Pub Date : 2024-05-01DOI: 10.1016/S1474-4422(24)00123-6
Gaël Nicolas
{"title":"Association of Pick's disease with the MAPT H2 haplotype.","authors":"Gaël Nicolas","doi":"10.1016/S1474-4422(24)00123-6","DOIUrl":"https://doi.org/10.1016/S1474-4422(24)00123-6","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 5","pages":"451-453"},"PeriodicalIF":48.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140858392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/S1474-4422(24)00126-1
Marianne de Visser, Elena Moro
{"title":"Fostering diversity, equity, and inclusion in Europe.","authors":"Marianne de Visser, Elena Moro","doi":"10.1016/S1474-4422(24)00126-1","DOIUrl":"https://doi.org/10.1016/S1474-4422(24)00126-1","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 5","pages":"462"},"PeriodicalIF":48.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140870612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/S1474-4422(24)00133-9
Abolfazl Avan, Vladimir Hachinski
{"title":"Dementia prevention: from idealism to realism.","authors":"Abolfazl Avan, Vladimir Hachinski","doi":"10.1016/S1474-4422(24)00133-9","DOIUrl":"https://doi.org/10.1016/S1474-4422(24)00133-9","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 5","pages":"460"},"PeriodicalIF":48.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140863318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/S1474-4422(24)00137-6
Marco De Ambrogi
{"title":"What we remember.","authors":"Marco De Ambrogi","doi":"10.1016/S1474-4422(24)00137-6","DOIUrl":"https://doi.org/10.1016/S1474-4422(24)00137-6","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 5","pages":"463"},"PeriodicalIF":48.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140874727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/S1474-4422(24)00099-1
Irene Cortese, Gina Norato, Patrick R Harrington, Therri Usher, Ilaria Mainardi, Guillaume Martin-Blondel, Paola Cinque, Eugene O Major, Virginia Sheikh
Progressive multifocal leukoencephalopathy is a rare but devastating demyelinating disease caused by the JC virus (JCV), for which no therapeutics are approved. To make progress towards addressing this unmet medical need, innovations in clinical trial design are needed. Quantitative JCV DNA in CSF has the potential to serve as a valuable biomarker of progressive multifocal leukoencephalopathy disease and treatment response in clinical trials to expedite therapeutic development, as do neuroimaging and other fluid biomarkers such as neurofilament light chain. Specifically, JCV DNA in CSF could be used in clinical trials as an entry criterion, stratification factor, or predictor of clinical outcomes. Insights from the investigation of candidate biomarkers for progressive multifocal leukoencephalopathy might inform approaches to biomarker development for other rare diseases.
进行性多灶性白质脑病是一种罕见的破坏性脱髓鞘疾病，由 JC 病毒（JCV）引起，目前尚无治疗药物获批。为了在满足这一尚未满足的医疗需求方面取得进展，需要在临床试验设计方面进行创新。脑脊液中的定量 JCV DNA 有可能成为临床试验中进行性多灶性白质脑病疾病和治疗反应的重要生物标志物，从而加快疗法的开发，神经影像学和神经丝轻链等其他体液生物标志物也是如此。具体来说，CSF 中的 JCV DNA 可作为临床试验的入选标准、分层因素或临床结果预测因子。对进行性多灶性白质脑病候选生物标志物的研究可能会为其他罕见病的生物标志物开发提供参考。
{"title":"Biomarkers for progressive multifocal leukoencephalopathy: emerging data for use of JC virus DNA copy number in clinical trials.","authors":"Irene Cortese, Gina Norato, Patrick R Harrington, Therri Usher, Ilaria Mainardi, Guillaume Martin-Blondel, Paola Cinque, Eugene O Major, Virginia Sheikh","doi":"10.1016/S1474-4422(24)00099-1","DOIUrl":"https://doi.org/10.1016/S1474-4422(24)00099-1","url":null,"abstract":"<p><p>Progressive multifocal leukoencephalopathy is a rare but devastating demyelinating disease caused by the JC virus (JCV), for which no therapeutics are approved. To make progress towards addressing this unmet medical need, innovations in clinical trial design are needed. Quantitative JCV DNA in CSF has the potential to serve as a valuable biomarker of progressive multifocal leukoencephalopathy disease and treatment response in clinical trials to expedite therapeutic development, as do neuroimaging and other fluid biomarkers such as neurofilament light chain. Specifically, JCV DNA in CSF could be used in clinical trials as an entry criterion, stratification factor, or predictor of clinical outcomes. Insights from the investigation of candidate biomarkers for progressive multifocal leukoencephalopathy might inform approaches to biomarker development for other rare diseases.</p>","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 5","pages":"534-544"},"PeriodicalIF":48.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140856968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/S1474-4422(24)00073-5
Rabi Tawil, Kathryn R Wagner, Johanna I Hamel, Doris G Leung, Jeffrey M Statland, Leo H Wang, Angela Genge, Sabrina Sacconi, Hanns Lochmüller, David Reyes-Leiva, Jordi Diaz-Manera, Jorge Alonso-Perez, Nuria Muelas, Juan J Vilchez, Alan Pestronk, Summer Gibson, Namita A Goyal, Lawrence J Hayward, Nicholas Johnson, Samantha LoRusso, Miriam Freimer, Perry B Shieh, S H Subramony, Baziel van Engelen, Joost Kools, Olof Dahlqvist Leinhard, Per Widholm, Christopher Morabito, Christopher M Moxham, Diego Cadavid, Michelle L Mellion, Adefowope Odueyungbo, William G Tracewell, Anthony Accorsi, Lucienne Ronco, Robert J Gould, Jennifer Shoskes, Luis Alejandro Rojas, John G Jiang
<p><strong>Background: </strong>Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38β MAPK) for the treatment of facioscapulohumeral muscular dystrophy.</p><p><strong>Methods: </strong>We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing.</p><p><strong>Findings: </strong>Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study.</p><p><strong>Interpretation: </strong>Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential impro
{"title":"Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial.","authors":"Rabi Tawil, Kathryn R Wagner, Johanna I Hamel, Doris G Leung, Jeffrey M Statland, Leo H Wang, Angela Genge, Sabrina Sacconi, Hanns Lochmüller, David Reyes-Leiva, Jordi Diaz-Manera, Jorge Alonso-Perez, Nuria Muelas, Juan J Vilchez, Alan Pestronk, Summer Gibson, Namita A Goyal, Lawrence J Hayward, Nicholas Johnson, Samantha LoRusso, Miriam Freimer, Perry B Shieh, S H Subramony, Baziel van Engelen, Joost Kools, Olof Dahlqvist Leinhard, Per Widholm, Christopher Morabito, Christopher M Moxham, Diego Cadavid, Michelle L Mellion, Adefowope Odueyungbo, William G Tracewell, Anthony Accorsi, Lucienne Ronco, Robert J Gould, Jennifer Shoskes, Luis Alejandro Rojas, John G Jiang","doi":"10.1016/S1474-4422(24)00073-5","DOIUrl":"10.1016/S1474-4422(24)00073-5","url":null,"abstract":"<p><strong>Background: </strong>Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38β MAPK) for the treatment of facioscapulohumeral muscular dystrophy.</p><p><strong>Methods: </strong>We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing.</p><p><strong>Findings: </strong>Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study.</p><p><strong>Interpretation: </strong>Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential impro","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 5","pages":"477-486"},"PeriodicalIF":48.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140856970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/S1474-4422(24)00117-0
Caroline Theoharides
{"title":"The need for partnerships in migration for medical workers.","authors":"Caroline Theoharides","doi":"10.1016/S1474-4422(24)00117-0","DOIUrl":"https://doi.org/10.1016/S1474-4422(24)00117-0","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":"23 5","pages":"459"},"PeriodicalIF":48.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140863436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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