METHODS: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm- and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies.
RESULTS: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global developmental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involvement (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities.
CONCLUSION: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders.
DESIGN: A prospective cohort study.
SETTING: The study was conducted across 623 ICUs of 224 hospitals in 114 cities in 37 African, Asian, Eastern European, Latin American, and Middle Eastern countries.
PARTICIPANTS: The study included 169,036 patients, hospitalized for 1,166,593 patient days.
METHODS: Data collection took place from January 1, 2014, to February 12, 2022. We identified CAUTI rates per 1,000 UC days and UC device utilization (DU) ratios stratified by country, by ICU type, by facility ownership type, by World Bank country classification by income level, and by UC type. To estimate CAUTI risk factors, we analyzed 11 variables using multiple logistic regression.
RESULTS: Participant patients acquired 2,010 CAUTIs. The pooled CAUTI rate was 2.83 per 1,000 UC days. The highest CAUTI rate was associated with the use of suprapubic catheters (3.93 CAUTIs per 1,000 UC days); with patients hospitalized in Eastern Europe (14.03) and in Asia (6.28); with patients hospitalized in trauma (7.97), neurologic (6.28), and neurosurgical ICUs (4.95); with patients hospitalized in lower-middle-income countries (3.05); and with patients in public hospitals (5.89).The following variables were independently associated with CAUTI: Age (adjusted odds ratio [aOR], 1.01; P < .0001), female sex (aOR, 1.39; P < .0001), length of stay (LOS) before CAUTI-acquisition (aOR, 1.05; P < .0001), UC DU ratio (aOR, 1.09; P < .0001), public facilities (aOR, 2.24; P < .0001), and neurologic ICUs (aOR, 11.49; P < .0001).
CONCLUSIONS: CAUTI rates are higher in patients with suprapubic catheters, in middle-income countries, in public hospitals, in trauma and neurologic ICUs, and in Eastern European and Asian facilities.Based on findings regarding risk factors for CAUTI, focus on reducing LOS and UC utilization is warranted, as well as implementing evidence-based CAUTI-prevention recommendations.
METHODS: A group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management.
FINDINGS: In round 1, we received 65 surveys from 35 countries and analyzed these results, which informed us that 73.3% of respondents agreed with 20 draft statements while 23.8% agreed somewhat. The mean percentage of agreement or somewhat agreement increased to 80.85% and 15.75%, respectively, in round 2. The final statements covered a wide range of topics related to epidemiology, pathophysiology, and strategies for screening and managing pediatric MAFLD.
CONCLUSIONS: The consensus statements and recommendations developed by an international expert panel serve to optimize clinical outcomes and improve the quality of life for children and adolescents with MAFLD. These findings emphasize the need for standardized approaches in diagnosing and treating pediatric MAFLD.
FUNDING: This work was funded by the National Natural Science Foundation of China (82070588, 82370577), the National Key R&D Program of China (2023YFA1800801), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-014), the Wuxi Taihu Talent Plan (DJTD202106), and the Medical Key Discipline Program of Wuxi Health Commission (ZDXK2021007).
METHODS: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.
RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.
CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.
IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.
METHODS: ICAR-Allergic Rhinitis 2023 employed established evidence-based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work.
RESULTS: ICAR-Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost.
CONCLUSION: The ICAR-Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment.
METHODS: A web-based survey in 13 languages was conducted among non-Japanese residents living in Japan during the COVID-19 situation. The State-Trait Anxiety Inventory assessed the level of anxiety-State (STAI-S) scores prorated from its six-item version. The multivariable logistic regression using the Akaike Information Criterion (AIC) method was performed to identify the associated factors of anxiety among participants.
RESULTS: From January to March 2021, we collected 392 responses. A total of 357 valid responses were analyzed. 54.6% of participants suffered from clinically significant anxiety (CSA). In multivariable logistic model analysis, the CSA status or the high level of anxiety was associated with three factors, including having troubles/difficulties in learning or working, decreased sleep duration, and decreased overall physical health (p<0.05).
CONCLUSION: Our study suggests several possible risk factors of anxiety among non-Japanese residents living in Japan undergoing the COVID-19 pandemic, including the troubles or difficulties in learning or working, the decrease in sleep duration, and the decrease in overall physical health.
METHODS: We implemented a multidimensional approach and an 8-component bundle in 374 ICUs across 35 low and middle-income countries (LMICs) from Latin-America, Asia, Eastern-Europe, and the Middle-East, to reduce VAP rates in ICUs. The VAP rate per 1000 mechanical ventilator (MV)-days was measured at baseline and during intervention at the 2nd month, 3rd month, 4-15 month, 16-27 month, and 28-39 month periods.
RESULTS: 174,987 patients, during 1,201,592 patient-days, used 463,592 MV-days. VAP per 1000 MV-days rates decreased from 28.46 at baseline to 17.58 at the 2nd month (RR = 0.61; 95% CI = 0.58-0.65; P
METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.
RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.
CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.