EClinicalMedicine最新文献

Background: Enteric fever is a major public health challenge in developing countries. We conducted a systematic analysis from the Global Burden of Diseases 2021 Study to provide updated estimates of enteric fever's burden.

Methods: We presented estimates for incident cases and deaths, age-standardized incidence and mortality rates, years of life lost (YLLs), and case-fatality rates spanning the study period of 2017-2021, stratified by region, country, socio-demographic index (SDI), and age group. Random-effects Poisson regression for longitudinal data was used to estimate the association between SDI and case-fatality rates, adjusting for antimicrobial resistance patterns.

Findings: In 2021, there were 9.3 million global cases of enteric fever (95% uncertainty interval: 7.3-11.9) and 107.5 thousand deaths (56.1-180.8). The age-standardized incidence rate decreased from 152/100,000 person-years (118-195) in 2017 to 128/100,000 person-years (100-163) in 2021, and the mortality rate decreased from 1.87/100,000 person-years (0.95-3.18) to 1.50/100,000 person-years (0.78-2.54). There were wide geographical differences, with South Asia contributing the most cases and deaths. Age-standardized incidence exceeded the threshold for "high burden" of enteric fever (100/100,000 person-years) in 23 countries in 2021.Children under five accounted for 40% of deaths and 47% of YLLs, with incidence and mortality peaking during the second year. Case-fatality was highest in low SDI countries and showed a global trend toward reduction, except among children aged 1-4 years. After adjusting for the prevalence of multidrug resistance, fluoroquinolone non-susceptibility, and third-generation cephalosporin resistance, a higher SDI was associated with a lower case-fatality rate, with a 1.1% (0.7-1.7) reduction for each percentage point increase in SDI.

Interpretation: Despite notable improvements, several countries still showed a high burden of enteric fever, which remains a significant global health concern, especially among children under five. Although enhancing water and sanitation systems is crucial, the most significant reductions in the global disease burden are likely to be achieved through broader vaccine coverage. This includes the use of typhoid conjugate vaccines, which are effective in infants and young children and offer extended protection, along with improved data collection and surveillance to guide vaccine distribution efforts across high-incidence areas.

Funding: This work was partially supported by "Ricerca Corrente" funding from Italian Ministry of Health to IRCCSHumanitas Research Hospital.

Background: Polycystic ovary syndrome (PCOS) represents a prevalent endocrine disorder affecting numerous females worldwide. Dysbiosis of gut microbiota has been linked to the occurrence of PCOS; however, research into the characteristics of gut microbiota in PCOS patients, especially those from different regions and with different testosterone level, remains limited. Additionally, it is still unclear whether gut microbiota helps to distinguish different PCOS subtypes.

Methods: We searched four electronic databases (PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov) from Jan 1, 2010 to May 1, 2024. This combined analysis included studies providing the raw data of gut microbiota in PCOS patients. We reanalyzed the characteristics of gut microbiota in PCOS patients from different regions and with different testosterone level.

Findings: Fourteen publications satisfying the inclusion criteria were included in the combined analysis. Based on data from 948 individuals, we found alpha-diversity was not significantly different between PCOS and healthy control (HC) groups. However, gut microbiota composition was distinct in PCOS patients compared with healthy individuals. Specifically, Fusobacterium, Ruminococcus_gnavus_group, and Escherichia-Shigella increased, while Dysosmobacter, Schaedlerella, Merdimonas, Clostridiisalibacter, Flintibacter et al. decreased in PCOS women. Regionally, Alistipes was enriched in primarily European patients, while Blautia and Roseburia were more abundant in Chinese patients. Subtype analysis revealed that the gut microbiota of PCOS patients with higher testosterone level (PCOS-HT) differed significantly from those with lower testosterone level (PCOS-LT). Prevotella, Blautia, Dialister, Ruminococcus_torques_group and UCG-002 were enhanced in PCOS-HT patients, while Alistipes, Dysosmobacter, Phocaeicola and Faecalibacterium were diminished. Importantly, a set of eight genera effectively differentiated PCOS-HT patients from PCOS-LT patients with an AUC of 0.95.

Interpretation: This systematic anatomization of gut microbiota revealed the microbial characteristics of PCOS patients, particularly those with different testosterone level, thus laying the foundations for further research into pathogenesis of PCOS, and the development of effective diagnostic, treatment, and intervention strategies.

Funding: This work was supported by the National Natural Science Foundation of China (No. 81973217, 82260304), the Hainan Province Clinical Medical Center (QWYH202175), and the Specific Research Fund of The Innovation Platform for Academicians of Hainan Province (YSPTZX202311).

Background: CVN424 is a GPR6 inverse agonist that provides selective pharmacological control of the indirect striatopallidal pathway. We assessed the safety and efficacy of CVN424 as an adjunctive treatment to levodopa for reducing OFF-time in individuals with Parkinson's disease (PD) experiencing motor-fluctuations.

Methods: This was a randomised, double-blind, placebo-controlled study conducted at 21 sites across the United States to evaluate two doses of CVN424 (NCT04191577). Patients with PD (Hoehn and Yahr stages 2-4) who were on a stable dose of levodopa and experiencing ≥2 h of daily OFF-time were randomised (1:1:1) to receive either once-daily CVN424 (50 mg or 150 mg) or placebo for a 28-day treatment period. The primary endpoints were safety and tolerability. The key secondary endpoint was the change from baseline to Day 27 in OFF-time.

Findings: The study was conducted from December 23, 2019, to October 14, 2021. Out of 198 participants screened, 141 eligible participants were randomised to one of the three treatment groups (n = 47 per group), and 127 participants completed the 28-day treatment period. The most common treatment emergent adverse events (TEAEs) were headache (2% with CVN424 50 mg, 9% with CVN424 150 mg, and 2% with placebo) and nausea (4% with CVN424 50 mg, 6% with CVN424 150 mg and 2% with placebo). No serious treatment-related adverse events were reported. On Day 27, the mean ± standard deviation (SD) change from baseline in daily OFF-time was -1.3 ± 3.0 h in the CVN424 50 mg group, -1.6 ± 2.5 h in the CVN424 150 mg group, and -0.5 ± 2.9 h in the placebo group. The placebo-adjusted LS mean ± standard error (SE) treatment difference was significant for the CVN424 150 mg dose (1.3 ± 0.56 h, [95 CI% -2.41 to -0.19], nominal p = 0.02).

Interpretation: Treatment with CVN424 was safe and well-tolerated. Despite the short study duration and small sample size, the 150 mg CVN424 dose provided a clinically meaningful reduction in daily OFF-time. This study supports the development of CVN424 for the treatment of PD.

Funding: Cerevance.

Background: Infectious keratitis (IK) is the leading cause of corneal blindness globally. Deep learning (DL) is an emerging tool for medical diagnosis, though its value in IK is unclear. We aimed to assess the diagnostic accuracy of DL for IK and its comparative accuracy with ophthalmologists.

Methods: In this systematic review and meta-analysis, we searched EMBASE, MEDLINE, and clinical registries for studies related to DL for IK published between 1974 and July 16, 2024. We performed meta-analyses using bivariate models to estimate summary sensitivities and specificities. This systematic review was registered with PROSPERO (CRD42022348596).

Findings: Of 963 studies identified, 35 studies (136,401 corneal images from >56,011 patients) were included. Most studies had low risk of bias (68.6%) and low applicability concern (91.4%) in all domains of QUADAS-2, except the index test domain. Against the reference standard of expert consensus and/or microbiological results (seven external validation studies; 10,675 images), the summary estimates (95% CI) for sensitivity and specificity of DL for IK were 86.2% (71.6-93.9) and 96.3% (91.5-98.5). From 28 internal validation studies (16,059 images), summary estimates for sensitivity and specificity were 91.6% (86.8-94.8) and 90.7% (84.8-94.5). Based on seven studies (4007 images), DL and ophthalmologists had comparable summary sensitivity [89.2% (82.2-93.6) versus 82.2% (71.5-89.5); P = 0.20] and specificity [(93.2% (85.5-97.0) versus 89.6% (78.8-95.2); P = 0.45].

Interpretation: DL models may have good diagnostic accuracy for IK and comparable performance to ophthalmologists. These findings should be interpreted with caution due to the image-based analysis that did not account for potential correlation within individuals, relatively homogeneous population studies, lack of pre-specification of DL thresholds, and limited external validation. Future studies should improve their reporting, data diversity, external validation, transparency, and explainability to increase the reliability and generalisability of DL models for clinical deployment.

Funding: NIH, Wellcome Trust, MRC, Fight for Sight, BHP, and ESCRS.

Background: Accurate staging of liver fibrosis (LF) is essential for clinical management in chronic liver disease. While non-contrast MRI (NC-MRI) yields valuable information for liver assessment, its effectiveness in predicting LF remains underexplored. This study aimed to develop and validate artificial intelligence (AI)-powered models utilizing NC-MRI for staging LF.

Methods: A total of 1726 patients from Shengjing Hospital of China Medical University, registered between October 2003 and October 2022, were retrospectively collected, and divided into development (n = 1208) and internal test (n = 518) cohorts. An external test cohort consisting of 337 individuals from six centers, registered between June 2015 and November 2022, were also included. All participants underwent NC-MRI (T1-weighted imaging, T1WI; and T2-fat-suppressed imaging, T2FS) and liver biopsies. Two classification models (CMs), named T1 and T2FS, were trained on respective image types using 3D contextual transformer networks and evaluated on both test cohorts. Additionally, three CMs-Clinic, Image, and Fusion-were developed using clinical features, T1 and T2FS scores, and their integration via logistic regression. Classification effectiveness of CMs was assessed using the area under the receiver operating characteristic curve (AUC). A comparison was conducted between the optimal models (OMs) with highest AUC and other methods (transient elastography, five serum biomarkers, and six radiologists).

Findings: Fusion models (i.e., OM) yielded the highest AUC among the CMs, achieving AUCs of 0.810 for significant fibrosis, 0.881 for advanced fibrosis, and 0.918 for cirrhosis in the internal test cohort, and 0.808, 0.868, and 0.925, respectively, in the external test cohort. The OMs demonstrated superior performance in AUC, significantly surpassing transient elastography (only for staging ≥ F2 and ≥ F3 grades), serum biomarkers, and three junior radiologists for staging LF. Radiologists, with the aid of the OMs, can achieve a higher AUC in LF assessment.

Interpretation: AI-powered models utilizing NC-MRI, including T1WI and T2FS, accurately stage LF.

Funding: National Natural Science Foundation of China (No. 82071885); General Program of the Liaoning Provincial Department of Education (LJKMZ20221160); Liaoning Province Science and Technology Joint Plan (2023JH2/101700127); the Leading Young Talent Program of Xingliao Yingcai in Liaoning Province (XLYC2203037).

Background: Guidelines recommend low-dose colchicine for secondary prevention in cardiovascular disease, but uncertainty remains concerning its efficacy for stroke, efficacy in key subgroups and about uncommon but serious safety outcomes.

Methods: In this trial-level meta-analysis, we searched bibliographic databases and trial registries form inception to May 16, 2024. We included randomised trials of colchicine for secondary prevention of ischaemic stroke and major adverse cardiovascular events (MACE: ischaemic stroke, myocardial infarction, coronary revascularisation, or cardiovascular death). Secondary outcomes were serious safety outcomes and mortality. A fixed-effect inverse-variance model was used to generate a pooled estimate of relative risk (RR) with 95% confidence intervals (CI). This study is registered with PROSPERO, CRD42024540320.

Findings: Six trials involving 14,934 patients with prior stroke or coronary disease were included. In all patients, colchicine compared with placebo or no colchicine reduced the risk for ischaemic stroke by 27% (132 [1.8%] events versus 186 [2.5%] events, RR 0.73 [95% CI 0.58-0.90]) and MACE by 27% (505 [6.8%] events versus 693 [9.4%] events, with RR 0.73 [0.65-0.81]). Efficacy was consistent in key subgroups (females versus males, age below versus above 70, with versus without diabetes, statin versus non-statin users). Colchicine was not associated with an increase in serious safety outcomes: hospitalisation for pneumonia (109 [1.5%] versus 106 [1.5%], RR 0.99 [0.76-1.30]), cancer (247 [3.5%] versus 255 [3.6%], RR 0.97 [0.82-1.15]), and gastro-intestinal events (153 [2.1%] versus 135 [1.9%]), RR 1.15 [0.91-1.44]. There was no difference in all-cause death (201 [2.7%] versus 181 [2.4%], RR 1.09 [0.89-1.33]), cardiovascular death (70 [0.9%] versus 80 [1.1%], RR 0.89 [0.65-1.23]), or non-cardiovascular death (131 [1.8%] versus 101 [1.4%], RR 1.26 [0.98-1.64]).

Interpretation: In patients with prior stroke or coronary disease, colchicine reduced ischaemic stroke and MACE, with consistent treatment effect in key subgroups, and did not increase serious safety events or death.

Funding: There was no funding source for this study.

Background: Anaemia in sickle cell disease (SCD) is a significant cause of morbidity and mortality, but few studies have reported on the burden and outcome of very severe anaemia. This study described the epidemiology of very severe anaemia by determining the prevalence and incidence, investigating associated clinical and laboratory factors, and assessing outcomes in SCD.

Methods: A 10-year prospective cohort study involving SCD patients of all ages was conducted at Muhimbili National Hospital in Tanzania between 2004 and 2013. SCD included Homozygous SS-Sickle cell anaemia and Sβ⁰ thalassemia at clinics and during hospitalization visits. Very severe anaemia was defined as Haemoglobin <5 g/dL at steady-state which was a period when a patient was stable with no blood transfusion in past 3 months or accute pain report in the previous month.

Findings: There were 28,293 (92.9%) clinic visits and 2158 hospitalisations amongst 3586 patients. Mean haemoglobin concentration at clinic was 7.4 g/dL, (95% CI: 7.4-7.5) compared to hospitalisation [6.4 g/dL, 95% CI: 6.3-6.5], p < 0.001. Prevalence of very severe anaemia at the clinic was 4.1%, and 23.8% during hospitalization, while the overall incidence was 114.1 (95% CI: 108.2-120.2) events per 1000 person years. Risk ratio of dying for patients with very severe anaemia was 4.78 times higher (95% CI: 3.65-6.25, p < 0.001) than in individuals without very severe anaemia. The risk ratio for mortality was highest in children aged <2 years, and was decreasing steadily with increase in age, from HR = 0.73 (95% CI: 0.39-1.35) in children aged 2-4 years to HR of 0.38 (95% CI: 0.20-0.71) in patients in age group 10-17 years when compared to those aged 0-1 years. Mortality risk ratio was higher (HR = 6.76 [95% CI: 4.31-10.62, p < 0.001]) in patients with steady-state haemoglobin <5 g/dL and presenting with very severe anaemia before death compared to those with steady state haemoglobin ≥5 g/dL and haemoglobin ≥5 g/dL before death.

Interpretation: The burden of very severe anaemia in SCD was high, especially during hospitalization, and was independent predictor of mortality. There is an urgent need to improve prevention, diagnosis, and interventions for very severe anaemia in SCD in Africa. More research to elucidate the aetiology and mechanisms of anaemia in this population is required.

Funding: Government of the United Republic of Tanzania, Wellcome Trust, United Kingdom (JKM 072064; Project grant 080025, Strategic award 084538).

Given the increased prevalence of mental health problems during adolescence, there is considerable interest in understanding potential biological mechanisms including the contribution of pubertal hormones. This systematic review of 55 papers aimed to synthesize the evidence for the effect of pubertal hormones on the risk for mental health problems in children and adolescents. The pattern of findings from included studies suggested associations of testosterone and estradiol with certain types of mental health problems, but with inconsistencies relating to DHEA and DHEA-S. However, the state of evidence for the causal effects of hormones was determined to be weak given assessment of bias from confounding, hormone measurement error, selection bias and missingness. Further investigations with careful consideration of study design and analysis, particularly accounting for short-term variation of hormone levels and appropriate selection of confounders, is necessary to advance our understanding of hormonal effects on mental health. Such efforts will improve knowledge of risk mechanisms, and may support the development of targeted intervention efforts for mental health problems.

Background: Campylobacter is the leading cause of bacterial gastroenteritis worldwide. It is generally associated with an acute gastrointestinal infection causing a self-limiting diarrheal episode. However, there is evidence that persistent/recurrent carriage of Campylobacter also occurs. In hyperendemic settings the epidemiology and consequences of persistent Campylobacter enteric infections is poorly studied.

Methods: Risk factors for and growth consequences of persistent Campylobacter infections detected by polymerase chain reaction (qPCR) were evaluated with data from the MAL-ED birth cohort study in children 0-24 months of age between November 2009 and February 2012. A persistent Campylobacter infection was defined as three or more consecutive Campylobacter positive monthly stools.

Findings: Across all study sites, 45.5% (781/1715) of children experienced at least one persistent Campylobacter episode. The average cumulative duration of days in which children with persistent Campylobacter were positive for Campylobacter spp. was 150 days (inter-quartile range: 28-236 days). Children who experienced a persistent Campylobacter episode had an attained 24-month length-for-age (LAZ) score that was 0.23 (95% (CI): -0.31, -0.15) less than children without a persistent Campylobacter episode. Among children who had at least one episode of Campylobacter over a 3-month or 9-month window, persistent episodes were not significantly associated with poorer 3-month weight gain (-28.7 g, 95% CI: -63.4 g, 6.0 g) but were associated with poorer 9-month linear growth (-0.134 cm 95% CI: -0.246, -0.022) compared to children with an episode that resolved within 31 days.

Interpretation: Persistent/recurrent Campylobacter infection is common among children and has a measurable negative impact on linear growth in early childhood.

Funding: Funding for this study was provided by the Bill and Melinda Gates Foundation (OPP1066146 and OPP1152146), the National Institutes of Health United States (R01AI158576 and R21AI163801 to MNK and CTP; K43TW012298 to FS; K01AI168493 to JMC; GOL was supported by K01AI145080. This research was also supported in part by USDA-ARS CRIS project 2030-42000-055-00D. The funders had no role in study design, study implementation, data analysis, or interpretation of the results.