Pub Date : 2025-12-04eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103685
Lorenzo Piemonti, Andrea Mario Bolla, Amelia Caretto, Raffaella Melzi, Alessia Mercalli, Valeria Sordi, Paolo Monti, Paola Magistretti, Vito Lampasona, Ilaria Marzinotto, Paola Maffi, Miriam Ramondetta, Nicoletta Cagni, Erica Pedone, Davide Catarinella, Massimo Cardillo, Rossana Caldara, Emanuele Bosi
Background: Current immunotherapies for type 1 diabetes (T1D) have shown limited success in durably preserving β-cell function. We tested a novel strategy that repurposes allogeneic islet transplantation not for metabolic replacement, but as a platform for antigen-specific immune education.
Methods: In this monocentric, open-label pilot study (April 2015-April 2023), six patients with recent-onset T1D received a minimal islet mass (median 3452 IEQ/kg; range 2980-4050) combined with short-term immunomodulation (ATG, transient mTOR inhibition, and G-CSF). The transplanted islet mass was intentionally insufficient for metabolic replacement. The primary endpoint was the change in stimulated 2-h C-peptide AUC at 52 weeks. Exploratory endpoints included immune cell phenotyping, cytokine/chemokine profiling, miR-375 release kinetics, analysis of islet-related autoantibodies, and monitoring of donor-specific HLA antibodies. ClinicalTrials.gov Identifier: NCT02505893.
Findings: The protocol was safe and well-tolerated. At 12 months, the median stimulated C-peptide AUC was preserved at 91-100% of baseline with all participants achieving a partial clinical remission (IDAA1c ≤ 9). At 5 years, median C-peptide AUC declined to 44-56% of baseline, with 2 patients maintaining stable secretion and 2 retaining ∼50% of initial function. Exploratory analyses demonstrated a structured pattern of immune resetting, with early lymphodepletion followed by memory and regulatory T-cell expansion; transient increases in IL-2 and IL-10; sustained early elevation of sCD25; biphasic miR-375 peaks indicating early β-cell stress; transient increases in autoantibodies without epitope spreading; and donor-specific class I HLA antibodies in five patients, with persistent class II DSA in two. No expansion of CD3+CD8+ T cells specific for GAD65 was detected.
Interpretation: This study introduces a paradigm shift in the use of islet transplantation-transforming it from a metabolic intervention into a tolerogenic stimulus through controlled antigen exposure. Further potentiation with stem-cell-derived islets may enable improved matching, graft modification, and iterative antigen delivery.
Funding: Supported by Fondazione Italiana Diabete (FID). The funder had no role in study design, data collection, data analysis, interpretation, manuscript preparation, or decision to publish.
{"title":"Induction of immune education in type 1 diabetes through controlled allogeneic islet rejection at onset: a monocentric open-label pilot study.","authors":"Lorenzo Piemonti, Andrea Mario Bolla, Amelia Caretto, Raffaella Melzi, Alessia Mercalli, Valeria Sordi, Paolo Monti, Paola Magistretti, Vito Lampasona, Ilaria Marzinotto, Paola Maffi, Miriam Ramondetta, Nicoletta Cagni, Erica Pedone, Davide Catarinella, Massimo Cardillo, Rossana Caldara, Emanuele Bosi","doi":"10.1016/j.eclinm.2025.103685","DOIUrl":"10.1016/j.eclinm.2025.103685","url":null,"abstract":"<p><strong>Background: </strong>Current immunotherapies for type 1 diabetes (T1D) have shown limited success in durably preserving β-cell function. We tested a novel strategy that repurposes allogeneic islet transplantation not for metabolic replacement, but as a platform for antigen-specific immune education.</p><p><strong>Methods: </strong>In this monocentric, open-label pilot study (April 2015-April 2023), six patients with recent-onset T1D received a minimal islet mass (median 3452 IEQ/kg; range 2980-4050) combined with short-term immunomodulation (ATG, transient mTOR inhibition, and G-CSF). The transplanted islet mass was intentionally insufficient for metabolic replacement. The primary endpoint was the change in stimulated 2-h C-peptide AUC at 52 weeks. Exploratory endpoints included immune cell phenotyping, cytokine/chemokine profiling, miR-375 release kinetics, analysis of islet-related autoantibodies, and monitoring of donor-specific HLA antibodies. ClinicalTrials.gov Identifier: NCT02505893.</p><p><strong>Findings: </strong>The protocol was safe and well-tolerated. At 12 months, the median stimulated C-peptide AUC was preserved at 91-100% of baseline with all participants achieving a partial clinical remission (IDAA1c ≤ 9). At 5 years, median C-peptide AUC declined to 44-56% of baseline, with 2 patients maintaining stable secretion and 2 retaining ∼50% of initial function. Exploratory analyses demonstrated a structured pattern of immune resetting, with early lymphodepletion followed by memory and regulatory T-cell expansion; transient increases in IL-2 and IL-10; sustained early elevation of sCD25; biphasic miR-375 peaks indicating early β-cell stress; transient increases in autoantibodies without epitope spreading; and donor-specific class I HLA antibodies in five patients, with persistent class II DSA in two. No expansion of CD3<sup>+</sup>CD8<sup>+</sup> T cells specific for GAD65 was detected.</p><p><strong>Interpretation: </strong>This study introduces a paradigm shift in the use of islet transplantation-transforming it from a metabolic intervention into a tolerogenic stimulus through controlled antigen exposure. Further potentiation with stem-cell-derived islets may enable improved matching, graft modification, and iterative antigen delivery.</p><p><strong>Funding: </strong>Supported by Fondazione Italiana Diabete (FID). The funder had no role in study design, data collection, data analysis, interpretation, manuscript preparation, or decision to publish.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103685"},"PeriodicalIF":10.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12720987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818634","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}
Pub Date : 2025-12-04eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103682
David A Jolliffe, Nicklas Brustad, Bo Chawes, Cyrus Cooper, Stefania D'angelo, Nicholas C Harvey, Augusto A Litonjua, Rebecca Moon, Shaun K Morris, John D Sluyter, Scott T Weiss, Adrian R Martineau
<p><strong>Background: </strong>Acute respiratory infections (ARIs) are a leading cause of mortality in infants. Vitamin D supports innate antimicrobial effector mechanisms in leucocytes and respiratory epithelium. Maternal vitamin D supplementation during pregnancy has been proposed as a preventive strategy, however, an up-to-date synthesis of available data from randomised controlled trials (RCTs) has not been conducted.</p><p><strong>Methods: </strong>We conducted a systematic review and meta-analysis of aggregate data from RCTs of maternal vitamin D supplementation for prevention of ARIs in offspring. Data were analysed using a random-effects model. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science and the ClinicalTrials.gov from database inception to 5th August 2025. No language restrictions were imposed. Double-blind RCTs of maternal vitamin D supplementation, with placebo or lower-dose vitamin D control, were eligible if approved by Research Ethics Committee and if ARI incidence in offspring was collected prospectively and pre-specified as an efficacy outcome. Sub-group analyses were done to determine whether effects of maternal vitamin D supplementation on offspring ARI risk varied according to maternal baseline circulating 25-hydroxyvitamin D (25 [OH]D) concentrations (<25 nmol/L, 25-49.9 nmol/L, 50-74.9 nmol/L, or ≥75 nmol/L). The study was registered with PROSPERO, CRD42024527191.</p><p><strong>Findings: </strong>Our search identified 405 unique studies, of which 4 RCTs (3678 participants) were eligible and included. For the primary comparison of any maternal vitamin D supplementation vs. placebo, the intervention did not significantly affect overall ARI risk in offspring (incidence rate ratio [IRR] 1.01, 95% CI 0.98-1.03, P = 0.66; 4 studies; I<sup>2</sup> 14.5%, absolute effects from GRADE assessment: 0.05 higher rate in vitamin D arm; moderate quality finding). Pre-specified subgroup analysis did not reveal evidence of effect modification by maternal baseline vitamin D status: <25 nmol/L group: IRR 1.12, 95% CI 0.98-1.27 (607 participants in 4 studies, I<sup>2</sup> 47.8%) vs. 25-49.9 nmol/L group: IRR 1.04, 95% CI 0.96-1.13 (1154 participants in 4 studies, I<sup>2</sup> 68.5%) vs. 50-74.9 nmol/L group: IRR 1.00, 95% CI 0.93-1.08 (789 participants in 4 studies, I<sup>2</sup> 64.9%) vs. ≥75 nmol/L group: IRR 0.97, 95% CI 0.89-1.06 (505 participants in 4 studies, I<sup>2</sup> 47.6%). A funnel plot did not indicate the presence of publication bias or small-study effects (P = 0.71, Egger's test).</p><p><strong>Interpretation: </strong>Our analysis of current data does not support routine antenatal vitamin D supplementation for the prevention of ARI in offspring. Key limitations of the study were the administration of a low dose vitamin D standard-of-care in some populations which may have attenuated effects of the intervention, and heterogeneity in ARI case definitions which may have introd
背景：急性呼吸道感染（ARIs）是婴儿死亡的主要原因。维生素D支持先天抗菌效应机制在白细胞和呼吸上皮。孕妇在怀孕期间补充维生素D已被建议作为一种预防策略，然而，尚未进行随机对照试验（rct）中可用数据的最新综合。方法：我们对母体补充维生素D预防后代ARIs的随机对照试验的总体数据进行了系统回顾和荟萃分析。数据采用随机效应模型进行分析。从数据库建立到2025年8月5日，我们检索了MEDLINE、EMBASE、Cochrane Central Register of Controlled Trials、Web of Science和ClinicalTrials.gov。没有施加语言限制。如果获得研究伦理委员会的批准，并且前瞻性地收集后代的ARI发病率，并预先指定作为疗效结果，则母体补充维生素D与安慰剂或低剂量维生素D对照的双盲随机对照试验符合条件。我们进行了亚组分析，以确定母亲补充维生素D对后代ARI风险的影响是否会根据母亲基线循环25-羟基维生素D （25 [OH]D）浓度而变化(研究结果：我们的搜索确定了405项独特的研究，其中4项随机对照试验（3678名参与者）符合条件并被纳入。对于任何母体补充维生素D与安慰剂的初步比较，干预没有显著影响后代的总体ARI风险（发病率比[IRR] 1.01, 95% CI 0.98-1.03, P = 0.66； 4项研究；I2 14.5%， GRADE评估的绝对效果：维生素D组的发生率高0.05；中等质量发现）。预先指定的亚组分析没有显示母体基线维生素D水平改变效果的证据：2 47.8%)vs. 25-49.9 nmol/L组：IRR 1.04, 95% CI 0.96-1.13(4项研究1154名参与者，I2 68.5%) vs. 50-74.9 nmol/L组：IRR 1.00, 95% CI 0.93-1.08(4项研究789名参与者，I2 64.9%) vs.≥75 nmol/L组：IRR 0.97, 95% CI 0.89-1.06（4项研究505名参与者，I2 47.6%）。漏斗图未显示存在发表偏倚或小研究效应（P = 0.71， Egger检验）。解释：我们对当前数据的分析不支持常规产前补充维生素D预防后代ARI。该研究的主要局限性是在一些人群中使用低剂量维生素D标准治疗，这可能会减弱干预的效果，以及ARI病例定义的异质性，这可能会导致误分类偏倚。缺乏人群的靶向补充可能需要进一步的研究。资金:没有。
{"title":"Association between maternal vitamin D supplementation during pregnancy and the risk of acute respiratory infections in offspring: a systematic review and meta-analysis.","authors":"David A Jolliffe, Nicklas Brustad, Bo Chawes, Cyrus Cooper, Stefania D'angelo, Nicholas C Harvey, Augusto A Litonjua, Rebecca Moon, Shaun K Morris, John D Sluyter, Scott T Weiss, Adrian R Martineau","doi":"10.1016/j.eclinm.2025.103682","DOIUrl":"10.1016/j.eclinm.2025.103682","url":null,"abstract":"<p><strong>Background: </strong>Acute respiratory infections (ARIs) are a leading cause of mortality in infants. Vitamin D supports innate antimicrobial effector mechanisms in leucocytes and respiratory epithelium. Maternal vitamin D supplementation during pregnancy has been proposed as a preventive strategy, however, an up-to-date synthesis of available data from randomised controlled trials (RCTs) has not been conducted.</p><p><strong>Methods: </strong>We conducted a systematic review and meta-analysis of aggregate data from RCTs of maternal vitamin D supplementation for prevention of ARIs in offspring. Data were analysed using a random-effects model. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science and the ClinicalTrials.gov from database inception to 5th August 2025. No language restrictions were imposed. Double-blind RCTs of maternal vitamin D supplementation, with placebo or lower-dose vitamin D control, were eligible if approved by Research Ethics Committee and if ARI incidence in offspring was collected prospectively and pre-specified as an efficacy outcome. Sub-group analyses were done to determine whether effects of maternal vitamin D supplementation on offspring ARI risk varied according to maternal baseline circulating 25-hydroxyvitamin D (25 [OH]D) concentrations (<25 nmol/L, 25-49.9 nmol/L, 50-74.9 nmol/L, or ≥75 nmol/L). The study was registered with PROSPERO, CRD42024527191.</p><p><strong>Findings: </strong>Our search identified 405 unique studies, of which 4 RCTs (3678 participants) were eligible and included. For the primary comparison of any maternal vitamin D supplementation vs. placebo, the intervention did not significantly affect overall ARI risk in offspring (incidence rate ratio [IRR] 1.01, 95% CI 0.98-1.03, P = 0.66; 4 studies; I<sup>2</sup> 14.5%, absolute effects from GRADE assessment: 0.05 higher rate in vitamin D arm; moderate quality finding). Pre-specified subgroup analysis did not reveal evidence of effect modification by maternal baseline vitamin D status: <25 nmol/L group: IRR 1.12, 95% CI 0.98-1.27 (607 participants in 4 studies, I<sup>2</sup> 47.8%) vs. 25-49.9 nmol/L group: IRR 1.04, 95% CI 0.96-1.13 (1154 participants in 4 studies, I<sup>2</sup> 68.5%) vs. 50-74.9 nmol/L group: IRR 1.00, 95% CI 0.93-1.08 (789 participants in 4 studies, I<sup>2</sup> 64.9%) vs. ≥75 nmol/L group: IRR 0.97, 95% CI 0.89-1.06 (505 participants in 4 studies, I<sup>2</sup> 47.6%). A funnel plot did not indicate the presence of publication bias or small-study effects (P = 0.71, Egger's test).</p><p><strong>Interpretation: </strong>Our analysis of current data does not support routine antenatal vitamin D supplementation for the prevention of ARI in offspring. Key limitations of the study were the administration of a low dose vitamin D standard-of-care in some populations which may have attenuated effects of the intervention, and heterogeneity in ARI case definitions which may have introd","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103682"},"PeriodicalIF":10.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12720986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818669","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}
Background: The development of fractional-dose inactivated poliovirus vaccine (fIPV, a fifth of a full IPV dose) has provided a dose-stretching, less costly, and immunogenic alternative to full dose IPV, enhancing global IPV introduction and accessibility. fIPV is administered intradermally, however, intradermal injection is considered difficult and requires skilled administration. This study aimed at assessing the non-inferiority of intramuscular versus intradermal administration of fIPV in young infants in Maputo, Mozambique.
Methods: This was an open label, randomized, non-inferiority trial conducted between 2020 and 2022 (Ref. NCT04027036). Healthy IPV-naive infants attending routine immunization services were enrolled in the study and block randomized to receive two sequential doses of fIPV (0.1 mL), either intramuscularly or intradermally, at two and four months of age. Blood samples were collected at four timepoints: baseline, two months after the first dose, one week after the second dose, and one month after the second dose. Samples were analyzed via microneutralization assays against all three poliovirus serotypes. The primary endpoint was defined as cumulative seroconversion rates to type 2 poliovirus after administration of two doses of intramuscular versus intradermal fIPV. The study has been completed, and data analyzed per protocol.
Findings: 382 infants (49.5% [189/382] female) were enrolled in the study between 12 August 2020 and 31 May 2022. Cumulative type 2 seroconversion after two fIPV doses reached 92.1% (139/151, 95% CI 86.5-95.8) in the intradermal group and 96.1% (148/154, 95% CI 91.7-98.6) in the intramuscular group (=0.15). The most common adverse events were upper respiratory tract infections, not related to the study vaccine. 12 serious adverse events occurred in the study, none were considered to be related to the study vaccines.
Interpretation: This is the second study demonstrating non-inferiority of fIPV administered intramuscularly compared with intradermally; and the first study assessing immunogenicity in young infants. The results informed vaccine policymaking, leading to a recent recommendation from the Strategic Advisory Group of Experts on Immunization from WHO on intramuscular administration of fIPV in outbreak response.
Funding: World Health Organization.
背景：部分剂量灭活脊髓灰质炎病毒疫苗（fIPV，完全IPV剂量的五分之一）的发展为完全剂量IPV提供了一种剂量延伸、成本较低和免疫原性的替代方案，加强了全球IPV的引入和可及性。fIPV是皮内给药，然而皮内注射被认为是困难的，需要熟练的给药。本研究旨在评估在莫桑比克马普托的婴儿中肌肉注射与皮内注射fIPV的非劣效性。方法：这是一项开放标签、随机、非劣效性试验，于2020年至2022年进行（参考编号：NCT04027036）。参加常规免疫服务的健康初生ipvv婴儿被纳入研究，并随机分组接受两个顺序剂量的fIPV (0.1 mL)，分别在2个月和4个月大时肌肉注射或皮内注射。在四个时间点采集血样：基线、第一次给药后两个月、第二次给药后一周和第二次给药后一个月。通过针对所有三种脊髓灰质炎病毒血清型的微量中和试验对样品进行分析。主要终点被定义为肌肉注射和皮内注射两剂fIPV后到2型脊髓灰质炎病毒的累积血清转化率。研究已完成，并按方案对数据进行了分析。研究结果：在2020年8月12日至2022年5月31日期间，382名婴儿（49.5%[189/382]名女性）入组研究。两次fIPV剂量后累积2型血清转化在皮内组达到92.1% (139/151,95% CI 86.5-95.8)，在肌内组达到96.1% (148/154,95% CI 91.7-98.6)（=0.15）。最常见的不良事件是上呼吸道感染，与研究疫苗无关。研究中发生了12起严重不良事件，没有一起被认为与研究疫苗有关。解释：这是第二项证明肌肉内注射fIPV与皮内注射相比无劣效性的研究；也是第一个评估婴儿免疫原性的研究。这些结果为疫苗决策提供了信息，导致世卫组织免疫战略咨询专家组最近提出了关于在疫情应对中肌肉注射fIPV的建议。资助：世界卫生组织。
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Pub Date : 2025-12-03eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103681
Cees-Jan Oostwouder, Karin Vos, Ivo J Lutke Schipholt, Mathijs R Merkus, Thomas Telders, David F A van Deursen, Max B de Smit, Marina D van Eijk, Hetty J Bontkes, Femke H Bouwman, Rob C I Wüst, Lara de Jong, Marinus van Hulst, Jos W R Twisk, Coenraad K van Kalken, Gwendolyne G M Scholten-Peeters
Background: Post-COVID involves persistent, multisystem symptoms which are associated with inflammation, immune dysregulation, and autonomic dysfunction. The effects of currently applied treatments for post-COVID are limited. This study assessed the effectiveness of subcutaneous lidocaine-hydroxypropyl-β-cyclodextrin (HP-β-CD) for the treatment of post-COVID.
Methods: This interrupted time series study was conducted at a Dutch outpatient clinic between August 2024 and April 2025. Adults with physician-diagnosed post-COVID (n = 103) underwent a 4-week pre-treatment observation followed by 24-36 weeks of home-based subcutaneous lidocaine 5% with HP-β-CD, administered using a 3-phase protocol: 500 mg every other day (weeks 1-7), 500 mg daily (weeks 7-14), and up to 1000 mg/day (after week 14, in non-responders). The primary outcome was health-related quality of life (Short Form-12 (SF-12), physical and mental component summary scores). Secondary outcomes included symptom burden (daily app-based questionnaire) and adverse events.
Findings: Among 103 participants (mean [SD] age 48·1 [13·0] years; 67% women; median [IQR] symptom duration 31·5 [24·3-43·3] months), 76% completed 24 weeks and 71% completed 36 weeks of treatment. At week 24, the physical and mental component scores increased by 2·20 and 5·16 points, respectively; at week 36, by 4·13 and 7·00 points (all p < 0·0001). Twenty-seven of 30 symptoms improved significantly at week 24 of treatment compared to pre-treatment. Mild adverse events occurred in 89% of participants, mostly injection-site reactions; no serious adverse events were reported.
Interpretation: Subcutaneous lidocaine-HP-β-CD was associated with significantly improved quality of life and symptom burden in patients with post-COVID. This home-administered intervention offers a scalable and potentially disease-modifying approach for a disabling condition with no approved treatment to date.
Funding: Excellent Care Clinics funded the treatment provided in this study.
{"title":"Effect of subcutaneous lidocaine-hydroxypropyl-β-cyclodextrin (HP-β-CD) on quality of life in patients with post-COVID condition: a 36-week observational interrupted time series study.","authors":"Cees-Jan Oostwouder, Karin Vos, Ivo J Lutke Schipholt, Mathijs R Merkus, Thomas Telders, David F A van Deursen, Max B de Smit, Marina D van Eijk, Hetty J Bontkes, Femke H Bouwman, Rob C I Wüst, Lara de Jong, Marinus van Hulst, Jos W R Twisk, Coenraad K van Kalken, Gwendolyne G M Scholten-Peeters","doi":"10.1016/j.eclinm.2025.103681","DOIUrl":"10.1016/j.eclinm.2025.103681","url":null,"abstract":"<p><strong>Background: </strong>Post-COVID involves persistent, multisystem symptoms which are associated with inflammation, immune dysregulation, and autonomic dysfunction. The effects of currently applied treatments for post-COVID are limited. This study assessed the effectiveness of subcutaneous lidocaine-hydroxypropyl-β-cyclodextrin (HP-β-CD) for the treatment of post-COVID.</p><p><strong>Methods: </strong>This interrupted time series study was conducted at a Dutch outpatient clinic between August 2024 and April 2025. Adults with physician-diagnosed post-COVID (n = 103) underwent a 4-week pre-treatment observation followed by 24-36 weeks of home-based subcutaneous lidocaine 5% with HP-β-CD, administered using a 3-phase protocol: 500 mg every other day (weeks 1-7), 500 mg daily (weeks 7-14), and up to 1000 mg/day (after week 14, in non-responders). The primary outcome was health-related quality of life (Short Form-12 (SF-12), physical and mental component summary scores). Secondary outcomes included symptom burden (daily app-based questionnaire) and adverse events.</p><p><strong>Findings: </strong>Among 103 participants (mean [SD] age 48·1 [13·0] years; 67% women; median [IQR] symptom duration 31·5 [24·3-43·3] months), 76% completed 24 weeks and 71% completed 36 weeks of treatment. At week 24, the physical and mental component scores increased by 2·20 and 5·16 points, respectively; at week 36, by 4·13 and 7·00 points (all p < 0·0001). Twenty-seven of 30 symptoms improved significantly at week 24 of treatment compared to pre-treatment. Mild adverse events occurred in 89% of participants, mostly injection-site reactions; no serious adverse events were reported.</p><p><strong>Interpretation: </strong>Subcutaneous lidocaine-HP-β-CD was associated with significantly improved quality of life and symptom burden in patients with post-COVID. This home-administered intervention offers a scalable and potentially disease-modifying approach for a disabling condition with no approved treatment to date.</p><p><strong>Funding: </strong>Excellent Care Clinics funded the treatment provided in this study.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103681"},"PeriodicalIF":10.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12719765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818694","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}
Pub Date : 2025-12-01DOI: 10.1016/j.eclinm.2025.103662
Emine Koc Cakmak, Aline Al Nahas, Bernadette Chimera, Giles Hanley-Cook, Jeroen Berden, Anthony Fardet, Edmond Rock, Carine Biessy, Geneviève Nicolas, Nathalie Kliemann, Fernanda Rauber, Renata Bertazzi Levy, Lorenzo Mangone, Mathilde Touvier, Bernard Srour, Emmanuelle Kesse-Guyot, Carl Lachat, Guri Skeie, Elisabete Weiderpass, Franziska Jannasch, Christina C Dahm, Daniel Borch Ibsen, Christina Dahl, Cecilie Kyrø, Mariem Hajji-Louati, Chloé Marques, Gianluca Severi, Verena Katzke, Rudolf Kaaks, Matthias B Schulze, Saverio Caini, Sabina Sieri, Maria Santucci De Magistris, Rosario Tumino, Carlotta Sacerdote, Raúl Zamora-Ros, Maria-José Sánchez, Ana Jimenez-Zabala, Jesús-Humberto Gómez, Marcela Guevara, Elio Riboli, Marc J Gunter, Inge Huybrechts, Paolo Vineis, Oliver J K Robinson
Background: Diet may modify colorectal cancer risk. We investigated the associations of three dietary patterns, ultra-processed food (UPF) consumption, healthy plant-based food consumption, and food biodiversity, separately and combined into a "3V" score with risk of colorectal cancer.
Methods: This study used data from the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which recruited participants between 1992, and 2000, from 23 centres in ten European countries. The 3V score was developed by standardising and summing the healthy plant diet index (hPDI) and dietary species richness per year (DSR) and subtracting UPF (Nova category 4) intake in % g/day. Associations with colorectal cancer risk were assessed among 450,111 middle-aged participants of the EPIC cohort using multivariable-adjusted Cox regression models. Independent associations of each 3V component were assessed using mutually adjusted models. Data-driven thresholds were applied to assess adherence to the 3V components, set at the minimum value of the fourth quintile for hPDI, DSR and low UPF.
Findings: During mean (standard deviation (SD)) follow-up of 14.9 (4) years, absolute colorectal cancer rates were 8.59 and 10.37 cases/10,000 person-years for the highest and lowest quintiles of the 3V score, respectively. Inverse associations were found for colorectal (hazard ratio (HR) comparing highest vs lowest quintile: 0.84; 95% confidence interval (CI): 0.76-0.94), colon (HR: 0.82; 95% CI: 0.72-0.93), and distal colon cancer (HR: 0.81; 95% CI: 0.67-0.99), with significant linear trends observed across quintiles. UPF intake was positively associated with colon cancer risk (HR per 1 SD increment: 1.06; 95% CI: 1.02-1.11) when mutually adjusted for the other 3V components. Adherence to low UPF, high hPDI, and high DSR was inversely associated with colorectal (HR: 0.73; 95% CI: 0.61-0.88), colon (HR: 0.72; 95% CI: 0.57-0.91), and rectal cancer (HR: 0.65; 95% CI: 0.46-0.91) compared to adhering to none.
Interpretation: Adherence to the 3V diet is associated with lower risk of colorectal cancers.
Funding: Cancer Research UK, World Cancer Research Fund.
{"title":"The 3V score and joint associations of low ultra-processed food, biodiverse and plant-based diets on colorectal cancer risk: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) study.","authors":"Emine Koc Cakmak, Aline Al Nahas, Bernadette Chimera, Giles Hanley-Cook, Jeroen Berden, Anthony Fardet, Edmond Rock, Carine Biessy, Geneviève Nicolas, Nathalie Kliemann, Fernanda Rauber, Renata Bertazzi Levy, Lorenzo Mangone, Mathilde Touvier, Bernard Srour, Emmanuelle Kesse-Guyot, Carl Lachat, Guri Skeie, Elisabete Weiderpass, Franziska Jannasch, Christina C Dahm, Daniel Borch Ibsen, Christina Dahl, Cecilie Kyrø, Mariem Hajji-Louati, Chloé Marques, Gianluca Severi, Verena Katzke, Rudolf Kaaks, Matthias B Schulze, Saverio Caini, Sabina Sieri, Maria Santucci De Magistris, Rosario Tumino, Carlotta Sacerdote, Raúl Zamora-Ros, Maria-José Sánchez, Ana Jimenez-Zabala, Jesús-Humberto Gómez, Marcela Guevara, Elio Riboli, Marc J Gunter, Inge Huybrechts, Paolo Vineis, Oliver J K Robinson","doi":"10.1016/j.eclinm.2025.103662","DOIUrl":"10.1016/j.eclinm.2025.103662","url":null,"abstract":"<p><strong>Background: </strong>Diet may modify colorectal cancer risk. We investigated the associations of three dietary patterns, ultra-processed food (UPF) consumption, healthy plant-based food consumption, and food biodiversity, separately and combined into a \"3V\" score with risk of colorectal cancer.</p><p><strong>Methods: </strong>This study used data from the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which recruited participants between 1992, and 2000, from 23 centres in ten European countries. The 3V score was developed by standardising and summing the healthy plant diet index (hPDI) and dietary species richness per year (DSR) and subtracting UPF (Nova category 4) intake in % g/day. Associations with colorectal cancer risk were assessed among 450,111 middle-aged participants of the EPIC cohort using multivariable-adjusted Cox regression models. Independent associations of each 3V component were assessed using mutually adjusted models. Data-driven thresholds were applied to assess adherence to the 3V components, set at the minimum value of the fourth quintile for hPDI, DSR and low UPF.</p><p><strong>Findings: </strong>During mean (standard deviation (SD)) follow-up of 14.9 (4) years, absolute colorectal cancer rates were 8.59 and 10.37 cases/10,000 person-years for the highest and lowest quintiles of the 3V score, respectively. Inverse associations were found for colorectal (hazard ratio (HR) comparing highest vs lowest quintile: 0.84; 95% confidence interval (CI): 0.76-0.94), colon (HR: 0.82; 95% CI: 0.72-0.93), and distal colon cancer (HR: 0.81; 95% CI: 0.67-0.99), with significant linear trends observed across quintiles. UPF intake was positively associated with colon cancer risk (HR per 1 SD increment: 1.06; 95% CI: 1.02-1.11) when mutually adjusted for the other 3V components. Adherence to low UPF, high hPDI, and high DSR was inversely associated with colorectal (HR: 0.73; 95% CI: 0.61-0.88), colon (HR: 0.72; 95% CI: 0.57-0.91), and rectal cancer (HR: 0.65; 95% CI: 0.46-0.91) compared to adhering to none.</p><p><strong>Interpretation: </strong>Adherence to the 3V diet is associated with lower risk of colorectal cancers.</p><p><strong>Funding: </strong>Cancer Research UK, World Cancer Research Fund.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103662"},"PeriodicalIF":10.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12719066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818612","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}
Pub Date : 2025-11-29eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103639
Siya Zhao, Aili V Langford, Qiuzhe Chen, Meng Lyu, Zhiwei Yang, Simon D French, Christopher M Williams, Chung-Wei Christine Lin
<p><strong>Background: </strong>International low back pain guidelines recommend providing education/advice to patients, discouraging routine imaging use, and encouraging judicious prescribing of analgesics. However, practice variation occurs and the effectiveness of implementation strategies to promote guideline-concordant care is unclear. This review aims to comprehensively evaluate the effectiveness of implementation strategies to promote guideline-concordant care for low back pain.</p><p><strong>Methods: </strong>Five databases (including MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL) and Physiotherapy Evidence Database (PEDro) were searched from inception until 22nd August 2024. Randomised controlled trials (RCTs) that evaluated strategies to promote guideline-concordant care (providing education/advice, discouraging routine imaging use, and/or reducing analgesic use) among healthcare professionals or organisations were included. Two reviewers independently conducted screening, data extraction, and risk of bias assessments. The primary outcome was guideline-concordant care in the medium-term (>3 months but <12 months), measured by the rate of patients receiving such care. The taxonomy recommended by the Cochrane Effective Practice and Organisation of Care (EPOC) group was used to categorise implementation strategies. Meta-analysis with a random effects model was conducted where possible. This systematic review was prospectively registered in PROSPERO (registration number: CRD42023452969).</p><p><strong>Findings: </strong>Twenty-seven RCTs with 32 reports were included. All strategies targeted healthcare professionals (7796 health professionals overseeing 34,890 patients with low back pain), and none targeted organisations. The most commonly used implementation strategies were educational materials (15/27) and educational meetings (14/27), although most studies (24/27) used more than one strategy ('multifaceted strategies'). In the medium-term, compared to no implementation, implementation strategies probably reduced analgesic use (number of studies [N] = 4, odds ratio [OR] = 1.21, 95% confidence interval [CI]: 1.05-1.40, <i>I</i> <sup><i>2</i></sup> = 0%, moderate certainty evidence), but probably made little to no difference in reducing the use of routine imaging (N = 5, OR = 1.16, 95% CI: 0.95-1.41, <i>I</i> <sup>2</sup> = 41%, moderate certainty evidence). Further, implementation strategies may make little to no difference in improving the rate of providing education/advice (N = 3, OR = 2.40, 95% CI: 0.89-6.49, <i>I</i> <sup><i>2</i></sup> = 95%, low certainty evidence). However, this should be interpreted with caution as the sensitivity analysis indicated a positive effect, albeit with low certainty evidence, suggesting that the results are unstable and may change with future research (N = 2, OR = 3.59, 95% CI: 1.68-7.69, <i>I</i> <sup><i>2</i></sup> = 75%). There was insufficient evidence to indicate o
{"title":"Effectiveness of strategies for implementing guideline-concordant care in low back pain: a systematic review and meta-analysis of randomised controlled trials.","authors":"Siya Zhao, Aili V Langford, Qiuzhe Chen, Meng Lyu, Zhiwei Yang, Simon D French, Christopher M Williams, Chung-Wei Christine Lin","doi":"10.1016/j.eclinm.2025.103639","DOIUrl":"10.1016/j.eclinm.2025.103639","url":null,"abstract":"<p><strong>Background: </strong>International low back pain guidelines recommend providing education/advice to patients, discouraging routine imaging use, and encouraging judicious prescribing of analgesics. However, practice variation occurs and the effectiveness of implementation strategies to promote guideline-concordant care is unclear. This review aims to comprehensively evaluate the effectiveness of implementation strategies to promote guideline-concordant care for low back pain.</p><p><strong>Methods: </strong>Five databases (including MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL) and Physiotherapy Evidence Database (PEDro) were searched from inception until 22nd August 2024. Randomised controlled trials (RCTs) that evaluated strategies to promote guideline-concordant care (providing education/advice, discouraging routine imaging use, and/or reducing analgesic use) among healthcare professionals or organisations were included. Two reviewers independently conducted screening, data extraction, and risk of bias assessments. The primary outcome was guideline-concordant care in the medium-term (>3 months but <12 months), measured by the rate of patients receiving such care. The taxonomy recommended by the Cochrane Effective Practice and Organisation of Care (EPOC) group was used to categorise implementation strategies. Meta-analysis with a random effects model was conducted where possible. This systematic review was prospectively registered in PROSPERO (registration number: CRD42023452969).</p><p><strong>Findings: </strong>Twenty-seven RCTs with 32 reports were included. All strategies targeted healthcare professionals (7796 health professionals overseeing 34,890 patients with low back pain), and none targeted organisations. The most commonly used implementation strategies were educational materials (15/27) and educational meetings (14/27), although most studies (24/27) used more than one strategy ('multifaceted strategies'). In the medium-term, compared to no implementation, implementation strategies probably reduced analgesic use (number of studies [N] = 4, odds ratio [OR] = 1.21, 95% confidence interval [CI]: 1.05-1.40, <i>I</i> <sup><i>2</i></sup> = 0%, moderate certainty evidence), but probably made little to no difference in reducing the use of routine imaging (N = 5, OR = 1.16, 95% CI: 0.95-1.41, <i>I</i> <sup>2</sup> = 41%, moderate certainty evidence). Further, implementation strategies may make little to no difference in improving the rate of providing education/advice (N = 3, OR = 2.40, 95% CI: 0.89-6.49, <i>I</i> <sup><i>2</i></sup> = 95%, low certainty evidence). However, this should be interpreted with caution as the sensitivity analysis indicated a positive effect, albeit with low certainty evidence, suggesting that the results are unstable and may change with future research (N = 2, OR = 3.59, 95% CI: 1.68-7.69, <i>I</i> <sup><i>2</i></sup> = 75%). There was insufficient evidence to indicate o","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103639"},"PeriodicalIF":10.0,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12766490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910966","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}
Pub Date : 2025-11-28eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103663
Kerstin Maehder, Luisa Peters, Sina Hübener, Anna Matysiak, Samuel Huber, Anne Toussaint, Antonia Zapf, Eik Vettorazzi, Philipp Weber, Katharina Stahlmann, Viola Andresen, Yvonne Nestoriuc, Ansgar W Lohse, Bernd Löwe
<p><strong>Background: </strong>Irritable Bowel Syndrome (IBS) and Ulcerative Colitis (UC) are chronic gastrointestinal conditions with differing pathologies but overlapping symptoms and shared risk factors contributing to symptom persistence. Illness-related anxiety and dysfunctional symptom expectations constitute two empirically proven mechanisms of symptom persistence. Yet, the efficacy of a targeted psychological intervention focussing on these mechanisms remains untested. The SOMA.GUT trial tested whether such a mechanism-based intervention can reduce gastrointestinal symptom severity in individuals with IBS or UC.</p><p><strong>Methods: </strong>The SOMA.GUT trial was an investigator-initiated, three-arm randomised controlled trial with nationwide recruitment in Germany of adult patients with either IBS or UC and at least moderate gastrointestinal symptom severity (Irritable Bowel Syndrome-Severity Scoring System, IBS-SSS ≥175). Patients were randomly assigned (1:1:1) to one of three groups: to standard care (SC) alone; to a targeted psychological intervention addressing illness-related anxiety and dysfunctional symptom expectations (GUT.EXPECT + SC); or to a supportive intervention designed to give insights into non-specific treatment effects (GUT.SUPPORT + SC). Randomisation was stratified by gender and diagnosis. Both intervention arms comprised four therapist-guided online sessions. The primary outcome was change in IBS-SSS gastrointestinal symptom severity between baseline and three months in the intention-to-treat population. Key secondary outcomes, measured at six weeks, three, six, and 12 months, included the mechanisms targeted by the GUT.EXPECT intervention. This trial was registered (ISRCTN30800023) and has been completed.</p><p><strong>Findings: </strong>Between April 2022, and February 2024, 2099 patients were screened online for eligibility. Of the 240 patients included in the full analysis set (UC: 126, IBS: 114), 176 (73.3%) self-identified as female, 62 (25.8%) as male and two (0.8%) as diverse. Change in IBS-SSS gastrointestinal symptom severity at three months did not differ significantly between groups (global p = 0.83); SC: -50.4 (95% CI -70.7 to -30.1), GUT.SUPPORT + SC: -55.4 (-75.0 to -35.9) and GUT.EXPECT + SC: -59.4 (-79.4 to -39.4). However, in exploratory analyses, the GUT.EXPECT intervention group showed relevant improvements in illness-related anxiety and expectations about symptom coping at three months compared to SC only, as well as in IBS-SSS gastrointestinal symptom severity at 12 months. No differential treatment effects were observed for UC and IBS, and no intervention-related serious adverse events were reported in any group.</p><p><strong>Interpretation: </strong>While gastrointestinal symptom severity remained similar between the groups at three months, the targeted psychological variables improved, and the symptom improvement observed at 12 months might indicate a delayed effect of the mechanism-bas
{"title":"Efficacy of a mechanism-based psychological intervention for persistent gastrointestinal symptoms in ulcerative colitis and irritable bowel syndrome: results of a three-arm randomised controlled trial (SOMA.GUT-RCT).","authors":"Kerstin Maehder, Luisa Peters, Sina Hübener, Anna Matysiak, Samuel Huber, Anne Toussaint, Antonia Zapf, Eik Vettorazzi, Philipp Weber, Katharina Stahlmann, Viola Andresen, Yvonne Nestoriuc, Ansgar W Lohse, Bernd Löwe","doi":"10.1016/j.eclinm.2025.103663","DOIUrl":"10.1016/j.eclinm.2025.103663","url":null,"abstract":"<p><strong>Background: </strong>Irritable Bowel Syndrome (IBS) and Ulcerative Colitis (UC) are chronic gastrointestinal conditions with differing pathologies but overlapping symptoms and shared risk factors contributing to symptom persistence. Illness-related anxiety and dysfunctional symptom expectations constitute two empirically proven mechanisms of symptom persistence. Yet, the efficacy of a targeted psychological intervention focussing on these mechanisms remains untested. The SOMA.GUT trial tested whether such a mechanism-based intervention can reduce gastrointestinal symptom severity in individuals with IBS or UC.</p><p><strong>Methods: </strong>The SOMA.GUT trial was an investigator-initiated, three-arm randomised controlled trial with nationwide recruitment in Germany of adult patients with either IBS or UC and at least moderate gastrointestinal symptom severity (Irritable Bowel Syndrome-Severity Scoring System, IBS-SSS ≥175). Patients were randomly assigned (1:1:1) to one of three groups: to standard care (SC) alone; to a targeted psychological intervention addressing illness-related anxiety and dysfunctional symptom expectations (GUT.EXPECT + SC); or to a supportive intervention designed to give insights into non-specific treatment effects (GUT.SUPPORT + SC). Randomisation was stratified by gender and diagnosis. Both intervention arms comprised four therapist-guided online sessions. The primary outcome was change in IBS-SSS gastrointestinal symptom severity between baseline and three months in the intention-to-treat population. Key secondary outcomes, measured at six weeks, three, six, and 12 months, included the mechanisms targeted by the GUT.EXPECT intervention. This trial was registered (ISRCTN30800023) and has been completed.</p><p><strong>Findings: </strong>Between April 2022, and February 2024, 2099 patients were screened online for eligibility. Of the 240 patients included in the full analysis set (UC: 126, IBS: 114), 176 (73.3%) self-identified as female, 62 (25.8%) as male and two (0.8%) as diverse. Change in IBS-SSS gastrointestinal symptom severity at three months did not differ significantly between groups (global p = 0.83); SC: -50.4 (95% CI -70.7 to -30.1), GUT.SUPPORT + SC: -55.4 (-75.0 to -35.9) and GUT.EXPECT + SC: -59.4 (-79.4 to -39.4). However, in exploratory analyses, the GUT.EXPECT intervention group showed relevant improvements in illness-related anxiety and expectations about symptom coping at three months compared to SC only, as well as in IBS-SSS gastrointestinal symptom severity at 12 months. No differential treatment effects were observed for UC and IBS, and no intervention-related serious adverse events were reported in any group.</p><p><strong>Interpretation: </strong>While gastrointestinal symptom severity remained similar between the groups at three months, the targeted psychological variables improved, and the symptom improvement observed at 12 months might indicate a delayed effect of the mechanism-bas","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103663"},"PeriodicalIF":10.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12704308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767494","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}
Pub Date : 2025-11-28eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103672
Lucinda Grummitt, Siobhan O'Dean, Louise Birrell, Sasha Bailey, Isobel Ivison, Emily Hunter, An Nguyen, Erin Veronica Kelly, Lauren A Gardner, Katrina E Champion, Cath Chapman, Maree Teesson, Nicola C Newton, Emma L Barrett
Background: Adolescence is a critical period for the onset of mental health challenges. We evaluated the efficacy of a school-based intervention (OurFutures Mental Health) in promoting mental health knowledge and preventing symptoms of depression and anxiety.
Methods: A two-arm cluster-randomised controlled trial was conducted from 2023 to 2024 with Year 8/9 students from 10 secondary schools in Australia. Schools were randomised (1:1) to the OurFutures Mental Health intervention or active control (usual health education) using the Blockrand function in R by an external statistician. Eligible participants were Year 8/9 students enrolled at participating schools. OurFutures Mental Health is a six-lesson, trauma-informed and gender- and sexuality-affirming intervention, employing a cognitive-behavioural approach. The three, pre-registered primary outcomes were mental health knowledge and depressive and anxiety symptoms at 3-months post-baseline. Linear mixed-effects regression models were run on the intention to treat sample, with random intercepts for participants and schools, tested whether receiving the intervention improved knowledge and reduced depression and anxiety symptoms relative to active control. The trial was registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12622001582741.
Findings: Between Dec 6, 2022 and April 12, 2024, we recruited 17 schools (1785 students), of which 10 schools (784 students) participated in the baseline assessment (mean age = 13.8 years; 467 [59.6%] male; intervention: 6 schools, 497 students; control: 4 schools, 287 students). Seven schools withdrew prior to baseline (6 control; 1 intervention). Knowledge scores were significantly higher in the intervention group post-intervention, but not at 3 months (β = 0.30, 95% CI: -0.32-0.91, p = 0.34). No significant intervention effects were observed for depressive symptoms at 3-months (β = -0.94, 95% CI: -1.88 to 0.04, p = 0.055). However, the intervention group showed a greater reduction in anxiety symptoms at 3-month follow-up compared to active control (β = -1.05, 95% CI: -1.93 to -0.12, p = 0.024). No adverse events were reported.
Interpretation: OurFutures Mental Health may be an efficacious intervention to improve mental health knowledge and prevent anxiety symptoms among adolescents in the short-term. Limitations of this trial include high participant attrition and withdrawal of several schools post-randomisation, limiting generalisability. The trial was also underpowered, limiting detection of smaller intervention effects. Further research is needed to improve efficacy for prevention of depression.
{"title":"Efficacy of a school-based, universal prevention programme for depression and anxiety in adolescents (OurFutures Mental Health): a two-arm cluster-randomised controlled trial.","authors":"Lucinda Grummitt, Siobhan O'Dean, Louise Birrell, Sasha Bailey, Isobel Ivison, Emily Hunter, An Nguyen, Erin Veronica Kelly, Lauren A Gardner, Katrina E Champion, Cath Chapman, Maree Teesson, Nicola C Newton, Emma L Barrett","doi":"10.1016/j.eclinm.2025.103672","DOIUrl":"10.1016/j.eclinm.2025.103672","url":null,"abstract":"<p><strong>Background: </strong>Adolescence is a critical period for the onset of mental health challenges. We evaluated the efficacy of a school-based intervention (<i>OurFutures Mental Health)</i> in promoting mental health knowledge and preventing symptoms of depression and anxiety.</p><p><strong>Methods: </strong>A two-arm cluster-randomised controlled trial was conducted from 2023 to 2024 with Year 8/9 students from 10 secondary schools in Australia. Schools were randomised (1:1) to the <i>OurFutures Mental Health</i> intervention or active control (usual health education) using the <i>Blockrand</i> function in R by an external statistician. Eligible participants were Year 8/9 students enrolled at participating schools. <i>OurFutures Mental Health</i> is a six-lesson, trauma-informed and gender- and sexuality-affirming intervention, employing a cognitive-behavioural approach. The three, pre-registered primary outcomes were mental health knowledge and depressive and anxiety symptoms at 3-months post-baseline. Linear mixed-effects regression models were run on the intention to treat sample, with random intercepts for participants and schools, tested whether receiving the intervention improved knowledge and reduced depression and anxiety symptoms relative to active control. The trial was registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12622001582741.</p><p><strong>Findings: </strong>Between Dec 6, 2022 and April 12, 2024, we recruited 17 schools (1785 students), of which 10 schools (784 students) participated in the baseline assessment (mean age = 13.8 years; 467 [59.6%] male; intervention: 6 schools, 497 students; control: 4 schools, 287 students). Seven schools withdrew prior to baseline (6 control; 1 intervention). Knowledge scores were significantly higher in the intervention group post-intervention, but not at 3 months (β = 0.30, 95% CI: -0.32-0.91, p = 0.34). No significant intervention effects were observed for depressive symptoms at 3-months (β = -0.94, 95% CI: -1.88 to 0.04, p = 0.055). However, the intervention group showed a greater reduction in anxiety symptoms at 3-month follow-up compared to active control (β = -1.05, 95% CI: -1.93 to -0.12, p = 0.024). No adverse events were reported.</p><p><strong>Interpretation: </strong><i>OurFutures Mental Health</i> may be an efficacious intervention to improve mental health knowledge and prevent anxiety symptoms among adolescents in the short-term. Limitations of this trial include high participant attrition and withdrawal of several schools post-randomisation, limiting generalisability. The trial was also underpowered, limiting detection of smaller intervention effects. Further research is needed to improve efficacy for prevention of depression.</p><p><strong>Funding: </strong>Paul Ramsay Foundation.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103672"},"PeriodicalIF":10.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12702296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762497","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}
Background: To quantify the extent of metabolic and cardiovascular rebound following the discontinuation of GLP-1 receptor agonist (GLP-1RA) therapy in adults with obesity, type 2 diabetes, or type 1 diabetes, and identify potential modifiers of these outcomes.
Methods: We conducted a systematic review and meta-analysis of randomized controlled trials including adults and adolescents treated with GLP-1RAs, followed by a post-discontinuation follow-up of at least 12 weeks. Databases searched included MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov, with no language restrictions, and published up to October 17, 2025. We assessed changes in anthropometric, glycemic, cardiovascular, and lipid parameters between the end of treatment and the post-cessation period. Random-effects models were used to calculate pooled mean differences. The risk of bias and certainty of evidence were evaluated using the Cochrane ROB 2.0 and GRADE frameworks. The study was registered with PROSPERO under CRD42025646185.
Findings: Eighteen RCTs (3771 participants) were included. Among individuals with obesity, discontinuation of GLP-1RA resulted in significant metabolic rebound, characterized by a body weight gain of 5.63 kg (95% CI: 3.52-7.73, I2 = 99.57%, moderate) and an increase in HbA1c of 0.25% (95% CI: 0.18-0.32, I2 = 98.45%, moderate). Waist circumference, BMI (Body Mass Index), SBP (Systolic Blood Pressure), and FPG (fasting plasma glucose) also showed significant deterioration. In the type 2 diabetes setting, weight gain was 2.03 kg (95% CI: 1.63-2.42, I2 = 42.28%, moderate), and HbA1c rose by 0.65% (95% CI: 0.22-1.08, I2 = 96.83%, moderate), while FPG remained stable (0.90 mmol/L; 95% CI: -0.36 to 2.17, I2 = 98.81%, moderate). Subgroup analyses revealed greater weight regain with longer follow-up (>26 weeks: 7.31 kg vs. 2.51 kg) and with semaglutide compared to liraglutide (8.21 kg vs. 4.29 kg). Semaglutide also led to greater increases in waist circumference (3.80 cm vs. 2.69 cm) and SBP (7.09 mmHg vs. 1.56 mmHg). Most outcomes showed no evidence of significant publication bias, with minor asymmetry detected for VLDL (very-low-density lipoprotein) levels in individuals with obesity and for weight change (kg) in patients with type 2 diabetes. The risk of bias assessment using the ROB 2.0 tool rated all included studies as having a low risk.
Interpretation: The magnitude and consistency of these effects underscore the physiological consequences of GLP-1RA discontinuation. As the clinical use of GLP-1RAs continues to grow in the management of obesity and diabetes, it is imperative that treatment guidelines address not only initiation and titration but also discontinuation and long-term maintenance strategies to sustain therapeutic gains.
{"title":"Metabolic rebound after GLP-1 receptor agonist discontinuation: a systematic review and meta-analysis.","authors":"Chih-Chen Tzang, Pei-Hsun Wu, Chiao-An Luo, Zi-Ting Chen, Yi-Ting Lee, Ewen Shengyao Huang, Yuan-Fu Kang, Wei-Chen Lin, Bor-Show Tzang, Tsai-Ching Hsu","doi":"10.1016/j.eclinm.2025.103680","DOIUrl":"10.1016/j.eclinm.2025.103680","url":null,"abstract":"<p><strong>Background: </strong>To quantify the extent of metabolic and cardiovascular rebound following the discontinuation of GLP-1 receptor agonist (GLP-1RA) therapy in adults with obesity, type 2 diabetes, or type 1 diabetes, and identify potential modifiers of these outcomes.</p><p><strong>Methods: </strong>We conducted a systematic review and meta-analysis of randomized controlled trials including adults and adolescents treated with GLP-1RAs, followed by a post-discontinuation follow-up of at least 12 weeks. Databases searched included MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov, with no language restrictions, and published up to October 17, 2025. We assessed changes in anthropometric, glycemic, cardiovascular, and lipid parameters between the end of treatment and the post-cessation period. Random-effects models were used to calculate pooled mean differences. The risk of bias and certainty of evidence were evaluated using the Cochrane ROB 2.0 and GRADE frameworks. The study was registered with PROSPERO under CRD42025646185.</p><p><strong>Findings: </strong>Eighteen RCTs (3771 participants) were included. Among individuals with obesity, discontinuation of GLP-1RA resulted in significant metabolic rebound, characterized by a body weight gain of 5.63 kg (95% CI: 3.52-7.73, I2 = 99.57%, moderate) and an increase in HbA1c of 0.25% (95% CI: 0.18-0.32, I<sup>2</sup> = 98.45%, moderate). Waist circumference, BMI (Body Mass Index), SBP (Systolic Blood Pressure), and FPG (fasting plasma glucose) also showed significant deterioration. In the type 2 diabetes setting, weight gain was 2.03 kg (95% CI: 1.63-2.42, I<sup>2</sup> = 42.28%, moderate), and HbA1c rose by 0.65% (95% CI: 0.22-1.08, I<sup>2</sup> = 96.83%, moderate), while FPG remained stable (0.90 mmol/L; 95% CI: -0.36 to 2.17, I<sup>2</sup> = 98.81%, moderate). Subgroup analyses revealed greater weight regain with longer follow-up (>26 weeks: 7.31 kg vs. 2.51 kg) and with semaglutide compared to liraglutide (8.21 kg vs. 4.29 kg). Semaglutide also led to greater increases in waist circumference (3.80 cm vs. 2.69 cm) and SBP (7.09 mmHg vs. 1.56 mmHg). Most outcomes showed no evidence of significant publication bias, with minor asymmetry detected for VLDL (very-low-density lipoprotein) levels in individuals with obesity and for weight change (kg) in patients with type 2 diabetes. The risk of bias assessment using the ROB 2.0 tool rated all included studies as having a low risk.</p><p><strong>Interpretation: </strong>The magnitude and consistency of these effects underscore the physiological consequences of GLP-1RA discontinuation. As the clinical use of GLP-1RAs continues to grow in the management of obesity and diabetes, it is imperative that treatment guidelines address not only initiation and titration but also discontinuation and long-term maintenance strategies to sustain therapeutic gains.</p><p><strong>Funding: </strong>This study received no funding.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103680"},"PeriodicalIF":10.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12702299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762454","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}
Pub Date : 2025-11-28eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103665
Martin Meuli, Clemens Schiestl, Fabienne Hartmann-Fritsch, Esther Middelkoop, Bong-Sung Kim, Kathrin Neuhaus, Jan A Plock, Daniel Rittirsch, Cornelis H van der Vlies, Bruno Azzena, Daniela Marino, Kathi Mujynya, Melinda Farkas, Jenny Bressan, Ernst Reichmann, Sophie Böttcher-Haberzeth
Background: For burn surgery, major therapeutic challenges are shortage of autologous donor sites for split-thickness skin, and massive devastating scarring. We investigated the therapeutic role of denovoSkin™, a bio-engineered autologous skin, in a prospective, randomized, controlled phase IIb clinical trial compared to the gold standard the split thickness skin graft (STSG).
Methods: Patients, ≥12 years, with deep partial and/or full-thickness burns requiring surgical wound coverage were enrolled at four sites in Switzerland, the Netherlands, and Italy. Two comparable skin defects (max. 98 cm2 each) per patient were intra-patient randomized to denovoSkin™ (experimental) or autologous STSG (control) treatment. Safety assessments were performed in all patients. Primary efficacy endpoint was the ratio of biopsy size to grafted area with take 4 weeks post-grafting. The analyses of the primary efficacy variable were performed on the modified Full Analysis Set (mFAS) and the per protocol set (PPS) with the analysis on the mFAS as the primary analysis. Other efficacy endpoints included wound closure and scar quality. Efficacy and safety follow-ups were conducted up to 12 months post-grafting. The trial started in March 2018 and completed recruitment in July 2022 and is registered at clinicaltrials.gov (NCT03227146).
Findings: 21 patients were enrolled between March 26, 2018, and July 26 2022. 13 patients were included in the PPS. There were no significant safety differences between denovoSkin™ and STSG. 164 serious adverse events were observed (81%). Only two (hematoma and partial skin necrosis) could be related to denovoSkin™. They rapidly healed spontaneously. The expansion ratio for denovoSkin™ versus STSG was 7·0 times larger for denovoSkin™ (p < 0·001). In the mFAS the mean expansion ratio for denovoSkin™ was 10·76 (SD 6·03), and for STSG it was 1·70 (SD 0·68). The mean ratio of the two expansion ratios (denovoSkin™/STSG) was 7·41 (SD 4·87). By month 3, experimental and control areas were fully epithelialized. Scar evaluation up to 12 months post-grafting revealed no clinically relevant scarring for denovoSkin™, but mostly hypertrophic scarring for STSG.
Interpretation: DenovoSkin™ is a novel and safe treatment option for deep burns. It lessens the need for conventional grafting and so spares donor sites. In sharp contrast to STSG, denovoSkin™ grafting showed minimal scarring, a finding never evidenced before in a randomized trial.
Funding: This study was financed by Wyss Zurich Translational Center (project "denovoSkin") and CUTISS AG.
{"title":"Safety and efficacy of bio-engineered, autologous dermo-epidermal skin grafts in adolescent and adult burn patients: 1-year results of a prospective, randomized, controlled, multicenter phase IIB clinical trial.","authors":"Martin Meuli, Clemens Schiestl, Fabienne Hartmann-Fritsch, Esther Middelkoop, Bong-Sung Kim, Kathrin Neuhaus, Jan A Plock, Daniel Rittirsch, Cornelis H van der Vlies, Bruno Azzena, Daniela Marino, Kathi Mujynya, Melinda Farkas, Jenny Bressan, Ernst Reichmann, Sophie Böttcher-Haberzeth","doi":"10.1016/j.eclinm.2025.103665","DOIUrl":"10.1016/j.eclinm.2025.103665","url":null,"abstract":"<p><strong>Background: </strong>For burn surgery, major therapeutic challenges are shortage of autologous donor sites for split-thickness skin, and massive devastating scarring. We investigated the therapeutic role of denovoSkin™, a bio-engineered autologous skin, in a prospective, randomized, controlled phase IIb clinical trial compared to the gold standard the split thickness skin graft (STSG).</p><p><strong>Methods: </strong>Patients, ≥12 years, with deep partial and/or full-thickness burns requiring surgical wound coverage were enrolled at four sites in Switzerland, the Netherlands, and Italy. Two comparable skin defects (max. 98 cm<sup>2</sup> each) per patient were intra-patient randomized to denovoSkin™ (experimental) or autologous STSG (control) treatment. Safety assessments were performed in all patients. Primary efficacy endpoint was the ratio of biopsy size to grafted area with take 4 weeks post-grafting. The analyses of the primary efficacy variable were performed on the modified Full Analysis Set (mFAS) and the per protocol set (PPS) with the analysis on the mFAS as the primary analysis. Other efficacy endpoints included wound closure and scar quality. Efficacy and safety follow-ups were conducted up to 12 months post-grafting. The trial started in March 2018 and completed recruitment in July 2022 and is registered at clinicaltrials.gov (NCT03227146).</p><p><strong>Findings: </strong>21 patients were enrolled between March 26, 2018, and July 26 2022. 13 patients were included in the PPS. There were no significant safety differences between denovoSkin™ and STSG. 164 serious adverse events were observed (81%). Only two (hematoma and partial skin necrosis) could be related to denovoSkin™. They rapidly healed spontaneously. The expansion ratio for denovoSkin™ versus STSG was 7·0 times larger for denovoSkin™ (p < 0·001). In the mFAS the mean expansion ratio for denovoSkin™ was 10·76 (SD 6·03), and for STSG it was 1·70 (SD 0·68). The mean ratio of the two expansion ratios (denovoSkin™/STSG) was 7·41 (SD 4·87). By month 3, experimental and control areas were fully epithelialized. Scar evaluation up to 12 months post-grafting revealed no clinically relevant scarring for denovoSkin™, but mostly hypertrophic scarring for STSG.</p><p><strong>Interpretation: </strong>DenovoSkin™ is a novel and safe treatment option for deep burns. It lessens the need for conventional grafting and so spares donor sites. In sharp contrast to STSG, denovoSkin™ grafting showed minimal scarring, a finding never evidenced before in a randomized trial.</p><p><strong>Funding: </strong>This study was financed by Wyss Zurich Translational Center (project \"denovoSkin\") and CUTISS AG.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103665"},"PeriodicalIF":10.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12702297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762429","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}
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