n=1), transfers and mobility (improvement: n=3; decrease: n=2), sports and physical function (improvement: n=1; decrease: n=1), pain and comfort (improvement: n=1; decrease: n=0), happiness (improvement: n=2; decrease: n=1), and global function (improvement: n=2; decrease: n=0). For the PAQ-A, a statistically significant improvement of 14% was observed in the group (P=.046).Multimedia Appendices 3-4show the pre- and postintervention results for each participant for the global domain of the PODCI and PAQ-A, respectively. For the APPT, 4 of 7 participants reported pain at baseline. One participant reported clinically meaningful improvement in the APPT at the end of the 12-week HEP; no changes were statistically significant. For ROM, improvements in shoulder abduction (P=.08), shoulder flexion (P=.07), wrist extension (P=.05), and knee extension (P=.04) were found to be statistically significant. No significant changes were observed in the other joints. The results for ROM for each joint are shown inTable 4. The results regarding the intervention’s effectiveness are promising. The GAS score, which was the main outcome measure to explore effectiveness, showed significant improvement at the end of the 12-week HEP. Among the 12 goals achieved measured using the GAS, 9 were achieved beyond expectations: endurance in manual labor, standing, and walking; sports (karate); and daily activities (buttoning up shirt, transfer ability, controlling stair descent, self-propelling a wheelchair, and using a fork). These large improvements might be due to the scaling of the goals using the GAS table. As most of the participants did not perform exercises before participating in this project, they may have demonstrated quicker gains. However, 2 participants with chronic pain did not achieve their pain goal, perhaps because of the multifactorial etiology of pain requiring management by an interdisciplinary team [31]. Another participant did not meet their initial goal for walking endurance as per the GAS score because of overestimation of baseline levels as reported by the participant; nonetheless, improvements during the final assessment (quicker walking pace) were noted. As the GAS allows for individualized and varied goals, it proved to be a versatile and sensitive measurement tool, given the high level of variability of joint involvement and physical function. There are benefits to using the GAS, but this tool requires some level of training and experience to develop goals that are SMART (specific, measurable, achievable, realistic and timed) [32]. After determining individualized goals in collaboration with participants, therapists need to scale the goals according to an expected level of change and predict potential improvement within the timeline, which may not always be intuitive. Although some clinically significant changes were measured with the PODCI, floor and ceiling effects were observed in a few participants. For example, in a participant with severe joint involvement, a floor effect was noted in all but the happiness domains. Large improvements in the transfer ability from wheelchair to exercise table in this participant were noted during the telerehabilitation sessions, yet the PODCI did not detect this change because the focus of the PODCI is mainly on ambulatory activities such as walking and running. The opposite effect occurred in participants who achieved maximum scores at baseline and, therefore, no positive change was detected. For these reasons, we conclude that the PODCI may not be an appropriate measure for our study, which used an exercise intervention for a heterogeneous group of youths. The baseline results from the PAQ-A were very low, yet they increased at the end of the 12-week HEP, with levels approaching those of typically developing adolescents [33]. The level of physical activity among participants with AMC remained lower than that among typically developing adolescents. This was similar to a study of adolescents with cerebral palsy [34]. With regard to ROM, we did not expect any significant changes because no participant selected ROM as their goal. Some statistically significant improvements were found, and they may have been explained by an improvement in muscle strength; however, these changes may not translate into clinically important changes. | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC8292936'] | ['34255680'] | ['figure4'] | Of the 114 patients with AMC followed at the SHC–Canada, 26 (22.8%) were eligible to participate and were able to be approached for participation. Of these, 10 individuals consented to the study, and an additional participant not actively followed at the SHC was recruited on social media. A total of 7 participants (5 boys) completed the intervention. The participants were recruited at the clinic (n=6) or through postal mail (n=2), phone (n=2), or social media (n=1). Of the 4 participants who withdrew, 2 consented at the clinic but never started the HEP because they could not be reached to schedule the initial assessment, and 2 withdrew after the start of the HEP because of personal reasons and lack of time.Figure 4shows the participation flow diagram. The participants’ median age was 16.9 years (range 11.3-20.8 years), and they represented 4 Canadian provinces with a median distance from the SHC–Canada of 227 km (range 7-3439 km). A total of 2 participants had Amyoplasia, 4 had distal arthrogryposis, and 1 had an unknown type of AMC. Joint involvement was distributed as follows: shoulders (n=5), elbows (n=6), wrists (n=6), hands (n=4), hips (n=3), knees (n=5), ankles (n=6), and spine (n=1), with a median of 6 joints (95% CI 3-8) involved. For the level of ambulation, 4 participants were classified as community ambulators, 2 were classified as household ambulators, and 1 was classified as nonambulatory. | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC8292936'] | ['34255680'] | [] | In this study on the use of telerehabilitation to deliver an HEP to youth with AMC, it was found that this approach is feasible and well accepted by participants. The GAS was a feasible measure in this pilot study because it provided the individualization of goals for the youths living with AMC who presented with varying levels of joint involvement. Overall, most of the GAS goals were achieved at the end of the 12-week HEP. In addition, some clinically meaningful improvements were observed in the PODCI and APPT scores, showing promising effects of an HEP. We also explored the reproducibility of using a virtual goniometer in this study and found good-to-excellent agreement overall. | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC8292936'] | ['34255680'] | [] | Most of the outcomes were standardized, although the HEP was based on individualized goals. The assessment provided did not always correspond to the needs of the participants because they did not provide objective information related to the individualized goals (eg, strength or endurance). For example, joint-specific ROM was measured for all participants, but it was only pertinent for 1 participant who had a dressing goal. For the interrater reliability of ROM measurement with a virtual goniometer, it would be best to compare those values with in-person measurements. However, in the context of this study, it was not possible to do so because the study design entailed remote visits only. Therefore, the ROM results should be interpreted with caution. The selected questionnaires for this study were validated for children aged up to 18 years, which corresponded to most of the participants included in this study (5/7, 71%). However, at the SHC–Canada, patients are followed until 21 years of age, and an older participant mentioned that the content of some of the questionnaires was not adapted to their reality. Finding standardized measures devised and validated for both pediatric and young adult populations is a challenge because measures are typically developed for either pediatric or adult populations. As this was a pilot study with the main objective being the assessment of its feasibility, no control group was included. A larger multicenter randomized controlled trial would be needed to ascertain the study power needed to draw conclusions on the effectiveness of an HEP. Initial and final assessments performed in person with follow-ups conducted remotely could also be a good compromise for future studies. | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC8292936'] | ['34255680'] | [] | The results of this pilot study suggest that it is feasible to use telerehabilitation to deliver an HEP for youth with AMC having different functional levels, having various goals, and living across different geographical regions. This approach also holds promise regarding the effectiveness of an HEP. Lessons can be learned from the challenges and positive aspects denoted in this study, which could lead to enhanced future protocols. | PMC8292936 | Original Paper; Original Paper | null | 34,255,680 | Using Telerehabilitation to Deliver a Home Exercise Program to Youth With Arthrogryposis: Single Cohort Pilot Study | Gagnon M, Marino Merlo G, Yap R, Collins J, Elfassy C, Sawatzky B, Marsh J, Hamdy R, Veilleux LN, Dahan-Oliel N. | J Med Internet Res. 2021 Jul 6;23(7):e27064. doi: 10.2196/27064. | Gagnon M | J Med Internet Res | 2,021 | 2021/07/13 | PMC8292936 | null | 10.2196/27064 | oa_comm/txt/all/PMC8292936.txt | 6deaa0d6340ab04886302541bec87f41 | J Med Internet Res. 2021 Jul 6; 23(7):e27064 | 2021-09-03 06:53:45 | CC BY | no |
['PMC9864789'] | ['36674229'] | ['B1-ijerph-20-01477', 'B2-ijerph-20-01477', 'B3-ijerph-20-01477', 'B4-ijerph-20-01477', 'B5-ijerph-20-01477', 'B6-ijerph-20-01477', 'B7-ijerph-20-01477', 'B8-ijerph-20-01477', 'B5-ijerph-20-01477', 'B6-ijerph-20-01477', 'B9-ijerph-20-01477', 'B5-ijerph-20-01477', 'B6-ijerph-20-01477', 'B9-ijerph-20-01477', 'B7-ijerph-20-01477', 'B8-ijerph-20-01477', 'B9-ijerph-20-01477', 'B10-ijerph-20-01477', 'B11-ijerph-20-01477', 'B12-ijerph-20-01477', 'B13-ijerph-20-01477', 'B13-ijerph-20-01477', 'B14-ijerph-20-01477', 'B15-ijerph-20-01477', 'B16-ijerph-20-01477', 'B17-ijerph-20-01477', 'B14-ijerph-20-01477', 'B18-ijerph-20-01477', 'B19-ijerph-20-01477', 'B20-ijerph-20-01477', 'B21-ijerph-20-01477', 'B22-ijerph-20-01477', 'B23-ijerph-20-01477', 'B14-ijerph-20-01477'] | Cognitive, especially executive, and motor functions, which tend to decline with age, are important in everyday life as the performance of some of the most basic activities requires the simultaneous involvement of both types of these functions [1,2,3]. Performing two activities at the same time (dual-task—DT) can pose a significant burden for executive functions (EF), especially in the elderly. One of the most important aspects of this mechanism is the interference effect (IE). The interference effect is defined as overlapping of similar pieces of information, which may inhibit or disrupt one another, thus making it easier to forget one or both [4]. Most often, the IE is explained on the basis of the limited resources [5,6] or bottleneck theories [7,8]. According to the first one, several tasks executed at the same time can exceed the capacity of cognitive resources [5,6]. These tasks can interfere with each other, causing the inhibition of highly automated operations over the less intuitive ones. The above phenomenon has long been known from research on the Stroop effect [9]. The completion time of dual-task, in comparison to the single-task, increases and more errors may appear; moreover, considerable attention resources and memory, thinking, planning, which are components of EF, are also used [5,6,9]. In turn, the bottleneck theory explains that attention is not an unlimited resource. The stimuli in the brain are filtered in such a way that only the most important ones reach it. Consequently, during DT, the priority will be set to one of the tasks. The interference is related to the effect of the time needed to decide which task should be performed first [7,8]. Research conducted on the basis of both theories shows that the IE may change and increase if the task is difficult, or it may be reduced in the course of the training [9,10,11,12]. Davidson, Zacks, and Williams [13] have shown that the reduction of the IE also occurs in the elderly compared to younger participants in the Stroop tasks. The elderly exhibited a greater interference effect than the younger subjects throughout the training. Older subjects made more mistakes, and it took them longer to complete the tasks. Importantly, however, in both groups, the effect of reduced interference during practice was observed, and the older adults showed the same trend of improvement as the younger participants. The authors concluded that the reduction of the interference effect during practice is present regardless of age. Similar results were also found in later studies [13,14,15,16,17]. In the Burger et al. [14] study, the elderly and younger subjects participated in 5-day training based on the Stroop tasks. The results revealed the significance of differences in the learning process in younger and elderly participants. The younger subjects generally showed a reduction of the interference effect at the final stage of training, whereas in the elderly, the reduction of the interference effect occurred regularly throughout the training. The number of years of formal education of the subjects played the most important role in predicting the benefits achieved in training. The greatest effect of reducing interference was observed in older participants with higher education. The IE reduction was also investigated in studies applying neurophysiological tests, using functional magnetic resonance (fMRI), electroencephalography (EEG), and functional near-infrared spectroscopy (fNIRS) in participants between 20 and 30 years old [18]. In the fMRI study, four different patterns of brain activity were distinguished during execution of cognitive-motor dual-tasks [19]. In the EEG study, the reduction of the P300 amplitude during DT execution compared to a single task was obtained [20,21]. The fNIRS study showed that the level of oxygenation in the prefrontal cortex increases during DT compared to a single task [22,23]. In summary, performing two activities simultaneously can overload a person’s cognitive resources, causing an interference effect. However, the IE may be reduced by multitasking training. As shown by contemporary works [14], the reduction of interference effect turns out to be more significant in seniors compared to young individuals. The reduction of the IE is also evident in neurophysiological tests, in studies with fMRI, EEG, and fNIRS. The cognitive mechanisms underlying the performance of two activities at the same time may explain supporting the elderly through the dual-task training. Unfortunately, the mechanism of reducing the interference effect has not been fully understood yet. Referring to the above-mentioned literature on the subject, the assumption is that the dual-task training is more cognitively demanding compared to the single-task training, consequently: The planning time will be longer, and the number of errors will be larger during the dual-task training, compared to the single-task training. The planning time will be shorter, and the number of errors will be reduced after all types of training. The main goal of this study is to answer the question of how the characteristics of dual-task training may be compared to the single-task training in the elderly. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | ['B23-ijerph-20-01477', 'ijerph-20-01477-t001'] | Sixty-five participants (16 men and 48 women), over 65 years of age, without neurological, psychiatric, cardiological, or orthopedic diseases/disorders, moving independently, were recruited from senior community centers in Warsaw. Exclusion criteria were a score below 24 points in the Polish version of the Mini-Mental State Examination test (the Polish adaptation and standardization of MMSE [23]), no vision correction and assisted walking. The total number of screened participants comprised 84 subjects. The participants of the study were randomly assigned to one of the three experimental groups and one control group (4 men, 16 women). Further, 58 of them completed the training (14 men and 44 women): 19 participants (5 men, 14 women) in the cognitive-motor group (4 individuals resigned), 20 (3 men, 17 women) in the cognitive group, 19 (6 men, 13 women) in the motor group (2 individuals dropped out). Six individuals dropped-out of the experimental groups due to the length of training. Only data obtained from the participants who completed the study were included in the statistical analysis. There were no training data from the control group. The mean age of the study participants was 71.2 (SD = 5.2), the number of years of education—15.3 (SD = 2.7), and the mean MMSE score was 29.1 (SD = 0.9). There were no demographic and clinical (MMSE score) differences between experimental and control groups. Detailed data are presented inTable 1. All participants agreed not to engage in any form of rehabilitation during the study period. All patients provided informed consent prior to inclusion. The research was completed in accordance with Helsinki Declaration. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | ['B19-ijerph-20-01477'] | Each examined person, after receiving a telephone notification, was randomly assigned by the project manager to one of four groups: Cognitive Motor Dual-Task Group (CM), Cognitive Task Group (CT), Motor Task Group (MT), or Control Group (C), and obtained a consecutive number from 1 to 20, in accordance with the simple randomization methodology [19]. Random assignment to groups was carried out using Microsoft Excel 2017 (365 Personal version). | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | ['ijerph-20-01477-f001'] | The participants were randomly assigned to one of three groups. The training in the CM group consisted in performing cognitive-motor tasks, the training in the CT group consisted in performing cognitive tasks, and the training in the MT group consisted in performing motor tasks. In the control group, the participants underwent two neuropsychological assessments (especially focusing on executive functions and attention), identical to the pre-test and post-test for the experimental groups, as well as the balance measurements. The control group did not participate in the training between the pre-test and post-test. After being assigned to one of the groups, the participants were informed about the research procedure, and they made an appointment for a pre-test. The post-test took place 4 weeks after the pre-test in all training groups and the control group. In the experimental groups, the meetings (10 training sessions for the CT and MT groups, 12 training sessions for the CM group, 3 times a week for 30 min) took place between the pre-test and the post-test training. A visual illustration of the training protocol has been provided inFigure 1. The difference in the number of the training sessions was due to the fact that the subjects in the CT and MT groups did the tasks faster compared to the subjects in the CM group. Group 1: in the dual-task training (CM), the participants planned their path through the maze and used body balancing on the posturographic platform to move through the maze. Group 2: in the cognitive training (CT), the participants planned their path through the maze and used a computer keyboard to move through the maze. Group 3: in the motor training (MT), the participants were to follow the route in the maze along the marked path, using body balancing on the posturographic platform to move through the maze. Control group: the participants not performing any exercises, neither cognitive nor motor. All participants, regardless of the training group, worked on the same cognitive material. In order to make the collected data as objective as possible, both the pre-test and the post-test were conducted by a project manager assistant other than the one responsible for the training sessions, and the project manager’s assistants had no insight into the pre-test or the training results. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | [] | Two DELL Inspiron (500 series) laptops (DELL LLC, Austin, TX, USA) with a 17.3″ screen and 2 Nintendo Wii Balance Board (Nintendo, Kioto, Japan) posturographic platforms of 30 × 50 cm, integrated for the OpenBCI services, were used in all training sessions. Moreover, an open-source DynamicCognition training on the basis of OpenBCI brain–computer interference platform (GNU GPL v3.0 license), operating with Ubuntu 14.04 software, was used. It is designed to improve planning and switching of attention during balance control exercises. The game consisted of 388 mazes (of increasing difficulty level of cognitive and motor skills) divided into 8 levels of difficulty—higher levels were characterized by a greater number of steps needed to reach the goal. Each maze board was made of 64 square areas (8 × 8). Participants were to navigate through mazes using a green ball, controlled, depending on the experimental group, either by the deviation of the feet pressure center on the posturographic platform (Nintendo Wii Balance Board) (CM and MT group) or by a computer keyboard (CT group). The participants’ task was to move the ball in such a way as to reach the green cross marking the end of the maze, without falling into the area of the “black hole” that would restart the level. After falling into the “black hole” three times, the player went back to the lower level of the task. When moving around the maze, the rules for the ball movement had to be taken into account: the ball moved in a straight line, and it moved until it hit an obstacle (walls, holes, or a cross). | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | ['B24-ijerph-20-01477'] | The Mini-Mental State Examination [24] (the Polish adaptation and standardization) was used for screening the general cognitive ability. The test examines basic cognitive abilities grouped into 6 areas: orientation in time and place, memorization, attention and counting, recalling, language functions, construction praxis. Twenty-four points is the cut-off point that may suggest the dementia process. The higher the MMSE score, the better the performance. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | [] | Special indicators that measured the interference effect were elaborated for the purpose of this study. The game that was created as part of this study allowed for collecting the orientation and planning time and the number of errors data. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | [] | In all three training groups, this indicator was related to the same time interval in seconds: from the moment the board was displayed until the first step was performed. However, due to the specificity of the training tasks, it measured slightly different functions in the CM and CT groups than in the MT group. In the MT group, the participants were to follow the route in the maze, paying attention to the marked path. In this group, the time of orientation and planning was therefore an indicator of the time needed to get to know the board—of focusing attention and of visual-spatial orientation. In the CM and CT groups, it was an indicator of the time needed to prepare for the task (as in the MT group) and plan the path through the maze. The material on which the participants worked (mazes) was the same for the CM, CT, and MT groups. In the study, the orientation and planning time was averaged for each participant and for all difficulty levels and presented separately for the three training groups. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | [] | For the participants in the CM and CT groups, this indicator applies to a slightly different construct than in the MT group, due to the specificity of the training tasks. In the CM and CT groups, the number of errors actually indicated the errors made in the planning process, namely incorrect steps. Incorrectly performed steps are additional moves—they were counted in the form of the difference between all the steps taken in a given maze and the minimum number of steps needed to complete the maze with the correct planning of the path. Planning skills were not tested in the MT group—this indicator concerned the number of deviations from the marked path that had to be followed by tilting the body on the posturographic platform. This error may have been caused by movement or attention difficulties in seniors and was counted each time the participant leaned out on the posturographic platform and kept leaning in a different direction than the path indicated. In the study, the number of errors was averaged for each participant and all levels of difficulty, separately for each of the training groups. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | ['B25-ijerph-20-01477', 'B26-ijerph-20-01477', 'B27-ijerph-20-01477', 'B26-ijerph-20-01477', 'B28-ijerph-20-01477', 'B26-ijerph-20-01477', 'B26-ijerph-20-01477', 'B26-ijerph-20-01477', 'B29-ijerph-20-01477'] | In order to establish whether the data sets had a normal distribution, the Shapiro–Wilk test was used with the significance levelp< 0.05 [25] corrected for Bonferroni’s multiple comparisonsp= 0.0125 [26]. The test indicated the lack of normal distribution for the obtained results. Therefore, further analysis was carried out using nonparametric tests. First, the results for orientation and planning time and the number of errors indicators between the training groups were compared for 8 levels of difficulty using theU- Mann–Whitney–Wilcoxon test [27], with the significance levelp< 0.05 and corrected for Bonferroni’s multiple comparisonsp= 0.0083 [26]. Secondly, theW-Wilcoxon test [28] with the significance level ofp< 0.05 and corrected for Bonferroni’s multiple comparisonsp= 0.0083 [26] was used for the comparison of orientation and planning time and the number of errors indicators within all training groups (cognitive-motor, cognitive, motor) on the consecutive 8 levels of difficulty. To compare the orientation and planning time and the number of errors between all training groups and during the whole training, theUMann–Whitney–Wilcoxon test [26] with the significance levelp< 0.05 and corrected for Bonferroni’s multiple comparisonsp= 0.0083 [26] was applied. In the end, the orientation and planning time and the number of errors were correlated using therho-Spearman (r) [29] with the significance level ofp< 0.05. Appropriate implementation from Python (version 2.7., SciPy version 0.14.0 an open-source library) was used to calculate the statistics. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | ['ijerph-20-01477-f002', 'ijerph-20-01477-t002', 'ijerph-20-01477-t003'] | In the cognitive-motor and cognitive groups, the plot line had similar shapes compared to the single-motor group (Figure 2). The orientation and planning time successively increased to the 5th level and afterwards, it started to decrease. In the MT group, the subjects needed more time at the beginning of the training. After three levels, the required time was quite short (about 1 s) and kept on the same level till the end of the training. The variety of results was smaller in the CM group compared to the CT group on most levels except the last one. In the MT group, the variety of results was rather small, the highest was observed at the beginning and after that, it remained stable during the rest of the training. The data inTable 2shows that the participants in the CT group spent most of the time planning the path compared to other groups in most levels except the last level. The participants who trained in the CM group needed more time for orientation and planning than the elderly in CT and MT groups. The data inTable 3show that the subjects in the CM group needed statistically significantly more time for orientation and planning the path on mazes from the 1st to the 5th level. The orientation and planning time was shorter after 6 levels. The participants in the CT group obtained corresponding results to the CM group. The subjects from the MT group needed more time only on the 1st level. Starting from the 2nd level, the required time did not change until the end of the training. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | ['ijerph-20-01477-f003', 'ijerph-20-01477-t002', 'ijerph-20-01477-t003'] | The results shown inFigure 3illustrate the similar dynamics of changes after cognitive-motor dual-task and cognitive single-training. The average number of errors increased to the 5th level, and after that, it gradually decreased till the end of the training in both groups. In a single-motor training group, the movement error meant going off the designed path. In MT groups, the errors usually appeared at the beginning of the training and after two levels, they successively decreased. In the CM group, the variety of results was constant, except for the 5th level, where the differentiation was lower. In the cognitive-motor training group, the variety of results was greater than in the cognitive single-task training group, except for the 3rd and 4th level. At these levels, the variation in the data in the CT group was much greater than in the CM group. In the MT group, the differentiation of the results was lower than in the CM and CT groups and it remained on a similar level throughout the whole training. The results shown inTable 2reveal that the participants in the CM group made the biggest number of errors compared to the CT and MT groups. Significant differences were especially noticeable when comparing the CM to CT and the CM to MT groups. The subjects who practiced in the CT group made similar errors to the MT group. Participants in the CT groups made more mistakes compared to the MT group on the 1st level. However, the task was difficult for participants in the CT group on the 3rd, 4th, and 7th level compared to the MT group. The results shown inTable 3indicate more errors from the beginning of the training to the 5th level. The significant reduction in the number of errors was obtained from the 6th to the 8th level. For participants in the CT group, an increasing number of errors was observed from the 1st level to the 5th level. From the 6th level, a decrease in the number of errors was noted. In the MT group, the number of errors remained constant and from the 4th level, a significant reduction in the number of errors was achieved. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | ['ijerph-20-01477-t004', 'ijerph-20-01477-t005'] | The data inTable 4suggest that the longest time for orientation and planning was required by the participants in the CT group compared to the CM and MT groups. The largest number of errors was made by participants in the CM group compared to the CT and MT groups. The correlation data inTable 5indicate that the orientation and planning time was strongly related to the number of errors in all groups. If the participants needed more time for orientation and planning, they also made more errors during the whole training. In the CM (r = 0.74,p< 0.04) and MT (r = 0.90,p< 0.002) group, strong relationships were obtained. Only in the CT group, the correlation was strong, but it was at the level of statistical trend (r = 0.70,p< 0.06). | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | [] | The study is of particular importance in the current literature because it shows the mechanism of reduction of the interference effect during dual-task training when compared to the single-task training. The novelty of this study is the analysis of the progress of dual-task and single-task training using two created indicators: orientation and planning time and number of errors. The results allow for a better understanding of the interference effect reduction mechanisms in the elderly. There were two general assumptions made on the basis of the literature, (1) that the planning time would be longer, and the number of errors would be larger during the dual-task training and that (2) the planning time would be shorter, and the number of errors would be reduced after all types of training (dual and single-tasks training). | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | ['B13-ijerph-20-01477', 'B14-ijerph-20-01477', 'B15-ijerph-20-01477', 'B16-ijerph-20-01477', 'B17-ijerph-20-01477'] | The obtained results have shown that the training in a dual-task condition was associated with a significantly greater number of errors, but not with a longer task planning time compared to a single-task condition training. The results of this study visibly differ from the classic studies about the Stroop interference effect [13,14,15,16,17]. In the studies based on the Stroop task paradigm, the elderly participants obtained a longer executive time and made more errors in interference color-word blocks compared to non-interference blocks. It is noteworthy that in this study, the time of task planning was analyzed, and in the discussed works, the actual time of task execution was considered. These are not the same variables. Due to technical reasons, it was impossible to analyze the time needed to complete the paths through the mazes in the three examined training groups. Another difference is the fact, that the Stroop interference tasks cannot be planned before their execution. Participants must react to the emerging stimuli. In this study, the subjects in the CM and CT training groups were given instructions and they were asked first to plan the task and then to execute it. In the cognitive-motor group, the participants had to plan the path, keep it in their working memory, and execute it using swings on the posturographic platform. Perhaps too many tasks were performed simultaneously, and they did not fit into the working memory capacity of the subjects. To reduce the interference effect in the CM group, the participants planned the whole path not at the beginning (according to the instruction), but they planned it after every few moves. The subjects in the CT group were supposed to plan the path and complete it by pressing arrows on the computer keyboard. The subjects performing only one operation at a time could plan the entire path at the beginning and keep it in their working memory. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | ['B8-ijerph-20-01477', 'B9-ijerph-20-01477', 'B10-ijerph-20-01477', 'B11-ijerph-20-01477', 'B5-ijerph-20-01477', 'B6-ijerph-20-01477'] | There was a decrease in the time needed to plan a path in the mazes among the subjects training in the cognitive-motor, cognitive, and motor groups. From the 6th level of difficulty, an increase of the required time in cognitive-motor and cognitive tasks was obtained. In the MT group, a significant reduction in the time needed to start a task was obtained on the 2nd level. There was a pronounced reduction in the number of errors made in the cognitive-motor, cognitive, and motor training. The subjects who performed cognitive-motor and cognitive exercises made fewer errors from the 6th level of difficulty. The participants training the motor tasks less frequently got off the path from the 3rd difficulty level. This result means that after all types of training, the number of errors and the planning time are reduced, but it happens at different moments during the training. These results are consistent with the current literature, where in tasks based on the Stroop interference effect, the elderly subjects obtained shorter execution times and made fewer errors [8,9,10,11]. Relating the results to the theory, the subjects learn to perform the task during cognitive-motor, cognitive, and motor training. Perhaps, following Kahneman’s [5,6] attention resources theory, cognitive and movement task balances the resources of attention in the elderly. Therefore, they make more mistakes than the respondents from the two single-training groups. In the process of learning, the task is automated, and the participants begin to make fewer mistakes and plan the route faster. The results indicate that after all types of training, the number of errors and the time needed to plan the path decreases, despite the increasing difficulty of the tasks. Depending on the type of training, the planning time and errors are reduced at different points in the training. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | [] | In comparison to the neuropsychological studies mentioned above, the dual-task training presented in this paper was more cognitively demanding. The interference effect was visible, especially at the beginning of the training and it was present up to the 6th difficulty level, after that it decreased. In the context of future research, an interesting one seems to be assessing the similarities of the learning effect for cognitive-motor and cognitive training. Perhaps the balance training was of a slight difficulty for the participants who practiced cognitive-motor tasks and the cognitive-motor and cognitive groups in fact worked on the same skills. Additionally, no significant effect of exercise training in the motor group was demonstrated. On the other hand, in the dual-task training, an increased number of errors was observed, and even a slight “strain” with the task that followed caused an interference. The obtained results will have significant applicability in practice. The dual-task training could be one of highly effective, additional methods of supporting older adults in terms of their cognitive and physical activity. What is more, it may become a possible means of providing rehabilitation, thus leading to maintaining their independence in everyday life. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
['PMC9864789'] | ['36674229'] | [] | Several limitations of the study should be considered. One of these limitations is the sample blinding method. In the discussed paper, the double-blind standard was not maintained. The project assistants knew to which groups the participants were assigned. Another limitation is the cognitive material (the maze game with increasing difficulty) used in the training sessions could be repetitive and monotonous for participants, possibly implicating reduced motivation. The last limitation would be the participants group. The participants were a group of healthy older adults, mostly women (73% of participants), seeking some cognitive activity. | PMC9864789 | Article | null | 36,674,229 | The Characteristics of the Reduction of Interference Effect during Dual-Task Cognitive-Motor Training Compared to a Single Task Cognitive and Motor Training in Elderly: A Randomized Controlled Trial | Wiśniowska J, Łojek E, Olejnik A, Chabuda A. | Int J Environ Res Public Health. 2023 Jan 13;20(2):1477. doi: 10.3390/ijerph20021477. | Wiśniowska J | Int J Environ Res Public Health | 2,023 | 2023/01/21 | PMC9864789 | null | 10.3390/ijerph20021477 | oa_comm/txt/all/PMC9864789.txt | 4dfc5a4ae36d9ad9ef6ec89d7166eb3a | Int J Environ Res Public Health. 2023 Jan 13; 20(2):1477 | 2023-01-24 23:30:08 | CC BY | no |
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