Heart Rhythm

Background. Durable mitral isthmus (MI) block remains challenging in persistent atrial fibrillation (PeAF) ablation. Recent epicardial vein of Marshall (VoM) recordings have shown incomplete MI transmurality and time-dependent conduction recovery after pulsed field ablation (PFA). Whether systematic VoM ethanol infusion (VoM-EI) followed by focal PFA provides stable acute MI block remains unknown. **Objectives.** To assess the incidence, timing, and procedural implications of early MI conduction recovery after systematic VoM-EI followed by focal Sphere-9 PFA. Methods.In this prospective single-center study, 55 consecutive patients undergoing first ablation for symptomatic PeAF with planned MI ablation were screened. VoM-EI was systematically attempted before left atrial access and successfully performed in 51 (92.7%), who constituted the study cohort. Pulmonary vein isolation, roof-line, and MI ablation were performed with the Sphere-9? lattice-tip catheter. After bidirectional MI block, conduction was systematically reassessed during a standardized 30-minute waiting period. Results.Mean age was 70.3 {+/-} 8.2 years, and 36 patients (70.6%) were men. Initial bidirectional MI block was achieved in 50/51 patients (98.0%). During the waiting period, conduction recovered in 9/50 (18.0%; 95% CI, 9.8%-30.8%), at a median of 16 minutes (IQR, 10-20; range, 8?23). Six of 9 patients with recovery (66.7%) required targeted coronary sinus (CS) ablation. Block was restored in all 9, yielding a final block rate of 50/51 (98.0%). Median procedure duration was 82 minutes (IQR, 73-95), with no major complications. Conclusions. Immediate bidirectional MI block was not synonymous with stable block. Despite systematic VoM-EI followed by focal Sphere-9 PFA, conduction recovered in approximately one in five patients, including beyond 20 minutes, and two thirds required targeted CS ablation. These findings support standardized 30-minute reassessment and targeted CS interrogation rather than reliance on immediate block. Chronic invasive remapping is required to determine whether this strategy improves long-term MI block durability.

Background: A dose finding trial evaluated safety and adherence for pre-cardiac surgery administration of sodium valproate. Integrated multi-omics analyses of myocardium were used to characterise mechanisms underlying the treatment effects. Methods: Adults undergoing cardiac surgery were randomised 1:1:1:1 with concealed allocation to no treatment (Controls), sodium valproate 15mg/kg/day for 1-2 weeks, 15mg/kg/day for 4-6 weeks, or 25mg/kg/day for 4-6 weeks pre-surgery. The primary analysis evaluated adherence and toxicity. Myocardial injury was defined by high sensitivity serum troponin at 24 hours post-surgery. Single-nucleus Assay for Transposase-Accessible Chromatin with sequencing (snATACseq) and single nuclei RNA sequencing (snRNAseq) of myocardial biopsies collected at surgery assessed treatment effects on chromatin accessibility and gene expression. Candidate mechanisms were validated in in vitro. Results: The analysis cohort included 42 participants enrolled between January 2020 and August 2024. Non-compliance (38%) was highest with longer and higher dosing. Sodium valproate 15mg/kg/day for 1-2 weeks had the highest levels of complete treatment adherence (70%), with 20% experiencing moderate/severe drug related adverse effects. An as-treated analyses demonstrated reductions in troponin release in participants receiving Valproate[≤]14 days. Myocardial biopsies from trial participants demonstrated activation of hormetic p53 and Akt-GSK-3{beta} ferroptosis protection pathways. Treatment effects were not attributable to chromatin accessibility. Treatment >14 days resulted in a heart failure phenotype with suppression of ferroptosis protection pathways, endothelial mesenchymal transition, and increased myocardial injury. Conclusions: Sodium valproate 15mg/kg/day for [≤]14 days pre-surgery is well tolerated in adults awaiting cardiac surgery. This treatment was associated with upregulation of ferroptosis protection pathways and reductions in myocardial injury.

Background: Bailout cardiac surgery during transcatheter aortic valve replacement (TAVR) is uncommon but remains associated with substantial morbidity and mortality. Although registries have described its incidence and major causes, they often provide limited detail regarding device-related failure mechanisms, attempted transcatheter rescue, and the clinical pathway leading to surgical conversion. We aimed at analyzing post-marketing safety reports from the U.S. Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database to characterize the mechanisms, management strategies, and reported outcomes of bailout surgery during or shortly after TAVR. Methods: We retrospectively analyzed FDA MAUDE reports received from July 1, 2016, through June 30, 2026. Eligible reports described unplanned urgent or emergent open cardiac surgery during or immediately after TAVR. Candidate reports were screened, adjudicated, and deduplicated at the clinical-event level. Events were classified by precipitating complication, transcatheter rescue, operative pathway, and reported outcome. Associations were evaluated using permutation tests, Fisher exact tests with Benjamini?Hochberg correction, adjusted regression models, and sensitivity analyses. Results: After screening 43,239 initial reports, we identified 376 bailout-surgery events, with survival status was documented in 254, including 104 deaths and 150 survivors, corresponding to 40.9% reported mortality. Valve embolization, migration, or malposition was the most frequent complication phenotype (32.4%), whereas ventricular perforation or laceration was associated with the highest mortality (74.1%; OR, 4.86; 95% CI, 1.97?11.99). Mortality differed across complication phenotypes (p<0.001) and operative pathways (p<0.001), but not across transcatheter rescue pathways (p=0.355). Valve explantation with SAVR was associated with lower reported mortality (18.9%; OR, 0.29; 95% CI, 0.12?0.69), whereas unspecified surgery or access/support alone was associated with higher mortality (56.9%; OR, 3.04; 95% CI, 1.80?5.12). Ancillary analyses identified potential platform-specific differences in complication and management patterns, while bailout timing was not independently associated with mortality after adjustment. Conclusions: In this MAUDE analysis, bailout cardiac surgery after TAVR was most commonly precipitated by valve embolization, migration, or malposition, whereas ventricular perforation or laceration was associated with the highest reported mortality. Outcomes differed across complication and operative pathways but not across transcatheter rescue strategies or bailout timing after adjustment. These findings identify clinically relevant post-marketing safety signals but should not be interpreted as incidence estimates, comparative device risks, or causal treatment effects.

Background: Percutaneous mechanical circulatory support (pMCS) is increasingly used in critically ill patients, yet its value in relation to cost and outcomes remains unclear. We evaluated national variation in utilization, outcomes, and cost, and introduced a value of care framework integrating risk-adjusted outcomes and expenditures. Methods: We performed a retrospective cohort study using the National Inpatient Sample to identify non-elective hospitalizations of critically ill patients undergoing intra-aortic balloon pump (IABP) or percutaneous left ventricular assist device (pLVAD) placement using ICD-10 codes. Multivariable logistic regression and generalized linear models were used to estimate expected outcomes and costs. Observed-to-expected (O/E) ratios were calculated, and a value index was derived to compare procedural strategies. Results: A total of 57,910 weighted hospitalizations were included (IABP 78%, pLVAD 22%). In-hospital mortality exceeded 30% across regions. Significant regional variation was observed, with the West demonstrating the highest costs and the Midwest the lowest (p<0.001). Mean hospital charges were higher for pLVAD compared with IABP ($403,731 vs $320,769). Both strategies achieved outcomes better than expected after risk adjustment (O/E 0.92); however, costs were higher than expected for both, with greater relative cost inflation observed for IABP (O/E 1.41) and higher absolute costs for pLVAD. In value-of-care analysis, IABP was associated with lower cost and comparable outcomes, while pLVAD demonstrated higher cost without proportional outcome improvement. Conclusion: Substantial variation exists in the cost, outcomes, and value of pMCS strategies. While both IABP and pLVAD achieve favorable risk-adjusted outcomes, pLVAD is associated with higher costs without commensurate clinical benefit.

Background. The imprecision of current metrics to capture the complex genetic admixture and racial identity among Hispanic/Latino individuals in the United States [US] is a concern. We examined the relationship of self-reported race and genetic ancestry with hypertension [HTN] among Hispanics/Latinos. Methods. Cross-sectional study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), including 10,586 Hispanic/Latino unrelated adults. Genetic ancestry: West African [AA], Amerindian [AI], and European [EA]. Self-reported race: White, Black, Native American, or Multiple/Missing (More than one race or Unknown/Not reported/Refused). HTN: systolic (SBP) [&ge;]130 mmHg, diastolic blood pressure (DBP) [&ge;]80 mmHg, and/or use of HTN medications. Age- and sex adjusted models were used. Results. Self-reported race was White (38{middle dot}6%), Black (3{middle dot}6%), Native American (4{middle dot}1%), and Multiple/Missing (53{middle dot}7%), with Unknown/Not reported/Refused representing 32{middle dot}7%. Black and White Hispanics/Latinos had the greatest AA (55{middle dot}7%) and EA (69{middle dot}3%) ancestries, respectively. Each 10% AA increase was associated with OR 1{middle dot}15, SBP beta +0{middle dot}9 mmHg, and DBP beta +0{middle dot}7 mmHg. Conversely, each 10% AI increase was associated with OR 0{middle dot}83, SBP beta -0{middle dot}4 mmHg, and DBP beta -0{middle dot}6 mmHg. HTN prevalence was highest among those with Black race or in the highest AA quantile (45{middle dot}6% and 48{middle dot}0%, respectively), and lowest among those with Native American race or in the highest AI quantile (37{middle dot}6% and 26{middle dot}7%, respectively). Conclusion. One-third of Hispanics/Latinos did not self-report race. Black or White self-reporting race did somewhat relate to AA or EA ancestry, respectively. HTN profiles were related to self-reported race and genetic ancestry in this admixed population.

Background: High-sensitivity cardiac troponin (hs-cTn) assays enable safe early discharge of patients at very low risk for myocardial infarction. We previously developed a single-sample rule-out pathway using the ARCHITECT hs-cTnI assay to risk stratify patients with suspected acute coronary syndrome. In a secondary analysis of the POC-ET (Point of Care Evaluation of High-sensitivity Cardiac Troponin) study, we evaluated performance of risk stratification with the Alinity hs-cTnI assay. Methods: Patients presenting with possible myocardial infarction in the POC-ET (NCT05665127) study were included. The primary outcome was type 1, 4b or 4c myocardial infarction or cardiac death at 30 days. Cardiac troponin I (cTnI) was measured in stored materials using the ARCHITECT and Alinity hs-cTnI assays. The sex-specific 99th percentile upper reference limit (URL) are 34 ng/L in men and 16 ng/L in women for both assays. Agreement was assessed with Bland-and-Altman limit of agreement method, Passing Bablok regression, and Pearson's correlation coefficient. Distributions of presentation measurements were compared with Kolmogorov-Smirnov test. Performance was evaluated in the overall population and prespecified subgroups. The negative predictive value (NPV) and sensitivity were determined and proportion of patients identified as low, intermediate, and high risk were calculated and modelled using ordinal logistic regression. Results: In 986 patients (60 [51-70] years, 38% female), 78 (7.9%) had a primary outcome. Strong agreement was found in the raw cTnI measurements (99% samples within the Bland-Altman limit of agreement; correlation coefficient r: 0.967 (95% CI 0.964-0.969, P<0.001); Passing Bablok regression: slope 1.12 [1.11-1.13], intercept -0.16 [-0.18 to -0.13]). At presentation, distributions of cTnI measurements by the two assays were similar (P=0.810). Both assays showed comparable diagnostic performance using a risk stratification threshold of <5 ng/L and the sex-specific diagnostic threshold, with the same NPV (Alinity 100 [99.7-100]% versus ARCHITECT 100 [99.7-100]%) and sensitivity (Alinity 100 [97.3-100]% versus ARCHITECT 100 [97.3-100]%). Similar proportions of patients stratified as low- (Alinity 67% versus ARCHITECT 67%), intermediate-risk (23% versus 24%) and high-risk (10% versus 9%) at presentation with minor reclassification. Similar efficacy was observed across subgroups stratified by sex, age, history of myocardial infarction, renal function, and symptom duration. Conclusions: The Alinity hs-cTnI and the ARCHITECT hs-cTnI assays can be used interchangeably in the assessment of suspected myocardial infarction with comparable safety and efficacy.

Contemporary national-scale electronic health record (EHR) trends in documented acute myocardial infarction (AMI) rates during the high-sensitivity cardiac troponin (hs-cTn) and Type 2 myocardial infarction (T2MI) era are not well characterized. We conducted a serial cross-sectional analysis of U.S. adults aged 18 years in Epic Cosmos from 2016-2024, encompassing 821,859,867 patient-years. Age- and sex-standardized AMI diagnosis rates increased 75.7%, from 343.1 to 602.7 per 100,000 patients. This increase was predominantly driven by T2MI, which increased 133.8% from 99.9 per 100,000 in 2018 to 233.4 per 100,000 in 2024; NSTEMI increased 13.8% while STEMI decreased 4.1%. Annual hs-cTn-tested encounters increased 34.5-fold from 2017 through 2024. The proportion of tested encounters associated with any AMI remained relatively stable after 2021, whereas T2MI continued to increase and surpassed NSTEMI in 2024 as the most frequently diagnosed AMI subtype per hs-cTn-tested encounters. Males had higher absolute AMI rates across all age groups, although relative increases were greater among females. Documented AMI epidemiology shifted substantially toward T2MI during expanding hs-cTn utilization, underscoring the need for evidence-based approaches to the evaluation and management of T2MI.

Background: Primary malignant cardiac tumors (PMCTs) are rare and histologically heterogeneous. Objective: To compare demographics, specific ICD-O-3 morphologies, first-course treatment patterns, annual registered case counts, and unadjusted overall survival between soft-tissue and hematologic PMCTs. Methods: We identified 730 PMCT cases diagnosed from 2000 to 2021 in SEER 18 (ICD-O-3 topography C38.0). Histologic lineage was assigned from ICD-O-3 morphology. Comparative analyses included soft-tissue (n=458) and hematologic (n=212) tumors. First-course variables were primary-site surgery, chemotherapy (yes versus no/unknown), and radiotherapy (radiation versus none/unknown). Groups were compared with chi-square tests. Overall survival was estimated with Kaplan-Meier methods; follow-up was truncated at 120 months. Results: Soft-tissue PMCTs occurred predominantly at ages 45-64 years (67.9%), whereas hematologic PMCTs occurred predominantly at age [&ge;]65 years (63.2%; p<0.001). Men comprised 59.9% of hematologic and 49.3% of soft-tissue cases (p=0.014). The leading soft-tissue morphology was hemangiosarcoma/angiosarcoma (ICD-O-3 9120/3; 201/458, 43.9%); synovial sarcoma accounted for 20/458 cases (4.4%). Diffuse large B-cell lymphoma, NOS, accounted for 131/212 hematologic tumors (61.8%). Any primary-site surgery was recorded in 66.6% of soft-tissue versus 15.6% of hematologic cases (p<0.001). Chemotherapy was recorded in 67.5% versus 51.1% (p<0.001), and radiotherapy in 9.0% versus 20.5% (p<0.001). In exploratory Kaplan-Meier analyses, hematologic patients with recorded chemotherapy had higher unadjusted 120-month overall survival than those without recorded chemotherapy (42.0% versus 12.2%; log-rank p=7.5x10-). Radiation-associated survival differences were not statistically significant in either lineage. Conclusions: Soft-tissue and hematologic PMCTs have distinct age distributions, named histologies, and first-course treatment patterns in SEER. These findings describe registry coding and do not establish treatment effectiveness or population incidence.

Background: Atrial fibrillation detected after stroke (AFDAS) is frequently diagnosed after embolic stroke of undetermined source (ESUS) and has important implications for secondary stroke prevention. Although prediction scores have been proposed to identify patients at increased risk of AFDAS, prospective evidence supporting their implementation to guide rhythm monitoring in routine clinical practice is limited. Methods: In this prospective, population-based implementation cohort study, adults with ESUS were enrolled between January 2022 and December 2024 across all stroke centers in Styria, Austria. The Graz AF Risk Score was prospectively implemented as part of a risk-adapted diagnostic pathway for cardiac rhythm monitoring. Patients with a score [&ge;]4 were recommended for implantable loop recorder monitoring, whereas monitoring in those with scores <4 remained at the treating physician's discretion. The primary outcome was AFDAS detection; recurrent ischemic stroke and recurrent stroke etiology were secondary outcomes. Results: Among 784 patients (median age 73 years [IQR 64-80], 45.7% women), AFDAS was detected in 166 patients (21.2%) during a median follow-up of 26.3 months (IQR 20-34). AFDAS detection was substantially higher in patients with a Graz AF Risk Score [&ge;]4 than <4 (38.1% vs. 3.9%; p<0.001). After adjustment for age, sex and ILR monitoring, a score [&ge;]4 independently predicted AFDAS (HR 6.3, 95% CI 3.5-11.2; p<0.001) and recurrent ischemic stroke (HR 2.2, 95% CI 1.1-4.1; p=0.023). Only one recurrent stroke in patients with a score <4 was attributable to atrial fibrillation (AF) (1/18, 5.6%). Conclusions: Prospective implementation of the Graz AF Risk Score identified patients with ESUS at markedly different risks of AFDAS. A Graz AF Risk Score [&ge;]4 was also independently associated with recurrent ischemic stroke. These findings support a risk-adapted approach to cardiac rhythm monitoring after ESUS.

Background: Higher Body Mass Index (BMI) is an established risk factor of sleep disturbance. It is not known if the effect is homogeneous across the lifecourse or if there is a particular time point in life that might be best to target. Methods: Two-sample Mendelian randomization (MR) was used to investigated the effect of childhood adiposity (adjusting on adulthood adiposity and obstructive sleep apnea (OSA)) on insomnia, morning chronotype, sleep duration, daytime sleepiness and daytime napping. Similarly, total, and direct effect of adulthood adiposity on these outcomes was explored. We used summary statistics from a genome-wide association study (GWAS) of UK Biobank for childhood and adulthood adiposity (n=453,169) and large-scale consortia of OSA (Million Veteran Program) (n=410,268), insomnia, and chronotype (23andMe) (n=1,978,022 and n=248,1000, respectively). Results: Two-sample univariable MR analysis provided no evidence of an effect of genetically predicted childhood adiposity on later life insomnia (Odds ratio (OR)= 0.94, 95% Confidence interval (CI)= 0.87, 1.03). Whereas, multivariable MR (adjusted for adulthood adiposity) analysis provide strong evidence of direct protective effect of genetically predicted childhood adiposity on later life insomnia (OR= 0.70, CI= 0.64, 0.77). Further, both in univariable and multivariable MR, a strong positive effect of increased childhood body size on morning chronotype was observed (OR= 1.16, CI= 1.01, 1.33 and OR= 1.36, CI= 1.15, 1.62, respectively) after accounting for adulthood body size. In both analysis the estimate did not change considerably after aditionally adjusting for OSA. However, childhood and adulthood adiposity found to be associated with OSA and OSA with insomnia. In both univariable and multivariable analysis, increased body size in adulthood increased the risk of having insomnia and a morning chronotype. Conclusions: The findings suggest that higher body size in childhood is not a risk factor for later life insomnia, whereas higher body size in adulthood was. Further, if healthy body size is maintained in adulthood, high childhood adiposity may decrease the risk of insomnia and increase the risk of being a morning person in later life. Keywords: childhood, adulthood, obesity, insomnia, morning chronotype, medelian randomization

BACKGROUND The optimal antiplatelet regimen in patients with acute coronary syndrome (ACS) and multivessel disease undergoing drug-coated balloon (DCB) angioplasty remains unclear. METHODS This was a prespecified subgroup analysis of the REC-CAGEFREE II trial, which was conducted at 41 sites in China and randomized 1948 exclusively DCB-treated participants with ACS to stepwise dual antiplatelet therapy (DAPT) de-escalation or standard DAPT. The primary endpoint was net adverse clinical events (NACE; including all-cause death, stroke, myocardial infarction, revascularization, and BARC type 3 or 5 bleeding) at 12 months. Participants were stratified into multivessel and single-vessel subgroups according to angiographic characteristics. RESULTS Overall, 720/1948 (37.0%) patients had multivessel disease. The multivessel subgroup was associated with a significantly higher risk of NACE compared with the single-vessel subgroup (12.5% versus 6.7%, HR IPTW:1.84, 95%CI:1.35-2.51, P<0.001). No significant interaction was observed between vessel status (multivessel or single-vessel) and treatment allocation with respect to NACE (Pinteraction=0.542). In the multivessel subgroup, NACE occurred in 44/368 (12.1%) and 45/352 (12.9%) in the stepwise de-escalation and standard DAPT groups (HR IPTW:0.95, 95%CI:0.62-1.75, P=0.818), respectively. In the single-vessel subgroup, NACE occurred in 43/607 (7.1%) and 39/621 (6.3%) in the stepwise de-escalation and standard groups (HR IPTW:1.12, 95%CI:0.72-1.70, P=0.611), respectively. For the prespecified hierarchical secondary endpoint, win ratio analyses yielded more wins for stepwise de-escalation in both subgroups. CONCLUSIONS Among patients with ACS undergoing DCB-only angioplasty, those with multivessel disease were associated with a higher risk of NACE than those with single-vessel disease. Stepwise DAPT de-escalation and standard DAPT exhibited similar risk-benefit profiles in both subgroups.

Background and Objectives: Preterm infants are commonly transfused, yet direct cardiorespiratory effects of red blood cell (RBC) transfusions remain poorly understood. We explored the feasibility of using multicentre electronic health data (EHD) to study such cardiorespiratory responses. Methods: Highly granular routine EHD were collected from preterm infants born <32 weeks gestational age at three European centres. Heart rate, oxygen saturation, and respiratory rate were evaluated 12 hours before and after the RBC transfusion. Results: A total of 321 transfusions in 164 infants were analysed. Overall, there was no significant change in the rate of bradycardia and apnoea following transfusion. Cardiorespiratory parameters varied substantially between infants; e.g. 20% of transfusions were associated with an unexpected, significant increase in heart rate. Respiratory rate and oxygen saturation exhibited similarly heterogenous patterns following transfusion. In sub-group analysis, the proportion of transfusions with increased heart rate was significantly higher within the first two weeks than later (32% vs 13%, p=0.0019). Conclusions: Multicentre EHD extraction allows to identify otherwise masked short-term effects of RBC transfusions on cardiorespiratory parameters, possibly indicating cardiac or pulmonary overload. Such effects may vary with adaptation to anaemia. Analysing EHD may ultimately enable personalized transfusion practice.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of cardioembolic stroke. Although polygenic risk scores (PRS) are well characterized to quantify inherited susceptibility for AF, they provide limited insight into the pathways and tissues underlying genetic risk, which are critical to uncover for individual risk prediction. In this study, we develop a pathway-level multi-omics representation learning framework that converts individual genetic profiles into interpretable biological features by integrating GWAS-derived pathway burden scores with tissue-specific transcriptomic pathway signals. We constructed machine learning models to assess population-level AF risk prediction performance across genomic and transcriptomic tissue contexts; the pathway-based global attention models substantially improved risk prediction performance over PRS and other baselines (AUROC improved from 0.601 to 0.738). Transformer and graph neural network frameworks then assessed individual-level pathway interpretability, revealing heterogeneous contributions from electrical signaling, cardiac development, and DNA repair pathways to AF risk. This added interpretability highlights the potential of this pathway approach to enable more mechanistically informed risk stratification than static PRS by capturing underlying heterogeneity. To independently assess whether prioritized pathways reflected cardiac regulatory biology, we compared pathway rankings with transcriptional effects predicted by the AlphaGenome foundation model. Variants in highly ranked pathways showed significantly greater predicted effects on expression in atrial and ventricular tissues (FDR = 0.032) relative to controls, providing orthogonal evidence that the model identifies biologically relevant mechanisms. Overall, this work reframes polygenic risk from a single measure of susceptibility to tissue-informed pathway mechanisms, providing a framework for interpretable genomic stratification in complex diseases.

Sub-Saharan African populations carry pharmacogenomic alleles poorly represented in the European-derived reference panels underlying most clinical genotyping tools. We present a curated, machine-readable catalog of nine actionable alleles across six pharmacogenes (CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP3A5, NAT2) with African-specific frequency ranges, functional annotations, and evidence levels derived from reanalysis of 661 high-coverage whole-genome sequences across seven 1000 Genomes Project African populations. Direct comparison against PharmCAT v3.4.0 shows that CYP2D6 produces zero diplotype calls (0/661 samples callable) due to monomorphic reference positions absent from standard variant-only VCF output, a known limitation whose consequences for African allele carriers had not been reported. afripharmagen's reduced-position strategy identifies 243 CYP2D617 and 134 CYP2D629 carriers from the same input. For CYP2B6, CYP2C9, CYP2C19, and NAT2, both tools show concordance of 95-100%. Frequency gradients (CYP2B66: 30-50%; CYP2D617: 15-35% in West Africa; CYP3A5*1: 60-95%) translate directly into prescribing risk for efavirenz, tramadol, tacrolimus, and isoniazid. Pharmacogenomic decision support in African settings must incorporate population-specific allele definitions and input-format-aware strategies.

We present our Stage-1 Registered Report as a full clinical trial article with all methods in past tense and including mock results, table and figures for the primary analysis. To remind the reader that this Stage-1 article is written before data collection, we highlight in color that these mock results are only for illustrative purposes and will be replaced by the actual results in the Stage-2 Registered Report. Background In patients experiencing out-of-hospital cardiac arrest, optimization of oxygen delivery during cardiopulmonary resuscitation is a critical. Although both positive end-expiratory pressure (PEEP) and zero end-expiratory pressure (ZEEP) are employed during CPR, their respective impacts on clinically relevant outcomes is yet to be clearly established. Methods This investigator-initiated, pragmatic, registry-based, multicenter, triple-blind randomized controlled superiority trial evaluates whether applying 8 cm H2O PEEP during cardiopulmonary resuscitation improves outcomes compared with ZEEP in adults with non-traumatic, non-drowning out-of-hospital cardiac arrest. Pre-randomized CPR kits (1:1 PEEP vs. sham) were used by ambulance sites during manual ventilation throughout the resuscitation process. The primary analysis was conducted in the principal stratum of patients who received either a supraglottic airway or endotracheal tube. The primary outcome was neurological status at hospital discharge measured by a utility-weighted score on the modified Rankin Scale. Secondary outcomes included prehospital return of spontaneous circulation, 30-day survival, and 6-month quality of life. The primary safety outcome was clinically significant pneumothorax.

Introduction Postoperative analgesic management after minimally invasive cardiac surgery (MICS) should facilitate early recovery while providing adequate pain control. However, direct evidence comparing postoperative remifentanil- and fentanyl-based analgesic strategies after MICS remains limited. We compared these strategies and explored their associations with postoperative recovery, postoperative nausea and vomiting (PONV), and pain management. Methods This retrospective single-center observational cohort study included patients who underwent MICS via a right mini-thoracotomy between January 2023 and June 2026. Patients were categorized according to postoperative remifentanil- or fentanyl-based analgesia in the intensive care unit. Outcomes included time to extubation, PONV, postoperative pain assessed using the numerical rating scale (NRS), additional analgesic use, and intensive care unit length of stay. Multivariable logistic regression examined the association between postoperative opioid strategy and PONV, adjusting for age, sex, and smoking history. Results PONV occurred less frequently in the remifentanil group than in the fentanyl group (20.6% vs 45.0%, P = 0.004), and this association remained significant after adjustment (adjusted odds ratio, 0.23; 95% confidence interval, 0.10-0.56; P = 0.001). Time to extubation was shorter with remifentanil (median, 179 [interquartile range, 134-240.5] vs 247 [190.2-276.5] min; P < 0.001). In contrast, NRS pain scores on postoperative day 0 were higher with remifentanil (3 [1-6] vs 1 [0-2]; P < 0.001), and additional analgesics were used more frequently (80.6% vs 33.3%; P < 0.001). Pain scores on postoperative day 1 did not differ significantly between groups. Conclusion Postoperative remifentanil-based analgesia after MICS was associated with less PONV and earlier extubation but also with greater early postoperative pain and more frequent additional analgesic use than fentanyl-based analgesia. Appropriate transition to longer-acting analgesics with multimodal analgesia may help preserve the potential benefits of remifentanil while maintaining adequate postoperative pain control.

Objective: Whether a scheduled antiseizure medication (ASM) continues on schedule across the ICU-to-floor transfer has not been characterized. We quantified ASM administration-gap frequency across this transfer and compared it with gap frequency during matched non-transfer intervals in the same patient and drug. Methods: In this retrospective MIMIC-IV (version 3.1) cohort study, we identified epilepsy and status-epilepticus admissions with an ICU stay followed by floor transfer and a scheduled ASM order active at ICU departure. A gap was defined as an interval exceeding 1.5 times the expected dosing interval between the last ICU dose and first floor dose, or no further dose before discharge, and compared with a matched non-transfer control interval in the same patient and drug (paired McNemar test). A multivariable model evaluated six prespecified clinical predictors; sociodemographic variables were summarized descriptively. Results: Among 2,469 ASM transition-by-drug observations (1,583 admissions, 1,335 patients), an administration gap occurred in 251 (10.2%; 95% CI, 8.7%-11.7%). Gap frequency across the transfer exceeded frequency during matched non-transfer control intervals in the same patient and drug: a paired rate difference of 5.8 percentage points (95% CI, 4.4-7.1; 7.5% vs 1.7%; P = 7.3 x 10^-22) before the transfer and 6.4 percentage points (95% CI, 4.9-7.9; 8.9% vs 2.5%; P = 1.9 x 10^-23) after. Gap rates were similar for intravenous-available (9.9%) and oral-only (11.4%) drugs (rate difference, 1.5 percentage points; 95% CI, -1.6 to 4.5; P = .34). None of six prespecified predictors reached significance after correction. Significance: An antiseizure medication administration gap occurred in approximately 1 of every 10 drug-transition observations at the ICU-to-floor transfer, exceeding matched non-transfer gap rates by 5.8 to 6.4 percentage points. This transfer-associated excess, rather than any single medication or patient characteristic, supports a structured medication-continuity check.

Background: Severe aortic stenosis is associated with systemic and splanchnic hemodynamic disturbances that may alter gut microbial metabolism and host inflammatory responses. Objectives: We aimed to determine whether TAVI remodels the gut microbiome-derived metabolome and whether post-procedural SCFA dynamics are associated with the inflammatory cytokine response. Methods: We conducted a prospective paired single-center study of patients undergoing elective TAVI at Bern University Hospital. Stool and blood samples were collected before and three months after the procedure. Gut microbial composition was profiled by full-length 16S rRNA sequencing, circulating short-chain fatty acids (SCFAs) by targeted metabolomics, and inflammatory mediators by multiplex cytokine analysis, and integrated with hemodynamic and clinical data. Results: Forty patients were enrolled. Following TAVI, microbial richness declined without significant restructuring of overall community composition. In contrast, circulating SCFA profiles were significantly remodeled, driven by selective reductions in butyrate and isovalerate. A greater decline in circulating butyrate was inversely associated with IL-18 elevation (rho=0.668, p<0.001, n=36), independent of aortic valve calcification burden, hemodynamic improvement, and cardiovascular medications. Baseline isovalerate was nominally associated with 1-month adjudicated adverse events (AUC 0.77; exploratory). Conclusions: TAVI is associated with selective changes in gut microbiome-derived metabolic output rather than broad alterations in microbial community structure. Declining circulating butyrate identifies a gut-metabolite-immune axis linked to IL-18 dynamics and represents a potential biomarker of inflammatory recovery following valve intervention.

Background: Vitamin K prophylaxis is universally recommended for newborns to prevent life threatening vitamin K deficiency bleeding. Although not on the immunization schedule, vitamin K prophylaxis is often coadministered with hepatitis B birth dose and erythromycin ophthalmic ointment, and rising hesitancy around vaccines/preventive care may spill over into vitamin K administration. Methods: We conducted a retrospective cohort study using Truveta electronic health record data with linked mother-child dyads. Live births to mothers aged 15-49 from January 1, 2019 through June 30, 2026 were included. Vitamin K administration was defined as documentation on the birth date or following day. Logistic regression assessed sociodemographic predictors of non-receipt, and interrupted time series analysis evaluated changes after January 2026. Results: Among 1,026,375 infants, 995,628 (96.97%) had documented vitamin K administration. Non-receipt increased from an average of 2.1% during 2019-2022 to 4.3% in 2025 and 6.1% in 2026, reaching 8.10% in June 2026. Older maternal age, non-Hispanic or Latino ethnicity, Medicaid or unknown insurance, and year of delivery were associated with greater odds of non-receipt. After January 2026, there was no immediate step change, but the odds of vitamin K receipt declined an additional 10% per month (OR: 0.90; 95% CI, 0.88-0.91). Conclusions: Vitamin K non-receipt increased over the study period and accelerated after January 2026. Because vitamin K recommendations were not changed by the January vaccine schedule, this association may reflect broader impacts to confidence in newborn preventive care. Future studies should examine causal mechanisms, parental decision-making, and associated clinical outcomes.

Disseminating study results to participants is an ethical responsibility for researchers but remains uncommon in low- and middle-income countries, and participants preferences for receiving study results are poorly understood. This study examined study result dissemination preferences among pregnant women in a phase III malaria prevention trial in Papua New Guinea (PNG). Participants completed an interviewer-administered questionnaire (survey) assessing their interest in and motivation for receiving trial results and preferences for dissemination methods and content. Associations between participants characteristics and dissemination preferences were explored using multivariable logistic regression analysis. Of 1172 trial participants, 96.0% (1125/1172) completed the survey, and of these 99.6% (1121/1125) wanted to learn about the trial results. The main motivation factors driving participants interest were an acknowledgment of their contribution to research (51.7%; n=579) and a better understanding of the study (45.0%; n=505). Most participants (78.9%; n=884) wanted to learn about the trial findings through written summary and a group meeting with other participants at the nearest clinic (31.1%, n=349). Multivariable regression analysis indicated that participants from rural/peri-urban clinics were more likely to choose non-electronic media dissemination approaches such as a group meeting as compared to urban-dwelling participants. Frequently selected items (>50% of participants) for content included information regarding good results of the study, purpose of the study, medical treatment advances, results specific to me, and how study was conducted. There was heterogenicity in the preference for dissemination content: compared to urban clinics rural clinics are less likely to want to learn about how and why study was conducted and medical and scientific advances. Overall, the majority wanted to learn about trial results, highlighting the importance of integrating dissemination into research activities in PNG. Variation in preferences for mode and content of dissemination between study clinics suggests that dissemination activities could be tailored to local context and preferences.