Studies show bilingualism entails an advantage in cognitive control tasks. There is evidence of a bilingual advantage in the context of aphasia, resulting in better cognitive outcomes and recovery in bilingual persons with aphasia compared to monolingual peers. This bilingual advantage also results in structural changes in the right hemisphere gray matter. Very few studies have examined the so-called bilingual advantage by reference to specific anomia therapy efficacy. This study aims to compare the effect of French-Phonological Component Analysis (Fr-PCA) in monolinguals and bilingual persons with aphasia, both at the linguistic and cognitive control level, and to examine the structural impact of left hemisphere lesion location and right hemisphere structural data. Eight participants with chronic aphasia received Fr-PCA for a total of 15 h over 5 weeks. The results showed improved accuracy for treated words and generalization to untreated items and discourse in both groups, and improved Flanker task performance for some participants. Bilingual participants improved more than monolinguals for picture-naming tasks and narrative discourse. Damage to the left postcentral gyrus and the middle frontal gyrus was associated with less therapy-induced improvement. Additionally, left hemisphere damage to the inferior parietal gyrus and postcentral gyrus was associated with reduced cognitive control pre-therapy. Undamaged right hemisphere cortical thicknesses were significantly different between groups; the inferior frontal gyrus and the middle frontal gyrus were greater for the bilingual participants and correlated with cognitive control skills. These results suggest a bilingual advantage in anomia recovery following Fr-PCA, potentially resulting from enhanced cognitive control abilities that could be supported by right hemisphere neural reserve. Aphasia is an acquired language disorder following brain injury occurring in over 1/3 of hospitalized stroke patients; an estimated 165,000–380,000 Canadians are affected with chronic aphasia . Aphasia1 than monolinguals, referred to as the bilingual advantage  report a bilingual advantage in cognitive performances in stroke survivors . ConcernIn impairment-based therapies targeting anomia, phonological therapies, such as Phonological Component Analysis PCA; , aim to Studies have been performed using phonological approaches to treat anomia in bilingual PWA and have reported good results, focusing on cross-linguistic therapy effects . To thisThis study aims to investigate the effects of Phonological Component Analysis delivered in French (Fr-PCA) with French monolingual (mPWA) and French-English bPWA on their linguistic and cognitive profiles, in relation to their respective lesion locations, and cortical thickness in the undamaged hemisphere. The specific questions concerning the efficacy of Fr-PCA, the lesion location’s impact, and the RH’s role addressed in this paper and their corresponding hypotheses are listed below. For each research question, we are interested in looking at improvement or performance for all participants, and across groups (mPWA vs. bPWA) when possible, allowing us to evaluate the efficacy of Fr-PCA and the potential influence of bilingualism.acquisition), untreated items and other object naming tasks , and other linguistic abilities and cognitive tasks ? If so, do bPWA show more significant treatment effects  when compared to mPWA?Does Fr-PCA lead to improvements in naming accuracy for treated items (acquisition) and untreated words , as reflected by higher accuracy scores on picture-naming probes. It is also hypothesized that Fr-PCA will improve standardized language test scores, connected-speech main concept scores , and cognitive control task performance (transfer). Moreover, in line with recent works and with the load of Fr-PCA on cognitive control, it is expected that improvement will be observed in both groups, with bilinguals showing better improvement levels  involved in language and cognitive control networks will lead to more severe linguistic and cognitive difficulties . We thusDoes RH cortical thickness vary across monolingual and bilingual PWA, and if so, does it relate to performance in cognitive and language tasks?Given the role of RH in language processing in PWA  and struAn exploratory research framework addresses the questions regarding the impact of lesion location (question 2) and the role of the RH (question 3).This is a pre-, post-therapy study with multiple baselines and repeated measures before and after Fr-PCA (three baseline probes and one post-therapy probe) across groups. To answer the specific questions, we use a mixed design with case series analysis accompanied by group analysis. Specific methods are described in section “Data analysis plan.”Eight participants with aphasia took part in this study; four monolingual and four bilingual participants with aphasia (mPWA – bPWA), matched for age, education, and time post-aphasia onset (TPO). See Mother tongue (L1) was French for all participants, and for bPWA, English was the second language (L2). All participants lived in the province of Quebec, a predominantly francophone province within the bilingual English-dominant country of Canada. Participants were recruited as part of a larger research project studying the efficacy of Fr-PCA through community-based aphasia associations and community advertising. They all presented with chronic aphasia following a single left hemisphere stroke (minimum of 6 months post-onset) and were MRI compatible. Participants did not have premorbid or concomitant neurological conditions , uncorrected hearing, or vision loss. Throughout the study, they did not receive any other speech-language therapy or therapy of any sort.The CRIUGM’s aging and neuroimagery research ethics committee (CMER RNQ 15-16-02) approved this project. All participants provided informed written consent to participate in the study.Participants completed a comprehensive battery of language and cognitive tests before and after Fr-PCA therapy  and performance variation on TDQ60, a francophone object-naming test. Tasks used to measure across-level generalization are the variation on DVL38, a verb naming test, on the sub-tasks in the MT86, and the variation on the narrative discourse main concept score.Participants underwent the Eriksen’s Flanker task  presenteImages were acquired using a 3 T MRI Siemens Trio scanner, which was updated (Prisma Fit) with a standard 32-channel head coil during data collection. A high-resolution structural image was obtained using a 3D T1-weighted imaging sequence using an MP-RAGE (TFE) sequence .The MRIs were acquired at the Functional Neuroimaging Unit in Montreal. For each participant, a lesion map was manually drawn, considered the golden standard for lesion mapping . FreeVie2, Linux Mint 17 Ubuntu 14.04_x86_64 , the final sound (”What sound does it end with?”), the number of syllables (”How many beats does the word have?”), providing a first sound associate (”What other word starts with the same sound?”) and a rhyme to the target (”What does this rhyme with?”)  .Fr-PCA therapy started immediately after the assessment. Participants received Fr-PCA for the items on List 1 (see above) for 15 1-h face-to-face sessions, three sessions per week for 5 weeks. Participants were met either at their homes or the research center, whichever they preferred. The PWA was asked to generate the answers to each cue; if this was not possible, they could choose between three valid options to promote active participation . All itez-scores were calculated using the normative mean and standard deviation values for the participant’s age and education level , evel see . The folZ-scores allow comparing language abilities and improvements following Fr-PCA across age and education levels. As per standard clinical guidelines used in speech-language pathology, z-scores below – 1.5 SD were considered mild impairment, and z-scores below – 2 SD were considered severe impairment , moderate evidence (if two or three of the methods were large or significant), weak evidence (if only one of the methods was large or significant), or no evidence of a treatment effect.Four analysis methods appropriate for single-subject research designs were used to investigate the effect of Fr-PCA on naming accuracy for treated items. The results of these methods were merged to indicate if there was naked eye  was calculated to determine clinical significance using the standardized difference approach . Following the guidelines given by An effect size equal to or greater than 4.0, 7.0, and 10.1 was considered a small, medium, or large magnitude of treatment effect .U Test of Trend, a non-parametric method used to measure non-overlap between two phases (A and B), was used to compare baseline accuracy scores to intervention accuracy scores. This analysis was performed using the Tau-U Calculator  and therapy sessions (15) are used.Third, the Tau lculator . For thet-test. More specifically, WEST-ROC and WEST-Trend were calculated to respectively verify that the rate of change (ROC) post-therapy is significantly greater than the expected null ROC at baseline while also accounting for existing trends in the data, and that existing linear trends in the data are accounted for, indicating significant improvement, over and above existing trends in the data (t-tests (one-tailed) were conducted per participant. Using the Holm–Bonferroni procedure, alpha was initially set at 0.05 and adjusted accordingly for all subsequent comparisons to 0.05/4 = 0.0125.Finally, individual participant naming accuracy  was analyzed by item, using the WEighted STatistics (WEST) method outlined by the data . In this3 were performed with the pre-therapy and post-therapy language z-scores for all PWA to see if Fr-PCA significantly improved language performance.First, to assess within-level generalization, we calculated individual effect sizes and WEST statistics with the untreated items following the same method described above. Furthermore, to complete the within-level generalization and to assess across-level generalization, Wilcoxon signed-rank testsU test was completed comparing pre- and post-therapy score differences  between groups for standardized language tests z-scores(variationscore = z−scorepost−therapy−z−scorepre−therapy).To verify the potential impact of bilingualism on therapy within- and across-level generalization, a non-parametric independent sample Mann–Whitney transfer following Fr-PCA, a Wilcoxon signed-rank test was also performed for the pre- and post-therapy outcome measures of the Flanker task to examine therapy transfer. A non-parametric independent sample Mann–Whitney U test was applied to compare post-therapy Flanker outcome measures between bPWA and mPWA to verify the potential impact of bilingualism on cognitive control, given that 2 monolingual participants could not perform the Flanker task before therapy.Finally, to investigate improvement U test was performed to compare the number of voxels within each identified ROI between groups.Considering the variability in lesion location among participants with strokes, a subset of ROIs damaged in at least 2 mPWA and 2 bPWA  was identified to perform the correlations described below. To account for potential differences in lesion location across groups (mPWAs and bPWAs), a Mann–Whitney To answer the question regarding the impact of lesion location on pre-therapy skills, a Spearman’s rank-order correlation was performed with the number of voxels in each ROI within the lesion mask and scores on language and cognitive performance tasks before therapy for all PWA. To assess the impact of the lesion location on therapy-induced improvements , a Spearman’s rank-order correlation was also performed between the number of voxels in each ROI within the lesion mask and variation scores on language performance tasks.rs = 0.00–0.19 was considered a very weak correlation, rs = 0.20–0.39, a weak correlation, rs = 0.40–0.59, a moderate correlation, rs = 0.60–0.79, a strong correlation, and rs = 0.80–1.0, a very strong correlation , within-level generalization , across-level generalization (improvement on other language abilities) and transfer (improvement on cognitive control task). Secondly, the impact of the lesion location on pre-therapy linguistic and cognitive performances is examined using correlations. Finally, the role of the RH is explored in relation to the status of bilingualism and pre-therapy linguistic and cognitive performances.To determine the efficacy of Fr-PCA, a mixed method was employed. Case series analysis is used to examine the acquisition with treated items using visual inspection of the data, analysis of effect size, Tau-U Test of Trend, and WEST statistics.Furthermore, therapy-induced generalization (within- and across-levels) is examined with case series analysis and group analysis. Within-level generalization (naming accuracy of untreated items) is also investigated with two case series methods: analysis of effect size and WEST statistics. Then, we investigate the effect of Fr-PCA by comparing pre-therapy scores on standardized language tests to post-therapy scores. Finally, we compare the improvements of mPWA and bPWA for a potential impact of bilingualism on therapy outcomes.To examine acquisition following Fr-PCA, case-series analyses were performed. The summary of the case series analysis incorporating four analysis methods can be found in U , the only analysis method supporting acquisition for MA1. Although MA1 showed a limited gain in accuracy, Fr-PCA produced improvement in response time and pronunciation level, not reflected with the main outcome variable in this study.MA1, the mPWA with the mildest aphasia , demonstrated weak acquisition following Fr-PCA. Although MA1 showed a higher mean accuracy rate during therapy phase (99%) than baseline phase (70%) and no overlapping points between the phases, visual inspection revealed that points in therapy phase did not exceed baseline trendline, as he showed a noticeable improvement between baseline sessions in terms of accuracy. Indeed, after improving at each baseline assessment, MA1 reached ceiling effect at the first therapy session. This suggests that therapy performances do not surpass the improvement already initiated during baseline assessments. Even if WEST-Trend is significant, it is recommended that the effect of treatment be considered significant when both the WEST-Trend and WEST-ROC analyses yield significant results . Thus, gU result . Finally, both WEST-ROC and WEST-Trend yielded significant results. All four methods support MA2’s acquisition following Fr-PCA.MA2, who had moderate to severe aphasia and mild to moderate apraxia, showed strong evidence of acquisition following Fr-PCA. She demonstrated a greater mean accuracy rate during the therapy phase (51%) than during the baseline phase (0%), she did not show overlap in performance between therapy and baseline phases, and therapy improvements exceeded baseline trendline. When looking at the effect size, MA2 showed a large effect size for acquisition following Fr-PCA (ES = 11.17) and a significant Tau-U result . Finally, both WEST-ROC and WEST-Trend yielded significant results. All four methods support MA3’s acquisition following Fr-PCA.MA3, who presented moderate to severe aphasia and mild apraxia, showed strong evidence of acquisition following Fr-PCA. There was greater mean accuracy rate during the therapy phase [compared to baseline phase (0%)], with no overlap in performance between therapy and baseline phases. Therapy improvements exceeded baseline trendline. When looking at the effect size, MA3 showed a large effect size for acquisition following Fr-PCA (ES = 27.91) and a significant Tau-U = 0.75; p = 0.058) further indicated overlap between phases. In addition, there were non-significant WEST-ROC and WEST-Trend results, indicating the improvement is neither greater than the null ROC expected at baseline, nor greater than the baseline trend. MA4 did show a small effect size for acquisition (ES = 4.00). However, none of the methods provided large or significant support for acquisition following Fr-PCA for MA4.MA4, who presented the most severe aphasia and moderate to severe apraxia, demonstrated no evidence of acquisition following Fr-PCA. Although MA4 showed a higher mean accuracy rate during therapy phase (15%) than baseline phase (5%), visual inspection revealed overlapping points between the baseline and therapy phases, and mean accuracy during therapy phase did not exceed baseline trendline. The non-significant Tau-U test . When looking at the effect size, MA3 showed a large effect size for acquisition following Fr-PCA (ES = 15.30). Finally, both WEST-ROC and WEST-Trend yielded significant results. All four methods converge in supporting BA1’s strong acquisition following Fr-PCA.BA1, who had moderate to severe aphasia and mild apraxia, showed strong evidence of acquisition following Fr-PCA. He demonstrated a greater mean accuracy rate during therapy phase (76%) than during baseline phase (7%), he did not show overlap between performance during therapy phase compared to baseline phase, and therapy improvements exceeded baseline trendline. This was confirmed by a significant Tau-U result . When looking at the improvement during therapy phase, both WEST-ROC and WEST-Trend yielded significant results, indicating the ROC post-treatment was significantly greater than the null ROC and that improvement was above existing trends in the data. However, looking at the effect size, BA2 showed a moderate effect size for acquisition following Fr-PCA (ES = 9.00). Thus, only three methods give large or significant support of acquisition following Fr-PCA for BA2.BA2, who presented mild to moderate aphasia and mild to moderate apraxia, showed moderate evidence of acquisition following Fr-PCA. There was a greater mean accuracy rate during therapy phase (95%) than during baseline phase (50%), she did not show overlap between performance during therapy phase compared to baseline phase and showed therapy improvements that exceeded baseline trendline. This was confirmed by a significant Tau-U result . However, looking at the improvement during therapy phase, although WEST-ROC yielded a significant result, WEST-Trend did not survive correction for multiple comparisons, indicating the improvement did not surpass existing trends in the data. Furthermore, looking at the effect size, BA3 showed only a moderate effect size for acquisition following Fr-PCA (ES = 8.95). Thus, only two of the four methods give large or significant support of acquisition following Fr-PCA for BA2.BA3, who had mild to moderate aphasia, showed moderate evidence of acquisition following Fr-PCA. He demonstrated a greater mean accuracy rate during the therapy phase (94%) than during the baseline phase (48%), did not show overlap between performance during therapy phase compared to baseline phase and showed therapy improvements that exceeded baseline trendline. This was confirmed by a significant Tau-U result . When looking at the effect size, MA3 showed a large effect size for acquisition following Fr-PCA (ES = 14.00). Finally, both WEST-ROC and WEST-Trend yielded significant results. All four methods converge in supporting BA4’s strong acquisition following Fr-PCA.BA4, who had moderate aphasia and mild apraxia, showed strong evidence of acquisition following Fr-PCA. He demonstrated a greater mean accuracy rate during the therapy phase (87%) than during the baseline phase (5%), he did not show overlap between performance during therapy phase compared to baseline phase and showed therapy improvements that exceeded baseline trendline. This was confirmed by a a significant Tau-In sum, for the mPWA group, one participant showed strong evidence of acquisition (MA3), one participant showed moderate acquisition (MA2), one participant showed weak evidence (MA1), and one participant showed no evidence (MA4). To examine within-level generalization, mixed-methods analyses were carried out. Two case series methods, namely analysis of effect size and WEST-ROC and WEST-Trend statistics, were employed to examine the improvement of untreated items. For untreated items, the analysis is based on baseline and post-therapy performance. When looking at z-scores, along with variation scores for the comprehensive language assessments, are included in 4 was conducted to determine if Fr-PCA significantly affected participants’ performance variance pre-therapy to post-therapy on standardized language tests. When examining within-level generalization with regard to a standardized test, Fr-PCA led to statistically significant improvements for object naming (TDQ-60) within our participants (p = 0.016). Participants BA2 and BA3 performed within the normal range pre-therapy, and participant MA1 was at ceiling performance pre-therapy on this test. All other participants showed severe impairment (<–2 SD) and improved significantly following Fr-PCA. Please refer to the Pre- and post-therapy Clinically, a variation greater than +1 SD generally indicates a significant improvement. Following Fr-PCA, on the TDQ60, MA1 showed no variation as he was already at ceiling pre-therapy, and BA3 showed only slight improvement (+0.450). All other participants showed significant variation scores .U test was conducted to see if there was a difference between mPWA and bPWA in variations from pre-therapy to post-therapy on the TDQ60 performance , verbal fluency task, and narrative discourse informativeness, showing across-level generalization in all participants with PWA, except for MA1, who was within normal range for all standardized test and did not improve significantly for the main concept score. These results are displayed in z-score = –1.066), also made clinically significant gains. All other participants performed within the normal range and did not show clinically significant variations. Considering the verbal fluency task performance, among the seven participants with severe impairment , only one participant (MA3) made clinically significant improvements. Post-therapy, two participants (BA2 and BA3) made sufficient gains to no longer meet the criteria for a severe impairment. Finally, when looking at the main concept scores for the Cinderella discourse, all participants that completed the task at both assessments improved, though a wide range of gains was found (CI95 [2–37]).Looking closer at the DVL38 results, in this sample, two participants showed severe impairments (MA2 and MA4) pre-therapy and made clinically significant gains (respectively +1.707 and +2.659). BA3, who showed impairments that did not quite reach the mild impairment criteria (To compare group differences (mPWA vs. bPWA), a Mann-Whitney U test was conducted using variation scores from the standardized test see . None ofSix PWA completed the Flanker task before and after therapy (two mPWA and four bPWA). Pre-therapy and post-therapy Flanker task outcome measures are included in Looking at the Flanker effect and raw response times for both conditions, 4 of the 6 participants who completed the task at both assessments  improved in terms of interference suppression and speed. BA1 and BA2 showed increased response times post-therapy for both conditions and an increased Flanker effect. In terms of error rates, MA1 showed an improvement for the incongruent condition (–0.05 in error rate), whereas MA3 showed an important increase (+0.11 in error rate) at the post-therapy assessment. BA1, BA2, BA3, and BA4 did not show any variation; all demonstrated between 0.00 and 0.01 error rates in both conditions. It is noteworthy that two monolingual participants who were unable to perform the task before therapy were able to perform the task after, an improvement that statistical analysis cannot capture.U test was performed to determine if there is any difference between mPWA and bPWA in the post-therapy Flanker task performance .A Mann–Whitney formance . There wLooking closer at the data, MA4 showed a lower Flanker effect than all bPWA, and MA3 showed a lower Flanker effect than BA1, BA2, and BA3, whereas MA1 and MA4 showed more significant Flanker effects than all bPWA. Regarding response times, MA2 and MA4 responded the slowest (RT > 1200 ms in both conditions). MA3 showed the fastest response times in all conditions, and MA1 showed faster response times than BA1, BA2, and BA3 for the congruent condition (at the cost of making more errors). In the incongruent condition, bPWA were faster than MA1, MA2, and MA4. In terms of error rates, in both conditions, mPWA showed higher error rates than bPWA (CI95 = [0.05–0.26] for the congruent condition and CI95 = [0.25–0.31] for the incongruent condition). MA3 was thus the fastest participant but maintained a higher error rate than bPWA.U test results are provided for all ROIs for which at least one participant per group shows damage. There was no significant difference between groups for lesion location and extent of damage (in voxel numbers).A subset of ROIs damaged in at least two mPWA and two bPWA was identified to perform the statistical analysis. All participants have a single left hemisphere stroke; thus, the damaged ROIs are all in the left hemisphere. The Table in The subset of ROIs damaged in at least two mPWA and two bPWA in our sample is composed of: the insular cortex, the frontal operculum cortex, the central opercular cortex, the frontal orbital cortex, the pars opercularis in the IFG, the MFG, the precentral gyrus, the postcentral gyrus, the temporal pole, Heschl’s gyrus (includes H1 and H2), the temporooccipital part of the MTG, the superior parietal lobule (SPL) and the planum polare. The subset covers ROIs throughout the frontotemporoparietal network known to be involved in language and cognitive control.It is important to note that 4 mPWA showed damage to the posterior division of the SMG, but only one bPWA showed damage to this ROI. Similarly, three mPWA showed damage to the AnG, but no bPWA showed damage to this ROI. Three mPWA showed damage to the parietal operculum cortex, but only 1 bPWA showed damage to this ROI. However, these ROIs were not included in the correlation analysis because participants from only one group showed lesions in the areas.rs = 0.740, p = 0.036) and the pars opercularis of the IFG . The pretherapy performance on the verbal fluency task correlated very strongly with the damage to MFG  and strongly with the amount of damage in the pars opercularis , the precentral gyrus , the temporal pole  and the anterior division of the STG .A Spearman’s correlation was performed between the number of voxels within the ROIs covered with the lesion mask and the pretherapy language scores, and the Flanker task performance , the temporal pole  and Heschl’s Gyrus  indicating difficulty in interference suppression with larger lesion size in these ROIs. The results presented do not survive correction for multiple comparisons.When considering the cognitive control task outcome measures, a strong positive correlation appears between the Flanker Effect and the damage to the pars opercularis , the central opercular gyrus , the MFG , the postcentral gyrus  and the SPL . The variation score of the untreated items correlated negatively to damage in the Heschl’s gyrus  and the postcentral gyrus . The change in the narrative discourse task is strongly correlated negatively to the damage in the insular cortex . These results showing negative correlations suggest that larger lesion size is related to less therapy-induced improvement in language performance. Finally, a strong positive correlation is found between the variation score in the repetition task and the damage in the SPL . However, this correlation is driven by participants without damage to the SPL performed at ceiling pretherapy and thus, did not show any variation. The results presented do not survive correction for multiple comparisons.A Spearman’s rank-order correlation was run to assess the relationship between the extent of the damage to ROIs and the variation of scores on linguistic tasks for all PWA see . The varU test was run with the cortical thickness generated by FreeSurfer to determine if there were differences between mPWA and bPWA. The ROIs with significant cortical thickness differences are presented in A Mann–Whitney rs = –0.943, p = 0.005), the precentral gyrus , the rostral middle frontal gyrus  and the frontal pole , indicating less interference effect with larger cortical thickness for the undamaged ROIs in the RH. Also, there were negative correlations for these ROIs and the error rates in the congruent  and the incongruent conditions , indicating faster response time on cognitive control task is related to larger cortical thickness for these ROIs.A Spearman’s rank-order correlation assessed the relationship between the cortical thickness in the RH for ROIs that were significantly different between mPWA and bPWA and the linguistic and cognitive control tasks performances before therapy for all participants. Significant correlations were found only in the cognitive control task outcomes  and showed better recovery of their L1, therefore qualifying for the French therapy program. All participants were compliant with therapy. To our knowledge, this is the first study investigating the effect of Fr-PCA across monolingual and bilingual PWA.acquisition as demonstrated by the case series (improved accuracy in naming treated items), more so in bPWAs. Participants also showed within-level generalization (improved accuracy in naming untreated items), across-level generalization (improved performance in other linguistic tasks), and transfer (improvement on outcome measures from the Flanker task). Secondly, performance on linguistic and cognitive tasks before Fr-PCA was related to the location of left hemisphere damage, and so was therapy gain. Lastly, several frontal regions in the RH, known for their role in cognitive control, showed increased cortical thickness in bPWA compared to mPWA, and this difference was related to pre-therapy cognitive performance. The set of findings is discussed by reference to the impact of bilingualism on aphasia recovery and, more precisely, in relation to the question of Fr-PCA efficacy, the impact of lesion location and the role of the RH in recovery.This study provides three main findings. First, Fr-PCA positively affected acquisition, within- and across-level generalization, and transfer indices of treatment effects.The first question investigated whether Fr-PCA would result in improvement for the Acquisition In line with previous studies on the effect of PCA with mPWA  than monolinguals , although this did not reach statistical significance. The bilingual group’s strengthened cognitive control mechanism could explain the larger across-level generalization seen in bPWA. Further looking at the effects of Fr-PCA on narrative discourse informativeness, main concept scores improved for all participants. Connected speech is considered the gold standard for aphasia rehabilitation and translation of therapy gains into everyday life improvement. It is one of the essential therapy outcomes for PWA  and faciThe hypothesis concerning transfer effects following Fr-PCA is partially confirmed. Although the statistical comparison between pre- and post-therapy was inconclusive, potentially due to the limited number of participants having completed the Flanker task at both pre- and post-therapy assessment sessions, we do find four participants reducing the Flanker effect , indicating less interference from distractors after intensive SLT. Two additional participants (MA2 and MA4) who could not perform the task during the pre-therapy assessment were able to perform the task after intensive SLT suggesting a therapy-induced change in cognitive control task performance. Two bPWA  demonstrated higher Flanker effects post-therapy , indicating more interference from distractors. At the post-therapy assessment, these participants verbalized specially focussing on gaining more accuracy in their performance, probably leading to a speed-accuracy trade-off. Although we do not observe any accuracy variation for these participants (both participants displayed a 0.00 error rate for the congruent condition and 0.01 for the incongruent condition), their Flanker effects were in typical ranges based on difference scores provided in previous literature . InteresWhen looking at trends in the data, there is much more variability within the mPWA group than in the bPWA in relation to initial impairments and gains made following Fr-PCA. The interaction between the performance on the Flanker task and the linguistic abilities also seems more present in the bPWA group. However, it is difficult to conclude that Fr-PCA is related to transfer in cognitive performance. Indeed, bPWA’s better performance than their monolingual peers at the Flanker task in this study  and the SMG . None of the bPWA show damage to the AnG, and only BA3 shows damage to the SMG. Within the current cohort, MA2, MA3, and MA4 showed damage to the AnG, previously associated with less recovery ; it is rFurther, another core region in the language network, the posterior division of the SMG , shows mParticipants with larger lesions in central ROIs in the cognitive control network  did exhiFinally, the lesion location data in this study also supports the relationship between cognitive control skills and discourse improvement, irrespective of the language group. We observe that more insular cortex damage  – part of the cognitive control network  – triggeThe third question looked at whether cortical thickness in the RH differed between bPWA and mPWA, given the role of RH in post-stroke language processing (or recovery) and bilingual experience-driven structural changes in the RH . FindingSo, improvements in the therapy outcomes in the bPWA may be related to the structural differences in the critical areas in the RH related to cognitive control that drive more benefits from intensive SLT like Fr-PCA therapy. In line with All participants benefitted from Fr-PCA, either in the form of acquisition, generalization, or transfer, and demonstrated a variety of recovery profiles. The differences in severity of aphasia and variability in baseline performance of the participants could explain individual differences in the current study. Previous studies have reported that persons with more severe aphasia make less gains following therapy . InteresInterestingly, damage in the cognitive control and language network regions was related to greater pre-therapy interference from distractors (as indicated by higher Flanker effect) and slower RTs on the Flanker task pre-therapy, along with less improvement in the treated items . This trThe number of participants in this study is higher than in previous works studying therapy-induced improvements following PCA. Still, a larger sample is required to argue better the role of bilingualism in following Fr-PCA-induced aphasia recovery, especially to corroborate the interpretations made from the neuroimaging data. The findings of this study should be interpreted cautiously, especially for the analyses based on subgroups of the total participants. These results should be considered a trend that can aid researchers in establishing sound hypotheses for future research with larger sample sizes.Considerable heterogeneity is found in the participants with aphasia in the current study that limit the strength of the claims that can be made, even if this variability is well documented in the literature . The varFuture research could explore the effect of bilingualism on cognitive control and aphasia recovery by focusing on inter-individual variability in different measures of bilingualism , such asFurthermore, a larger sample is required to understand the effect of different predictor variables – aphasia-related and lesion-related – in the context of bilingualism. Finally, considering the growing evidence on the network correlates of cognitive and neural advantages in bilinguals showing equivalent behavioral performances , future The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by CRIUGM’s Aging and Neuroimagery Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.MM-T: conceptualization, data curation, formal analysis, investigation, methodology, writing – original draft, and writing – review and editing. TD: conceptualization, formal analysis, supervision, and writing – review and editing. PB: formal analysis and methodology. AA: funding acquisition, resources, methodology, supervision, and writing – review and editing. All authors contributed to the article and approved the submitted version.


The Coronavirus Diseases 2019 (COVID-19) directly affects HIV prevention and sexual health services utilization among men who have sex with men (MSM). This study investigated changes in human immunodeficiency virus (HIV) testing utilization among MSM before and after the COVID-19 pandemic received initial control in Shenzhen, China.This study was a sub-analysis of a prospective observational cohort study conducted among MSM in Shenzhen, China between August 2020 and May 2021. Participants were recruited through outreaching in gay venues, online recruitment, and peer referral. Participants completed a baseline online survey between August and September 2020 and a follow-up online survey between April and May 2021. This study was based on 412 MSM who reported to be HIV-negative/unknown sero-status at baseline, 297 (72.1%) of them completed the follow-up online survey. Multilevel logistic regression models  were fitted.p < 0.001). After adjusting for age group, education level, current employment status and monthly personal income, two predisposing factors were associated with higher uptake of HIV testing during the follow-up period. They were: (1) condomless anal intercourse with male non-regular male sex partners at follow-up only  and (2) sanitizing before and after sex at baseline . Regarding enabling factors, utilization of HIV testing  and STI testing  6 months prior to the baseline survey was associated with higher uptake of HIV testing during the follow-up period. Having the experience that HIV testing service providers reduced service hours during the follow-up period was also positively associated with the dependent variable .When comparing follow-up data with baseline data, a significant increase was observed in the uptake of any type of HIV testing (77.9% at Month 6 vs. 59.2% at baseline, HIV testing utilization among MSM might rebound to the level before the COVID-19 outbreak after the pandemic received initial control in China. This study offered a comprehensive overview to identify potential reasons that can influence the uptake of HIV testing among Chinese MSM. The human immunodeficiency virus (HIV) epidemic among men who have sex with men (MSM) remains out of control across countries . A systeThe Coronavirus Diseases 2019 (COVID-19) is a serious health threat worldwide . The COVIt is also helpful to understand factors associated with HIV testing utilization in the “post-pandemic era.” The Predisposing, Reinforcing and Enabling Constructs in Educational/Ecological Diagnosis and Evaluation (PRECEDE) model was used as the theoretical framework . This moTo address the knowledge gaps, we conducted a longitudinal observational study to investigate the changes in HIV testing service utilization among MSM during the COVID-19 pandemic. We also investigated factors associated with HIV testing utilization during the follow-up period, including socio-demographics, predisposing factors , enabling factors .This study was a sub-analysis of a prospective observational cohort study conducted among MSM in Shenzhen, China between August 2020 and May 2021. Participants completed a baseline survey between August and September 2020 and a follow-up survey between April and May 2021.Participants of the cohort study were: (1) Chinese-speaking men living in Shenzhen, (2) aged 18 years or above, (3) had oral or anal intercourse with at least one man in the past year, and (4) willing to leave contact information and complete the follow-up survey. We recruited participants through multiple sources. Trained and experienced fieldworkers approached prospective participants in venues frequently visited by MSM  at different time slots during weekdays and weekends. An online outreaching was also conducted by periodically posting study information on two commonly used social media platforms in China . Recruitment was supplemented by peer referrals. On-site or through telephone/live chat applications, fieldworkers briefed prospective participants about the study details and invited them to add the project's official WeChat account. Fieldworkers screened the eligibility of prospective participants and assured participants that their identifiable information  would be kept confidential, they had the right to discontinue participation in the study at any time, and their refusal or withdrawal from the study would not have any consequences. The project's official WeChat account would delink with participants' WeChat accounts after the project ended. Participants signed an electronic consent form sent by WeChat. Participants were also informed that their electronic consent form would be separated from the database and stored in a password-protected computer. The same approach to protect participants' personal information was used in a published study .n = 265, online: n = 67, and referral: n = 80). A flowchart of recruitment was shown in We developed an online self-administered questionnaire using Questionnaire Star, a commonly used online survey platform in China. Quick response codes were generated and sent to consented participants through WeChat. Participants scanned the quick response codes to complete the survey. Each mobile device was only allowed to access the online questionnaire once to avoid duplicate responses. The baseline survey had 105 items (about 20 items per page for five pages), which took about 20 min to complete. The follow-up survey was shorter (80 items), which took about 15 min to complete. We assigned a unique study ID to each participant to link their baseline and follow-up data. The Questionnaire Star tool performed completeness checks before the questionnaire was submitted. Participants were able to review and change their responses through a “Back” button. An electronic coupon of 20 Chinese Yuan (the US $3.0) was sent to participants upon completion of each survey. All data was stored in the online server of Questionnaire Star and protected by a password. Only the principal investigator of the study had access to the database. The fieldworkers approached 460 prospective participants in gay venues, 435 added the project's official WeChat account, 405 were screened eligible through WeChat, 135 refused to participate and 270 completed the baseline survey. Regarding online recruitment, 97 prospective participants contacted the fieldworkers, 85 were screened to be eligible, 18 refused to participate and 67 completed the baseline survey. Among 122 prospective participants referred by peers, 110 were screened to be eligible, 27 refused to participate and 83 completed the baseline survey. In sum, 420 participants completed the baseline survey. We excluded eight participants who self-reported to be HIV-positive at the baseline as this study focused on the changes in HIV testing behaviors. This study was based on 412 participants who self-reported to be HIV-negative/unknown sero-status at baseline  HIV testing at community-based organizations in Shenzhen, (2) HIV testing at public hospitals or CDC in Shenzhen, (3) HIV testing at private hospitals in Shenzhen, (4) HIV testing at other organizations in Shenzhen, (5) HIV testing outside Shenzhen, and (6) home-based HIV self-testing. These measurements were adapted from previous studies among Chinese MSM , 24, 25.Participants reported the presence of condomless anal intercourse with regular male sex partners, non-regular male sex partners, and male sex workers, and sexualized drug use in the last 6 months prior to the baseline and follow-up surveys. Regular male sex partners were defined as their lovers or stable boyfriends, while non-regular male sex partners were defined as casual sex partners. Sexualized drug use was defined as the use of any of the following psychoactive substances  before or during sexual intercourse , 26. TheParticipants also reported the frequency of using COVID-19 preventive measures during sexual behaviors 6 months prior to the baseline survey . These preventive measures were: (1) only having sex with your partner who has had sex with you before, (2) avoiding group sex, (3) only having sex at home, (4) asking your partner if they have COVID-19 symptoms, (5) avoiding kissing during sex, (6) washing hands before and after sex, and (7) sanitizing before and after sex.At baseline, participants were also asked whether they were concerned about being infected with COVID-19 when taking up HIV testing (response categories: from 1 = strongly disagree to 5 = strongly agree). Two single items measured the perceived effectiveness of COVID-19 control measures taken by organizations providing HIV testing was measured  and the level of panic of COVID-19 .Participants reported the utilization of sexually transmitted infections (STI) testing, pre-exposure prophylaxis, and other HIV/STI prevention services 6 months prior to the baseline and follow-up surveys. Experiences about HIV testing service providers suspending their services or reducing service hours, difficulty in obtaining HIV self-testing kits, history of home/centralized quarantine, and avoiding unnecessary travel or going to crowded places were recorded at follow-up.At follow-up, participants were asked whether their male sex partners or peers suggested them not take up HIV testing in the past 6 months.t-tests (for continuous variables). We filled the missing outcome values at Month 6 with multiple imputations. Markov Chain Monte Carlo methods were used for data with the arbitrary pattern of missing values, while Monotone methods were used for data having a monotone pattern of missing values. Predictors included baseline background characteristics and baseline values of the variables with missing values at Month 6. Utilization of any type and specific type of HIV testing and sexual behaviors at baseline and follow-up were compared using McNemar tests. Using uptake of any type of HIV testing during the follow-up period as the dependent variable, and sociodemographic characteristics as independent variables, crude odds ratios (OR) were obtained using multilevel logistic regression models . After adjusting for background characteristics in univariate analysis, the associations between independent variables of interest  and the dependent variable were investigated by using multivariate multilevel logistic regression models . Random intercept models were used to allow the intercept of the regression model to vary across sources for recruitment, which could account for intra-correlated nested data. Each multivariate multilevel logistic regression model involved one of the independent variables of interest and age group, education level, current employment status, and monthly personal income. In the literature, age, education level, occupation, and monthly income were associated with HIV testing uptake among Chinese MSM  or independent sample nese MSM , 30, 31.nese MSM –34. SPSSn = 297) and those who were loss-to-follow-up (n = 115). These baseline characteristics were: (1) sexual orientation (p < 0.001), (2) performed HIV testing outside Shenzhen (p = 0.03), (3) uptake of any type of HIV testing (p = 0.02), (4) COVID-19 preventive measures during sexual behaviors (p = 0.001 to 0.009), and (5) perceived effectiveness of COVID-19 control measures taken by organizations providing HIV testing (p = 0.02) (The majority of the participants were aged 18–30 years (76.5%), currently single (80.4%), received tertiary education (60.9%), full-time employed (70.6%), and self-identified as homosexual (71.6%). Significant differences were found in the following baseline characteristics between those who completed the follow-up survey ( = 0.02) .p < 0.001), HIV testing at community-based organizations in Shenzhen , and HIV testing at public hospitals/CDC in Shenzhen   .p = 0.002) and male sex workers , and sexualized drug use  at Month 6. Within individuals, 19.4, 11.0, and 4.3% increased condomless anal intercourse with regular male sex partners, non-regular male sex partners, and male sex workers over the study period, and 14.0% increased sexualized drug use  condomless anal intercourse with male non-regular male sex partners at follow-up only  and (2) sanitizing before and after sex at baseline . Regarding enabling factors, utilization of HIV testing  and STI testing  6 months prior to the baseline survey was associated with higher uptake of HIV testing during the follow-up period. Having the experience that HIV testing service providers reduced service hours during the follow-up period was also positively associated with the dependent variable  .To our knowledge, this is one of the first prospective cohort studies to investigate the changes in HIV testing utilization among MSM before and after the COVID-19 pandemic received initial control. As compared to baseline data, significant increases in the uptake of any type of HIV testing, facility-based HIV testing , and HIV self-testing were observed at follow-up. COVID-19 preventive measures during sexual behaviors and HIV-related service utilization at baseline and changes in sexual behaviors and barriers caused by COVID-19 and its control measures over the study period were associated with HIV testing uptake during the follow-up period. The use of the PRECEDE model provided a more comprehensive overview of factors influencing HIV testing uptake and expanded the application of such a model.About 60% of the sampled MSM used any type of HIV testing between February and July 2020. Such uptake rate was slightly lower than the level before the COVID-19 outbreak (about 70%) , 36. OurThe changes in the utilization of specific types of HIV testing provided a more comprehensive picture of the impacts of the COVID-19 pandemic. Before the COVID-19 outbreak, community-based organizations, public hospitals, and CDC provided over 80% of HIV testing services for MSM, while private hospitals and other organizations provided almost 30% of HIV testing services for them . Our finOur findings suggested some reasons to explain the changes in HIV testing utilization and provided some empirical implications to enhance HIV testing coverage among MSM in the “post-pandemic era.” Similar to the findings of a previous study, MSM without a full-time job were less likely to use HIV testing during the follow-up period . In addiChanges in condomless anal intercourse with non-regular male sex partners was a significant predisposing factor of HIV testing utilization during the follow-up period. As compared to those without/reduced condomless anal intercourse with non-regular male sex partners during the follow-up period, an increase in condomless anal intercourse with non-regular male sex partners was associated with higher HIV testing uptake. It is possible that those with an increase in condomless anal intercourse with non-regular male sex partners would perceive a higher risk of HIV transmission, which motivated them to take up HIV testing. Although condomless anal intercourse with regular male sex partners, condomless anal intercourse with male sex workers, and sexualized drug use significantly increased over the follow-up period, such increase did not motivate them to receive HIV testing. Health communication messages that condomless anal intercourse with regular male sex partners and sexualized drug use are independent risk factors of HIV acquisition should be disseminated to MSM to increase their awareness , 45. UseUtilization of HIV, STI, and other HIV/STI prevention services prior to the baseline survey was associated with higher uptake of HIV testing during the follow-up period. Previous studies suggested that frequent users of HIV testing were more likely to take up HIV testing again , 49. MSMOur study has some policy and program implications. After the control of the COVID-19 pandemic, MSM would increase sexual activities and hence have a stronger need for HIV testing. Therefore, local government and service providers should resume their workforce and working hours for HIV prevention services. Our findings also suggested that facility-based HIV testing services were most affected during the COVID-19 outbreak. Local service providers should consider promoting home-based HIV self-testing and relevant supporting services  to mitigate the negative impact caused by the COVID-19 pandemic.This study had a number of limitations. First, participants were recruited by non-probability sampling in the absence of a sampling frame. The findings may not be representative of MSM in Shenzhen. Since we only conducted the study in one Chinese city, caution should be taken when generalizing the findings to other parts of China. As compared to other less developed cities in China, more organizations are providing HIV testing services for MSM in Shenzhen. Moreover, given the higher income level, MSM in Shenzhen would have lower financial barriers to use chargeable HIV testing services provided by private clinics or to purchase HIV self-testing kits. Therefore, the findings in this article could not apply to other Chinese cities with a general or lower economy. The COVID-19 pandemic might have a greater impact on HIV testing services in other smaller or less developed Chinese cities. Second, the results were self-reported and subject to social desirability bias. Participants might over-report HIV uptake and under-report sexual risk behaviors. Third, attribution bias existed. As compared to those who were followed up, dropouts had lower utilization of HIV testing and were less likely to use COVID-19 preventive behaviors during sexual intercourse at baseline. Therefore, the prevalence of HIV testing uptake at follow-up might be overestimated. Fourth, we were not able to obtain the characteristics of participants who refused to join the study. Participants and refusals might have different characteristics. Selection bias existed. However, the response rate was relatively high as compared to other published studies in China. Finally, we did not find validated measurements based on the PRECEDE model that were applicable to HIV testing behaviors under the COVID-19 pandemic. Therefore, we self-constructed the measurements based on panel discussion involving public health researcher, epidemiologist, psychologist, local MSM, and staff of local community-based organizations.As compared to the baseline data, the uptake of any type of HIV testing, facility-based HIV testing at community-based organizations, public hospitals/CDC, private hospitals, other organizations, and HIV self-testing increased significantly at follow-up. HIV testing utilization among MSM might rebound to the level before the COVID-19 outbreak after the pandemic received initial control in China. Using the PRECEDE model, this study offered a comprehensive overview to identify potential reasons that can influence the uptake of HIV testing among Chinese MSM in the post-pandemic era.The data presented in this study are available from the corresponding author upon request. The data are not publicly available as they contain sensitive personal behaviors.The studies involving human participants were reviewed and approved by the Institutional Review Boards of Longhua District Center for Disease Control and Prevention (CDC) (reference: 2021009). Informed consent was obtained from all participants involved in the study.KZ and ZW: conceptualization, methodology, and supervision. KZ, HCa, HCh, TH, YC, and XZ: data curation and project administration. ZW, SC, and PC: formal analysis. ZW, SC, YF, and PC: writing-original draft preparation and writing-review and editing. All authors have read and agreed to the published version of the manuscript.This study was funded by the High-Level Project of Medicine in Longhua, Shenzhen (HLPM201907020105) and the Key Discipline of Infectious Diseases Control and Prevention of Longhua (grant number 2020-2014).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Vaccination against SARS-CoV-2 has become a central public health issue, primarily for vulnerable populations such as individuals with Chronic Liver Disease (CLD). Increased COVID-19-related mortality and disease severity has been noted in this subgroup of patients. Severe COVID-19 tends to further deregulate liver function in patients with chronic liver failure or cirrhosis and even reactivate hepatitis in people living with HBV or HCV. In addition, impaired hepatic function leads to several limitations in possible therapeutic interventions. Chronic hepatic dysregulation, along with the underlying cirrhosis-associated immune dysfunction (CAID), leads to a decreased immune response to vaccination that, in turn, may result in reduced efficacy rates and lowered lasting protection. According to current guidelines, timely vaccination and frequent booster shot administration are deemed necessary in this context. Vaccination-related adverse events are mostly mild in nature and similar to those reported in the general population, whereas the incidence of liver injury following vaccination is relatively rare. We aimed to review available evidence and recommendations associated with COVID-19 vaccination in patients with chronic liver disease, and provide insight to current issues and future directions. Severe Acute Respiratory Syndrome Coronavirus 2, most commonly known as SARS-CoV-2 is an RNA virus first detected in Wuhan, China, on December 2019 that has caused global mayhem with its spread that led to the COVID-19 pandemic. In the following 3 years, the coronavirus disease resulted in significant mortality and morbidity, especially in people with chronic conditions and multiple comorbidities , the sigCOVID-19 is primarily regarded as a respiratory tract infection by patients and physicians alike. However, the systemic distribution of viral particles and the presence of their ligand, including—but not limited to—ACE2 receptor, throughout the body, makes the scene for a systematic disease, that may affect all organ systems ,6. Even Pre-existing liver disease influences the outcome, as well as, the severity of SARS-CoV-2 infection ,10,11. CAlthough, mostly associated with bacterial insult, viral infections have been described to cause acute-on-chronic liver failure . COVID-1Another particularity of patients with CLD is the limitations that they may face in standard-of-care treatment for COVID-19. Patients with impaired liver function, defined as elevations of alanine or aspartate aminotransferase (ALT or AST)  ≥ 5× upper limit of normal (ULN) are not to be administered remdesivir, while caution is advised when prescribing tocilizumab due to its hepatoxic potential . BaricinPatients with pre-existing liver pathology are at a noticeably higher risk of COVID-19 infection as well as COVID-19-related death . The maiAs far as the function of the immune system in CLD is concerned, the ratio of CD8+/CD4+ effector cells increases as the disease progresses. This increase in CD8+ counts plays an important role in sustaining liver dysfunction and partially participates in the dysregulation of all innate and adaptive immunity cells . DefectiThe overall immune dysfunction that is observed in CLD may lead to hypo-responsiveness to vaccination against communicable diseases . In factRegarding CLD in general, vaccination against viral pathogens has proven safe, although not entirely effective. A recent meta-analysis of 12 studies that measured immunological response following seasonal flu vaccination estimated the seroconversion rate in patients with CLD at 80% for influenza A and at 87% for influenza B, when the recommended lower accepted threshold is at 40%. No difference was noted, however, in all-cause hospitalization or mortality . HBV vacRegarding SARS-CoV-2, existing real world data on CLD patients’ vaccination, primarily concern the most widely distributed vaccines, namely the two mRNA vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 , and the adenovirus vector (AdV) based vaccine Ad26.COV2.S . A recent study from the U.S. comparing CLD patients to liver transplant recipients demonstrated that 75% of patients with CLD without cirrhosis and 77% of patients with cirrhosis mounted a sufficient antibody response to the mRNA COVID-19 vaccine. In contrast, the Ad26.COV2.S vaccine was associated with poor immunogenicity, as was liver transplant recipient status . PrelimiDespite the relative lack of quality evidence in vaccine efficacy rates, a retrospective study’s results from the U.S. investigating the efficacy and safety of the two mRNA vaccines in cirrhotic populations reveal a reduction in both hospitalization rates and reported infections for both compensated and decompensated subgroups, even after a single dose administration . AnotherMoreover, studies have been carried out to assess the immune reaction and identify potential predictors of low response in CLD. Ruether et.al.  comparedTaking into account that both SARS-CoV-2 vaccine platforms (mRNA and AdV) are newly licensed, vaccination-related adverse events have become a subject of great interest for scientists and common public alike. As stated in the Vaccine Adverse Event Reporting System (VAERS), the most frequent adverse effects concerning the mRNA vaccines are injection site pain (70.9%), fatigue (33.5%), and headache (29.5%), where for the J&J vaccine, they were, additionally to the aforementioned, myalgia (47.8%), fever (34.7%), and chills (34.2%) . AnaphylEvidence in patients with CLD and vaccine associated adverse events comes from a recent metanalysis including five studies  reporting adverse events with 1360 subjects . PrevaleRare incidents of immune-mediated hepatitis and liver injury have also been reported following SARS-CoV-2 vaccination. The largest case series to date highlights the rarity of such events with only 84 cases identified across 14 countries and points to the fact that most of them are in fact immune-mediated . The patAt the moment, vaccination and boosters are strongly recommended in patients with CLD and LT recipients according to recent American Association for the study of Liver Diseases (AASLD) and European Society for Liver Diseases (EASL) guidelines schedule ,62. As tHowever, when surveyed, although more than 85% of participants with various kinds of chronic liver or gastrointestinal conditions agreed on the safety of vaccination and even stated that they would take the COVID-19 vaccine if available, about 8% completely disagreed and concerns about vaccination were expressed on 33% of participants. Female sex, black race, and lower household income by zip code were associated with higher hesitancy .CLD includes a wide spectrum of conditions each with a distinct and highly variable underlying immune profile. Currently available vaccines have provided us with a useful tool for CLD patients to deal with COVID-19 pandemic; however, a number of issues are still of concern. Knowledge gaps remain as to effectiveness, safety, and durability in patients with CLD based on liver disease etiology, comorbidities, Child–Turcotte–Pugh class, and Model for End-Stage Live Disease score, reflecting different amount of immunosuppression. Novel vaccine platforms have not yet been thoroughly tested in all CLD subgroups with variable degrees of immunocompromise also depending on underlying medication. Similarly, difference in vaccine effectiveness, safety, and optimal timing is yet to be elucidated in patients previously infected with SARS-CoV-2, even though booster shots are clearly recommended even in this subgroup of patients. Data are—and are condemned to be—limited to currently circulating variants of concern. In the context of an evolving pandemic, available information is to be constantly reassessed in order to optimize best practice and also define long-term COVID-19 effects in patients with CLD. In the setting of an already diverse population including different racial and ethnic backgrounds, experience in CLD patients with need of vaccine platform combination following adverse events or failure is lacking, although partially studied in the general population. Determination of antibody cut-offs, interpretation of serology and cell-mediated immunity assays are pivotal, but still ambiguous in these patients in the setting of their comorbidities. We are looking forward to the results of several randomized i.e., NCT04775069, NCT04794946, and observational trials i.e., NCT04798625, NCT04775056, testing immunogenicity and safety exclusively in this population and providing more insight to unresolved matters of concern .Patients with CLD carried a significant burden of morbidity and mortality during COVID-19 pandemic. Experience with currently available vaccines is encouraging in these patients, confirming adequate immunogenicity and good safely profile, in line with results in general population. Nonetheless, a number of issues are still to be elucidated in this diverse—in terms of etiology and disease severity—population. Liver specialists, except for infectious diseases practitioners attending patients with CLD should embrace and advocate the importance of adequate and timely vaccination, as a method of eliminating pandemic resurgence and protecting this most vulnerable patient group. Increase of patient awareness and education remains pivotal.


This study exclusively contributes to the health-environment discourse by using mortality rates, carbon emissions , renewable energy and real per capita income to investigate these intrinsic relationships. This study uses an unbalanced sample of 47 Sub-Saharan African countries from 2005–2019 to reveal that: (1) both carbon emissions and renewable energy are associated with higher mortality rates; (2) real per capita income is associated with reducing mortality rates; (3) per capita income attenuates the effect of renewable energy on mortality rates, (4) persistency in mortalities exist; and (5) the health-environment-energy-income dynamics differ across income groups. Additionally, this study submits that the interaction of renewable energy and real per capita income dampens the positive effect of renewable energy on mortality rates and supports the argument that income levels lessen the extent of mortalities. Besides, these results vividly show that real per capita income reduces the devastating effect of renewable energy on infant and under-5 mortality rates from 0.942% to 0.09%, 2.42% to 0.55%, 1.04% to 0.09% and 2.8% to 0.64% for high and middle-income countries, respectively. This is a novel and significant contribution to the health-environment literature. Hence, real per capita income is a crucial determinant of mortality rate. Policy recommendations are discussed. One of the most utilized child health indicators are infant and under-5 mortality rates ))controlla, 2018) –68. The Also, across all model specifications, renewable energy (columns  and 3]))3]) has conditonal effect of renewable energy is therefore computed as [2.5282 –)3]) reveFor the control variables, contrary to expectations, a percentage change in health expenditures exacebates mortality rates between 0.22 and 0.26 percent. The plausible explanation for this outcome which contradicts Nkalu and Edeme  and BoacThe sample is further divided into three to observe if the results hold across income groups (Note: We are unable to perform robustness checks using renewable electricity variable due to few data points for high income countries having only 2 countries)) and the outcomes are presented in Also, renewable energy consumption is positively associated in high- and middle-income countries while real income per capita shows a negative association with infant and under-5 mortalities in high income countries but positive association in middle-income countries. Our study shows that real per capita income is a significant channel to reducing mortality rate in SSA. Following These results vividly show that real per capita income is essential in reducing the positive association of renewable energy on infant and under-5 mortality rates from 0.942% to 0.09%, 2.42% to 0.55%, 1.04% to 0.09% and 2.8% to 0.64% for high and middle-income countries, respectively. This is a novel and significant contribution to the health-environment literature.On the control variables, health expenditure per capita is positively associated with infant and under-5 mortalities in high and medium-income groups. Moreover, inflation is a positive predictor of infant and under-5 mortalities in high-income countries. Female education reduces mortality rates in low and middle-income countries but aggravates in high-income countries. Similarly, access to basic sanitation shows a reducing effect on mortality rates in middle-income countries while it increases mortalities in high-income countries. Finally, urbanization has a significant negative effect on infant and under-5 mortalities in high and middle-income groups, but its effect is positive in low-income countries. Overall, we observe that these outcomes are significantly different across income groups.Controlling for heteroscedasticity, omitted variables and serial correlation, we estimate a dynamic model to test for the persistency of mortality rates. The results displayed in AR(2) statistics further suggest no evidence of second-order serial correlation while the Hansen statistics confirm the validity of the instruments. Hence, the findings obtained from the augmented regression models can be used for inferences.Similar to Since our results from the effect of health expenditure and renewable energy are counter-intuitive, we probe further by: 1) engaging a quadratic analysis to test the second-order effect of health expenditure on mortality rate and observe if there are significant differences across the full sample and income groups. The results are displayed in columns  engaging of TableFrom column , the intThis paper takes a multi-dimensional approach towards the actualisation of the 2030 United Nations Sustainable Development Goals 3 and 11 by examining the effect of carbon emissions, renewable energy and real per capita income on mortality rate in Sub-Saharan Africa (SSA). Using an unbalanced panel data on 47 SSA countries and a battery of econometric techniques, specifically, this study focused on infant and under-5 infant mortality rates because mortality rates are development determinants and crucial to assessing human capital development. We also considered five key questions related to carbon emissions, use of renewable energy, including per capita GDP. In addition, we accounted for the contribution of other factors, female secondary school enrolment, health expenditure per capita, urbanization, access to basic sanitation and consumer prices. Consistent findings from a multi-analytical approach using bootstrapped least squares dummy variables and difference generalised method of moments reveal that: (1) both carbon emissions and renewable energy are significantly associated with high mortality rates; (2) per capita income is significantly associated with reducing mortality rates; (3) per capita income weakens the devastating effect of renewable energy on mortality rates, (4) both infant and under-5 mortality rates are persistent at the 1% significance levels, and (5) the health-environment-energy-income dynamics differ across income groups. In other words, with respect to the presence of renewable energy sources, we find that despite the availability of environmentally-friendly energy sources, there is a significant increase in infant and under-5 mortality rates. Furthermore, this study submits that the interaction of renewable energy and income dampens the positive effect of renewable energy on mortality rates and supports the argument that income levels lessen the extent of mortalities. Hence, per capita income is a crucial determinant of mortality rates.Policy recommendations are not far-fetched. First, there is need for policy makers to initiate interventions to tackle health challenges of babies and children in SSA; secondly, need to extend the factors considered as health outcomes determinants and actively address environmental factors; thirdly, by giving cognizance to environmental factors, policymakers and development practitioners will be able to come up with solutions that ensure that most babies and children do not die in their early ages but live and reach their potential which enables them to contribute to the continued advancement of the region. Giving available data, the mediating effect of carbon emissions on the energy-health dynamics may be taken up in future research.S1 File(XLSX)Click here for additional data file.


Multitarget stool DNA (mt-sDNA) is approved for average-risk colorectal cancer screening; test performance in persons with prior radiation therapy (RT) has not been studied. RT can induce gastrointestinal bleeding and alter DNA methylation, which may affect mt-sDNA accuracy. Among patients previously treated with RT, we aimed to measure the positive predictive value (PPV) of mt-sDNA and compare these results to historical estimates of mt-sDNA PPV among average-risk patients.P values were generated by 2-tailed Fisher’s exact testing in comparisons of colorectal neoplasia (CRN) rates between groups.After institutional review board approval, we conducted a retrospective cohort study of a multisite academic and community-based practice. Patients with RT and subsequent mt-sDNA use during the study period (2014–2016) were identified. The findings at diagnostic colonoscopy were compared with published reports among average-risk patients. Nominal P = 1.00). Detection of advanced CRN (36%) was nominally higher than previously published retrospective (27%) and prospective (20%) studies. The median time from the start of RT to mt-sDNA use was 7  years.There were 220 patients who had RT before mt-sDNA testing. RT was delivered along the aerodigestive tract in 108 patients. Mt-sDNA tests were positive in 45 of 220 patients (20%), and colonoscopy findings were available for 42; 31 of 42 patients (74%) had CRN. PPV by mt-sDNA was similar when stratified by site of prior RT (along vs outside the aerodigestive tract; With a test positivity rate and PPV for CRN similar to reports among average-risk patients, prior RT does not appear to adversely affect mt-sDNA performance. Evidence for the prevention of cancers among cancer survivors are lacking.9 one-third of all eligible adults are unscreened for colorectal cancer (CRC).10 Among the general population, adherence to CRC screening is improved through utilization of noninvasive screening, which will likely shape the future of CRC screening.11 Of the United States Preventive Services Task Force recommendations for CRC screening, the annual fecal immunochemical test (FIT) and multitargeted stool DNA (mt-sDNA) test every 1–3 years are the most commonly used stool-based modalities.14 However, the optimal approach to CRC screening in cancer survivors is uncertain, particularly for those who have received cancer radiation therapy (RT) to the gastrointestinal tract.Colon cancer prevention is hampered by several challenges, well described in the average-risk population. Despite remaining the second leading cause of cancer-related deaths among men and women combined,15 For example, in reference to the general population, the treatment effects for Hodgkin lymphoma are associated with increased risk for colorectal advanced neoplasia (AN), including advanced sessile serrated polyps.16 RT to the gastrointestinal tract also raises the risks of complications during endoscopy, including screening colonoscopy,17 and these risks have increased both patient and provider interest in noninvasive, stool-based CRC screening for cancer survivors. However, RT may have lasting effects on gastrointestinal anatomy and physiology that could theoretically adversely affect the accuracy of stool-based testing. Radiation-induced gastrointestinal bleeding could lead to artifactual occult bleeding and subsequent unnecessary use of diagnostic colonoscopy. Mt-sDNA detects fecal hemoglobin through an immunoassay and additionally quantifies tumor-associated DNA markers  and reports a positive/negative result based upon a validated algorithm.18 The inclusion of DNA markers contributes to greater sensitivity for CRC and other AN when compared with FIT in average-risk patients.21 However, radiation directly alters DNA methylation both acutely22 and during cellular regrowth needed for tissue healing, which could theoretically lead to additional false-positive mt-sDNA testing.23RT can induce a broad spectrum of complications, such as secondary malignancy, fistula, fibrosis, and bleeding.Despite the concern for false-positive stool-based testing in those with prior RT, there is a paucity of literature to support this or to further aid in decision-making for noninvasive CRC screening. To address this knowledge gap, we aimed to describe the use of mt-sDNA testing in those with a history of RT stratified by radiation site (aerodigestive vs nonaerodigestive tract) and measure the positive predictive value (PPV) at diagnostic colonoscopy. These findings were then compared with previously published reports of mt-sDNA performance among patients at average risk for CRC, without prior RT, to infer whether RT alters the PPV of mt-sDNA.A multicenter retrospective cohort study was conducted after institutional review board approval. Data were collected from patients who had undergone mt-sDNA testing between September 25, 2014, and December 30, 2016, at any of the Mayo Clinic referral centers  or surrounding community practices of the Mayo Clinic Health System .The Unified Data Platform of Mayo Clinic maintains an electronic search engine (advanced cohort explorer) to query patient data across the collective Mayo Clinic enterprise. This clinical data repository contains clinic notes that can be searched by natural language processing as well as functionality to search fixed diagnosis or billing codes. Because of the changes in the electronic medical record system in the Mayo Clinic Enterprise, information on exposure to RT could only be queried from the Unified Data Platform through the calendar year 2016, using the following validated search heuristic.First, mt-sDNA use and test results were identified through diagnostic and procedure billing codes. Then, a multifaceted search strategy was used to explore the mt-sDNA cohort to identify those with a potential history of RT or cancer whose medical records would then undergo dedicated review . The seaA trained data extraction team verified RT history, date of mt-sDNA use, and post-mt-sDNA colonoscopy results through individual chart review. Abstracted patient characteristics included sex, age, and tobacco use. History of colonoscopy before mt-sDNA was recorded. For those with positive mt-sDNA who underwent diagnostic colonoscopy, the presence of colorectal neoplasia (CRN) neoplasia, CRN architecture , dysplasia grade (high vs low), CRN size , and/or CRC was abstracted. Hyperplastic polyps regardless of size were not counted as neoplasia. Specific clinical variables that would classically exclude a patient from approved use of mt-sDNA  were noted, but these patients were not excluded from the primary analysis. For the historical malignancy treated by RT, the stage was recorded from clinical notes or pathology reports generated during the patient’s care but was not updated to the current American Joint Committee on Cancer staging guidelines. If a patient had a history of more than one primary cancer, the initial malignancy was abstracted. The most recent RT course start and end dates were recorded, and exposure defined by radiation field  and type . The RT exposed mt-sDNA cohort was grouped by radiation site ,19 a prospective cross-sectional cohort observational trial designed to estimate mt-sDNA sensitivity and specificity, in comparison to blinded FIT and criterion standard colonoscopy. The second comparative study was a retrospective review of mt-sDNA testing across all Mayo Clinic sites from October 1, 2014, through December 31, 2017.24 As the RT cohort may have met inclusion criteria within this comparative study, the final RT cohort was cross-referenced with this published report and when present were included only in the RT cohort to ensure comparisons between unique patients.The test positivity rate of mt-sDNA and findings at diagnostic colonoscopy in those without a history of RT was compared with 2 published reports of mt-sDNA use among independent patients at average risk for CRC. The first was the pivotal trial for mt-sDNA Food and Drug Administration (FDA) approval; the “DeeP-C” study , whereas proportions were compared by the Fisher’s exact test. PPV was estimated as the number of positive findings relative to the total number of patients undergoing diagnostic colonoscopy with corresponding 95% confidence intervals (CIs). The Chi-square goodness-of-fit test with 3 degrees of freedom was used to compare the observed number of positive mt-sDNA results within the total radiation cohort relative to the expected number of positive mt-sDNA results based on an age- and sex-matched cohort of patients (independent of CRC risk) that underwent mt-sDNA testing at Mayo Clinic between 2014 and 2019. As the effect size on PPV from prior RT exposure was not known, an 24; the 46 overlapping patients were analyzed only as members of the RT cohort.During the study period, 7368 patients had undergone mt-sDNA testing across all Mayo Clinic sites. After this group was cross-referenced to established databases and registries and searched by natural langue processing and diagnostic codes, 411 unique patients were identified and underwent individual chart review. From these, 220 patients met inclusion criteria . These 219The median age of the post-RT mt-sDNA cohort was 71  years, and most were female ; both were significantly greater for the RT mt-sDNA cohort when compared with prior cohorts of mt-sDNA-tested patients ; the RT For the RT cohort, the field of therapy had been directed to include the aerodigestive tract for 108 of 220 (49%), and of those, cancers of male genitourinary tract were the most common . For nonaerodigestive RT, breast cancer was the most common indication  had a history of colonoscopy, and only 12 patients had CRN detected at prior colonoscopy; 3 of whom had high-risk CRN (polyp size ≥10 mm or 5–10 adenoma <10 mm).24 although the rate of colonoscopy compliance was similar . Of the 45 patients with a +mt-sDNA, 42 (93%) underwent diagnostic colonoscopy. The mt-sDNA test positivity rate after RT was greater in comparison to average-risk patients without RT from our institution similar .19 Additional subcategorization of the highest graded neoplasms at post-mt-sDNA colonoscopy is shown (P = 1.00).At colonoscopy after +mt-sDNA among the RT cohort, 31 of 42  had any CRN, and 15 of 42  had advanced CRN, both greater in comparison to the DeeP-C study .is shown . The PPVP = .1154). For patients without FDA labeling exclusions for mt-sDNA and post-mt-sDNA colonoscopy, PPV for CRN was 28 of 34 , and for those with mt-sDNA exclusions the PPV was 3 of 8 .Of the 220 patients with radiation history, 25 patients had criteria that should have excluded the use of mt-sDNA . Among the 25 patients with standard exclusion criteria, 8  had a +mt-sDNA. Among 195 patients with no FDA labeling exclusion criteria for mt-sDNA use, 37  had a +mt-sDNA vs 20% in the overall positivity rate in an age–sex balance cohort of non-RT patients (P = .3947). Similarly, there were 97 women with nonaerodigestive RT with 18 (13%) +mt-sDNA findings compared with the expected number of 18.1 (P = .6353). For 55 men receiving RT along the aerodigestive tract, 14 (25%) had +mt-sDNA findings compared with the expected number of findings of 13.3 (P = .7757). There were 5 men with RT at non-aerodigestive sites with 2 (40%) +mt-sDNA findings compared with the expected number of 1.1 findings (P = .2657). Overall, when stratified by sex and age, the mt-sDNA positivity rate is similar among patients without RT history vs the RT cohort  +mt-sDNA findings compared with the expected number of findings of 6.8 +mt-sDNA findings based on an age-matched female cohort of  and nominally higher than the PPV reported among historical cohorts of average-risk patients without RT history. When excluding RT patients who had FDA labeling exclusions for the use of mt-sDNA, the PPV increased to 82%. This high rate is supported by the findings of Ykema et al26 who are the only investigators to prospectively compare the use of FIT and mt-sDNA among Hodgkin lymphoma survivors with colonoscopy as the reference standard. This study was conducted at 4 Dutch centers, and among the 2 noninvasive tests, the PPV for AN ranged from 41% to 63%; mt-sDNA had the greatest sensitivity (68%) in comparison to FIT (37%).Mt-sDNA test performance in patients who have had RT appears similar to or greater than that seen in previous studies of the general average-risk population. A high PPV was observed despite the concern of RT-induced gastrointestinal bleeding19 Colonoscopy yield was later studied for a subset of this same group of colonoscopists when aware (unblinded) of the +mt-sDNA result, and significantly more polyps were found.27 This change in performance was thought to result, in part, to greater colonoscopist attention as withdrawal times were significantly longer among those unblinded. This phenomenon may explain the greater CRN and advanced CRN detection among the RT cohort by unblinded colonoscopists evaluating +mt-sDNA results, compared with the DeeP-C study. Advanced CRN was found for 15 (7%) of all 220 patients screened by mt-sDNA in the RT cohort, which is very similar to what would be expected for advanced CRN yield by screening colonoscopy (7.6% in DeeP-C). This high rate of advanced CRN detection by mt-sDNA may similarly have been influenced by unblinded diagnostic colonoscopy. In addition, the higher observed PPV for advanced CRN is also possibly a result of increased CRN risk after undergoing RT itself,32 other cancer treatments,35 or for patients having a history of extracolonic cancer.37Real-world mt-sDNA test use in the general population provides valuable context for the observations in this study. In the DeeP-C study, colonoscopists were blinded to mt-sDNA results.38If a history of RT accelerates the natural history of CRN, testing at more frequent intervals may be required to optimize screening effectiveness. Although mt-sDNA test performance after RT appears comparable to that of the general population, the optimal and most cost-effective interval of mt-sDNA testing in patients with prior RT has yet to be determined. The testing interval for mt-sDNA in average-risk patients is based on the Archimedes model  in which the risk factors for CRC include age, gender, race, and body mass index. Although annual mt-sDNA performed similarly to colonoscopy; mt-sDNA testing at an interval of 3 years had greater cost-effectiveness and patient adherence.24 and a prospectively enrolled cohort where the majority of patients were enrolled outside our centers,26 that mt-sDNA PPV for CRN and advanced CRN were comparable. Furthermore, as a study of real-life clinical practice, patients with a negative mt-sDNA did not undergo colonoscopy. As such, we are not able to calculate the negative predictive value. Our study design is also unable to determine whether RT induces hypomethylation to BMP3 and NDRG4 genomic loci, ultimately resulting in a false-negative mt-sDNA. With these limitations in mind, we conducted further data extraction post-hoc for the 175 patients who had a negative mt-sDNA test between 2014 and 2016. Among this group, we reviewed the electronic medical record through March 1, 2022. For 105 of 175 (60%) of the patients, there was subsequent mt-sDNA or colonoscopy use. Subsequent colonoscopy was conducted for 25 of 105 (24%) patients, whereas mt-sDNA was pursued by 80 of 105 (76%). For those with subsequent mt-sDNA use, the test positivity rate was 27.5% , which is similar to 45 of 220  to first round testing. The median time from first round testing to the second mt-sDNA (N = 80) was 3.4 years . Diagnostic colonoscopy was done for 20 of 22 patients, neoplasia was found for 11 of 20 patients , and 35%  had AN compared with 31 of 42 (74% [95% CI 58%–86%]) and 15 of 42  for first round testing. For the 25 patients with colonoscopy use after prior negative mt-sDNA, the median time was 3.1 years , and neoplasia was diagnosed for 9 of 25  of which 16%  was AN. Thus, the test positive rate and the PPV of mt-sDNA on subsequent screening appear similar to the first round of screening, lowering the possibility of missed screen relevant lesions on the first round. Importantly, there were no symptomatic or screen-detected colorectal cancers diagnosed after prior negative mt-sDNA. There are other notable study limitations. Although the time from RT to mt-sDNA was similar among aerodigestive vs nonaerodigestive radiation exposure, there was a wide distribution of time from RT to mt-sDNA testing; therefore, this cohort may not be representative of those who are tested by mt-sDNA beyond 20 years from RT start time. We note that radiobiologic models as well as clinical data suggest that radiation carcinogenesis is a stochastic effect, not dose dependent, as such we suspect little utility in further qualifying the influence of radiation dose and the performance of mt-sDNA.40 Generalizability of our findings may be limited, as the overall cohort had more women than men, but our additional analysis of mt-sDNA comparing outcomes by sex and age among patients with and without RT found no differences (7 Finally, the small subset of patients in the cohort with brachytherapy may be perceived as a study limitation. However, brachytherapy is only used in select situations and is anticipated to comprise a smaller proportion of RT.Although informative, this study is limited by the retrospective design. Therefore, we had no control of variables, such as cancer type, stage, and cumulative radiation exposure. However, it is reassuring that when compared with real-life observations across the same centers by Eckmann et alferences . The higOverall, mt-sDNA testing appears to be a promising method for colorectal cancer screening among those with a history of RT. Given the high PPV of mt-sDNA for both any CRN and advanced CRN among those with or without prior RT, a positive test should be promptly followed by diagnostic colonoscopy.1