EClinicalMedicine最新文献

Background: Infections and sepsis are leading causes of morbidity and mortality in women during pregnancy and the post-pregnancy period. Using data from the 2017 WHO Global Maternal Sepsis Study, we explored the use of early warning systems (EWS) in women at risk of sepsis-related severe maternal outcomes.

Methods: On April 27, 2023, we searched the literature for EWS in clinical use or research in obstetric populations. We calculated the proportion of women for whom each existing EWS identified them as at risk for developing severe maternal outcomes by infection severity (complications and severe maternal outcomes). Sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratios, and J statistics were calculated to assess EWS performance. Machine learning was used to test the diagnostic potential of routine maternal sepsis markers.

Findings: 21 EWS were assessed in 2560 women from 46 countries with suspected or confirmed infections. The NICE Risk Stratification tool, Modified Shock Index, maternity Systemic Inflammatory Response Syndrome, and Early Maternal Infection Prompts scores had high sensitivity (88.1-97.5%) for identifying sepsis-related severe maternal outcomes. The quick Sequential Organ Failure Assessment (SOFA) in Pregnancy score and Obstetrically modified SOFA had high specificity (90.4-100%) for identifying women with sepsis-related severe maternal outcomes. Furthermore, combinations of sepsis markers had very low sensitivity and high specificity using machine learning.

Interpretation: No score demonstrated enough diagnostic accuracy to be used alone to identify sepsis. However, obstetric-and sepsis-specific EWS performed better for early identification of maternal sepsis than non-obstetric and non-sepsis-specific scoring systems. There are limitations to applying EWS to real-world data, mainly due to the incompleteness of medical data that hinders EWS effectiveness. There is a need to continue developing and testing criteria for early identification of maternal sepsis.

Funding: UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), WHO, Merck for Mothers, U.S. Agency for International Development, Wellcome Trust, and National Institute for Health and Care Research.

Background: Neuroblastoma is the most prevalent extracranial solid tumor in pediatric populations worldwide, representing 8-10% of childhood malignancies and contributing to approximately 15% of pediatric cancer-related fatalities. This study aims to report global trends in the incidence, mortality, and disability-adjusted life years (DALYs) of childhood neuroblastoma from 1990 to 2021.

Methods: The study utilized data from the Global Burden of Disease (GBD) database to analyze neuroblastoma incidence, mortality, and DALYs in children aged 0-14 years. Rates for incidence, mortality, and DALYs were calculated per 100,000 population, with 95% uncertainty intervals (UIs). Data from 204 countries and territories were stratified by age, sex, and location. Trends were assessed using Joinpoint regression models to compute the annual percent change (APC) and log-transformed linear regression models to calculate the estimated average annual percentage change (EAPC).

Findings: Globally, the incidence of neuroblastoma in children in 2021 was 5560 cases (95% UI, 3734.21-7560.03), with 1977 deaths (95% UI, 1445.04-2528.54), and 174,186.30 DALYs (95% UI, 127,104.64-223,265.92). From 1990 to 2021, the incidence increased by 30.26% (95% UI, -1.24% to 72.51%), mortality by 20.35% (95% UI, -12.44% to 63.30%), and DALYs by 20.08% (95% UI, -12.89% to 63.27%). The incidence rate rose from 0.25 (95% UI, 0.18-0.33) per 100,000 individuals in 1990 to 0.28 (95% UI, 0.19-0.38) per 100,000 individuals in 2021, an overall increase of 12.60% (95% UI, -14.62% to 49.12%). Among the five Sociodemographic Index (SDI) regions, the highest EAPCs were observed in the low-to-mid SDI regions for incidence (1.87%; 95% CI, 1.64%-2.10%), mortality (1.22%; 95% CI, 1.09%-1.34%), and DALYs (1.36%; 95% CI, 1.15%-1.57%). Regionally, Central Asia exhibited the fastest annual increase in incidence (EAPC = 2.76%; 95% CI, 2.18%-3.34%). At the national level, India had the highest number of neuroblastoma cases globally in 2021, with 685 cases (95% UI, 404.16-1007.67).

Interpretation: The global trends for incidence, mortality, and DALYs related to pediatric neuroblastoma initially increased and then decreased, although an overall increasing trend was observed. However, the burden of disease remains significant in low-, low-middle-, and middle-SDI regions. A comprehensive understanding of the epidemiology of neuroblastoma in children is crucial for enhancing disease prevention and control efforts.

Funding: This research was funded by the Guangxi Natural Science Foundation (Grant No. 2024GXNSFAA010420) and the Youth Science Foundation of Guangxi Medical University (Grant No. GXMUYSF202404).

Background: Due to limited data on managing immunotherapy-induced secondary adrenal insufficiency (SAI) in melanoma survivors, this study investigated its management strategies and outcomes.

Methods: This retrospective cohort study analyzed melanoma patients treated with immune checkpoint inhibitors (ICIs) with SAI (Mel_SAI, n = 161), without SAI (Mel_CON, n = 168), and patients with pituitary adenoma-related SAI (Pit_SAI, n = 106) at our institution from January 2013 to November 2023. We compared glucocorticoid management patterns, quality of life using distress scores, and the impact of different glucocorticoid types on survival outcomes using Kaplan-Meier analysis.

Findings: Mel_SAI received significantly higher initial (median: 30 mg; IQR: 20-30 mg) and maintenance (median: 25 mg; IQR: 20-30 mg) hydrocortisone doses than Pit_SAI (initial: 20 mg; IQR: 15-30 mg; maintenance: 15 mg; IQR: 15-23 mg). Over half of Mel_SAI received prednisone as initial glucocorticoid replacement (n = 89, 55%), compared to 27% (n = 29) of Pit_SAI. Distress scores were significantly higher in Mel_SAI (median: 3; IQR: 2-5) than in Pit_SAI (median: 2; IQR: 1-3), but similar between Mel_CON. Prednisone use was associated with decreased survival in Mel_SAI (hazard ratio: 2.31; 95% CI: 1.14-4.46).

Interpretation: Higher glucocorticoid doses and prednisone use in melanoma patients with SAI may be due to higher distress scores rather than SAI itself. Given the negative impact on survival and potential side effects, we recommend hydrocortisone at standard doses as the preferred glucocorticoid replacement in melanoma patients with SAI.

Funding: None.

Background: Digital interventions are important treatment solutions for suicidal ideation, but premature disengagement is a significant threat to their effectiveness. We tested the adherence to, and efficacy of, two versions of an app-based intervention (app only, app + engagement strategy) for suicidal ideation, compared to a sham app.

Methods: This was an online double-blind, three-arm parallel randomised controlled trial in Australia. Recruitment occurred between May 30 and August 8, 2023 and eligible participants were aged 17-24 years and had suicidal ideation in the prior 30 days. They were randomly assigned 1:1:1 to receive (i) LifeBuoy-an app which delivered third wave cognitive behavioural therapy (CBT) skills, (ii) the LifeBuoy app plus a digital engagement strategy, or (iii) a sham app to minimise expectancy bias. The primary efficacy outcome was change in suicidal ideation scores, measured by the Suicidal Ideation Attributes Scale (SIDAS), at 30-, 60- and 120- days post-baseline. The primary engagement outcome was the number of app modules completed at 60-days post-baseline. The final assessment occurred on December 6, 2023. All data was analysed using intention-to-treat. This trial was registered at anzctr.org.au, trial number: ACTRN12621001247864.

Findings: 692 participants were assigned (mean age: 19.9 [SD 2.5]; 70% female; intervention (combined): n-459, control: n-233). Significant reductions in ideation scores were observed in the combined intervention condition at 60- (d 0.48) and 120- (d 0.29) days after random assignment compared to the control condition. There were no differences in the number of modules completed between the intervention conditions (OR 1.10, 1.03, respectively) and no significant differences in their ideation scores at any time (ds -0.15 to 0.08). Serious adverse events (hospital presenting non-suicidal self-harm and/or suicide attempts) were reported by 6% of participants during the trial (control condition: 9%; combined intervention condition: 4%). No deaths were reported.

Interpretation: A third wave CBT app helped to reduce ideation severity, however providing additional online resources to promote therapeutic engagement did not enhance these effects.

Funding: This trial and MT was funded by the National Health & Medical Research Council, Matana Foundation for Young People, Alex Roth Foundation.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, deadly lung disease with several factors, including respiratory tract infections (RTI), for disease worsening. There's no comprehensive data on RTI incidence in IPF patients across different therapies, including antifibrotic (nintedanib or pirfenidone), investigative or placebo treatments.

Methods: A systematic search of databases Medline, EMBASE, Cochrane Central, Web of Science and Scopus was conducted on September 30th 2024 (PROSPERO registration number: CRD42023484213). Only randomized controlled trials of drugs intended for IPF treatment in adults and reporting RTI incidence were included. Pooled risk ratio with 95% confidence interval (CI), risk of bias, GRADE and CINEMA assessments were conducted along with subgroup analyses for upper and lower RTI and for different antifibrotic doses.

Findings: A total of 27 trials of different drugs aimed for IPF therapy were pooled in a pairwise meta-analysis, 11,542 patients were analyzed with an overall number of 4156 RTI events, representing an average incidence of 38.4 ± 23.5%. Most therapies did not affect RTI risk in IPF, although single trials with everolimus and trimethoprim/sulfamethoxazole showed a significant decrease compared to placebo. For antifibrotics, RTI incidence was similar with pirfenidone treatment compared to nintedanib (RR: 0.98 CI: [0.71; 1.36]) and compared to placebo (RR: 0.88 CI: [0.69; 1.10]) and nintedanib compared to placebo (RR: 0.89 CI: [0.71; 1.12]).

Interpretation: RTIs are frequently reported adverse events in IPF patients over a one-year period, with different investigated treatments showing no profound impact compared to placebo. Future clinical trials should focus on targeting treatable traits like RTIs.

Funding: None.

Background: Post-traumatic stress disorder (PTSD) and depression are common after mild traumatic brain injury (mTBI), but their biological drivers are uncertain. We therefore explored whether polygenic risk scores (PRS) derived for PTSD and major depressive disorder (MDD) are associated with the development of cognate TBI-related phenotypes.

Methods: Meta-analyses were conducted using data from two multicenter, prospective observational cohort studies of patients with mTBI: the CENTER-TBI study (ClinicalTrials.gov ID NCT02210221) in Europe (December 2014-December 2017) and the TRACK-TBI study in the US (March 2014-July 2018). In both cohorts, the most common causes of injury were road traffic accidents and falls. Primary outcomes, specifically probable PTSD and depression, were defined at 6 months post-injury using scores ≥33 on the PTSD Checklist-5 and ≥15 on the Patient Health Questionnaire-9, respectively. We calculated PTSD-PRS and MDD-PRS for patients aged ≥17 years who had a Glasgow Coma Scale score of 13-15 upon hospital arrival and assessed their association with PTSD and depression following TBI. We also evaluated the transferability of the findings in a cohort of African Americans.

Findings: Overall, 11.8% (219/1869) and 6.7% (124/1869) patients were classified as having probable PTSD and depression, respectively. The PTSD-PRS was significantly associated with higher adjusted odds of PTSD in both cohorts, with a pooled odds ratio (OR) of 1.55 [95% confidence interval (CI) 1.30-1.84, p < 0.001, I ²  = 20.8%]. Although the MDD-PRS increased the risk of depression after TBI, it did not reach significance in the individual cohorts. However, in a combined analysis, the risk was significantly elevated with a pooled OR of 1.26 [95% CI 1.03-1.53, p = 0.02, I ²  = 0%]. The addition of PRSs improved the proportion of outcome variance explained in the two study cohorts from 19.5% and 30.3% to 21.6% and 34.0% for PTSD; and from 11.0% and 22.5% to 12.8% and 22.6% for depression. Patients in the highest cognate PRS quintile had increased odds of 3.16 [95% CI 1.80-5.55] and 2.03 [95% CI 1.04-3.94] of developing PTSD or depression compared to the lowest quintile, respectively.

Interpretation: Associations of PRSs with PTSD and depression following TBI are not disorder-specific. However, the overlap between MDD-PRS and depression following TBI is less robust compared to PTSD-PRS and PTSD. PRSs could improve risk prediction, and permit enrichment for interventional trials.

Funding: This study was supported by funding by an FP7 grant from the European Union, Hannelore Kohl Stiftung, Integra LifeSciences Corporation, NeuroTrauma Sciences, US National Institutes of Health, US Department of Defense, National Football League Advisory Board, US Department of Energy, and One Mind.

Variation in outcomes definitions and reporting limit the utility of clinical trial results. The Core Outcome Research Measures in Anal Cancer (CORMAC) project developed a core outcome set (COS) for chemoradiotherapy trials for anal squamous cell carcinoma (ASCC) through an international healthcare professional and patient consensus process. The CORMAC-COS comprises 19 outcomes across 4 domains (disease activity, survival, toxicity, life impact). In CORMAC-2 we have established standardised definitions for the 11 disease activity and survival outcomes in the CORMAC COS. Definitions were agreed through a 3 step process, initially identifying existing definitions through systematic review (registered with PROSPERO, CRD42016036540), using these to populate a two-round Delphi questionnaire completed by 51 experts from 13 countries, and finally ratification through an online consensus meeting. Standardising the definitions for these core outcomes facilitates real world utilisation of the CORMAC-COS, thereby increasing the quality of data available for clinical decision-making and ultimately enhancing patient care.

Background: Immune checkpoint inhibitors (ICIs) have demonstrated their efficacy with a 7.5-year overall survival (OS) close to 50% for advanced stages. The design of clinical trials provides for treatment until progression or toxicity, or for a maximum duration of two years. Prolonged follow-up of responders after treatment cessation shows sustained response and a low risk of relapse in the months following cessation. To date, the optimal duration of anti-PD-1 therapy for metastatic melanoma remains unestablished. The objective of this work was to evaluate the optimal duration of ICI administration.

Methods: We emulated target trials using the cloning, weighting and censoring approach. Each emulation trial aimed to compare the effect of discontinuing versus continuing ICIs at a specific timepoint, among patients still under treatment and with disease control at that time. Patients were from MelBase between 2015 and 2021.

Findings: 435 participants in the MelBase cohort were eligible and were included in the 6-month discontinuation emulated trial. The results showed significantly lower OS when treatment was discontinued, than when treatment was prolonged for at least three months. The 48-month survival difference was 37.8% (95% confidence interval [CI] 19.8-60.5), and the corresponding restricted mean survival time difference was 8.3 months (95% CI: 4.1-12.7). Neither the 12-month nor the 18-month discontinuation emulated trials showed evidence of benefit of either discontinuing or continuing ICIs at either of these timepoints. The 24-month discontinuation emulated trial results were more in favor of discontinuing than continuing treatment at that time point, with an absolute 48-month survival rate that was 10.5% higher (95% CI 4.4-18.1).

Interpretation: These results suggest that a one-year course of immunotherapy is both necessary and sufficient for patients with advanced melanoma. Prolonged treatment beyond 2 years does not appear to be beneficial in terms of survival and could even be detrimental.

Funding: This work was supported by a grant from Bristol Myers Squibb, Merck Sharp Dhome, Pierre Fabre, Novartis, Sun Pharm, Regeneron, Sanofi, Nektar, Therapeutics and Oncyte.

Background: Few data are available about the impact of oral anticoagulants (OAC) in patients with Atrial Fibrillation (AF) and clinical complexity (CC).

Methods: We conducted a retrospective study utilising data from the TriNetX network. Based on ICD-10-CM codes entered between 2020 and 2022, AF patients aged ≥75 years on long-term OAC with CC were categorised into two groups based on OAC use in the year before entering the study (maintained vs discontinued). CC was defined as BMI ≤23 kg/m², and/or history of bleeding, and/or chronic kidney disease. The primary outcomes were the one-year risk of all-cause death, major cardiovascular events (MACE), and major bleeding. Cox regression analyses were used to calculate hazard ratios (HRs) and 95% CIs before and after 1:1 propensity score matching (PSM).

Findings: We identified 6554 AF CC patients who discontinued OAC (mean age 81.5 ± 6.0 years, 46.7% females) and 23,212 AF patients with CC who maintained OAC (81.3 ± 6.0 years, 49.4% females). Before PSM, AF CC patients who discontinued OAC had a higher prevalence of intracranial, gastrointestinal haemorrhages, and antiplatelet use, with no significant differences after PSM. OAC discontinuation was associated with a higher risk of all-cause death (HR 1.22, 95% CI 1.11-1.35) and MACE (HR 1.38, 95% CI 1.25-1.53). The one-year risk of major bleeding was similar in those who discontinued or maintained OAC (HR 1.05, 95% CI 0.94-1.18), although it was significantly higher during the early follow-up (HR 1.51, 95% CI 1.24-1.83). The risk of primary outcomes decreased over time, with the risk of bleeding becoming not significant.

Interpretation: AF CC patients who discontinued OAC have a high risk of adverse events. New antithrombotic and integrated care approaches to reduce thrombotic risk without increasing bleeding risk are needed in these patients.

Funding: This study received no funding.

Background: The advent of disease-modifying treatments (DMT) has changed natural history in 5q Spinal muscular atrophy (SMA). The aim of this study was to report survival and functional aspects in all the Italian type I children born since 2016.

Methods: The study included all symptomatic children with type I SMA born since January 1st, 2016, when DMTs became available in Italy. All the Italian SMA referral centers provided data on survival and motor, respiratory, and nutritional status. To compare survival rate pre and post DMTs approval, we also included similar data from SMA I patients born between January 1st, 2010, and December 31st, 2015. A two-proportion z-test was conducted to compare the two cohorts. The significance level was set at p < .05.

Findings: 241 infants (98%) had type I SMA. Mean follow-up was 3.48 years (SD 2.33). Among type I patients, 42/241 did not survive (25 untreated), while 199 were alive at last follow-up (all treated; mean treatment age 0.6 years), with 25 needing >16 h/day ventilation or tracheostomy with continuous invasive ventilation. 130 of the 199 survivors (65%) achieved independent sitting, and 175 (87.9%) did not require tube feeding.

Interpretation: Our study provides a picture of the 'new natural history' of type I SMA, confirming the impact of the new therapies on the progression of type I with longer survival r and has better motor, respiratory and nutritional.

Funding: This research was partially funded by grants from the Italian Ministry of Health.