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PubMed2026

CHEK2 Germline Variants in Cancer Predisposition: Whole Genome Sequencing Results.

While pathogenic germline CHEK2 variants are known to increase cancer risk, there is currently insufficient evidence regarding the precise risk of developing malignant neoplasms associated with specific missense variants or variants of uncertain significance. As a result, no clear clinical guidelines exist regarding consultation, monitoring and specific treatment options for those patients. For the first time in Russia, clinical data and whole-genome sequencing (WGS) results were analyzed for 3150 patients with cancer and suspected hereditary cancer syndromes (HCS) and 5163 healthy individuals. This dataset formed the basis for assessing the role of germline CHEK2 variants in the development of different cancer types. The chromosomal coordinates and coding sequence coordinates are given in accordance with the GRCh38 (hg38) genome assembly and the NM_007194.4 transcript. Pathogenic (P) and likely pathogenic (LP) variants of CHEK2 significantly increased the risk of breast cancer (OR = 2.015 [95% CI: 1.27-3.21]; p = 0.0031), but the association with colorectal cancer was not statistically significant (OR = 1.354 [95% CI: 0.42-4.42]; p = 0.616). A moderate increase in cancer risk was identified for the c.1100del variant (OR = 2.263 [95% CI: 1.19-4.32]; p = 0.0132) and for the common P/LP variants c.1100del, c.444+1G>A and c.433C>T (OR = 2.219 [95% CI: 1.40-3.51]; p = 0.0007). Notably, our study confirmed that CHEK2 c.470T>C (p.Ile157Thr) is the most common variant in the patient group, identified in 3.8% of cases (120/3150), compared with 3.0% in the control group (155/5163). Although the association between the most common CHEK2 variant c.470T>C and cancer risk reached nominal statistical significance (OR = 1.279 [95% CI: 1.00-1.63]; p = 0.0463), the effect size was minimal, suggesting that the contribution of this variant to hereditary cancer risk in the Russian population is modest. Additional studies are required before this variant can be definitively excluded from clinical interpretation.

Humans↗

PubMed2026

First detection of African swine fever in a swine farm in Taiwan.

INTRODUCTION: African swine fever (ASF) is a highly contagious, high-consequence transboundary animal disease that poses a critical threat to global swine production and agricultural economics. Since its emergence in China in 2018, ASF has spread to over 20 Asia-Pacific countries, causing significant economic disruption. While Taiwan previously detected ASF virus several times in dead pigs drifting offshore, or in illegal pork-related products brought by international tourists and inspected at airport and seaport border controls, no local domestic swine farm had tested positive before this October 2025 ASF event. However, maintaining this disease-free status requires constant vigilance against evolving regional biosecurity threats. METHODS: The first ASF detection in a domestic swine herd in Taichung City, Taiwan, reported on October 22, 2025, was triggered by abnormal alerts of the monitoring system in the rendering plant; the index farm captured a cumulative herd mortality rate of 35.2% that exceeded the predefined threshold (3% mortality daily in the nursery to finish pigs). Five finisher pigs were submitted for diagnostic evaluation, which subsequently confirmed ASFV infection via real-time PCR, pathological examination, immunohistochemistry, virus isolation, and whole-genome sequencing. RESULTS: Affected pigs showed clinical signs including wheezing, sudden death, nasal bleeding, uncoagulated blood in the nostrils, and mild hemorrhage on the skin surface of the neck, abdomen, and buttocks. Histopathological examination revealed severe multisystemic hemorrhagic lesions. Based on assay results of the P72, P54, P30, and CD2v genes, and whole-genome sequence, phylogenetic analysis confirmed that the isolate (ASFV/TWN/2025) is a genotype I/II recombinant strain, most similar to prevailing strains isolated in China and Vietnam, sharing 99.95%-99.97% and 99.92%-99.97% nucleotide similarity of whole genome sequence, respectively. DISCUSSION: Upon confirmation of the ASF case, authorities immediately implemented a nationwide swine movement standstill for 15 days to mitigate transmission risk. To date, no secondary cases have been detected. This article details the early monitoring and rapid diagnosis process of the first case of ASF infection in a farm in Taiwan, and highlights the information from this case to provide lessons for disease diagnosis and prevention in ASF-free areas.

African swine fever↗

PubMed2024

LRP4 mutations promote tumor progression and resistance to anti-PD-1 therapy in recurrent hepatocellular carcinoma.

BACKGROUND AND AIMS: HCC recurrence is a major factor limiting long-term survival and the cause of most deaths in patients with HCC. However, molecular characterization and potential therapeutic targets of recurrent HCC remain mostly unknown. APPROACH AND RESULTS: We performed whole-exome sequencing in 63 matched primary and recurrent HCC tumors and combined the data with whole-genome sequencing results in 43 paired samples from our previous study. Sanger sequencing was used to identify all low-density lipoprotein receptor-related protein 4 ( LRP4 ) coding exons in 203 additional patients with recurrent HCC. We identified LRP4 somatic mutations in 7.8% (24/309) of recurrent tumors and only 0.97% (3/309) of primary tumors ( p <0.001). Prognosis after the second liver resection was poorer in patients with an LRP4 mutation. Biofunctional investigations demonstrated that inactivating LRP4 mutations promoted tumor progression and immunosuppression. Mechanistically, mutated LRP4 reduced intratumoral conventional type 1 dendritic cell and CD8 + T cell infiltration by repressing C-C motif chemokine ligand 4 expression and secretion through activation of β-catenin signaling, resulting in resistance to anti-programmed cell death protein-1 therapy. Patients with recurrent HCC carrying an LRP4 mutation did not benefit from anti-programmed cell death protein-1 treatment after their second resection surgery. A β-catenin inhibitor-reversed LRP4-induced resistance to anti-programmed cell death protein-1 therapy in humanized tumor-bearing mice. CONCLUSIONS: Our results identified novel LRP4 mutations important in recurrent HCC. Inactivating LRP4 mutations were associated with resistance to anti-programmed cell death protein-1 therapy and could be useful biomarkers for precision therapy in patients with recurrent HCC.

Humans↗

PubMed2026

Heterozygous germline mutations in MSH3, and probably MLH3, act as classical tumour suppressors, leading to excess somatic deletion mutations, signature ID4 and increased colorectal cancer risk.

BACKGROUND: MSH3 and MLH3 are non-canonical DNA mismatch repair genes, involved in repairing insertion-deletion mutations. Colorectal cancer (CRC) and adenomas have been reported in patients with bi-allelic germline MSH3 mutations, and in a very few bi-allelic MLH3 mutation carriers. OBJECTIVES: We hypothesised that germline loss-of-function MSH3 and MLH3 mutations were akin to constitutional mismatch repair deficiency (cMMRd) and Lynch syndrome, such that CRC could result from either bi-allelic germline mutations or heterozygous germline mutations after second hits. DESIGN: About 12 000 CRC and multiple polyp cases and 460 000 controls were studied. 2023 patients underwent cancer genome sequencing. RESULTS: One CRC/multiple polyp case had bi-allelic MSH3 mutations and another, bi-allelic MLH3 mutations. MSH3 and MLH3 germline heterozygotes had an increased risk of CRC (2.2-fold, p=6.6×10-5 and 1.6-fold, p=0.028, respectively), owing to somatic 'second hits' that inactivated the wildtype allele. Single second hits sometimes inactivated both MSH3 and the nearby APC gene. All CRCs with MSH3 or MLH3 deficiency were microsatellite-stable but hypermutant. Deletions of ≥2 bp were particularly increased (~12-fold) and signature ID4 was usually present (p<0.0001). CRCs from heterozygotes without 'second hits' showed no hypermutation. CONCLUSION: The phenotypes of bi-allelic MSH3 and MLH3 mutation carriers resemble some patients with cMMRd. Heterozygous germline MSH3 and MLH3 alleles have incomplete penetrance, but increase CRC risk via hypermutation, phenotypically resembling PMS2-mutant Lynch syndrome. A causal association with specific mutations has not previously been reported for ID4 in human tumours. ID4 probably does not have a single aetiology, but can result from MSH3 or MLH3 deficiency.

COLONIC POLYPS↗

PubMed2026

Antimicrobial susceptibility patterns of commensal fecal bacteria isolated from pigs with an intentional genomic alteration that included the selectable marker gene nptII.

INTRODUCTION: Animals with intentional genomic alterations (IGAs) hold promise for meeting increasing worldwide demand for animal-source proteins. As part of regulatory risk assessment for introducing animals with IGAs into the food chain, monitoring commensal bacterial microbiota is recommended due to concern that antimicrobial resistance genes used during IGA selection could be transferred, via horizontal gene transfer, to gastrointestinal or environmental bacterial populations, potentially contributing to antimicrobial resistance. The objective of this study was to assess the antimicrobial susceptibility patterns in commensal bacteria isolated from fecal samples of GalSafe™ pigs that have an IGA that includes the aminoglycoside resistance gene nptII. METHODS: Antimicrobial resistance rates observed in Escherichia coli, Salmonella, Campylobacter and Enterococcus isolated from GalSafe™ pigs were compared to resistance rates observed in conventional pigs at slaughter. Bacterial isolates were tested for antimicrobial resistance genes by PCR and one isolate underwent whole genome sequencing. RESULTS: In total, 137 bacterial isolates recovered from 55 fecal samples collected from 47 individual adult GalSafe™ pigs were evaluated. Prevalence of antimicrobial resistance in GalSafe™ pigs was generally similar to, or lower than, resistance prevalence reported from conventional pigs at slaughter, based on National Antimicrobial Resistance Monitoring System (NARMS) data. Higher resistance rates in GalSafe™ pigs were observed only for quinolones in Campylobacter coli (ciprofloxacin and nalidixic acid) and nitrofurantoin in Enterococcus spp. One isolate (E. coli) was positive for nptII neomycin resistance gene, the same gene used for IGA selection in GalSafe™ pigs, and the remaining 136 isolates were negative for nptII. However, the positive isolate did not appear to contain nptII derived from the GalSafe™ pig genome as the sequences flanking the gene did not match the IGA. DISCUSSION: We did not detect evidence of nptII gene transformation into bacterial species of potential human health importance in this population of GalSafe™ pigs.

NARMS↗

PubMed2025

Genetic analysis of three patients from two unrelated Chinese families with autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, spasticity, and sensorimotor peripheral neuropathy. This disorder is caused by homozygous or compound heterozygous variants in the sacsin (SACS) gene on chromosome 13q12.12. Three patients with ARSACS from two unrelated Chinese families were recruited for this study. Patient #1 was an 18-year-old male who had been walking unstably for 12 years. Patient #2, the younger sister of Patient #1, was a 5-year-old girl who had been walking unstably for 2 years. Patient #3 was a 19-year-old female who had been walking unstably and a tendency to fall for 17 years. For Patient #1, whole-exome sequencing (WES) identified a hemizygous variant c.8310_8313delAGAT (p.Asp2771fs4*) in SACS (NM_014363.6), with the father being heterozygous, the mother wild-type, and Patient #2 hemizygous, as verified by Sanger sequencing. Additional copy number variant analysis of the WES data indicated that Patient #1 had a heterozygous gross deletion of chr13q12.12 (chr13:23,808,732 - 24,890,322). Low-coverage whole-genome sequencing results revealed that Patient #2 carried a chr13q12.12 deletion (chr13:23,520,000-24,940,000). Together with Sanger sequencing results, this gross deletion was speculated to have been inherited from the mother, further explaining the hemizygous state of c.8310_8313delAGAT (p.Asp2771fs4*) in Patients #1 and #2. Through WES, Patient #3 was identified as having suspected compound heterozygous variants of c.2881 C > T (p.Arg961*) and c.6409 C > T (p.Gln2137*), inherited from the father and mother, respectively, as confirmed by Sanger sequencing. This study identified three variants in SACS. The c.8310_8313delAGAT (p.Asp2771fs4*) is novel, whereas c.2881 C > T (p.Arg961*) and c.6409 C > T (p.Gln2137*) have been reported previously. Moreover, this study highlights the growing trend that ARSACS has become increasingly prevalent worldwide rather than being localized to a specific region or race. As an increasing number of patients with ARSACS are diagnosed, the genetic spectrum of ARSACS will gradually broaden, providing an accurate genetic basis for prenatal diagnosis of mothers in the years ahead, if possible.

Adolescent↗

PubMed2026

Parallel single-cell host immune profiling and pathogen genomic characterization in Klebsiella-associated sepsis: a pilot study.

OBJECTIVES: Sepsis is a life-threatening syndrome characterized by profound immune dysregulation and substantial biological heterogeneity. Here, we conducted a pilot study to explore host immune remodeling in Klebsiella-associated sepsis by combining single-cell RNA sequencing of peripheral blood mononuclear cells with whole-genome sequencing of the corresponding bloodstream isolates. METHODS: In this prospective observational pilot study, we analyzed peripheral blood mononuclear cells (PBMCs) from two patients with Klebsiella-associated sepsis and two healthy controls (HC) using single-cell RNA sequencing. PBMC composition, differential transcriptional responses, and pathway analysis were assessed across immune subsets. The corresponding bloodstream isolates were characterized by phenotypic antimicrobial susceptibility testing and whole-genome sequencing. RESULTS: Compared to HC, septic patients showed expansion of the myeloid compartment and contraction of the NK/T compartment. High-resolution analysis suggested shifts within lymphoid populations. At the transcriptional level, sepsis was associated with compartment-specific enrichment of interferon-related and host-defence pathways, as well as oxidative phosphorylation, ATP synthesis, and mitochondrial electron transport signatures across multiple PBMC subsets. Classical monocytes exhibited a coordinated decrease in MHC class II-related transcripts. The sepsis-associated isolates were identified as Klebsiella pneumoniae and Klebsiella variicola and were notable for overall antimicrobial susceptibility, limited resistomes, and absence of canonical hypervirulence determinants. CONCLUSION: Our data provide a preliminary description of immune remodeling during Klebsiella-associated sepsis and suggest that severe clinical disease may be associated with isolates lacking classical multidrug-resistance or hypervirulence features. These findings should be interpreted as preliminary and hypothesis-generating and require validation in larger cohorts with detailed clinical severity assessment.

Female↗

PubMed2024

Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder.

PURPOSE: The thousand and one kinase (TAOK) proteins are a group of serine/threonine-protein kinases involved in signaling pathways, cytoskeleton regulation, and neuronal development. TAOK1 variants are associated with a neurodevelopmental disorder (NDD) characterized by distinctive facial features, hypotonia, and feeding difficulties. TAOK2 variants have been reported to be associated with autism and early-onset obesity. However, a distinct TAOK2-NDD has not yet been delineated. METHODS: We retrospectively studied the clinical and genetic data of individuals recruited from several centers with TAOK1 and TAOK2 variants that were detected through exome and genome sequencing. RESULTS: We report 50 individuals with TAOK1 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (83%), and hypotonia (58%). We report male genital anomalies and hypoglycemia as novel phenotypes. Thirty-seven unique TAOK1 variants were identified. Most of the missense variants clustered in the protein kinase domain at residues that are intolerant to missense variation. We report 10 individuals with TAOK2 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (75%), autism (75%), and obesity (70%). CONCLUSION: We describe the largest cohort of TAOK1-NDD to date, to our knowledge, expanding its phenotype and genotype spectrum with 30 novel variants. We delineated the phenotype of a novel TAOK2-NDD associated with neurodevelopmental abnormalities, autism, macrocephaly, and obesity.

Humans↗

PubMed2026

Aztreonam-avibactam Activity against Enterobacterales from Asia Pacific and Latin American Medical Centres: Summary of 5 years of Surveillance prior to Clinical Use (2020-2024).

OBJECTIVES: To assess the in vitro activity of aztreonam-avibactam against Enterobacterales from the Asia Pacific region (APAC) and Latin America (LATAM) during a 5-year period prior to its approval for clinical use in these regions. METHODS: 12,039 Enterobacterales isolates were consecutively collected in 2020-2024 from 17 medical centres in APAC (n=7,369) and 10 in LATAM (n=4,670) then susceptibility tested by broth microdilution. Carbapenem-resistant Enterobacterales (CRE) and isolates with elevated aztreonam-avibactam MICs (>4 mg/L) were submitted to whole genome sequencing. RESULTS: Aztreonam-avibactam was active against 99.9% of Enterobacterales from APAC and LATAM and exhibited potent activity against CRE isolates (MIC50/90, 0.25/2 mg/L; 97.3% susceptible in APAC and MIC50/90, 0.25/0.5 mg/L; 99.4% susceptible in LATAM). Cefiderocol was active against 91.2% of CREs from APAC and LATAM. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam showed limited activity against CRE isolates from LATAM (53.5% to 64.8% susceptibility) and APAC (27.3% to 38.8% susceptible). The occurrence of carbapenemases varied clearly among the countries evaluated. In general, metallo-β-lactamases (MBLs) prevailed in APAC and KPCs predominated in LATAM, but with great variability among countries within a region. Decreased susceptibility to aztreonam-avibactam was largely due to PBP3 alterations plus the production of CMY and/or CTX-M β-lactamases among Escherichia coli, and decreased membrane permeability associated with KPC production among Klebsiella pneumoniae. CONCLUSIONS: The results of this investigation provide a baseline for monitoring the activity of aztreonam-avibactam in APAC and LATAM and emphasize the importance of surveillance programs to monitor the emergence of resistance markers.

Aztreonam-avibactam↗

PubMed2026

Predictive value of Rectal and Throat-nose Screening for the presence of Multidrug-Resistant Organisms in Duodenal Fluid as a Risk of Duodenoscope Contamination: A Multicenter Study.

BACKGROUND: Duodenoscopes have been implicated in patient-to-patient transmission of multidrug-resistant organisms (MDROs). Current gastrointestinal MDRO surveillance relies on rectal screening, yet the duodenum is the primary site of duodenoscope exposure. This study evaluated the predictive value of rectal and throat-nose screening for detecting duodenal MDROs as a marker of duodenoscope contamination risk. METHODS: Adult patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) at tertiary care centers in the Netherlands and India were included. Rectal swabs, throat-nose swabs, and duodenal aspirates were analyzed for MDROs. The detected MDROs were compared using species identification, antibiotic susceptibility patterns, and whole-genome sequencing. RESULTS: Among 512 participants (Netherlands: 339; India: 173), rates of duodenal and rectal MDRO carriage were higher in India (56.6% (98/173); 79.8% (138/173), respectively) than in the Netherlands (5.6% (19/339); 10.3% (35/339)). Given the low prevalence of throat-nose carriage, only the predictive value of rectal screening was assessed. Rectal screening sensitivity for genetically related strains in duodenal fluid was 32.7% in India and 68.4% in the Netherlands . For detecting any duodenal MDRO, sensitivity reached 91.8% in India and 84.2% in the Netherlands, with specificities of 36.0% and 94.1%. Positive predictive value (PPV) was low (India: 65.2%; Netherlands: 45.7%), while negative predictive value was 77.1% and 99%, respectively. CONCLUSIONS: Rectal screening is unreliable for detecting strain-specific duodenal MDROs and overestimates true carriage due to low PPV values. However, it provides excellent rule-out value in low-prevalence settings. Consequently, its utility for guiding infection prevention strategies for duodenoscope contamination is greatest in low-MDRO-prevalence regions.

Bacterial↗

PubMed2025

The efficacy of a filtered handheld far-ultraviolet disinfection device for decontamination of high-touch surfaces in healthcare settings: a genomic bacterial analysis.

BACKGROUND AND OBJECTIVES: Enhanced environmental disinfection is linked to reduced hospital-acquired infection rates. In this study, we aimed to evaluate the efficacy of an emerging disinfection technology, a filtered far-UV-C handheld (FFUHH) device, for reducing bacterial loads on high-touch surfaces in shared clinical workrooms, and to isolate, identify and characterize clinically significant environmental pathogens. METHODS: We compared samples from high-touch items (dictation device, mouse, armchair, desk, and keyboard) before and after FFUHH treatment. Samples were collected weekly: contact plates for colony counts and swabs before and after intervention on standardized adjacent areas for each surface, respectively. The swabs were enriched and cultured on selective media to isolate pathogens. Environmental samples, as well as clinical samples collected from patients during the study period, were validated using MALDI-TOF and whole genome sequencing. RESULTS: Among the 440 collected plates (220 before and 220 after treatment), the highest mean colony count pre-treatment was detected from armchairs, and the lowest from keyboards. The mean reduction of colony-forming units ranged 53% and 83% and was statistically significant (P < 0.05) across all surfaces except for the keyboard. We characterized multidrug-resistant Staphylococcus epidermidis ST5 and ST16 strains, a carbapenem-resistant Acinetobacter baumannii, and a Klebsiella pneumoniae genetically related to a clinical isolate with a rare sequence type not previously detected in our institution. CONCLUSION: The FFUHH effectively reduced the microbial burden on high-touch surfaces. It can offer an advantage for surface disinfection and an alternative to routinely used biocides.

Humans↗

PubMed2025

Multiple features of cell-free mtDNA for predicting transarterial chemoembolization response in hepatocellular carcinoma.

BACKGROUND: Transarterial chemoembolization (TACE) is the primary treatment modality for advanced HCC, yet its efficacy assessment and prognosis prediction largely depend on imaging and serological markers that possess inherent limitations in terms of real-time capability, sensitivity, and specificity. Here, we explored whether multiple features of cell-free mitochondrial DNA (cf-mtDNA), including copy number, mutations, and fragmentomics, could be used to predict the response and prognosis of patients with HCC undergoing TACE treatment. METHODS: A total of 60 plasma cell-free DNA samples were collected from 30 patients with HCC before and after the first TACE treatment and then subjected to capture-based mtDNA sequencing and whole-genome sequencing. RESULTS: Comprehensive analyses revealed a clear association between cf-mtDNA multiple features and tumor characteristics. Based on cf-mtDNA multiple features, we also developed HCC death and progression risk prediction models. Kaplan-Meier curve analyses revealed that the high-death risk or high-progression-risk group had significantly shorter median overall survival (OS) and progression-free survival than the low-death risk or low-progression-risk group (all p<0.05). Moreover, the change in cf-mtDNA multiple features before and after TACE treatment exhibited an exceptional ability to predict the risk of death and progression in patients with HCC (log-rank test, all p<0.01; HRs: 0.36 and 0.33, respectively). Furthermore, we observed the consistency of change between the cf-mtDNA multiple features and copy number variant burden before and after TACE treatment in 40.00% (12/30) patients with HCC. CONCLUSIONS: Altogether, we developed a novel strategy based on profiling of cf-mtDNA multiple features for prognosis prediction and efficacy evaluation in patients with HCC undergoing TACE treatment.

Humans↗

PubMed2026

Influenza-related Deaths in Young Children: Observations From a German Case Series.

BACKGROUND: Seasonal influenza virus infections remain a major public health burden. During the last years, several case reports of severe influenza infections in children have been published. CASES: We report 4 fatal influenza cases in young children (2-6 years old) which occurred in Southwest Germany in the seasons 2022/23 and 2023/24. All 4 children were previously healthy; a forensic autopsy was conducted due to an unknown cause of death. Postmortem samples from the respiratory tract and organ tissues were tested for respiratory viruses via real-time polymerase chain reaction (RT-PCR) and analyzed by whole-genome sequencing. RESULTS: In 1 child, RT-PCR revealed influenza B virus, and 3 children died with influenza A (H1N1)pdm09 infection. No mutations associated with high virulence were detected. In 1 case, influenza A(H1N1)pdm09 could be cultivated in cell culture from brain tissue. CONCLUSIONS: This case series underlines the potential risk of fatal outcomes of influenza infections in children. This should be considered when re-evaluating the vaccination recommendations for healthy children.

Humans↗

PubMed2025

Clinical and laboratory profiles of Oropouche virus disease from the 2024 outbreak in Manaus, Brazilian Amazon.

BACKGROUND: The 2024 Oropouche virus (OROV) outbreak in Brazil raised public health concerns due to its unprecedented rapid spread, high incidence, and potential neurological complications. OROV symptoms overlap with locally endemic arbovirus diseases, like dengue virus (DENV), complicating diagnosis. The study aimed to compare clinical, laboratory, and immunological profiles in OROV and DENV cases, crucial for improving diagnosis and management. METHODS: This study analyzed 51 OROV and 78 of DENV cases consecutively enrolled in Manaus, Amazonas, Brazil, and monitored for 28 days. OROV diagnosis was performed by real-time PCR (RT-PCR) using serum and urine samples. OROV RT-PCR positive samples were genotyped. A paired Plaque Reduction Neutralization Test (PRNT) was conducted on samples collected at D1 and D28. Patients with a ≥ 4-fold increase in neutralizing antibody titer between D1 and D28 were considered OROV-positive. Clinical manifestations, hematology, biochemistry, and cytokine profiles were analyzed. Statistical analysis included comparison between OROV and DENV patients. RESULTS: Genome sequencing of OROV isolates confirmed presence of a previously reported novel reassortment event, consistent with ongoing localized transmission. Urine RT-PCR demonstrated low positivity compared to serum samples. The paired PRNT increased sensitivity in 45%. Clinically, OROV infection was associated with significantly higher frequencies of severe headache, myalgia, arthralgia, and rash compared to DENV infection (p < 0.001). Elevated alanine aminotransferase (ALT) levels were also observed in OROV patients (p < 0.001). Immunologically, OROV infection induced significantly increased levels of acute-phase CCL11 (eotaxin), CXCL10, IFN-γ, IL-1RA, and IL-10, which declined by day 28, while IL-5 increased during recovery. In contrast, DENV patients exhibited elevated levels of CCL2, G-CSF, and CCL3 in recovery phase. CONCLUSION: OROV symptoms overlap with DENV underscores the need for syndromic diagnostic approach in endemic regions. Continued genomic surveillance and expanded clinical studies are vital to assess long-term consequences. Given OROV's expanding geographic range, targeted public health measures are essential to mitigate future outbreaks and better understand its pathophysiology.

Humans↗

PubMed2026

Hospital transmission of methicillin-resistant Staphylococcus aureus driven by addictive mupA plasmids.

BACKGROUND: Resistance to mupirocin, a cornerstone of Staphylococcus aureus decolonization, is a recognized cause of decolonization failure. Its role in hospital transmission is unknown. METHODS: We conducted genomic surveillance of >10,000 S. aureus isolates from adult patients at two urban hospitals where mupirocin decolonization is routine. Bacterial phenotypes and fitness were evaluated in vitro and in murine colonization models to interpret surveillance results. RESULTS: Genome sequencing identified 475 hospital transmission events; conventional surveillance detected none. The plasmid-mediated resistance determinant mupA ( ileS2 ) was enriched eightfold in methicillin-resistant S. aureus (MRSA) relative to methicillin-susceptible strains. mupA was associated with nearly threefold greater hospital transmission, especially within healthcare-associated MRSA lineages. Surprisingly, multiple independently evolved inactivating mutations in the essential chromosomal gene ileS1 co-occurred with mupA , creating plasmid addiction in which mupA became indispensable for bacterial survival. Plasmid carriage activated the stringent response and reduced colonization fitness, but also conferred collateral tolerance to disinfectants such as ethanol and peroxide. Although addiction further reduced S. aureus fitness, it increased plasmid transfer, promoting spread despite these costs. Unexpectedly, we found a mupirocin-dependent vulnerability to isoleucine limitation, revealing a potential strategy to target mupA -mediated resistance. CONCLUSIONS: Hospital transmission of mupirocin-resistant MRSA is promoted by plasmids that create an evolutionary trap in which mupirocin use selects for bacterial dependence on costly resistance elements. These findings suggest that reducing mupirocin use alone is unlikely to eliminate resistance, underscore the need for genomic surveillance and resistance testing, and provide a framework for strategies to preserve mupirocin effectiveness. MAJOR POINT: This work shows that mupirocin resistance promotes hospital transmission of MRSA, identifies a previously unappreciated mechanism of plasmid addiction, and exposes a collateral vulnerability. These findings underscore the need for genomic surveillance and provide a framework to preserve mupirocin effectiveness.

Journal Article↗

PubMed2025

Genetic Determinants of Leisure-Time Physical Activity in the Taiwanese Population: A Genome-Wide Association Study.

BACKGROUND: Physical inactivity contributes to systemic disease burden and premature mortality worldwide. Leisure-time physical activity (LTPA) improves health outcomes; however, its genetic determinants, particularly in Asian populations, remain unclear. This study aimed to identify genetic loci associated with LTPA in the Taiwanese population. METHODS: We conducted genome-wide association studies in 122,258 Taiwan Biobank participants. LTPA was assessed both as a binary trait (regular exerciser vs non-exerciser) and an ordinal trait (categorized by MET-hours per week into low, moderate, and high physical activity levels). Logistic and ordinal logistic regression models were used under an additive genetic model, adjusting for age, age 2 , sex, body mass index, smoking, and the first 10 genetic principal components. Candidate nonsynonymous mutations were further examined in 1494 whole-genome sequenced participants. RESULTS: Binary trait genome-wide association studies identified genome-wide significant (GWS) loci at ATXN2 (12q24.12), FTO (16q12.2), and NOTCH4 (6p21.32), with associations for FTO and NOTCH4 only observed in body mass index (BMI)-adjusted models. Ordinal trait analysis (<10, 10-<20, ≥20 MET·h·wk -1 ) identified a single GWS locus at BRAP (12q24.12). Fine-mapping of 12q24.12 revealed multiple GWS single-nucleotide polymorphisms (SNPs) in strong linkage disequilibrium with lead variants; these signals largely disappeared after conditional analysis, consistent with a single underlying association. Whole-genome sequencing and linkage disequilibrium analysis identified three GWS nonsynonymous mutations, with ALDH2 rs671 emerging as the most likely causal variant. CONCLUSIONS: ATXN2-ALDH2 region on chromosome 12q24.12 was identified as a key locus for LTPA in Taiwanese individuals. These findings enhance our understanding of the genetic basis of physical activity and may inform future precision medicine and public health strategies.

Adult↗

PubMed2026

Evaluation of amplicon-based nanopore sequencing for foot-and-mouth disease viruses in clinical and environmental samples.

Foot-and-mouth disease (FMD) causes severe global economic loss, necessitating rapid viral characterization. Nanopore sequencing provides a simple, real-time workflow suitable for on-site outbreak response, addressing the limitations of conventional methods. In this study, we optimized a previously published amplicon-based protocol and used this method to characterize a diverse range of samples (vesicular fluid, epithelium, serum, nasal/oral swabs, and environmental samples) collected during FMD outbreaks in 2025 in the Republic of Korea. Of the 129 samples collected, we successfully recovered complete genomes from 37 samples and VP1 sequences from 85 samples. Amplifying the S-fragment in isolation and separately barcoding each pool of PCR amplicons markedly improved sequence recovery. Furthermore, sequencing success depended on viral load and sample type. Based on comparisons with real-time RT-PCR results, whole-genome sequence (WGS) recovery exceeded 77.3% at cycle threshold (Ct) values ≤25 across all clinical samples. In the Ct > 30 category, serum samples yielded the highest WGS recovery rates (44.4%). This rate was markedly higher than the success rates observed for epithelium (20.0%) and nasal swabs (9.1%), whereas oral swabs and environmental samples failed to yield any sequences (0%). However, VP1 recovery from environmental samples reached 80% at Ct ≤ 30 (8/10), providing an approach to enable non-invasive monitoring. These findings demonstrate that amplicon-based nanopore sequencing is a practical method for the rapid generation of genomic data during FMD outbreaks.IMPORTANCEAlthough rapid detection and genomic data analysis are crucial for effective foot-and-mouth disease (FMD) control, the collection of these data can be challenging for certain sample types and impacted by reduced viral loads that result from nationwide FMD vaccination. This study provides a practical solution through large-scale evaluation of an optimized amplicon-based nanopore sequencing protocol to enhance the sequencing success rates for both clinical and environmental samples. Using a modified protocol to enhance genome recovery, we demonstrated that sequence data could be retrieved from diverse sample types (even with high real-time RT-PCR cycle threshold values). We identified serum as the most suitable sample, with environmental sample sequencing allowing for non-invasive monitoring during outbreaks. These results support the use of nanopore sequencing for rapid genomic analysis, particularly in outbreak responses, such as rapid surveillance, emergency vaccine selection, and epidemiological monitoring.

Foot-and-Mouth Disease↗

PubMed2026

Are Staphylococcus aureus fracture-related infections clonal, and what are the implications for bacteriophage therapy?

Fracture related infections (FRI) are a devastating complication of orthopedic trauma care, most commonly caused by Staphylococcus aureus. The organisms' ability to form biofilms complicates conventional antibiotic therapy and drives demands for novel therapeutics. One promising novel approach is bacteriophage therapy, however this therapeutic has a narrow host range. Thus, understanding whether S. aureus FRIs are clonal or polyclonal is crucial for development of bacteriophage therapy. Consequently, the aim, of this study, was to evaluate 15 S. aureus clinical FRI isolates to determine clonality. For each individual FRI, eight colonies underwent whole-genome sequencing and results were compared to a reference strain to determine genomic variants. Isolates from each individual patient demonstrated greater than 92% shared genomic variants and over a 98% overlap with a merged variant profile, indicating clonal infections across all 15 FRIs. Furthermore, we assessed bacteriophage K activity to the planktonic states of the isolates for which there was similar activity against each individual FRI but different activity amongst the 15 FRI isolates. Lastly, we evaluated variations of genes associated with bacteriophage attachment receptors glycosylation (tarS, M, P) in which there were identical sequences across colonies for each individual FRI, indicating limited intra-infection variation in glycosylation potential of this receptor. This data supports that S. aureus FRI are clonal infections which typically have uniform bacteriophage attachment receptor glycosylation profiles within individual infections. These findings are vital for the development of bacteriophage therapy, suggesting that a single S. aureus colony is sufficient to conduct in vitro testing to determine bacteriophage activity to planktonic forms of S. aureus FRI in vivo. Yet further similar studies evaluating sessile heterogeneity are warranted. Nonetheless, the foundation of knowledge seen here supports further translational research and refinement of bacteriophage therapeutic strategies for S. aureus FRI.

Bacteriophage therapy↗