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PubMed2026

Emerging trends in invasive Streptococcus dysgalactiae subsp. equisimilis infections in Denmark, 2014 to 2024: a nationwide genomic and registry-based study.

BACKGROUNDIncreasing incidence rates of invasive Streptococcus dysgalactiae subspecies equisimilis (iSDSE) have been detected worldwide.AIMWe aimed to investigate iSDSE infection incidence rates in Denmark during 2014-2024, and characterise the genomic population structure of a subset of iSDSE isolates and their antimicrobial resistance (AMR).METHODSUsing national register data, we estimated overall and sex-/age-stratified iSDSE incidences during 2014-2024, by retrospectively identifying cases of invasive infections with group C and G streptococci or S. dysgalactiae (including specified as subspecies equisimilis). From the voluntary national beta-haemolytic streptococci laboratory surveillance system, whole-genome-sequenced isolates from August 2020-September 2022 were used to investigate the iSDSE genomic population structure. Susceptibility to penicillin, erythromycin and clindamycin was determined and AMR genes identified.RESULTSDuring 2014-2024, iSDSE incidence rates increased significantly (linear trend analysis p < 0.001) with mean annual incidence ranging between 10.3 and 16.4 per 100,000, peaking in 2023. Incidence was higher in males, increasing with older age. Nearly 75% of the 1,223 iSDSE isolates belonged to four of 14 genetic clusters. Sequence types (STs) ST20 and ST17 were most prevalent, while emm-type stG62647, a variant associated internationally with higher virulence, dominated. All isolates were phenotypically susceptible to penicillin but approximately 10% were respectively erythromycin and clindamycin resistant. High erythromycin resistance prevalence (57%; 39/68), coinciding with gene ermA, occurred in one genetic cluster.CONCLUSIONThe findings illustrate the need for national registry-based surveillance to detect epidemiological changes and potential outbreaks. Further, continuous genomic surveillance can monitor the occurrence and expansion of genetic clades and AMR genes.

Denmark↗

PubMed2026

Plasma donation rates and infection risk: A multicentre observational study in Denmark.

BACKGROUND AND OBJECTIVES: The demand for plasma-derived medicinal products underscores the need to assess health effects of plasma donation. This study examines the association between plasma donation rates and infection risk in a country with voluntary, non-remunerated donation. MATERIALS AND METHODS: From 2016 to 2024, 45,615 first-time plasma donors were enrolled in a cohort study with time-varying exposure. Follow-up began 90 days after the first plasma donation, with donation rates recalculated every 90 days. Donation rates were categorized as 0, 1 (reference), 2-3, 4-5 or 6-8 donations. Infection was defined using Danish health registers. Survival models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: The median plasma donation rate was 2 (Q1, 1; Q3, 4). During follow-up, 15,498 donors experienced an infection. A trend of decreasing HRs for infection was observed with higher donation rates compared with a single donation (0 donations: HR: 0.89, 95% CI: 0.86-0.93; 2-3 donations: HR: 0.85, 95% CI: 0.81-0.89; 4-5 donations: HR: 0.65, 95% CI: 0.59-0.72; and 6-8 donations: HR: 0.48, 95% CI: 0.36-0.62). Findings were consistent across multiple regression models. CONCLUSION: In this study, higher plasma donation rates were associated with lower infection risk. Importantly, this inverse association is likely due to bias inherent to observational designs, particularly the internal healthy donor effect, which limits interpretation. Thus, no causal relationship between plasma donation rates and infection risk can be inferred. This underscores the challenges of assessing plasma donation safety using non-randomized data.

Adult↗

PubMed2026

Risk of neurodevelopmental disorders associated with paternal use of valproate during spermatogenesis: a living meta-analysis-version 1.

OBJECTIVE: To evaluate the association of paternal use of valproate during spermatogenesis compared with paternal use of lamotrigine or levetiracetam on offspring risk of neurodevelopmental disorders (NDDs). METHODS: Eligibility criteria: observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate vs lamotrigine or levetiracetam during spermatogenesis. INFORMATION SOURCES: the databases PubMed, Embase, Cochrane Library and Web of Science were systematically searched from January 1995 to October 2025.Synthesis of results and risk of bias: a random-effects model was used to estimate pooled HRs and 95% CI, with heterogeneity assessed using I2 statistic for any NDD.We present a meta-analysis of observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate versus lamotrigine or levetiracetam during spermatogenesis. Given the major regulatory implications of paternal valproate safety, the recent emergence of new population-based data, and the expectation of further large studies, we designed this work as a living systematic review and meta-analysis that will be updated as new eligible evidence becomes available. RESULTS: We identified three eligible studies based on data from (1) Norway and Sweden, (2) Norway and Taiwan and (3) Denmark. As two studies included Norwegian data, their results are referred to as 'Norway 1' and 'Norway 2' for clarity. In the meta-analysis of data from Denmark, Sweden and Norway 1, the pooled HR of offspring NDDs was 1.05 (95% CI 0.87 to 1.27; I2=0.0%), and in meta-analysis of data from Denmark, Sweden and Norway 2, it was 1.03 (95% CI 0.85 to 1.24; I2=0.0%).In the meta-analysis including Taiwan, Denmark, Sweden and Norway 1, the pooled HR was 1.06 (95% CI 0.88 to 1.27; I2=0.0%), and when including data from Taiwan, Denmark, Sweden and Norway 2, the pooled HR was 1.04 (95% CI 0.87 to 1.25; I2=0.0%). CONCLUSIONS: In this living meta-analysis, we found no evidence that paternal exposure to valproate compared with lamotrigine/levetiracetam during spermatogenesis was associated with increased risk of NDDs in offspring.

Humans↗

PubMed2025

High-Dose vs Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: A Prespecified Secondary Analysis of the DANFLU-2 Randomized Clinical Trial.

IMPORTANCE: The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior protection against laboratory-confirmed influenza infection vs standard-dose IIV (SD-IIV); however, data regarding its effectiveness against cardiovascular (CV) outcomes are mainly from observational studies or specific high-risk groups. OBJECTIVE: To investigate the relative vaccine effectiveness (rVE) of HD-IIV vs SD-IIV against CV outcomes in the general older adult population in Denmark. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of DANFLU-2, a pragmatic, open-label, individually randomized clinical trial (RCT) using nationwide administrative health registries in Denmark during the 2022/2023 to 2024/2025 influenza seasons. Older adults (age ≥65 years) were eligible for inclusion regardless of comorbidity. The trial design specified that if the primary end point was neutral, no hypothesis testing would be performed for secondary or exploratory end points. Data were analyzed from June 29 to August 12, 2025. INTERVENTIONS: Individual-level 1:1 randomization to HD-IIV or SD-IIV. Participants re-enrolling in additional seasons were rerandomized. MAIN OUTCOMES AND MEASURES: Severe CV outcomes were prespecified secondary and exploratory end points in the trial, occurring from 14 days after vaccination through May 31 the following year. RESULTS: A total of 332 438 participants (170 900 [51.4%] male; mean [SD] age, 73.7 [5.8] years) were randomized (166 218 to HD-IIV and 166 220 to SD-IIV), of whom 91 026 (27.4%) had a history of CV disease. HD-IIV did not significantly reduce the trial's primary end point of hospitalization for influenza or pneumonia. The incidence of hospitalization for any cardiorespiratory disease was lower in the HD-IIV group than the SD-IIV group (rVE, 5.7% [95% CI, 1.4% to 9.9%]; absolute difference, -0.13 [95% CI, -0.24 to -0.03] percentage points), and rVE did not differ by history of CV disease compared with no CV disease at baseline. Hospitalization for any CV disease occurred in fewer participants in the HD-IIV group than the SD-IIV group (rVE, 7.5% [95% CI, 1.5% to 12.5%]; absolute difference, -0.10 [95% CI, -0.18 to -0.02] percentage points) as did hospitalization for heart failure (rVE, 19.5% [95% CI, 3.3% to 33.1%]; absolute difference, -0.03 [95% CI, -0.06 to -0.01] percentage points). CONCLUSIONS AND RELEVANCE: This study found reduced incidence of cardiorespiratory hospitalization among those who received HD-IIV vs SD-IIV, driven by a lower incidence of CV hospitalizations, and particularly heart failure hospitalizations. These differences should be interpreted as exploratory findings in the setting of a large RCT with a neutral primary outcome. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05517174.

Aged↗

PubMed2027

Effectiveness of high-dose versus standard-dose influenza vaccines against hospitalisation according to frailty risk: a prespecified analysis of the randomised trial DANFLU-2.

BACKGROUND: Frailty is a major risk factor for influenza-related complications and can influence vaccine effectiveness. We aimed to assess the relative vaccine effectiveness (rVE) of high-dose (HD-IIV) versus standard-dose inactivated influenza vaccine (SD-IIV) in older adults aged 65 years or older according to frailty risk. METHODS: This study was a prespecified analysis of DANFLU-2, an open-label, individually randomised trial, conducted in Denmark during three consecutive influenza seasons (2022-23, 2023-24, and 2024-25). Adults aged 65 years or older were randomised (1:1) to the HD-IIV or SD-IIV group. The primary endpoint was hospitalisation for influenza or pneumonia. Frailty was defined according to the validated Hospital Frailty Risk Score (HFRS) based on ICD-10 codes within 10 years before randomisation. Participants were stratified into three HFRS categories, namely low (<5 points), intermediate (5-15 points), and high (>15 points) frailty risk. The rVE of HD-IIV versus SD-IIV against the primary endpoint was assessed across prespecified HFRS categories and treating HFRS as a continuous variable. Pearson's chi-square test was used to compare safety events across frailty risk groups and randomisation groups. FINDINGS: Among 332 438 randomised participants (mean age 73·7 years [SD 5·8]; 161 538 [48·6%] were female), 276 173 (83·1%) had low frailty risk, 52 395 (15·8%) had intermediate frailty risk, and 3861 (1·2%) had high frailty risk. The primary endpoint of hospitalisation for influenza or pneumonia occurred in 1424 (0·5%) of 276 173 participants with low frailty risk, 761 (1·5%) of 52 395 with intermediate frailty risk, and 163 (4·2%) of 3861 with high frailty risk (relative risk [RR] for intermediate vs low frailty risk 2·8 [95% CI 2·6-3·1]; RR for high vs low frailty risk 8·2 [7·0-9·6]). HFRS as a continuous variable significantly modified the effect of HD-IIV versus SD-IIV against the primary endpoint with higher rVE estimates with increasing HFRS (pinteraction=0·020). The rVE was 0·2% (95% CI -10·8 to 10·2) among those with low frailty risk, 13·1% (-0·4 to 24·8) among those with intermediate frailty risk, and 19·9% (-10·3 to 42·1) among those with high frailty risk. No significant interaction was observed when HFRS was assessed according to the prespecified categorical frailty groups (pinteraction=0·17). The proportion of participants with at least one serious adverse event increased across frailty risk groups (13 366 [4·8%] of 275 795 for low frailty risk, 5475 [10·5%] of 52 315 for intermediate frailty risk, and 777 [20·2%] of 3850 for high frailty risk; p<0·0001), with similar proportions of serious adverse events in the HD-IIV and SD-IIV groups for each frailty risk group. INTERPRETATION: Among adults aged 65 years or older in Denmark, frailty risk might modify the effects of HD-IIV versus SD-IIV against hospitalisation for influenza or pneumonia, with higher rVE estimates with increasing frailty risk. These findings might support considering high-dose influenza vaccines for frail older adults. However, effect modification was not evident when frailty was assessed using prespecified categorical subgroups, and subgroup-specific estimates were imprecise, with 95% CIs crossing the null. These results should be considered exploratory, warranting further investigation. FUNDING: The DANFLU-2 trial was funded by Sanofi.

Journal Article↗

PubMed2026

Ketoacidosis with SGLT2 inhibitors in routine clinical practice of type 2 diabetes: Scandinavian cohort and nested case-control study.

BACKGROUND: SGLT2 inhibitors increase the risk of ketoacidosis, but data from routine clinical practice are scarce. We used nationwide registers with the aim of assessing the incidence, risk factors, and prognosis of ketoacidosis during SGLT2 inhibitor treatment in patients with type 2 diabetes. METHODS: In this cohort and nested case-control study we used data from three Scandinavian countries. In a cohort of SGLT2 inhibitor-treatment episodes among patients with type 2 diabetes aged at least 18 years in Sweden, Denmark, and Norway, we estimated ketoacidosis incidence. Using a nested case-control design (matched on age, sex, region of birth, calendar time, and time since treatment initiation), we assessed risk factors and precipitating or co-occurring events. Changes in diabetes medications were evaluated. FINDINGS: The study period was Jan 1, 2013, to Dec 31, 2021, in Denmark and Sweden, and Jan 1, 2013, to Dec 31, 2022, in Norway. We included 322 597 treatment episodes among 282 282 patients with type 2 diabetes (mean age 63 years, 116 521 [36·1%] of 322 597 women). During a median (IQR) follow-up of 1·3 (0·7-2·8) years, 1452 ketoacidosis events occurred (incidence 2·43 per 1000 person-years). Although highest shortly after initiation, risk persisted throughout follow-up. Strong risk factors included high HbA1c (≥83 vs ≤52 mmol/mol: odds ratio [OR] 15·37 [95% CI 11·50-20·53]), malnutrition (OR 10·54 [7·32-15·18]), previous ketoacidosis (OR 10·40 [7·09-15·24]), low BMI (<20 kg/m2vs 20 to <25 kg/m2: OR 9·98 [5·68-17·53]), and recent hypoglycaemia (OR 5·22 [2·60-10·49]). Infection was the most common precipitating or co-occurring event (454 [31·8%] of 1428 vs 862 [6·1%] of 14 233 for ketoacidosis cases vs controls; OR 7·60 [6·62-8·71]). The strongest associations were observed for alcohol intoxication, acute renal events, acute abdomen, stroke, and major surgery, although associations for some transient exposures, particularly milder conditions, might have been overestimated because of under-registration among controls. Exploratory analyses suggested that the observed associations were largely general to patients with type 2 diabetes rather than specific to SGLT2 inhibitor use. At 1 year after ketoacidosis, 211 (25·1%) of 842 remained on SGLT2 inhibitors and insulin use increased from 269 (31·9%) of 842 to 615 (73·0%) of 842. INTERPRETATION: Ketoacidosis risk with SGLT2 inhibitors varies greatly by patient characteristics and is not confined to early in treatment. Risk should be assessed throughout treatment, and patients should be instructed to pause treatment during acute illness and stress. FUNDING: Region Stockholm, Swedish Society of Medicine, Karolinska Institutet.

Journal Article↗

PubMed2026

Treatment of localized rectal cancer in the Nordic countries-comparison of Nordic to Dutch, ESMO, and NCCN guidelines.

BACKGROUND: Rectal cancer treatment in Nordic countries has traditionally differed, especially regarding neoadjuvant treatment. The aim of this review is to give an overview of the current rectal cancer guidelines in the Nordics and compare these to international guidelines. METHODS: Oncologists and colorectal surgeons from the Nordic countries (Denmark, Finland, Norway, and Sweden) and the Netherlands were invited to participate in this narrative review. Two consensus meetings were held to agree on the content. All authors provided recommendations from their national guidelines. In addition, recommendations from the European Society of Medical Oncology (ESMO) and from the US National Comprehensive Cancer Network (NCCN) guidelines were extracted. RESULTS: Several differences between the included guidelines were identified. The radiological "sigmoid take-off" definition for the upper margin of the rectum has been adapted in Denmark and the Netherlands, whereas the other guidelines rely on distance from the anal verge on rigid sigmoidoscopy. Indications for direct surgery vary considerably, where the NCCN guidelines recommend more aggressive neoadjuvant treatment, primarily total neoadjuvant therapy (TNT), the Nordic and European guidelines open for direct surgery more often, and reserve especially TNT for high-risk cases. European countries more often recommend short-course radiotherapy, whereas NCCN maintains chemoradiotherapy as the mainstay. Whereas intentional and opportunistic organ preservation is an established part of the Dutch, NCCN, and ESMO guidelines, its use is mostly restricted to clinical trials in the Nordics. The Nordics and the Netherlands are restrictive in terms of adjuvant treatment, which is frequently recommended in ESMO and NCCN. Whereas neoadjuvant immunotherapy is recommended for mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) rectal cancer in NCCN, this use is off-label in Europe and not routinely recommended. CONCLUSION: Although all guidelines rely on the same evidence, there are considerable differences, especially in the indications and type of oncologic treatment, both in the neoadjuvant and in the adjuvant setting.

Rectal Neoplasms↗

PubMed2025

Estimating Re and overdispersion in secondary cases from the size of identical sequence clusters of SARS-CoV-2.

The wealth of genomic data that was generated during the COVID-19 pandemic provides an exceptional opportunity to obtain information on the transmission of SARS-CoV-2. Specifically, there is great interest to better understand how the effective reproduction number [Formula: see text] and the overdispersion of secondary cases, which can be quantified by the negative binomial dispersion parameter k, changed over time and across regions and viral variants. The aim of our study was to develop a Bayesian framework to infer [Formula: see text] and k from viral sequence data. First, we developed a mathematical model for the distribution of the size of identical sequence clusters, in which we integrated viral transmission, the mutation rate of the virus, and incomplete case-detection. Second, we implemented this model within a Bayesian inference framework, allowing the estimation of [Formula: see text] and k from genomic data only. We validated this model in a simulation study. Third, we identified clusters of identical sequences in all SARS-CoV-2 sequences in 2021 from Switzerland, Denmark, and Germany that were available on GISAID. We obtained monthly estimates of the posterior distribution of [Formula: see text] and k, with the resulting [Formula: see text] estimates slightly lower than estimates obtained by other methods, and k comparable with previous results. We found comparatively higher estimates of k in Denmark which suggests less opportunities for superspreading and more controlled transmission compared to the other countries in 2021. Our model included an estimation of the case detection and sampling probability, but the estimates obtained had large uncertainty, reflecting the difficulty of estimating these parameters simultaneously. Our study presents a novel method to infer information on the transmission of infectious diseases and its heterogeneity using genomic data. With increasing availability of sequences of pathogens in the future, we expect that our method has the potential to provide new insights into the transmission and the overdispersion in secondary cases of other pathogens.

COVID-19↗

PubMed2025

Bivalent RSV Prefusion F Protein-Based Vaccine for Preventing Cardiovascular Hospitalizations in Older Adults: A Prespecified Analysis of the DAN-RSV Trial.

IMPORTANCE: Respiratory syncytial virus (RSV) infection is linked to elevated cardiovascular risk, particularly in individuals with preexisting cardiovascular disease (CVD). A bivalent RSV prefusion F protein (RSVpreF) vaccine was recently approved for preventing RSV-related lower respiratory tract illness, but its effectiveness against cardiovascular outcomes has not been evaluated in a randomized trial. OBJECTIVE: To investigate the vaccine effectiveness of RSVpreF compared with no vaccine against cardiovascular outcomes among adults aged 60 years or older. DESIGN, SETTING, AND PARTICIPANTS: Prespecified secondary analysis of the DAN-RSV trial, a pragmatic, open-label, individually randomized clinical trial conducted in Denmark during the 2024-2025 winter season. The first participant was enrolled on November 18, 2024. Adults aged 60 years or older were eligible for inclusion regardless of comorbidity status. INTERVENTIONS: Participants were randomized 1:1 to receive RSVpreF (n = 65 642) or no vaccine (n = 65 634). MAIN OUTCOMES AND MEASURES: Hospitalization for any cardiorespiratory disease was a prespecified secondary outcome, and hospitalizations for any CVD, heart failure, myocardial infarction, stroke, and atrial fibrillation were prespecified exploratory outcomes. Outcomes were assessed from 14 days after booked study visit through May 31, 2025. Vaccine effectiveness was calculated as 1 - incidence rate ratio, expressed as a percentage. RESULTS: Of 131 276 participants included (mean age, 69.4 [SD, 6.5] years; 50.3% male), 28 662 (21.8%) had preexisting CVD. All-cause cardiorespiratory hospitalization incidence was lower in the RSVpreF group compared with the control group (26.3 vs 29.2 events per 1000 participant-years [PY]; absolute rate reduction, 2.90 [95% CI, 0.10-5.71] per 1000 PY; vaccine effectiveness, 9.9% [95% CI, 0.3%-18.7%]; P = .04). There was no significant interaction by baseline CVD status (CVD at baseline: vaccine effectiveness, 5.0% [95% CI, -11.2% to 16.7%]; no CVD at baseline: vaccine effectiveness, 15.2% [95% CI, 2.2%-27.1%]; P = .27 for interaction). For the RSVpreF group vs control group, respectively, incidence rates of all-cause cardiovascular hospitalization were 16.4 vs 17.7 events per 1000 PY (vaccine effectiveness, 7.4% [95% CI, -5.5% to 18.8%]; P = .24), and incidence rates of stroke were 3.0 vs 3.8 events per 1000 PY (vaccine effectiveness, 19.4% [95% CI, -8.6% to 40.4%]; P = .14). There were also no statistically significant between-group differences for myocardial infarction, heart failure hospitalization, and atrial fibrillation. CONCLUSIONS AND RELEVANCE: In adults aged 60 years or older, all-cause cardiorespiratory hospitalization was significantly lower with RSVpreF than with no vaccine. The findings suggest potential downstream cardiorespiratory benefits of RSV immunization, although the effect on all-cause cardiovascular hospitalization was not statistically significant. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06684743.

Aged↗

PubMed2024

Genome-Wide Association Study of Accessory Atrioventricular Pathways.

IMPORTANCE: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited. OBJECTIVE: To investigate the genetics of APs and affiliated arrhythmias. DESIGN, SETTING, AND PARTICIPANTS: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024. EXPOSURES: Sequence variants. MAIN OUTCOMES AND MEASURES: Genome-wide significant association of sequence variants with APs. RESULTS: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response. CONCLUSIONS AND RELEVANCE: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.

Humans↗

PubMed2025

Clinical and Genetic Findings in Patients With Palmoplantar Keratoderma.

IMPORTANCE: Palmoplantar keratoderma poses diagnostic challenges due to its clinical and genetic heterogeneity, and knowledge on the value of systematic genetic testing on clinically well-described patient cohorts is sparse. OBJECTIVE: To improve knowledge of the clinical and genetic spectrum of patients with palmoplantar keratoderma. DESIGN, SETTING, AND PARTICIPANTS: This cohort study prospectively recruited patients and affected family members with palmoplantar keratoderma between September 1, 2016, and December 31, 2022. Patients were recruited from private practitioners in dermatology and dermatology departments in Denmark. Study participants were patients 18 years or older either newly diagnosed with palmoplantar keratoderma or being followed up for the disease at referral centers. MAIN OUTCOMES AND MEASURES: Phenotypes and clinical subtypes were classified. Genetic testing was performed by whole-exome or genome sequencing using an in silico panel containing genes related to palmoplantar keratoderma, or by Sanger sequencing for specific variants. Descriptive analysis, such as proportions and frequency, were used to describe clinical characteristics, distribution of disease-causing variants, and genotype-phenotype associations. RESULTS: This study included 142 study participants from 76 families (90 [63%] female; median [range] age, 52 [18-92] years). Clinical subtypes included 42 punctate (55%), 26 diffuse (34%), 5 focal (7%), and 3 striate (4%). A genetic diagnosis was found in 63 of 76 families (83%), including 27 disease-causing variants within 13 different genes: AAGAB (n = 39), DSG1 (n = 8), KRT1 (n = 3), DSP (n = 2), KRT9 (n = 2), AQP5 (n = 2), KRT16 (n = 1), SERPINA12 (n = 1), ABCA12 (n = 1), COL7A1 (n = 1), CARD14 (n = 1), DST (n = 1), and LORICRIN (n = 1). All participants with AAGAB variants presented with punctate palmoplantar keratoderma, showing a clear genotype-phenotype correlation. The other subtypes (diffuse, focal, and striate) proved more challenging to clinically subclassify, and disease-causing variants were identified in 12 genes, contributing to more complex genotype-phenotype patterns. Patients with palmoplantar keratoderma due to DSP variants were found, which is important to identify because of an associated risk of cardiomyopathy. CONCLUSION AND RELEVANCE: This study provides novel insights into the clinical and genetic spectrum of patients with palmoplantar keratoderma. It demonstrates the value of genetic testing for accurate diagnoses and to distinguish between different subtypes. The established and well-described cohort lays the foundation for future research in palmoplantar keratoderma.

Humans↗

PubMed2026

Gene transfer from NDM-5-producing and OXA-48-producing Enterobacter hormaechei ST79 on contaminated dicloxacillin capsules to other Enterobacterales in Europe, 2020-23: a retrospective, observational, molecular epidemiological study.

BACKGROUND: In February, 2023, an outbreak of Enterobacter hormaechei ST79 carrying blaNDM-5 and blaOXA-48 was linked to contaminated dicloxacillin capsules administered to approximately 79 000 individuals in Denmark. Initial clonal outbreak investigations identified 11 patients with the E hormaechei ST79 outbreak strain, which carried blaNDM-5 on a distinct IncX3 plasmid, and in nine cases, blaOXA-48 was on a distinct IncL plasmid. Interspecies plasmid transfer was observed in one patient, suggesting a potential plasmid-mediated outbreak involving other Enterobacterales. However, no studies have characterised the progression of a clonal outbreak originating from a contaminated medicine into plasmid-mediated dissemination of carbapenemase genes. Hence, we aimed to characterise the clonal and plasmid-mediated spread of carbapenemase genes in this outbreak. METHODS: We conducted a retrospective genomic and epidemiological investigation using existing short-read whole-genome sequencing data from all carbapenemase-producing Enterobacterales (CPE) from the Danish national surveillance, collected between Jan 1, 2014, and Oct 1, 2023. All confirmed CPE isolates were eligible for inclusion. Using in-silico screening for unique fragments of the two outbreak plasmids, we selected 160 isolates for long-read sequencing to obtain complete plasmid sequences for outbreak investigation. Analyses were descriptive and included comparison of sequence identity and coverage to define outbreak-associated plasmids and summary statistics of patient characteristics. FINDINGS: Data from 1829 isolates were obtained. We detected 16 of 53 isolates involved in the outbreak using conventional outbreak detection methods. The remaining 37 isolates were detected using plasmid-specific screening and long-read sequencing. 15 patients carried the outbreak E hormaechei strain, including the 11 patients previously reported. Three of the 15 patients presented with at least one additional bacterial species carrying one or both outbreak plasmids (pDcap_OXA-48 and pDcap_NDM-5). A further 24 patients, sampled between July 1, 2020, and Oct 1, 2023, presented with other Enterobacterales carrying one or both outbreak-associated plasmids but not the original E hormaechei ST79 strain. In four cases, outbreak-associated plasmids differed structurally from the original outbreak plasmid. INTERPRETATION: This study describes how a clonal CPE outbreak caused by a contaminated medicine evolved into a complex plasmid-mediated outbreak involving multiple Enterobacterales species. Most patients related to the outbreak did not present with the original E hormaechei ST79 outbreak strain and were therefore not identified using standard outbreak detection methods. These findings highlight the importance of using plasmid-focused approaches in outbreak investigations. FUNDING: The Danish Ministry of Health, SSI-Seq (cofunded by EU4Health).

Humans↗

PubMed2024

The role of co-occurring conditions and genetics in the associations of eating disorders with attention-deficit/hyperactivity disorder and autism spectrum disorder.

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981-2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD or ASD diagnosis. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44%-100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal half sibling with ASD had increased risk of AN compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk whereas a negative association was found between AN-PGS and ADHD. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and genetic associations between ASD-PGS and AN and between AN-PGS and ADHD were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

Humans↗

PubMed2026

Empirical Meropenem Versus Piperacillin/Tazobactam for Critically Ill Adults With Sepsis: Feasibility of a Randomised Trial.

BACKGROUND: Meropenem and piperacillin/tazobactam are commonly used empirical antibiotics in critically ill adults with sepsis, but whether one is superior to the other is uncertain. METHODS: The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an ongoing investigator-initiated, randomised, open-label, adaptive clinical trial with an integrated feasibility phase comparing empirical treatment with meropenem versus piperacillin/tazobactam in critically ill adults with sepsis. The integrated feasibility phase enrolled 200 participants across 10 intensive care units (ICUs) in Denmark between 28 June and 12 December 2025. Five pre-specified feasibility criteria were evaluated; if all feasibility criteria were met, the trial would proceed unaltered, whereas failure to meet one or more criteria would require intervention and re-evaluation. RESULTS: We randomised 200 of 284 screened patients (70.4%). The median age was 70 years (interquartile range (IQR): 60-77), 65.5% were males. At randomisation, 80.0% received vasopressors or inotropes, and 43.5% were on invasive mechanical ventilation. Four of five pre-specified feasibility criteria were met: time to completion of the feasibility phase (5.5 months vs. threshold < 12.0 months), recruitment proportion (70.4% vs. threshold ≥ 50.0%), proportion of participants without consent to the continued collection of data (2.5% vs. threshold < 5.0%) and protocol adherence (81.0% vs. threshold ≥ 75.0%). The proportion of participants with timely primary outcome data availability (30-day mortality) within 45 days was 85.5% and below the pre-specified threshold of ≥ 95.0%. The proportions were low in the first 3 months (33.3%, 22.2% and 30.8%, respectively), increasing to 95.8% in the last month of the feasibility phase. All-cause mortality at 30 days was 30.5%, and specific serious adverse reactions occurred in 4.0% of participants. CONCLUSIONS: In this integrated feasibility evaluation of the EMPRESS trial comparing empirical meropenem versus piperacillin/tazobactam in critically ill adults with sepsis, four of five pre-specified feasibility criteria were met. The unmet criterion, timely primary outcome data availability, improved substantially during the feasibility phase. We consider the trial feasible and will proceed without modifications. EDITORIAL COMMENT: This feasibility study assessed recruitment, randomised allocation and data collection for the multicentre EMPRESS trial. For adaptive trials on trial platforms, careful interim checking of trial design functions is an important and necessary process. TRIAL REGISTRATION: Clinical Trials Information System EUCT number: 2023-509703-33-00; ClinicalTrials.gov identifier: NCT06184659; Universal Trial Number: U1111-1301-6379.

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PubMed2026

Beyond borders: plasmids drive a shared antibiotic resistome in European urban water systems.

BACKGROUND: Urban wastewater systems (UWSs) act as reservoirs and conduits for the dissemination of antibiotic resistance genes (ARGs), with plasmids playing a central role in their spread. Despite their significance, the diversity and persistence of plasmids in UWSs remain underexplored. RESULTS: This study applies a multi-omics approach, including metagenomic and direct plasmidome sequencing, high-throughput qPCR array, and whole genome sequencing of plasmid isolates, to comprehensively profile the microbial plasmidome and resistome on 78 samples across UWSs in Denmark, Spain, and the UK. We successfully uncovered an extensive plasmid and ARG diversity that could not be fully captured by a single method, especially identified 78,574 plasmids, including 20,925 plasmids previously unreported. We also observed that plasmids carried a disproportionate share of clinically relevant ARGs, particularly beta-lactamase resistance genes; most importantly, they were preferentially located on transmissible plasmids. Furtherly, plasmids harbor ARG can enhance their persistence in wastewater ecosystems, especially harboring multiple types of ARGs. Moreover, Bacteroides emerged as a unique persistent ARG reservoir not only for harboring and disseminating diverse resistance genes especially in residential-relevant areas, but also emerged as a major driver of antimicrobial resistance dynamics across different wastewater treatment processes. CONCLUSIONS: Overall, this work provides the first attempt at a holistic description of the UWSs' resistome, its structure, dynamics, and mobility and significantly expands the current knowledge. Video Abstract.

Plasmids↗

PubMed2026

Hidradenitis Suppurativa and Smoking, Obesity, Psoriasis, Inflammatory Bowel Disease, and Systemic Sclerosis: Results From A 2-Sample Mendelian Randomization Study.

IMPORTANCE: Smoking and obesity are associated with risk of hidradenitis suppurativa, and both are considered important environmental risk factors. However, a causal relationship remains unproven. OBJECTIVE: To primarily investigate the relationship between body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) and smoking and HS, and secondarily to investigate potential relationships between 3 inflammatory diseases (psoriasis, inflammatory bowel disease [IBD], and systemic sclerosis [SSc]) and HS. DESIGN, SETTING, AND PARTICIPANTS: A mendelian randomization (MR) study conducted in 2024 on 5 exposure phenotypes (BMI, smoking, psoriasis, IBD, and SSc) on the outcome of phenotype HS was conducted. The MR analyses used large genetic White European cohorts from genome-wide association studies (GWAS) of each of the 6 phenotypes. Initial analyses were conducted May, 2024, and were updated in May, 2025. EXPOSURE: The 5 exposure phenotypes using predetermined genome-wide significant single-nucleotide variants as proxies for each particular exposure. RESULTS: The GWAS on HS included 4814 case patients and more than 1.2 million controls from Denmark, Iceland, Finland, the UK, and the US. The BMI GWAS involved 700 000 individuals from the UK Biobank and GIANT consortium. Smoking data were obtained from 1.23 million participants in an international consortium. The psoriasis GWAS analyzed 39 498 case patients and 286 769 controls from White European populations and a DNA genetic testing company. The IBD GWAS meta-analysis included 38 155 case patients and 48 485 controls from the International Inflammatory Bowel Disease (IBD) Genetics Consortium. The SSc GWAS included 9095 case patients and 17 584 controls from White European populations. Genetic correlations (rg) were found between HS and all exposure phenotypes except SSc (BMI: rg = 0.36, P < .001; smoking: rg = 0.33, P < .001; IBD: rg = 0.25, P < .001; psoriasis: rg = 0.34, P < .001; SSc: rg = 0.33, P = .22). MR analyses supported an effect of BMI on HS (β = 0.87; odds ratio [OR] per BMI unit, 1.20; 95% CI, 1.17-1.23; P < .001) without signs of pleiotropy (slope: β = 0.91, P < .001, P for intercept = .76). Smoking showed a significant causal estimate (β = 0.59, P < .001), but results became inconclusive in subsequent sensitivity analyses. Among IBD, psoriasis, and SSc, results supported a causal effect of IBD on HS (β = 0.18, OR = 1.20; 95% CI, 1.15-1.24; P < .001), without signs of pleiotropy. CONCLUSIONS AND RELEVANCE: These findings indicate causal effects of IBD and increased BMI on the risk of HS. This information may help physicians inform patients about disease risk contributed by modifiable lifestyle behaviors, which can be beneficial for planning lifestyle interventions.

Humans↗

PubMed2026

Effects of time-restricted eating on markers of glucose metabolism and regulation in individuals with prediabetes or type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.

AIMS/HYPOTHESIS: This systematic review and meta-analysis aimed to investigate the effects of time-restricted eating (TRE) on glucose metabolism and regulation in individuals with prediabetes (fasting blood glucose of 5.6-6.9 mmol/l or HbA1c of 39-47 mmol/mol [5.7-6.4%]) or type 2 diabetes (fasting blood glucose ≥7 mmol/l or HbA1c ≥48 mmol/mol [6.5%]). METHODS: A literature search was performed in MEDLINE, Embase and CENTRAL from inception to 5 August 2025. Moreover, forward and backward citation searches were performed. Eligible studies were RCTs in adults with prediabetes or type 2 diabetes, lasting ≥2 weeks, reporting markers of glucose metabolism and regulation, comparing TRE (≤12 h eating window) with a non-time-restricted control diet. Studies involving pregnancy, other fasting regimens, or non-peer-reviewed publications were excluded. Data were pooled as weighted mean differences with 95% CIs using random-effects generic inverse variance models in Cochrane Review Manager Web, and results are presented as forest plots. The certainty of evidence was defined using Grading of Recommendations, Assessment, Development and Evaluations methodology, and risk of bias was estimated by using the Revised Cochrane risk-of-bias tool for randomised trials (RoB 2). RESULTS: Out of 2043 records identified through the database search, as well as 1249 from forward and backward citation searches, ten RCTs including 599 participants were included. The mean length of the studies was 4 months, and the eating windows ranged from 4 to 10 h per day. The pooled meta-analysis showed no overall effect of TRE on HbA1c (-3.33 mmol/mol; 95% CI -6.87, 0.20 (-0.30% points; -0.63, 0.02); p=0.06, moderate certainty). Nevertheless, following stratification by subgroups, TRE resulted in a reduction in HbA1c of 0.93 mmol/mol (-1.70, -0.17 [-0.09% points; -0.16, -0.02]; p=0.02) in individuals with prediabetes but not in individuals with type 2 diabetes (-4.68 mmol/mol; -10.08, 0.72 (-0.43% points; -0.92, 0.07); p=0.09). TRE reduced fasting blood glucose in the pooled analysis (-0.30 mmol/l; -0.53, -0.07; p<0.01, moderate certainty) as well as in the subgroup analyses in individuals with prediabetes (-0.14 mmol/l; -0.27, -0.01; p=0.03) and with type 2 diabetes (-0.48 mmol/l; -0.78, -0.17; p<0.01). Moreover, TRE lowered body weight by 1.6 kg (-2.2, -1.0; p<0.001) in the pooled analysis. The evidence was limited by imprecision arising from wide confidence intervals in some of the included studies, which may be due to small sample sizes. Lastly, the effects of TRE on markers of insulin sensitivity, beta cell function and continuous glucose monitoring measurements were inconclusive. CONCLUSIONS/INTERPRETATION: Moderate-certainty evidence indicates that TRE reduces fasting blood glucose but not HbA1c. The subgroup analyses revealed that TRE improved HbA1c and fasting glucose in individuals with prediabetes and improved fasting glucose in individuals with type 2 diabetes. Future large-scale studies should investigate long-term effects of TRE in prevention and treatment of type 2 diabetes. TRIAL REGISTRATION: PROSPERO CRD42024523591 FUNDING: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Three authors (JS, A-DT, THA) are employed at Steno Diabetes Center Copenhagen, a public hospital and research institution under the Capital Region of Denmark, partly funded by a grant from the Novo Nordisk Foundation.

Humans↗

PubMed2026

Neurological effects of encapsulated dexamethasone sodium phosphate in children aged 6-9 years with ataxia telangiectasia (NEAT): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Ataxia telangiectasia is a rare, multisystem disorder with progressive cerebellar neurodegeneration and no approved treatments. The efficacy of corticosteroids, including erythrocyte encapsulated dexamethasone sodium phosphate (eDSP), which have been studied for two decades in this disease, has not yet been proven in randomised trials. We aimed to investigate the safety and efficacy of eDSP in children aged 6-9 years with ataxia telangiectasia. METHODS: NEAT was a multicentre, randomised, double-blind, placebo-controlled phase 3 study, conducted at 20 sites across nine countries (Denmark, Germany, Italy, Norway, Poland, Spain, Switzerland, UK, and USA). Eligible participants were children aged 6 years or older weighing at least 15 kg, with a genetic diagnosis of ataxia telangiectasia and presence of neurological symptoms. Participants were randomly assigned (1:1) to the eDSP or placebo group via an independent interactive web response system and were stratified by age (6-9 years or ≥10 years), sex, and region (USA vs other countries). All participants, investigators, sponsors, and raters were masked to treatment assignments. eDSP was given intravenously every 21-30 days for six doses. All randomly assigned participants were included in the intention-to-treat (ITT) and safety populations; the primary and secondary efficacy analyses were conducted in participants aged 6-9 years in the ITT population. The primary efficacy endpoint was the change in Rescored Modified International Cooperative Ataxia Rating Scale (RmICARS) score between baseline and month 6, and a mixed-model-repeated-measures analysis was used. The trial was registered at ClinicalTrials.gov, NCT06193200, and is completed. FINDINGS: Between June 24, 2024, and Dec 17, 2025, we screened 125 participants for eligibility, of whom 105 (84%) were randomly assigned to the eDSP group (n=51 [49%]) or the placebo group (n=54 [51%]) and received at least one dose of treatment. The mean age was 8·5 years (SD 1·9) in the eDSP group and 8·6 years (2·3) in the placebo group (overall age range 6-17 years). In the eDSP group, 24 (47%) of 51 participants were girls and 27 (53%) were boys and, in the placebo group, 26 (48%) of 54 were girls and 28 (52%) were boys. Of ITT participants aged 6-9 years, 38 (95%) of 40 in the eDSP group and 41 (95%) of 43 in the placebo group completed the study. Compared with the placebo group, no significant differences were identified in change in RmICARS score from baseline to 6 months in participants aged 6-9 years: least squares mean difference -1·30 (95% CI -2·77 to 0·18; p=0·085). Adverse events were reported in 47 (92%) of 51 participants in the eDSP group and in 50 (93%) of 54 participants in the placebo group. The most common treatment-emergent adverse events were vomiting, pyrexia, pruritus, nasopharyngitis, cough, headache, and fatigue. There were no reports of treatment-related serious adverse events or deaths. Safety laboratory parameters did not identify adverse effects on growth, metabolism, bone mineral density, or endocrine function in any of the treatment groups. INTERPRETATION: The primary efficacy endpoint was not achieved, because the effect of eDSP on neurological symptoms did not reach statistical significance. The favourable safety profile of eDSP, previously described in a large study of children with ataxia telangiectasia, was confirmed in this trial. The eDSP programme, comprising two randomised studies and treating the largest cohort of patients with ataxia telangiectasia to date, underscores the need for rigorously designed trials of sufficient duration to detect sustained clinical benefit. FUNDING: Quince Therapeutics.

Humans↗