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Timeliness of publication of randomized controlled trials in rheumatology: A systematic review.

OBJECTIVE: To systematically review the (1) timeliness of publication of randomized controlled trials (RCTs) in rheumatology, (2) impact of the COVID-19 pandemic on time to publication, and (3) factors associated with publication delays. METHODS: We searched Medline, Embase, EBM Reviews, Cochrane Central Register of Controlled Trials, and Scopus from January 1, 2018, to June 30, 2023 for Phase 3, superiority, parallel-design RCTs that evaluated any treatment for a rheumatologic illness or a rheumatologic treatment for COVID-19 and reported clinical primary efficacy outcome. Outcomes of interest were time to publication after trial completion and publication delay of >2 years after trial completion. RESULTS: 448 RCTs were included in this systematic review. Median time from completion to publication was 549 days and 65.9 % RCTs were published within 2 years of completion. Compared with RCTs on rheumatologic diseases, RCTs on COVID-19 were published sooner (253 vs. 549 days; p < 0.001) and were more likely to be published within 2 years (adjusted OR 9.49, 95 % CI 2.07 to 43.61). Compared with RCTs completed before March 1, 2020, RCTs completed after March 1, 2020, were published sooner (327 vs. 724 days; p < 0.001) and were more likely to be published within 2 years (adjusted OR 9.40, 95 % CI 5.14 to 17.21). Time from RCT completion to submission accounted for most (67 %) of the time to publication. CONCLUSIONS: Publication delay continues to be an important concern in dissemination of clinical research. Most of the delays in publication were attributable to delays in submission to journals after trial completion.

Humans

Trends in demographic and health survey publications based on a bibliometric analysis.

BACKGROUND: The Demographic and Health Surveys (DHS) Program, launched in 1984, provides high-quality population health data that underpins a vast body of global health research. However, the scale and growth patterns of DHS-based publications remain underexplored, particularly as donor funding uncertainties threaten program sustainability. OBJECTIVE: We examine temporal trends in DHS-based research output from 1984 to 2025, quantifying growth patterns and publication delays to inform understanding of the program's global research expansion. METHODS: A systematic bibliometric review was conducted following PRISMA guidelines across PubMed, Scopus, Web of Science, Dimensions, Wiley, and CINAHL. Eligible peer-reviewed articles using DHS data between 1984 and 2025 were identified. Annual publication counts were analyzed, segmented regression identified growth inflection points, and timeliness was assessed by calculating lag between survey completion and publication. RESULTS: Over 10,000 DHS-based publications were identified. Annual output rose from isolated studies in the 1980s to several hundred annually by the 2010s. Segmentation analysis revealed two rapid growth phases: a 56-publications/year increase from 2004-2012, and a 71-publications/year increase from 2012 to 2024. Despite this growth, median lag from survey completion to publication remained approximately 5 years, with only a modest recent improvement (Kendall's &#x3c4;&#x2009;=&#x2009; -0.623, p&#x2009;<&#x2009;0.001). CONCLUSION: DHS data have fueled exponential growth in global health research over four decades, confirming their vital role in evidence generation. However, persistent publication delays highlight the need to shorten the pathway from data collection to dissemination through strengthened research capacity in low- and middle-income countries. Sustained funding is essential to maintain this critical evidence source.

Bibliometrics

Understanding FDA's reasons for nonapproval: A systematic review of complete response letters in cell and gene therapy.

BACKGROUND AIMS: Cell and gene therapy products face unique regulatory challenges due to their biological complexity and the stringent expectations for manufacturing control, analytical testing, and clinical assessment. As the pipeline grows, understanding the drivers of FDA non&#x2011;approval is increasingly important for improving first&#x2011;cycle success and reducing development delays. In this study, we aimed to characterize the frequency and impact of refuse&#x2011;to&#x2011;file actions, major amendments, and complete response letters issued for biologics licensing applications; and to identify recurring patterns of deficiencies contributing to delayed approval. METHODS: Publicly available documents were extracted from the FDA website. Data from each approved cell and gene therapy product's regulatory history-including complete responses, major amendments, inspection timing, and cited deficiencies-were compiled and categorized across clinical, quality, and labeling domains. RESULTS: Analysis showed that informational deficiencies were common across modalities. Major amendments occurred in roughly half of applications, and complete responses had the most significant impact. Quality deficiencies appeared in all complete responses and were the predominant barrier, while clinical and labeling issues were less frequent but meaningful when present. CONCLUSION: Overall, these findings highlight the need for proactive FDA engagement, comprehensive readiness, and early inspection preparation to reduce regulatory risk and improve first cycle approval outcomes.

Humans

The 2026 Bundibugyo Ebola Outbreak: A Warning for Global Preparedness for Future Epidemics.

Dear Editor, The 2026 Bundibugyo Ebolavirus (BDBV) outbreak has once again demonstrated that the threat of emerging diseases remains a major global health challenge. The outbreak, first detected in the Democratic Republic of Congo (DRC) and spread to Uganda, is not only a regional crisis but also a test of the world's preparedness for pathogens with epidemic potential. Unlike Zaire Ebolavirus (EBOV), which has benefited from effective vaccines and treatments in recent years, BDBV still lacks a licensed vaccine or specific treatment[1]. As of June 6, a total of 515 laboratory-confirmed cases and 91 deaths have been reported in DRC, while Uganda has reported 19 laboratory-confirmed cases and two deaths. The occurrence of unexplained deaths among both the community and healthcare workers, along with prior reports of an unidentified hemorrhagic fever, suggest that the outbreak has been likely originated in March 2026 or even earlier. Accordingly, the virus is believed to have spread unnoticed for several weeks before being identified through genomic sequencing in mid-May 2026[2]. The resurgence of Ebola in Africa results from a complex interaction of environmental, social, and political factors. Deforestation, the development of mining activities, the expansion of agriculture, and increased human contact with wildlife have elevated the likelihood of spillovers from wildlife reservoirs, particularly fruit bats, which are considered the most likely natural hosts of ebolaviruses. Moreover, weak disease surveillance systems and limited access to health services have delayed the identification of early cases. The similarity of the initial symptoms of Ebola to other endemic diseases in the region, such as malaria, makes early diagnosis difficult and provides ample opportunity for transmission to spread. Insecurity, misinformation, attacks on healthcare facilities, and armed conflict in the region have also posed serious challenges to the implementation of contact tracing programs and rapid response to the epidemic[3,4]. One of the most critical challenges highlighted by this outbreak is the weakness of diagnostic capacities in the affected areas. The initial 2007 outbreak of BDBV proved that delayed lab confirmation paralyzes public health responses[5]. Now, dealing with a much larger outbreak in 2026, the persistence of this challenge highlights a dangerous failure to invest in diagnostic infrastructure over the last 19 years. Many health facilities do not have access to molecular laboratories, rapid sample transport systems, and biosafety infrastructure[6]. These limitations delay the diagnosis and isolation of patients, thus perpetuating disease transmission. Investment in the development of mobile laboratories, rapid point-of-care diagnostic tests, and digital reporting systems can dramatically reduce the time to diagnosis and response to an outbreak. The BDBV outbreak shows that laboratory preparedness must be considered an essential part of global health security. Furthermore, the early detection of emerging pathogens depends not only on diagnostic technologies but also on the expertise of local scientists who are able to recognize unusual epidemiological and laboratory patterns. During the current outbreak, suspected Ebola cases initially tested negative using common diagnostic tests (designed for Zaire Ebola Virus), which delayed the identification of the BDBV. Specifically, field-based diagnostics in Bunia were calibrated exclusively to detect the EBOV responsible for recent Congolese outbreaks. Consequently, patient samples collected throughout late April and early May yielded negative results, requiring cross-country transport to Kinshasa for genomic confirmation[2]. This experience revealed a major vulnerability in outbreak preparedness: diagnostic tools designed for known threats may be ineffective in detecting less common or unexpected pathogens. Therefore, strengthening local scientific capacities, developing genomic surveillance, and expanding access to flexible and adaptable diagnostic platforms should be considered as a top priority for global health security. The lack of a licensed vaccine for BDBV was one of the most significant challenges of this epidemic. While the rVSV-ZEBOV vaccine has played a significant role in controlling Zaire ebolavirus, there is no licensed vaccine for BDBV. In response to this outbreak, efforts to develop mRNA-based vaccines, adenoviral vectors, rVSV-based vaccines, and multipotent vaccines have been accelerated[7]. However, the experience of this epidemic has shown that the development of medical products for rare diseases continues to face financial and investment constraints. This challenge highlights the need for sustained support from governments and international institutions for research and development of pathogens with epidemic potential. The 2026 Bundibugyo outbreak provides several key lessons for the global community. First, early detection and rapid diagnosis are the most important factors in containing the epidemic. The 19-year interval between the 2007 BDBV outbreak and the 2026 outbreak underscores persistent shortcomings in investment toward decentralized, pan-ebolavirus diagnostic infrastructure, with diagnostic delays hindering timely outbreak identification in both instances. Second, the trust and active participation of local communities are as important as medical interventions. Additionally, the rapid cross-border transmission dynamics between the DRC and Uganda demonstrate that blanket travel restrictions and border closures are impractical. As communities in the Great Lakes region routinely cross national borders for trade and healthcare, coordinated regional surveillance and timely information sharing are likely to be more effective than broad border closures in mitigating disease transmission[8]. Third, the protection of health workers must be a priority in preparedness plans. Fourth, a "One Health" approach is essential for simultaneous monitoring of humans, animals, and the environment. Although BDBV is not a new pathogen, the lack of licensed medical interventions and limited investment in research reflect many of the vulnerabilities associated with the concept of "Disease X."[9]. Unlike Zaire Ebola Virus, for which licensed vaccines and monoclonal antibody therapies are available, BDBV forces public health responses to rely almost entirely on non-pharmaceutical interventions such as isolation and infection control[10]. This gap reflects the structural inequity in global health research and development funding, with pathogens affecting resource-limited regions receiving insufficient attention until they spark an international emergency[2]. The BDBV outbreak proves that global epidemic preparedness cannot be pathogen-selective; it requires proactive investment in broad-spectrum countermeasures and resilient frontline health systems[8]. In conclusion, the 2026 BDBV outbreak is a serious wake-up call for the global health system. The epidemic revealed that gaps in surveillance systems, diagnostic capacities, vaccine development, and preparedness for emerging diseases persist. Investing in health infrastructure, developing Pan-Ebolavirus vaccines, strengthening laboratories, expanding the One-Health approach, and supporting research on emerging zoonotic pathogens must be at the top of global health security priorities. Otherwise, the BDBV outbreak may be just a prelude to larger crises to come.

Ebolavirus

Metaviromic profiling of mosquito excreta using superhydrophobic collection devices expands the known RNA virome of North America.

Nearly 30% of emerging infectious disease events worldwide are transmitted by arthropod vectors, and this proportion continues to rise. Rapid and accurate detection is critical for directing vector control interventions, thereby reducing the likelihood of widespread transmission. Surveillance of infected mosquitoes can provide an early warning of impending human infection; however, conventional virus testing relies on processing large pools of mosquitoes and requires labor-intensive pre-processing. During rapidly developing epidemic or panzootic events, these delays may limit the effectiveness of public health responses. Mosquito excreta has recently emerged as a promising alternative substrate for pathogen detection. Sugar-fed mosquitoes regularly excrete gut contents, offering a rich source of nucleic acids. In this study, we developed and applied custom superhydrophobic excreta-collection funnels that efficiently aggregate excreta produced by field-collected Culex mosquitoes into attached microcentrifuge tubes. Shotgun metagenomic sequencing of this material revealed a diverse RNA virome, including both globally distributed viruses and those reported here for the first time from the Americas. Beyond virus detection, additional analyses enabled confirmation of host mosquito species and identification of trypanosomatid parasites, demonstrating the broader utility of mosquito excreta for integrated surveillance. We anticipate that methods and devices of this type will become valuable components of vector surveillance programs, particularly in remote or resource-limited settings where repeated collections are challenging. Overall, our findings highlight the potential of excreta-based monitoring to improve early detection of emerging or unknown pathogens of One Health importance, refine our understanding of mosquito virome biogeography, and facilitate the discovery of previously undescribed viruses.IMPORTANCEMany infectious diseases that affect people and animals are spread by mosquitoes and other biting insects, and the number of these outbreaks is increasing. Detecting pathogens in mosquito populations early can provide a critical warning before human cases begin, allowing health officials to act quickly. However, traditional surveillance requires collecting and processing large numbers of mosquitoes, which can be slow and labor-intensive during fast-moving outbreaks. Here we demonstrate a simpler approach: testing mosquito waste. When mosquitoes feed on sugar, they excrete material that contains genetic traces of viruses and other organisms. Using specially designed collection devices and modern genetic sequencing, we show that mosquito excreta can reveal a wide range of viruses and parasites while also identifying the mosquito species present. This method could make disease surveillance faster and more practical in remote or resource-limited settings, improving our ability to detect emerging pathogens that threaten human, animal, and environmental health.

Animals

Non-syndromic premature ovarian insufficiency associated with monoallelic LIG4 mutation via haploinsufficiency.

BACKGROUND: Premature ovarian insufficiency (POI) is a heterogeneous reproductive disorder, with genetic factors, particularly defects in DNA damage response pathways, increasingly implicated in its pathogenesis. DNA ligase IV (LIG4) is a key enzyme in the non-homologous end joining (NHEJ) pathway responsible for repairing DNA double-strand breaks (DSBs). However, its role in non-syndromic POI remains unclear. This study aimed to investigate the potential contribution of LIG4 variants to non-syndromic POI. RESULTS: Whole-exome sequencing identified a heterozygous frameshift variant in LIG4 (c.1271_1275del) in a three-generation Han Chinese family with non-syndromic POI, which co-segregated with affected individuals. AlphaFold-based structural modeling predicted truncation of the C-terminal XRCC4 interaction region. Functional experiments demonstrated that the mutant LIG4 protein showed reduced stability and was predominantly mislocalized to the cytoplasm of cells. In ovarian KGN cells, LIG4 depletion reduced cell viability, induced stress-associated cellular senescence, and impaired DNA damage repair capacity. In LIG4 knockout 293T cells, co-transfection of wild-type and mutant constructs revealed dose-dependent functional impairment, resulting in increased apoptosis under basal conditions and after phleomycin induced DNA damage, together with delayed repair of DSBs. Reanalysis of public single-cell RNA sequencing data further showed stage specific upregulation of LIG4 during oocyte maturation. Co-expression network analysis revealed enrichment in the Fanconi anemia pathway, phosphatidylinositol 3-kinase signaling pathway, and glycan metabolism. CONCLUSIONS: Our findings suggest that monoallelic LIG4 mutations may represent a potential genetic etiology for non-syndromic POI with sex-limited penetrance. While further validation in more physiologically relevant models is warranted, our data indicate that LIG4 haploinsufficiency may impair DSB repair and disrupt molecular pathways crucial for oocyte maturation and survival, highlighting a potential role of the NHEJ pathway in maintaining human ovarian function.

Humans

Civil liability in oral & maxillofacial surgery: &#x391; systematic review.

Maxillofacial surgery is a surgical specialty with anatomical, functional, and aesthetic requirements, which makes it a field at increased risk of medical negligence and subsequent legal claims. The review was conducted in accordance with the PRISMA guidelines and used international medical and legal databases. Studies that analyzed court decisions, insurance claims, or recorded compensation data related to maxillofacial surgery were included. The extracted data included, among others, the year and country of publication, the causes of action, and the amounts of financial compensation. Most lawsuits originate from countries with developed medical liability systems, primarily the United States and the United Kingdom, and there has been an increasing trend in publications over the last two decades. The most common causes of lawsuits involve nerve injuries, delayed or incorrect diagnoses, technical errors during surgery, and inadequate informed consent. The amounts of compensation vary widely, from lower five-digit amounts in milder cases to particularly high amounts in cases of permanent functional or aesthetic damage, placing a significant overall financial burden on health systems. Medical negligence in maxillofacial surgery constitutes an important forensic and socioeconomic issue. Understanding the causes of lawsuits and their financial consequences can help improve clinical practice, inform patients, and prevent legal disputes.

Humans

Expanding the Clinical Spectrum of DHX30-Related Neurodevelopmental Disorder: A Case Report and a Scoping Review.

BACKGROUND: Whole exome sequencing (WES) has improved diagnostic rates for neurodevelopmental disorders (NDDs) while introducing challenges in novel variant interpretation. DHX30-related NDD (DHX30-NDD) is a recently described condition with an evolving phenotypic spectrum. OBJECTIVES: To expand the understanding of the DHX30-NDD genotype-phenotype spectrum by integrating a case-based WES interpretation with a scoping review. METHODS: We performed comprehensive genetic analysis (karyotyping, microarray, WES) on a proband with global developmental delay (GDD). A systematic literature search of PubMed/MEDLINE, Scopus and Google Scholar from database inception to April 2026 identified 10 publications including 51 individuals with DHX30-NDD. Clinical and genetic data were extracted to characterize the genotype-phenotype spectrum. RESULTS: The proband presented with GDD and right microtia, harbouring a de novo heterozygous pathogenic DHX30 missense variant (c.1478G&#x2009;>&#x2009;A; p.Arg493His), confirming DHX30-NDD. To our knowledge, this is the first reported individual with DHX30-NDD and microtia. The scoping review confirmed DHX30 variants are formed predominantly de novo and affected both sexes (22 males; 29 females). Hallmark manifestations were motor delay (50/51; 98.0%), GDD/ID (48/49; 98.0%), hypotonia (48/51; 94.1%), feeding difficulties (38/51; 74.5%), ataxia (17/23; 73.9%), abnormal brain imaging (36/49; 73.5%) and absent expressive language (35/48; 72.9%). Digital anomalies (31/51; 60.8%), eye anomalies (28/51; 54.9%), autistic behaviours (24/44; 54.5%), sleep disturbances (26/51; 51.0%), joint hypermobility (25/51; 49.0%), microcephaly (23/51; 45.1%) and ear anomalies (22/51; 43.1%) were also frequent. CONCLUSIONS: This study potentially expands the phenotypic spectrum of DHX30-NDD, highlights the clinical utility of WES for diagnosing GDD and underscores the importance of ongoing WES reanalysis for evolving variant interpretation.

DHX30

Novel potential treatment options for infections caused by multi-drug and extensively drug-resistant Neisseria gonorrhoeae strains.

INTRODUCTION: Neisseria gonorrhoeae has evolved antimicrobial resistance (AMR) since antimicrobial treatment of gonorrhea was introduced. The AMR development is driven by the bacterium's high capacity for genetic adaptation, antimicrobial overuse and misuse, and insufficient surveillance. Novel therapeutic options are urgently needed. AREAS COVERED: This review summarizes novel gonorrhea treatment options, with special emphasis on the novel oral antimicrobials zoliflodacin and gepotidacin that obtained US FDA-approval for treatment of uncomplicated urogenital gonorrhea in December 2025. It also highlights compounds in early clinical or preclinical development that have demonstrated promising in vitro activity against N. gonorrhoeae. EXPERT OPINION: Zoliflodacin and gepotidacin have the potential to optimize gonorrhea management as oral alternatives to current injectable ceftriaxone. Their successful long-term use will depend on optimized use strategies, including indications, evidence-based approved dosing, adherence, surveillance, and population-specific considerations. Public-health agencies and clinicians will need to balance broad clinical access with antimicrobial stewardship measures to delay the AMR emergence. Looking ahead, gonorrhea management will hopefully shift from empirical, syndromic treatment toward etiology-guided and AMR-informed therapy, driven by advances in rapid point-of-care testing and whole-genome sequencing technologies. Continuous phenotypic and genomic surveillance remains essential to detect early AMR signals, transmission of AMR strains, and inform treatment guidelines.

AMR

The effect of low birth weight as an intrauterine exposure on the early onset of sarcopenia through possible molecular pathways.

Sarcopenia, a musculoskeletal disease characterized by the progressive loss of skeletal muscle mass, strength, and physical performance, presents significant challenges to global public health due to its adverse effects on mobility, morbidity, mortality, and healthcare costs. This comprehensive review explores the intricate connections between sarcopenia and low birth weight (LBW), emphasizing the developmental origins of health and disease (DOHaD) hypothesis, inflammatory processes (inflammaging), mitochondrial dysfunction, circadian rhythm disruptions, epigenetic mechanisms, and genetic variations revealed through genome-wide studies (GWAS). A systematic search strategy was developed using PubMed to identify relevant English-language publications on sarcopenia, LBW, DOHaD, inflammaging, mitochondrial dysfunction, circadian disruption, epigenetic mechanisms, and GWAS. The publications consist of 46.2% reviews, 21.2% cohort studies, 4.8% systematic reviews, 1.9% cross-sectional studies, 13.4% animal studies, 4.8% genome-wide studies, 5.8% epigenome-wide studies, and 1.9% book chapters. The review identified key factors contributing to sarcopenia development, including the DOHaD hypothesis, LBW impact on muscle mass, inflammaging, mitochondrial dysfunction, the influence of clock genes, the role of epigenetic mechanisms, and genetic variations revealed through GWAS. The DOHaD theory suggests that LBW induces epigenetic alterations during foetal development, impacting long-term health outcomes, including the early onset of sarcopenia. LBW correlates with reduced muscle mass, grip strength, and lean body mass in adulthood, increasing the risk of sarcopenia. Chronic inflammation (inflammaging) and mitochondrial dysfunction contribute to sarcopenia, with LBW linked to increased oxidative stress and dysfunction. Disrupted circadian rhythms, regulated by genes such as BMAL1 and CLOCK, are associated with both LBW and sarcopenia, impacting lipid metabolism, muscle mass, and the ageing process. Early-life exposures, including LBW, induce epigenetic modifications like DNA methylation (DNAm) and histone changes, playing a pivotal role in sarcopenia development. Genome-wide studies have identified candidate genes and variants associated with lean body mass, muscle weakness, and sarcopenia, providing insights into genetic factors contributing to the disorder. LBW emerges as a potential early predictor of sarcopenia development, reflecting the impact of intrauterine exposures on long-term health outcomes. Understanding the complex interplay between LBW with inflammaging, mitochondrial dysfunction, circadian disruption, and epigenetic factors is essential for elucidating the pathogenesis of sarcopenia and developing targeted interventions. Future research on GWAS and the underlying mechanisms of LBW-associated sarcopenia is warranted to inform preventive strategies and improve public health outcomes.

Humans

A framework for automated scalable designation of viral pathogen lineages from genomic data.

Pathogen lineage nomenclature systems are a key component of effective communication and collaboration for researchers and public health workers. Since February 2021, the Pango dynamic lineage nomenclature for SARS-CoV-2 has been sustained by crowdsourced lineage proposals as new isolates were sequenced. This approach is vulnerable to time-critical delays as well as regional and personal bias. Here we developed a simple heuristic approach for dividing phylogenetic trees into lineages, including the prioritization of key mutations or genes. Our implementation is efficient on extremely large phylogenetic trees consisting of millions of sequences and produces similar results to existing manually curated lineage designations when applied to SARS-CoV-2 and other viruses including chikungunya virus, Venezuelan equine encephalitis virus complex and Zika virus. This method offers a simple, automated and consistent approach to pathogen nomenclature that can assist researchers in developing and maintaining phylogeny-based classifications in the face of ever-increasing genomic datasets.

Animals

Emerging hantavirus risks in mass gatherings: epidemiology, diagnostic challenges, and outbreak preparedness.

Hantaviruses are emerging rodent borne zoonotic pathogens of increasing global public health concern because of their high mortality, expanding ecological distribution, and potential for international dissemination. Although traditionally associated with sporadic rural outbreaks, recent ecological disruption, climate variability, urbanization, and increased global mobility have heightened concerns regarding hantavirus risks in mass gathering settings. This review critically examines the epidemiology, transmission uncertainty, diagnostic and surveillance challenges, and preparedness strategies related to hantavirus infections in the context of mass gatherings, including religious events, refugee settlements, cruise tourism, sporting events, and temporary accommodations. Particular emphasis is placed on the 2026 multinational cruise ship associated outbreak linked to the MV Hondius, which highlighted vulnerabilities related to delayed diagnosis, international passenger dispersal, and uncertainties surrounding possible human to human transmission of Andes virus. Current evidence indicates that hantavirus transmission occurs primarily through inhalation of aerosolized rodent excreta; however, controversies regarding limited interpersonal transmission, environmental persistence, and asymptomatic infections continue to complicate risk assessment and outbreak preparedness. Diagnostic limitations, underreporting, insufficient environmental surveillance, and lack of mass gathering specific preparedness frameworks remain major public health challenges, especially in resource limited settings. Strengthening proactive preparedness through integrated One Health approaches, ecological surveillance, genomic monitoring, AI driven epidemic intelligence, and coordinated international response systems is essential for mitigating future risks. The review emphasizes the urgent need for multidisciplinary research and evidence based policy development to improve global preparedness against emerging hantavirus associated threats in increasingly interconnected mass gathering environments.

Humans

Surgical management of esophageal atresia with tracheoesophageal fistula in extremely low birth weight neonates: A systematic review.

BACKGROUND: Surgical management of esophageal atresia/tracheoesophageal fistula (EA/TEF) in extremely low birth weight (ELBW) neonates remains challenging and controversial. This study systematically reviews surgical strategies and outcomes in this population. METHODS: Following PRISMA guidelines, Cochrane, Embase, MEDLINE, Scopus, and Web of Science (2004-2024) were searched in February 2025 for studies on surgical management of ELBW neonates with EA/TEF (PROSPERO CRD42025636228). Fatal chromosomal abnormalities were excluded. Demographics, comorbidities, surgical techniques, and complications were analyzed descriptively. Risk of bias was assessed. RESULTS: Eleven publications (five case reports and six case series) comprising 30 patients (Gross type B/C = 1/29) met the eligibility criteria. Mean gestational age was 28.1 (23-34) weeks, and mean birth weight was 760.4 (422-995) g. Twelve primary repairs (PR) and 18 delayed primary repairs (DPR) were performed, including staged repair (n = 11), lower esophageal banding (n = 4), and other techniques (n = 3). Postoperatively, four anastomotic leaks were managed conservatively, six strictures and one recurrent TEF required endoscopic intervention, three fundoplications and two aortopexies were reported (follow-up: 1-198 months, n = 19). Overall mortality was 30% (PR: 8.3%; DPR: 44.4%). Mortality was 60% among neonates with major congenital heart defects (CHD) and 40% among those with VACTERL association. EA/TEF-related complications contributed to 33.3% of deaths. CONCLUSIONS: Mortality in this cohort remains high, particularly with major CHD, and is largely unrelated to EA/TEF-specific complications. In selected cases, PR appears feasible as an alternative to DPR, although conclusions are limited by the small sample size and heterogeneous studies.

Humans

Phenotypes of Hereditary Diseases Associated With Rauch-Steindl Syndrome.

PURPOSE: Prenatal phenotypic manifestations of genetic disorders associated with NSD2 variants remain poorly characterized. This study presents our institutional experience with the prenatal diagnosis of NSD2-associated genetic disorders, specifically Rauch-Steindl syndrome (RAUST), aiming to improve understanding of both the molecular and clinical features of RAUST. METHODS: We performed a retrospective analysis of six fetuses and one adult diagnosed with RAUST at our institution and thoroughly reviewed the prenatal ultrasound reports of six fetuses. Prenatal and postnatal phenotypes of RAUST cases were summarized alongside findings from previously published literature. Correlations between NSD2 variant locations, variant types, and phenotypes were analyzed. Additionally, protein modeling was used to visualize structural changes in NSD2 protein before and after C-terminal variants. We integrated single-cell transcriptomic and gene expression data from multiple public databases to investigate spatiotemporal expression patterns of NSD2 during human fetal development. RESULTS: Fetal growth restriction (FGR) was the most prevalent prenatal manifestation in RAUST fetuses, followed by microcephaly. Bilateral renal hypoplasia emerged as a novel prenatal ultrasonographic feature. Postnatally, speech and motor developmental delays were the most commonly reported phenotypes, followed by physical developmental delays and intellectual disability. Genotype-phenotype correlation analysis revealed an association between N-terminal truncating variants in NSD2 and impaired fetal growth parameters. Notably, C-terminal truncating variants-predicted not to directly impact NSD2 functional domains-also exerted disease-causing effects. CONCLUSION: This study provides a comprehensive analysis of prenatal phenotypes in RAUST cases, enriching the prenatal phenotypic spectrum of the disease and facilitating early diagnosis and clinical management of RAUST. Furthermore, our genotype-phenotype correlation findings lay a foundational basis for future research into the complex molecular mechanisms underlying NSD2-associated genetic disorders.

Humans

Aneurysmal subarachnoid hemorrhage care in a middle-income public healthcare system: A real-world neurocritical care cohort.

BACKGROUND AND PURPOSE: Although aneurysm treatment capacity has expanded worldwide, outcomes after aneurysmal subarachnoid hemorrhage (aSAH) remain strongly influenced by neurocritical care (NCC) delivery, referral pathways, and access to specialized treatment. Contemporary data describing real-world aSAH care in resource-limited healthcare systems remain scarce. We aimed to characterize treatment patterns, NCC delivery, complications, and outcomes in a large Brazilian public referral center. METHODS: This retrospective cohort study included consecutive adults with confirmed aSAH admitted between June 2018 and March 2022 to a high-volume Brazilian tertiary referral center. Only patients admitted within five days of symptom onset were included. Demographic, clinical, radiological, treatment, complication, and outcome data were extracted from institutional records. Primary outcomes were in-hospital mortality and 3-month functional outcome assessed by the modified Rankin Scale (mRS). RESULTS: Seventy-four patients were included. Disease severity was high, with 45% presenting WFNS grades 4-5, 73% modified Fisher grade 4 hemorrhage, and 64% hydrocephalus. Endovascular treatment was performed in 73% of cases, and median time from admission to aneurysm treatment was 1&#xa0;day. Despite early treatment capability, only 28% of patients were admitted to an ICU within 48&#xa0;h, while 38% never received ICU care. Delayed cerebral ischemia occurred in 43%, radiologic vasospasm in 58%, ventriculitis in 22%, and infectious complications in 57%. External ventricular drainage was required in 42%, and vasoactive drugs were used in 85%. In-hospital mortality was 42%, and 66% had unfavorable 3-month outcomes (mRS 4-6). CONCLUSIONS: This real-world cohort highlights the substantial neurocritical care burden of aSAH in a middle-income public healthcare system. Despite timely access to definitive aneurysm treatment, patients experienced frequent neurological and systemic complications, emphasizing that contemporary aSAH care extends well beyond aneurysm occlusion.

Humans

Loss of PBRM1 accelerates pancreatic cancer progression by inducing acquisition of mesenchymal phenotype and inflammatory cancer-associated fibroblasts reprogramming.

BACKGROUND: PBRM1 is an important subunit of the SWI/SNF complex, which broadly regulates gene transcription by chromatin remodeling. Genomic alterations of PBRM1 have been found in patients with pancreatic ductal adenocarcinoma (PDAC), but its molecular functions remain unclear. METHODS: Clinical relevance of PBRM1 was analyzed by using human PDAC samples and public genomic datasets. Mice with concomitant pancreas-specific Pbrm1 deletion in Kras-driven genetic PDAC models were generated. Single-cell transcriptomics were performed to determine tumor phenotype and microenvironment reprogramming. RESULTS: Reduction of PBRM1 expression was observed in human PDAC tissues and correlated with poor prognosis and metastasis. Pbrm1 loss promoted ductal metaplasia and delayed epithelial recovery in mice with caerulein-induced pancreatic injury. In PDAC model with either mutant Kras alone or in combination with Trp53 mutation, lack of Pbrm1 markedly accelerated tumor development and progression. Bulk transcriptomics and scRNA-seq identified reprogramming of both tumor compartment with mesenchymal phenotype acquisition and stroma compartment with inflammatory cancer-associated fibroblasts (iCAFs) transformation. Mechanistically, Pbrm1 deletion induced Zeb1 upregulation through epigenetic chromatin remodeling, thereby enhancing epithelial-mesenchymal and basal-like subtype transition. CONCLUSIONS: These findings indicated a tumor-suppressing role of PBRM1 in PDAC. PBRM1-deficient PDAC constitutes a specific subgroup of patients with aggressive phenotype and prognostic significance.

Animals

Policy paper of the Committee on Ethics and Task Force on Migration and Mental Health: Migration and mental health of migrants, refugees, asylum seekers - Ethical dilemmas and concerns.

BACKGROUND: International migration is a complex phenomenon of global and historical relevance. It includes voluntary, forced, and workforce migration, shaped by diverse determinants. Push factors comprise war, persecution, and political instability, while pull factors include stability, economic opportunities, education, and favorable living conditions. Forced migration is frequently associated with displacement and a disproportionate burden of mental health disorders, which are urgent yet difficult to address due to structural, cultural, and legal barriers. METHODS: Evidence demonstrates that restricted health care access exacerbates psychiatric disorders, while treatment delays contribute to poorer outcomes. Barriers include administrative limitations, linguistic and cultural differences, stigma, and resource shortages. This policy paper was developed by the Committee on Ethics and the Task Force on Migration and Mental Health of the European Psychiatric Association (EPA). Relevant literature was reviewed and combined with the professional expertise of committee members. The draft was subsequently evaluated by the Publication Committee and the EPA Board, and revised accordingly. RESULTS: Ethical principles in refugee care are insufficiently implemented in many European countries. Core principles of medical ethics - beneficence, respect for autonomy, non-maleficence, and justice - as well as the obligation to advance psychiatric standards and apply psychiatric expertise for societal benefit, are inconsistently upheld. CONCLUSIONS: The primary duty of physicians is to promote health and well-being through competent, timely, and compassionate care. The EPA therefore advocates coordinated strategies to mitigate the mental health consequences of war, displacement, and trauma, and to secure equitable access to psychiatric services for migrants and refugees.

Humans

Association of Baloxavir Treatment Timing with Serial Interval and Household Transmission of Influenza through a Likelihood-Based Analysis.

BACKGROUND: Baloxavir treatment is associated with reduced influenza transmission within households, and the serial interval varies by treatment status. However, it remains unclear how baloxavir-induced changes in the serial interval relate to household transmission. We aimed to quantify the model-based association between baloxavir treatment timing and the serial interval and household transmission risk. METHODS: We conducted a household survey of influenza cases in Japan between October 2018 and February 2019. We defined the likelihood-based model integrating the serial interval distribution by treatment status and the secondary attack rate (SAR) using individual-level data from index cases. Using this model, we estimated the reduction in the serial interval associated with baloxavir treatment. RESULTS: Compared with untreated index cases, baloxavir-treated cases were estimated to have a serial interval density reduced by 21.42% following treatment. Treatment within 24 hours was associated with a 0.1685 reduction in the area under the curve, with smaller reductions as treatment was delayed. Earlier treatment was associated with a shorter, more concentrated distribution, whereas treatment 72 hours after onset resembled untreated cases. CONCLUSIONS: Our findings highlight that baloxavir treatment is associated with a shorter serial interval and lower estimated secondary household transmission risk. We provide model-based estimates suggesting that earlier administration is associated with a greater reduction in serial interval density and estimated transmission risk, which may inform public health strategies for infection control.

Influenza