EClinicalMedicine最新文献

{"title":"Safety and activity of lenalidomide in combination with obinutuzumab in patients with relapsed indolent non-Hodgkin lymphoma: a single group, open-label, phase 1/2 trial.","authors":"Ashwath Gurumurthi, Collin K Chin, Lei Feng, Nathan H Fowler, Paolo Strati, Fredrick B Hagemeister, Luis E Fayad, Jason R Westin, Chizobam Obi, Janine Arafat, Ranjit Nair, Raphael E Steiner, Sattva S Neelapu, Christopher R Flowers, Loretta J Nastoupil","doi":"10.1016/j.eclinm.2024.102747","DOIUrl":"10.1016/j.eclinm.2024.102747","url":null,"abstract":"<p><strong>Background: </strong>Rituximab and lenalidomide is a preferred option for relapsed indolent B cell non-Hodgkin lymphoma. Obinutuzumab may be a superior combination partner with lenalidomide given enhanced antibody dependent cellular cytotoxicity and phagocytosis compared to rituximab. Our aim was to determine the recommended phase 2 dose, safety, and activity of lenalidomide in combination with fixed dose of obinutuzumab in relapsed and refractory indolent B cell non-Hodgkin lymphoma.</p><p><strong>Methods: </strong>In this single-arm, open-label, phase 1/2 trial, we enrolled patients with relapsed or refractory WHO Grade 1-3A follicular lymphoma, marginal zone lymphoma and small lymphocytic lymphoma and adequate performance status (ECOG 0-2) at the MD Anderson Cancer Center. We excluded patients with evidence of ongoing transformation to aggressive lymphoma. During phase 1, 1000 mg intravenous obinutuzumab was administered with three predefined levels of oral lenalidomide in a 3 + 3 dose escalation design to establish lenalidomide 20 mg as the recommended phase 2 dose. During phase 2, patients received induction therapy with six 28-day cycles of lenalidomide 20 mg with intravenous obinutuzumab 1000 mg. In accordance with our prior experience with lenalidomide plus rituximab, patients who were responding to the combination could receive up to 6 additional cycles (up to 12 cycles in total) of combination therapy. Dosing of obinutuzumab was continued in all responding patients after cycle 6 every 2 months for a total of 30 months from the start of therapy. The decision of number of cycles of combination therapy beyond 6 was at discretion of the investigator and was included to allow individualisation of therapy to maximise response while minimising exposure. The co-primary objectives were to evaluate the safety and overall response, defined as the proportion of patients who achieved a complete or partial response in relapsed and refractory indolent non-Hodgkin lymphoma at the end of induction therapy, according to Cheson and colleagues (2007 criteria). The secondary endpoints were complete response after induction therapy and time to event endpoints including time to progression, progression free survival, and overall survival. Analyses were intent to treat in the efficacy cohort and per-treated in the safety population in all patients who received at least one dose of either investigational agent. This trial is registered with ClinicalTrials.gov, NCT01995669.</p><p><strong>Findings: </strong>Between June 03, 2014, and 07 March 2019, we completed planned enrolment, and 66 patients started therapy including 9 patients in phase 1 and 57 patients in phase 2. All patients were evaluated for safety and the 60 patients treated at the recommended phase 2 dose of lenalidomide 20 mg were evaluable for activity. Grade 3-4 haematological toxicities included neutropenia 21% (14/66) and thrombocytopenia 11% (7/66) with no cases of febrile neutropenia","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11332795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Considering chronotype to improve hypertension management.","authors":"Tomas Baka, Darlynn M Rojo-Wissar, Fedor Simko","doi":"10.1016/j.eclinm.2024.102768","DOIUrl":"10.1016/j.eclinm.2024.102768","url":null,"abstract":"","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The association between cytomegalovirus infection and neurodegenerative diseases: a prospective cohort using UK Biobank data.","authors":"Xuning Ma, Zijun Liao, Henghui Tan, Kaitao Wang, Cuilian Feng, Pengpeng Xing, Xiufen Zhang, Junjie Hua, Peixin Jiang, Sibo Peng, Hualiang Lin, Wen Liang, Xiaoya Gao","doi":"10.1016/j.eclinm.2024.102757","DOIUrl":"10.1016/j.eclinm.2024.102757","url":null,"abstract":"<p><strong>Background: </strong>Certain viral infections have been linked to the development of neurodegenerative diseases. This study aimed to investigate the association between cytomegalovirus (CMV) infection and five neurodegenerative diseases, spinal muscular atrophy (SMA) and related syndromes, Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and disorders of the autonomic nervous system (DANS).</p><p><strong>Methods: </strong>This prospective cohort included white British individuals who underwent CMV testing in the UK Biobank from January 1, 2006 to December 31, 2021. A Cox proportional hazard model was utilized to estimate the future risk of developing five neurodegenerative diseases in individuals with or without CMV infection, adjusted for batch effect, age, sex, and Townsend deprivation index in Model 1, and additionally for type 2 diabetes, cancer, osteoporosis, vitamin D, monocyte count and leukocyte count in Model 2. Bidirectional Mendelian randomization was employed to validate the potential causal relationship between CMV infection and PD.</p><p><strong>Findings: </strong>A total of 8346 individuals, consisting of 4620 females (55.4%) and 3726 males (44.6%) who were white British at an average age of 56.74 (8.11), were included in this study. The results showed that CMV infection did not affect the risk of developing AD (model 1: HR [95% CI] = 1.01 [0.57, 1.81], <i>P</i> = 0.965; model 2: HR = 1.00 [0.56, 1.79], <i>P</i> = 0.999), SMA and related syndromes (model 1: HR = 3.57 [0.64, 19.80], <i>P</i> = 0.146; model 2: HR = 3.52 [0.63, 19.61], <i>P</i> = 0.152), MS (model 1: HR = 1.16 [0.45, 2.97], <i>P</i> = 0.756; model 2: HR = 1.16 [0.45, 2.97], <i>P</i> = 0.761) and DANS (model 1: HR = 0.65 [0.16, 2.66], <i>P</i> = 0.552; model 2: HR = 0.65 [0.16, 2.64], <i>P</i> = 0.543). Interestingly, it was found that participants who were CMV seronegative had a higher risk of developing PD compared to those who were seropositive (model 1: HR = 2.37 [1.25, 4.51], <i>P</i> = 0.009; model 2: HR = 2.39 [1.25, 4.54], <i>P</i> = 0.008) after excluding deceased individuals. This association was notably stronger in males (model 1: HR = 3.16 [1.42, 7.07], <i>P</i> = 0.005; model 2: HR = 3.41 [1.50, 7.71], <i>P</i> = 0.003), but no significant difference was observed in the female subgroup (model 1: HR = 1.28 [0.40, 4.07], <i>P</i> = 0.679; model 2: HR = 1.27 [0.40, 4.06], <i>P</i> = 0.684). However, a bidirectional Mendelian randomization analysis did not find a genetic association between CMV infection and PD.</p><p><strong>Interpretation: </strong>The study found that males who did not have a CMV infection were at a higher risk of developing PD. The findings provided a new viewpoint on the risk factors for PD and may potentially influence public health approaches for the disease.</p><p><strong>Funding: </strong>National Natural Science Foundation of China (81873776), Natural Science Foundation of Guangdong Province, Ch","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11327475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations between socioeconomic inequalities and progression to psychological and cognitive multimorbidities after onset of a physical condition: a multicohort study.","authors":"Yaguan Zhou, Mika Kivimäki, Lijing L Yan, Rodrigo M Carrillo-Larco, Yue Zhang, Yangyang Cheng, Hui Wang, Maigeng Zhou, Xiaolin Xu","doi":"10.1016/j.eclinm.2024.102739","DOIUrl":"10.1016/j.eclinm.2024.102739","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Chronic physical conditions (e.g., heart diseases, diabetes) increase with population ageing, contributing to psychological and cognitive multimorbidities. Yet, little is known about socioeconomic inequalities in this process. We examined the associations between socioeconomic status (SES) and progression to psychological and cognitive multimorbidities after onset of a physical condition.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We used harmonized individual-level data from five prospective cohort studies across 24 countries in the US, Europe and Asia, with repeated morbidity measurements between 2002 and 2021. Participants with at least one new-onset physical conditions (hypertension, diabetes, heart diseases, stroke, chronic lung diseases, cancer, or arthritis) were followed up for progression to physical-psychological multimorbidity, physical-cognitive multimorbidity, and physical-psychological-cognitive multimorbidity. SES was determined based on educational level and total household wealth at the onset of a physical condition. Time to and incidence rates of progressing psychological and cognitive multimorbidities were estimated in analyses stratified by SES. Fine-Gray subdistribution hazard models and multi-state models were used to estimate the associations between SES and progression to psychological and cognitive multimorbidities.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Among 20,250 participants aged ≥45 years (mean age at a physical condition onset 65.38 years, standard deviation 8.37) with at least one new-onset physical conditions in the analysis, 7928 (39.2%) progressed to psychological and cognitive multimorbidities during a median follow-up of 8.0 years (168,575 person-years). The mean survival time free from physical-psychological-cognitive multimorbidity was 11.96 years (95% confidence interval 11.57-12.34) in low SES individuals, compared to 15.52 years (15.40-15.63) in high SES individuals, with the corresponding incidence rate of 18.44 (16.32-20.82) and 3.15 (2.48-4.01) per 1000 person-years, respectively. The associations of education, household wealth and SES with multimorbidities followed a dose-dependent relation, with subdistribution hazard ratios per decreasing SES category being 1.24 (1.19-1.29) for physical-psychological multimorbidity, 1.47 (1.40-1.54) for physical-cognitive multimorbidity, and 1.84 (1.72-1.97) for physical-psychological-cognitive multimorbidity. The strongest SES-multimorbidities associations were observed in participants with arthritis, hypertension or diabetes. In multi-state models SES was linked to all five transitions from physical condition to physical-psychological multimorbidity, physical-cognitive multimorbidity and physical-psychological-cognitive multimorbidity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;Socioeconomic inequalities are associated with the progression of a chronic physical condition, with the lower SES groups had both an earlier time to and a higher incidence of p","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11327438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"10th Congress of the European Academy of Neurology-Helsinki 2024.","authors":"","doi":"10.1016/j.eclinm.2024.102773","DOIUrl":"https://doi.org/10.1016/j.eclinm.2024.102773","url":null,"abstract":"","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11321306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimal human papillomavirus vaccination strategies in the context of vaccine supply constraints in 100 countries.","authors":"Kiesha Prem, Tania Cernuschi, Stefano Malvolti, Marc Brisson, Mark Jit","doi":"10.1016/j.eclinm.2024.102735","DOIUrl":"10.1016/j.eclinm.2024.102735","url":null,"abstract":"<p><strong>Background: </strong>Countries are recommended to immunise adolescent girls routinely with one or two doses of human papillomavirus (HPV) vaccines to eliminate cervical cancer as a public health problem. With most existing vaccine doses absorbed by countries (mostly high-income) with existing HPV vaccination programmes, limited supply has been left for new country introductions until 2022; many of those, low- and middle-income countries with higher mortality. Several vaccination strategies were considered by the Strategic Advisory Group of Experts on Immunization to allow more countries to introduce vaccination despite constrained supplies.</p><p><strong>Methods: </strong>We examined the impact of nine strategies for allocating limited vaccine doses to 100 pre-introduction countries from 2020 to 2030. Two algorithms were used to optimise the total number of cancer deaths that can be averted worldwide by a limited number of doses (knapsack and decreasing order of country-specific mortality rates), and an unoptimised algorithm (decreasing order of Human Development Index) were used.</p><p><strong>Findings: </strong>Routinely vaccinating 14-year-old girls with either one or two doses and switching to a routine 9-year-old programme when supply is no longer constrained could prevent the most cervical cancer deaths, regardless of allocation algorithm. The unoptimised allocation averts fewer deaths because it allocates first to higher-income countries, usually with lower cervical cancer mortality.</p><p><strong>Interpretation: </strong>To optimise the deaths averted through vaccination when supply is limited, it is important to prioritise high-burden countries and vaccinating older girls first.</p><p><strong>Funding: </strong>WHO, Bill & Melinda Gates Foundation.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of antihypertensive treatment for target organ protection in patients with masked hypertension (ANTI-MASK): a multicentre, double-blind, placebo-controlled trial.","authors":"Jian-Feng Huang, Dong-Yan Zhang, De-Wei An, Ming-Xuan Li, Chang-Yuan Liu, Ying-Qing Feng, Qi-Dong Zheng, Xin Chen, Jan A Staessen, Ji-Guang Wang, Yan Li","doi":"10.1016/j.eclinm.2024.102736","DOIUrl":"10.1016/j.eclinm.2024.102736","url":null,"abstract":"<p><strong>Background: </strong>Masked hypertension is associated with target organ damage (TOD) and adverse health outcomes, but whether antihypertensive treatment improves TOD in patients with masked hypertension is unproven.</p><p><strong>Methods: </strong>In this multicentre, randomised, double-blind, placebo-controlled trial at 15 Chinese hospitals, untreated outpatients aged 30-70 years with an office blood pressure (BP) of <140/<90 mm Hg and 24-h, daytime or nighttime ambulatory BP of ≥130/≥80, ≥135/≥85, or ≥120/≥70 mm Hg were enrolled. Patients had ≥1 sign of TOD: electrocardiographic left ventricular hypertrophy (LVH), brachial-ankle pulse wave velocity (baPWV) ≥1400 cm/s, or urinary albumin-to-creatinine ratio (ACR) ≥3.5 mg/mmol in women and ≥2.5 mg/mmol in men. Exclusion criteria included secondary hypertension, diabetic nephropathy, serum creatinine ≥176.8 μmol/L, and cardiovascular disease within 6 months of screening. After stratification for centre, sex and the presence of nighttime hypertension, eligible patients were randomly assigned (1:1) to receive antihypertensive treatment or placebo. Patients and investigators were masked to group assignment. Active treatment consisted of allisartan starting at 80 mg/day, to be increased to 160 mg/day at month 2, and to be combined with amlodipine 2.5 mg/day at month 4, if the ambulatory BP remained uncontrolled. Matching placebos were used likewise in the control group. The primary endpoint was the improvement of TOD, defined as normalisation of baPWV, ACR or LVH or a ≥20% reduction in baPWV or ACR over the 48-week follow-up. The intention-to-treat analysis included all randomised patients, the per-protocol analysis patients who fully adhered to the protocol, and the safety analysis all patients who received at least one dose of the study medication. This study is registered with ClinicalTrials.gov, NCT02893358.</p><p><strong>Findings: </strong>Between February 14, 2017, and October 31, 2020, 320 patients (43.1% women; mean age ± SD 53.7 ± 9.7 years) were enrolled. Baseline office and 24-h BP averaged 130 ± 6.0/81 ± 5.9 mm Hg and 136 ± 8.6/84 ± 6.1 mm Hg, and the prevalence of elevated baPWV, ACR and LVH were 97.5%, 12.5%, and 7.8%, respectively. The 24-h BP decreased on average (±SE) by 10.1 ± 0.9/6.4 ± 0.5 mm Hg in 153 patients on active treatment and by 1.3 ± 0.9/1.0 ± 0.5 mm Hg in 167 patients on placebo. Improvement of TOD occurred in 79 patients randomised to active treatment and in 49 patients on placebo: 51.6% (95% CI 43.7%, 59.5%) versus 29.3% (22.1, 36.5%; p < 0.0001). Per-protocol and subgroup analyses were confirmatory. Adverse events were generally mild and occurred in 38 (25.3%) and 43 (26.4%) patients randomised to active treatment and placebo, respectively (p = 0.83).</p><p><strong>Interpretation: </strong>Our results suggest that antihypertensive treatment improves TOD in patients with masked hypertension, highlighting the need of treatment. However, the long-term benefit ","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GEMA-Na and MELD 3.0 severity scores to address sex disparities for accessing liver transplantation: a nationwide retrospective cohort study.","authors":"Manuel Luis Rodríguez-Perálvarez, Gloria de la Rosa, Antonio Manuel Gómez-Orellana, María Victoria Aguilera, Teresa Pascual Vicente, Sheila Pereira, María Luisa Ortiz, Giulia Pagano, Francisco Suarez, Rocío González Grande, Alba Cachero, Santiago Tomé, Mónica Barreales, Rosa Martín Mateos, Sonia Pascual, Mario Romero, Itxarone Bilbao, Carmen Alonso Martín, Elena Otón, Luisa González Diéguez, María Dolores Espinosa, Ana Arias Milla, Gerardo Blanco Fernández, Sara Lorente, Antonio Cuadrado Lavín, Amaya Redín García, Clara Sánchez Cano, Carmen Cepeda-Franco, José Antonio Pons, Jordi Colmenero, David Guijo-Rubio, Alejandra Otero, Alberto Amador Navarrete, Sarai Romero Moreno, María Rodríguez Soler, César Hervás Martínez, Mikel Gastaca","doi":"10.1016/j.eclinm.2024.102737","DOIUrl":"10.1016/j.eclinm.2024.102737","url":null,"abstract":"<p><strong>Background: </strong>The Gender-Equity Model for liver Allocation corrected by serum sodium (GEMA-Na) and the Model for End-stage Liver Disease 3.0 (MELD 3.0) could amend sex disparities for accessing liver transplantation (LT). We aimed to assess these inequities in Spain and to compare the performance of GEMA-Na and MELD 3.0.</p><p><strong>Methods: </strong>Nationwide cohort study including adult patients listed for a first elective LT (January 2016-December 2021). The primary outcome was mortality or delisting for sickness within the first 90 days. Independent predictors of the primary outcome were evaluated using multivariate Cox's regression with adjusted relative risks (RR) and 95% confidence intervals (95% CI). The discrimination of GEMA-Na and MELD 3.0was assessed using Harrell c-statistics (Hc).</p><p><strong>Findings: </strong>The study included 6071 patients (4697 men and 1374 women). Mortality or delisting for clinical deterioration occurred in 286 patients at 90 days (4.7%). Women had reduced access to LT (83.7% vs. 85.9%; p = 0.037) and increased risk of mortality or delisting for sickness at 90 days (adjusted RR = 1.57 [95% CI 1.09-2.28]; p = 0.017). Female sex remained as an independent risk factor when using MELD or MELD-Na but lost its significance in the presence of GEMA-Na or MELD 3.0. Among patients included for reasons other than tumours (n = 3606; 59.4%), GEMA-Na had Hc = 0.753 (95% CI 0.715-0.792), which was higher than MELD 3.0 (Hc = 0.726 [95% CI 0.686-0.767; p = 0.001), showing both models adequate calibration.</p><p><strong>Interpretation: </strong>GEMA-Na and MELD 3.0 might correct sex disparities for accessing LT, but GEMA-Na provides more accurate predictions of waiting list outcomes and could be considered the standard of care for waiting list prioritization.</p><p><strong>Funding: </strong>Instituto de Salud Carlos III, Agencia Estatal de Investigación (Spain), and European Union.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11304699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and durability of mRNA-1273-induced SARS-CoV-2 immune responses in adolescents: results from the phase 2/3 TeenCOVE trial.","authors":"Amparo L Figueroa, Kashif Ali, Gary Berman, Honghong Zhou, Weiping Deng, Wenqin Xu, Stephanie Lussier, Bethany Girard, Frank J Dutko, Karen Slobod, Anne Yeakey, Frances Priddy, Jacqueline M Miller, Rituparna Das","doi":"10.1016/j.eclinm.2024.102720","DOIUrl":"10.1016/j.eclinm.2024.102720","url":null,"abstract":"<p><strong>Background: </strong>Longitudinal changes in vaccination-induced immune response remain inadequately characterized in adolescents. We present long-term safety, immunogenicity, and COVID-19 incidence following a 2-dose mRNA-1273 100-μg primary series, and immunogenicity following a single dose of mRNA-1273 50 μg in vaccine-naïve adolescents.</p><p><strong>Methods: </strong>TeenCOVE (NCT04649151) Part 1 randomized adolescents (12-17 years) to 2-dose mRNA-1273 100 μg (n = 2490) or placebo (n = 1243) 28 days apart. Subsequently, placebo recipients (n = 91) could receive open-label mRNA-1273. Primary objectives included prespecified adverse events through 12 months; secondary objectives were COVID-19 incidence and neutralizing and spike-binding antibodies (nAbs/bAbs) against SARS-CoV-2 (ancestral/variants) through 12 months (study period: December 2020-January 2022). In Part 2, vaccine-naïve adolescents (n = 52) received up to 2 doses of mRNA-1273 50 μg; interim analysis included Day 28 (D28) nAbs post-injection 1 in SARS-CoV-2-baseline-positive participants (serologic/virologic evidence of prior infection).</p><p><strong>Findings: </strong>In SARS-CoV-2-baseline-negative adolescents (N = 369), mRNA-1273 induced robust nAb responses versus baseline (geometric mean concentration [GMC] = 11; 95% CI, 11-12) at D28 (1868 [1759-1985]), 6 months (625 [583-670]) and 12 months (550 [490-618]) post-injection 2. Similar bAb responses were observed to alpha/beta/delta/gamma variants; nAb/bAb responses were similar in SARS-CoV-2-baseline-positive adolescents. The 2-dose mRNA-1273 100-μg primary series was generally well-tolerated; one case of nonserious, moderate, probable acute myocarditis resolved by 8 days from symptom onset. A single dose of mRNA-1273 50 μg in SARS-CoV-2-baseline-positive adolescents induced higher D28 nAb GMCs against ancestral SARS-CoV-2 than 2-dose mRNA-1273 100 μg in young adults (geometric mean ratio = 4.322 [3.274-5.707]).</p><p><strong>Interpretation: </strong>The overall risk-benefit profile of mRNA-1273 remains favorable in adolescents, with durable 12-month immune responses against SARS-CoV-2 (ancestral/variants). A single mRNA-1273 50-μg injection in vaccine-naïve adolescents elicited robust immune responses against SARS-CoV-2.</p><p><strong>Funding: </strong>This project has been funded in whole or in part with federal funds by the Department of Health and Human Services, United States; Administration for Strategic Preparedness and Response, United States; Biomedical Advanced Research and Development Authority, United States, under Contract No. 75A50120C00034. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Department of Health and Human Services or its components.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term efficacy and safety of continued complement C1s inhibition with sutimlimab in cold agglutinin disease: CADENZA study Part B.","authors":"Alexander Röth, Sigbjørn Berentsen, Wilma Barcellini, Shirley D'Sa, Bernd Jilma, Marc Michel, Ilene C Weitz, Masaki Yamaguchi, Jun-Ichi Nishimura, Josephine M I Vos, Joan Cid, Michael Storek, Nancy Wong, Ronnie Yoo, Deepthi Jayawardene, Shruti Srivastava, Marek Wardęcki, Frank Shafer, Michelle Lee, Catherine M Broome","doi":"10.1016/j.eclinm.2024.102733","DOIUrl":"10.1016/j.eclinm.2024.102733","url":null,"abstract":"<p><strong>Background: </strong>Cold agglutinin disease (CAD) is a rare autoimmune haemolytic anaemia mediated by the classical complement pathway (CP). Sutimlimab selectively targets complement C1s inhibiting classical CP activation. In CADENZA Part A (26-weeks), a placebo-controlled study in patients without recent transfusion history, sutimlimab reduced haemolysis, anaemia, and fatigue, and was generally well tolerated.</p><p><strong>Methods: </strong>The CADENZA study (NCT03347422) started in March 2018 (Part A) and completed in December 2021 (Part B). All patients in Part B were eligible to receive sutimlimab for up to 1 year after the last patient completed Part A. Efficacy and safety was assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout.</p><p><strong>Findings: </strong>In total, 32/39 patients completed Part B; median treatment duration: 99 weeks. Similar sustained improvements in haemolysis, anaemia, and quality of life were observed in patients switching to sutimlimab and those continuing sutimlimab. Mean LV values for the combined group (ie, placebo-to-sutimlimab group and sutimlimab-to-sutimlimab group) improved from baseline for haemoglobin (≥11.0 g/dL on-treatment <i>vs</i> 9.3 g/dL at baseline), bilirubin (≤20.0 μmol/L on-treatment <i>vs</i> 35.0 μmol/L at baseline), and FACIT-Fatigue scores. Following a 9-week washout, inhibition of CP activity was reversed, and haemolytic markers approached baseline levels. Overall, sutimlimab was generally well tolerated throughout the study. No patients developed systemic lupus erythematosus or meningococcal infections. During the 9-week washout, most adverse events could be attributed to recurrence of underlying CAD.</p><p><strong>Interpretation: </strong>The CADENZA Part B results support the sustained efficacy and safety of sutimlimab for treatment of CAD; however, upon discontinuation disease activity reoccurs.</p><p><strong>Funding: </strong>Sanofi.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}