EClinicalMedicine最新文献

Background: Scoring systems have demonstrated their usefulness in predicting short-term mortality when applied by emergency medical services (EMS). However, their implementation should be supported by validation studies using real-world data. This work aims to validate a previously developed modified Sequential Organ Failure Assessment (mSOFA) score and conduct external revalidation for its use in prehospital critical care to predict short-term mortality.

Methods: This prospective, observational, multicentre, EMS-based validation and external validation study, was conducted across three EMS systems in Spain (one for validation and two for revalidation). Adults with undifferentiated acute conditions who were transported with high priority to the emergency department (ED), excluding pregnancy, cardiac arrest, and palliative patients. The primary outcome was 2-day all-cause in-hospital mortality. Prehospital and in-hospital demographic data, vital signs, and point-of-care testing variables were collected to calculate mSOFA and SOFA scores. Score performance was evaluated through validation/revalidation and a random quasi-stratified K-fold cross-validation scheme.

Findings: Between January 1, 2021, and March 30, 2025, a total of 12,212 patients were enrolled (validation cohort#1 (n = 9063), revalidation cohort#2 (n = 1816), and revalidation cohort#3 (n = 1333)). The median age was 67 years (IQR: 51-80), and 41.1% (5040 patients) were female. The overall 2-day mortality rate was 5% (609 cases). The mSOFA score showed an AUC of 0.949 (95% CI: 0.939-0.958) in the validation cohort, and 0.939 (95% CI: 0.925-0.954) and 0.944 (95% CI: 0.921-0.967) in the two revalidation cohorts. Comparison between mSOFA and SOFA scores for 2-day mortality revealed statistically significant differences (p < 0.0001), with AUCs of 0.947 (95% CI: 0.939-0.954) for mSOFA and 0.927 (95% CI: 0.917-0.937) for SOFA.

Interpretation: Our findings suggest that the mSOFA score shows good discriminatory power for predicting short-term mortality, consistent across different cohorts. Study limitations included not blinded extractors, time limit of primary outcome, and patients' heterogeneity. This validates score performance in other health systems and demonstrates a better mSOFA performance over the SOFA score. Future work will pursue clinical validation of the score via a randomized clinical trial.

Funding: This work was supported by the Institute of Health Carlos III, co-financed by the European Union, by the Basque Government, and by the University of the Basque Country.

Background: Adverse life events and other stressors were central to historical 'Freudian' models of functional neurological disorder (FND), which have been increasingly replaced by more nuanced biopsychosocial models. Studies of the aetiological relevance of stressors have been limited by small sample sizes.

Methods: Retrospective cohort analyses using a large international electronic health records network (TriNetX), including ICD-10 codes, were performed. Between 2015 and 2025, 147,595 individuals were diagnosed with FND. The rates of adverse life events and psychosocial stressors were compared to matched cohorts with migraine and generalised anxiety disorder (GAD) diagnoses. We also investigated associations between FND and the presence of stressors, including the stressor type and whether it occurred in childhood or adulthood.

Findings: Rates of abuse or neglect (1·33%), assault (2·42%), and psychosocial and socioeconomic difficulties (10·63%) were significantly higher in FND compared to migraine (0·42%/0·93%/3·43%, respectively) and GAD (0·75%/1·29%/7·69%, respectively) (p < ·0001 for all comparisons). A history of physical and sexual abuse was more prevalent in FND than in comparison groups. Psychological abuse was more common in FND than in migraine, but not when compared to GAD. FND cases with recorded stressors were younger, more often female, and more frequently diagnosed with functional/dissociative seizures than those without stressors. Further, these stressors were associated with an increased prevalence of psychiatric comorbidities, pain, and fatigue. Different stressor types had distinct influences on clinical presentations. Adult-onset adversity was associated with higher rates of psychiatric comorbidities, pain and fatigue.

Interpretation: A record of adversities was at least 2·5 times more common in FND than in migraine, and about 1·5 times more common than in GAD, varying by stressor type. Psychosocial stressors were particularly common. The presence of stressors, as well as their type, shapes the presentation of FND. Life history should therefore be considered when assessing individuals with FND.

Funding: None.

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.

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.

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.

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.