Outcomes of nonemergency cardiac surgery after overnight operative workload: A statewide experience.

Objective: Cardiac surgeons experience unpredictable overnight operative responsibilities, with variable rest before same-day, first-start scheduled cases. This study evaluated the frequency and associated impact of a surgeon's overnight operative workload on the outcomes of their same-day, first-start operations. Methods: A statewide cardiac surgery quality database was queried for adult cardiac surgical operations between July 1, 2011, and March 1, 2021. Nonemergency, first-start, Society of Thoracic Surgeons predicted risk of mortality operations were stratified by whether or not the surgeon performed an overnight operation that ended after midnight. A generalized mixed effect model was used to evaluate the effect of overnight operations on a Society of Thoracic Surgeons composite outcome (5 major morbidities or operative mortality) of the first-start operation. Results: Of all first-start operations, 0.4% (239/56,272) had a preceding operation ending after midnight. The Society of Thoracic Surgeons predicted risk of morbidity and mortality was similar for first-start operations whether preceded by an overnight operation or not (overnight operation: 11.3%; no overnight operation: 11.7%, P = .42). Unadjusted rates of the primary outcome were not significantly different after an overnight operation (overnight operation: 13.4%; no overnight operation: 12.3%, P = .59). After adjustment, overnight operations did not significantly impact the risk of major morbidity or mortality for first-start operations (adjusted odds ratio, 1.1, P = .70). Conclusions: First-start cardiac operations performed after an overnight operation represent a small subset of all first-start Society of Thoracic Surgeons predicted risk operations. Overnight operations do not significantly influence the risk of major morbidity or mortality of first-start operations, which suggests that surgeons exercise proper judgment in determining appropriate workloads.

Comparative Effectiveness of Pneumococcal Vaccination Strategies to Prevent Invasive Pneumococcal Disease: A Population-Based Cohort Study at the Veterans Health Administration in the United States.

OBJECTIVES: Comparative effectiveness of pneumococcal 13-valent conjugate vaccine (PCV13), 23-valent polysaccharide vaccine (PPSV23), and their combinations for adults in preventing invasive pneumococcal disease (IPD) has yet to be thoroughly investigated. We aimed to estimate the comparative effectiveness of preventing IPD, using population-based data from the Veterans Health Administration (VHA) in the United States (US). METHODS: We included all patients who were between 65 and 74 years, had established primary care within VHA between 2005 and 2021, and had not received any prior pneumococcal vaccination. We measured time-to-event from cohort enrollment to the onset of IPD, considering death a competing risk event, and used Cox regression models to estimate cause-specific hazards. PCV13 only, PPSV23 only, PCV13 after PPSV23, and PPSV23 after PCV13 were incorporated into models as time-dependent covariates. Patient demographics and comorbidities were also included in the model. RESULTS: 3,044,067 patients were enrolled in the cohort, with 863,958 deaths (28.4%) and 1,731 cases of IPD (0.06%) during the study period. The overall incidence rate of IPD in this population was 5.36 per 100,000 patient-years. 921,070 patients (30.3%) received at least one dose of effective pneumococcal vaccine. In multivariate analysis adjusted for comorbidities, PCV13 alone was not associated with the reduced risk of IPD, while PPSV23 had protective association with IPD incidence (adjusted hazard ratio [aHR]: 0.70 [95% confidence interval (CI): 0.59-0.83]). When combined, PCV13 followed by PPSV23 had a stronger protective association (aHR: 0.54 [0.36-0.83]) compared to PPSV23 followed by PCV13 (aHR: 0.73 [0.58-0.91]). CONCLUSIONS: In this large cohort study at the VHA, the combination of PCV13 and PPSV23, particularly PCV13 followed by PPSV23, was associated with a lower risk of IPD, indicating additional benefits in combined vaccinations with potential importance in vaccination order. Further studies are needed to evaluate the effect of newer pneumococcal vaccines.

Serious Illness Communication Training for Surgical Critical Care Fellows: A Pilot Implementation Study.

OBJECTIVE: Effective communication about serious illness is pivotal in delivering surgical palliative care-a crucial component of comprehensive surgical critical care (SCC). However, limited educational strategies exist for fellow-level trainees, who are often directing clinical decision-making and building mutual trust with patients and families. This pilot study assess implications of a novel serious illness communication training opportunity tailored specifically for SCC fellows. DESIGN: Prospective implementation of a multimodal training session (1 hour-didactic lecture, 2 hours-live-action simulation), using pre- and postcourse surveys to assess self-perceived confidence. SETTING: University of Michigan in Ann Arbor, Michigan. PARTICIPANTS: Eleven ACGME-accredited SCC fellows during the 2023 to 2024 academic year participated and completed all 3 survey assessments. RESULTS: Following the course, 6 of 7 confidence domains showed improvement, with 2 reaching statistical significance-communication skills to discuss goals of care and/or code status (3.73 vs. 4.36, p = 0.018) and end-of-life care or transition to comfort-focused care (3.36 vs. 4.18, p = 0.023) with a patient or family member. At 6-month follow up, fellows reported further increases in all queried domains, though changes were nonsignificant. Greatest absolute increases were noted in delivering serious news (4.18 vs. 4.55, p = 0.143) and expressing nonverbal empathy (4.09 vs. 4.50, p = 0.197). The majority (91%) of respondents felt more comfortable having serious illness conversations with patients and families due to their training course experience. CONCLUSION: Implementation of a 3-hour training course tailored for SCC fellows significantly boosted both the immediate and long-term confidence in their serious illness communication skills and ability to manage complex care scenarios.

Comparative Outcomes of Autologous Chondrocyte Implantation and Osteochondral Allograft Transplantation with Patellar Realignment for Patellar Instability with Associated Cartilage Defects.

PURPOSE: The purpose of this study was to determine clinical and functional outcomes in patients treated with autologous chondrocyte implantation (ACI) or osteochondral allograft (OCA) transplantation for chondral defects secondary to patellar instability with concomitant medial patellofemoral ligament (MPFL) reconstruction and tibial tubercle osteotomy (TTO) for patellar realignment. METHODS: A retrospective review identified patients who underwent ACI or OCA transplantation with concomitant MPFL reconstruction and TTO . Patients were excluded if they did not have concomitant MPFL reconstruction and TTO, had the presence of other intra-articular pathologies, or failed to complete postoperative subjective outcome evaluations at a minimum of 2 years following surgery. Subjective outcome measures included the Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR), International Knee Documentation Committee (IKDC) evaluation, and Short Form Health Survey (SF-12) physical scores, collected a minimum of 2 years after surgery. Defect location, size, complications, and rate of subsequent surgery were determined. RESULTS: Eighteen total patients were included in this study. The ACI cohort included 11 patients with 13 total defects that were treated with ACI. The OCA cohort included 7 patients with 10 total defects that were treated with OCA. This was due to a number of patients in either group having multiple cartilage defects. Twenty-three total chondral defects were compared to analyze clinical and functional outcomes following surgical correction (ACI: n=13, OCA: n=10). Five defects were noted on the femoral condyle and 18 on the patellar facets/central ridge. Defects were comparable between groups including, size measured during index-arthroscopy (ACI = 3.34 cm2, 95% CI [2.3 cm2 - 4.4 cm2] vs OCA = 4.03 cm2, 95% CI [3.1 cm2 - 5.0 cm2]; P=.351), Outerbridge classification (ACI = 54.8% grade 4 vs OCA = 60.0% grade 4; P=1.000), and AMADEUS score (ACI = 47.1 vs OCA = 58.6; P=.298). Postoperative outcomes were comparable including revision rate (ACI = 15.4% vs OCA = 10.0%; P=1.000) and 2-year IKDC scores (ACI = 74.2, 95% CI [65.2 - 83.2] vs OCA = 51.2, 95% CI [30.3 - 72.1]; P=.077). ACI did have significantly higher 2-year KOOS JR (85.1, 95% CI [76.9 - 93.3] vs 63.7, 95% CI [49.1 - 78.3]; P=.031) and SF-12 scores (54.1, 95% CI [52.0 - 56.2] vs 42.6, 95% CI [35.8 - 49.4]; P=.007) compared to OCA. CONCLUSION: ACI or OCA transplantation for chondral defects with concomitant MPFL reconstruction and TTO can be safely performed in an outpatient setting with functional and clinical outcomes being comparable. LEVEL OF EVIDENCE: Retrospective Case Series Study (Level 3).

Long-term Risk of Right Coronary Artery Injury Following Catheter Ablation of Cavotricuspid Isthmus-dependent Flutter.

BACKGROUND: Radiofrequency ablation (RFA) of cavotricuspid isthmus (CTI)-dependent atrial flutter requires ablation of the tricuspid annulus overlying the right coronary artery (RCA). While considered safe, reports of acute and subacute RCA injury in human and animal studies raise the possibility of late RCA stenosis. OBJECTIVE: To compare the incidence and severity of angiographic RCA stenoses in patients who have undergone CTI RFA to a control group to assess the long-term risk of RCA damage. METHODS: A two-center retrospective case-cohort study was performed including all patients from 2002-2018 undergoing atrial fibrillation (AF) with CTI ablation (CTI+AF) or AF ablation alone with subsequent coronary angiography (CAG). The AF alone group served as controls due to anticipated similarity of baseline characteristics. Coronary arteries that are anatomically remote to the CTI were examined as prespecified falsification endpoints. CAG was scored by a blinded observer. RESULTS: 156 patients who underwent PVI with subsequent CAG (CTI+AF, n=81; AF alone, n=75) had no difference in baseline characteristics including age, sex, comorbidities, and medications. Mean time from ablation to CAG was similar (CTI+AF 5.0±3.7 years vs AF alone 5.4 ±3.9 years, p=0.5). The mid and distal RCA showed no difference in the average number of angiographic stenoses or lesion severity. In regression analysis, CTI ablation was not a predictor of RCA stenosis severity (p=0.6). There was no difference in coronary disease at sites remote to the CTI ablation (p=NS for all). CONCLUSION: There was no observed relationship between CTI RFA and the number or severity of angiographically apparent RCA stenoses in long-term follow up.

Mexiletine versus lamotrigine in non-dystrophic myotonias: a randomised, double-blind, head-to-head, crossover, non-inferiority, phase 3 trial.

BACKGROUND: Non-dystrophic myotonias are skeletal muscle channelopathies caused by ion channel dysfunction. Symptom onset is frequently in the first decade of life, causing disability in a young cohort. Although there is no cure, symptomatic treatments exist. Previous trials provide evidence of the efficacy of mexiletine. More recently, lamotrigine has been shown to be effective. Both treatments have different profiles, including pharmacokinetics and adverse events. This trial aimed to investigate whether lamotrigine is non-inferior to mexiletine to directly inform clinical practice. METHODS: We did a randomised, double-blind, crossover, non-inferiority, phase 3 trial at the National Hospital for Neurology and Neurosurgery (London, UK). Participants (aged ≥18 years) who had genetically confirmed symptomatic non-dystrophic myotonia were randomly assigned (1:1), by means of a block randomisation schedule created by a computer program, to receive either mexiletine for 8 weeks followed by lamotrigine for 8 weeks, or lamotrigine followed by mexiletine, with a 7-day washout period in between. Investigators and participants were masked to treatment allocation. The primary outcome measure was the mean interactive voice response (IVR) diary stiffness score (0-9 scale) over the participant's final 2 weeks of diary reporting in each treatment period. Non-inferiority was assessed using a mixed-effects model with a predefined margin of 0·5 and included all randomly assigned participants who contributed at least 7 days of IVR-diary data in either treatment period. The trial is registered at ClinicalTrials.gov, NCT05017155, and EudraCT, 2020-003375-17. FINDINGS: Between Aug 1, 2021, and Dec 12, 2022, of 60 participants were screened (24 females and 36 males) and randomly assigned between Aug 1, 2021 and Dec 12, 2022, to either the mexiletine-lamotrigine sequence (n=30) or the lamotrigine-mexiletine sequence (n=30). 53 participants contributed data to the primary analysis. The mean IVR stiffness score after treatment with mexiletine was 2·54 (95% CI 1·98 to 3·10) versus 2·77 (2·21 to 3·32) with lamotrigine (mean mexiletine-lamotrigine difference -0·23 [95% CI -0·63 to 0·17]). The most common adverse event with both treatments was indigestion-reflux (eight participants, 208 participant-days receiving mexiletine; seven participants, 130 participant-days receiving lamotrigine). No serious adverse events were reported. INTERPRETATION: We were unable to conclude that lamotrigine is non-inferior to mexiletine; however, improvements in all outcome measures from baseline were similar between lamotrigine and mexiletine. Lamotrigine is an important treatment consideration in non-dystrophic myotonias alongside mexiletine; we propose a treatment algorithm to guide clinical practice. FUNDING: Neuromuscular Study Group, Jon Moulton Charity Trust, UCLH BRC Fast Track Grant.

Human CSTF2 RNA Recognition Motif Domain Binds to a U-Rich RNA Sequence through a Multistep Binding Process.

The RNA recognition motif (RRM) is a conserved and ubiquitous RNA-binding domain that plays essential roles in mRNA splicing, polyadenylation, transport, and stability. RRM domains exhibit remarkable diversity in binding partners, interacting with various sequences of single- and double-stranded RNA, despite their small size and compact fold. During pre-mRNA cleavage and polyadenylation, the RRM domain from CSTF2 recognizes U- or G/U-rich RNA sequences downstream from the cleavage and polyadenylation site to regulate the process. Given the importance of alternative cleavage and polyadenylation in increasing the diversity of mRNAs, the exact mechanism of binding of RNA to the RRM of CSTF2 remains unclear, particularly in the absence of a structure of this RRM bound to a native RNA substrate. Here, we performed a series of NMR titration and spin relaxation experiments, which were complemented by paramagnetic relaxation enhancement measurements and rigid-body docking, to characterize the interactions of the CSTF2 RRM with a U-rich ligand. Our results reveal a multistep binding process involving differences in ps-ns time scale dynamics and potential structural changes, particularly in the C-terminalα-helix. These results provide insights into how the CSTF2 RRM domain binds to U-rich RNA ligands and offer a greater understanding for the molecular basis of the regulation of pre-mRNA cleavage and polyadenylation.

Home- vs Office-Based Narrowband UV-B Phototherapy for Patients With Psoriasis: The LITE Randomized Clinical Trial.

Importance: Office-based phototherapy is cost-effective for psoriasis but difficult to access. Home-based phototherapy is patient preferred but has limited clinical data, particularly in patients with darker skin. Objective: To compare the effectiveness of home- vs office-based narrowband UV-B phototherapy for psoriasis. Design, Setting, and Participants: The Light Treatment Effectiveness study was an investigator-initiated, pragmatic, open-label, parallel-group, multicenter, noninferiority randomized clinical trial embedded in routine care at 42 academic and private clinical dermatology practices in the US. Enrollment occurred from March 1, 2019, to December 4, 2023, with follow-up through June 2024. Participants were 12 years and older with plaque or guttate psoriasis who were candidates for home- and office-based phototherapy. Interventions: Participants were randomized to receive a home narrowband UV-B machine with guided mode dosimetry or routine care with office-based narrowband UV-B for 12 weeks, followed by an additional 12-week observation period. Main Outcomes and Measures: The coprimary effectiveness outcomes were Physician Global Assessment (PGA) dichotomized as clear/almost clear skin (score of ≤1) at the end of the intervention period and Dermatology Life Quality Index (DLQI) score of 5 or lower (no to small effect on quality of life) at week 12. Results: Of 783 patients enrolled (mean [SD] age, 48.0 [15.5] years; 376 [48.0%] female), 393 received home-based phototherapy and 390 received office-based phototherapy, with 350 (44.7%) having skin phototype (SPT) I/II, 350 (44.7%) having SPT III/IV, and 83 (10.6%) having SPT V/VI. A total of 93 patients (11.9%) were receiving systemic treatment. At baseline, mean (SD) PGA was 2.7 (0.8) and DLQI was 12.2 (7.2). At week 12, 129 patients (32.8%) receiving home-based phototherapy and 100 patients (25.6%) receiving office-based phototherapy achieved clear/almost clear skin, and 206 (52.4%) and 131 (33.6%) achieved DLQI of 5 or lower, respectively. Home-based phototherapy was noninferior to office-based phototherapy for PGA and DLQI in the overall population and across all SPTs. Home-based phototherapy, compared to office-based phototherapy, was associated with better treatment adherence (202 patients [51.4%] vs 62 patients [15.9%]; P < .001), lower burden of indirect costs to patients, and more episodes of persistent erythema (466 of 7957 treatments [5.9%] vs 46 of 3934 treatments [1.2%]; P < .001). Both treatments were well tolerated with no discontinuations due to adverse events. Conclusions and Relevance: In this randomized clinical trial, home-based phototherapy was as effective as office-based phototherapy for plaque or guttate psoriasis in everyday clinical practice and had less burden to patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03726489.

The association between bullying victimization and back pain in young people: a systematic literature review and meta-analysis.

ABSTRACT: Back pain is a common and recurrent health complaint in adolescence. Psychosocial factors may be associated with the onset and persistence of back pain symptoms. This systematic review aims to determine the association between bullying victimization and back pain in young people. Observational studies that quantified the association between bullying victimization and back pain in participants were included in this systematic review. Estimates of associations and confidence intervals were extracted. A random effects meta-analysis of estimates of association was performed. The quality of evidence was assessed using the Joanna Briggs Institute critical appraisal checklist for analytical cross-sectional studies. Database searches yielded 18,311 citations. Nineteen studies (n = 212,058, 51.4% female) were included in our review. Meta-analysis showed a positive association between bullying victimization and back pain (odds ratio 1.93, confidence interval 1.75-2.13). Subgroup analysis showed no statistically significant effect of sex, age, bullying type, pain type, recall periods, bullying frequency, back pain frequency, risk estimate adjustment, and study critical appraisal rating. All studies were rated at moderate-high risk of bias. Our synthesis of evidence found a weak-moderate association between bullying victimization and back pain in young people. Methodological shortcomings and heterogeneity in the field limit causal inference. Future longitudinal studies are required.

Discovery of steroidal alkaloid metabolites and their accumulation in pigs after short-term tomato consumption.

Studies suggest steroidal alkaloids contribute to the health properties of tomato-rich diets. Untargeted studies have detected tomato steroidal alkaloid metabolites in plasma, tissues, and urine, but concentrations remain unknown. Here we utilize UHPLC-MS/MS to characterize 31 steroidal alkaloid metabolites representing 10 unique masses, and a validated UHPLC-MS method to quantify them in blood plasma. In a two-week parallel-arm study, piglets (n = 20) were fed diets containing 10 % tomato powder or a macronutrient-matched control. Concentrations averaged to 107.7 nmol/L plasma, comprising of phase I (66 %) and phase II (4.5 %) metabolites. Primary phase I metabolites were hydroxylated isomers. MS/MS fragments (m/z 253, 271, 289) in conjunction with analysis of diet profile provided higher confidence when identifying hydroxylated metabolites. These results are the first to report quantitative levels of steroidal alkaloid metabolites in plasma, contributing to an understanding of physiologically relevant concentrations. This data is useful for contextualizing research on the health benefits of tomatoes.

SCAMPI: A scalable statistical framework for genome-wide interaction testing harnessing cross-trait correlations.

Family-based heritability estimates of complex traits are often considerably larger than their single-nucleotide polymorphism (SNP) heritability estimates. This discrepancy may be due to non-additive effects of genetic variation, including variation that interacts with other genes or environmental factors to influence the trait. Variance-based procedures provide a computationally efficient strategy to screen for SNPs with potential interaction effects without requiring the specification of the interacting variable. While valuable, such variance-based tests consider only a single trait and ignore likely pleiotropy among related traits that, if present, could improve power to detect such interaction effects. To fill this gap, we propose SCAMPI (Scalable Cauchy Aggregate test using Multiple Phenotypes to test Interactions), which screens for variants with interaction effects across multiple traits. SCAMPI is motivated by the observation that SNPs with pleiotropic interaction effects induce genotypic differences in the patterns of correlation among traits. By studying such patterns across genotype categories among multiple traits, we show that SCAMPI has improved performance over traditional univariate variance-based methods. Like those traditional variance-based tests, SCAMPI permits the screening of interaction effects without requiring the specification of the interaction variable and is further computationally scalable to biobank data. We employed SCAMPI to screen for interacting SNPs associated with four lipid-related traits in the UK Biobank and identified multiple gene regions missed by existing univariate variance-based tests. SCAMPI is implemented in software for public use.

Home visits versus fixed-site care by community health workers and child survival: a cluster-randomized trial, Mali.

Objective: To test the effect of proactive home visits by trained community health workers (CHWs) on child survival. Methods: We conducted a two arm, parallel, unmasked cluster-randomized trial in 137 village-clusters in rural Mali. From February 2017 to January 2020, 31 761 children enrolled at the trial start or at birth. Village-clusters received either primary care services by CHWs providing regular home visits (intervention) or by CHWs providing care at a fixed site (control). In both arms, user fees were removed and primary health centres received staffing and infrastructure improvements before trial start. Using lifetime birth histories from women aged 15-49 years surveyed annually, we estimated incidence rate ratios (IRR) for intention-to-treat and per-protocol effects on under-five mortality using Poisson regression models. Findings: Over three years, we observed 52 970 person-years (27 332 in intervention arm; 25 638 in control arm). During the trial, 909 children in the intervention arm and 827 children in the control arm died. The under-five mortality rate declined from 142.8 (95% CI: 133.3-152.9) to 56.7 (95% CI: 48.5-66.4) deaths per 1000 live births in the intervention arm; and from 154.3 (95% CI: 144.3-164.9) to 54.9 (95% CI: 45.2-64.5) deaths per 1000 live births in the control arm. Intention-to-treat (IRR: 1.02; 95% CI: 0.88-1.19) and per-protocol estimates (IRR: 1.01; 95% CI: 0.87-1.18) showed no difference between study arms. Conclusion: Though proactive home visits did not reduce under-five mortality, system-strengthening measures may have contributed to the decline in under-five mortality in both arms.

Dose-Response Relationships Between Radiation Exposure, Bone Marrow Function as Measured by 18F-Fluorothymidine Positron Emission Tomography, and Lymphocyte Counts During Chemoradiation for Non-Small Cell Lung Cancer.

PURPOSE: 18F-fluorothymidine (FLT) positron emission tomography (PET) enables sensitive imaging of bone marrow (BM) proliferation. Sequential FLT-PET/computed tomography scans before and during chemoradiation therapy (CRT) for non-small cell lung cancer were repurposed to investigate the dose-response effects of radiation on BM proliferation. METHODS AND MATERIALS: Twenty-six non-small cell lung cancer patients underwent platinum-based CRT to 60 Gy in 30 fractions with FLT-PET/computed tomography scans at baseline, week 2 (20 Gy), and week 4 (40 Gy). FLT uptake in BM was isolated using Medical Image Merge software. Weeks 2 and 4 FLT-PET BM scans were fused with contemporaneous radiation isodose distributions. Relationships between radiation dose and FLT BM uptake (highest standardized uptake values within the volume and visual parameters) were analyzed using generalized linear and restricted cubic spline models. Percentage volumes of total BM without appreciable FLT uptake ("ablated") on weeks 2 and 4 FLT-PET scans were calculated by comparisons with baseline scans. RESULTS: Thoracic FLT uptake was ablated in BM regions exposed to cumulative radiation doses ≥3 Gy by week 2. In all cases, BM FLT's highest standardized uptake values within the volume declined rapidly as the radiation dose increased. BM proliferation significantly decreased by >95% after ≥3 to 4 Gy at 2 weeks and ≥4 to 5 Gy at 4 weeks. The ablated BM volume increased from week 2 to week 4 as BM in the penumbra accumulated radiation dose. The median percentage of total BM ablated was 13.1% (range, 5.6%-20.3%) at 2 weeks and 15.7% (range, 9.2%-24.1%) at 4 weeks. Mean lymphocyte counts fell from a baseline of 2.01 × 109/L to 0.77 at week 2 and 0.60 at week 4. Lymphocyte decline strongly correlated with the percentage of total BM ablated by week 4 (y = -46 to 1.64x; R2adj = 0.34; P = .001). CONCLUSIONS: BM ablation associated with low-dose radiation exposure during CRT correlated significantly with lower week 4 lymphocyte counts. BM is a potential organ at risk, and reducing the BM volume exposed to ≥3 Gy may help preserve lymphocytes, which is essential for effective adjuvant immunotherapy.

Interatrial Shunt Treatment for Heart Failure: The Randomized RELIEVE-HF Trial.

BACKGROUND: An interatrial shunt may provide an autoregulatory mechanism to decrease left atrial pressure and improve heart failure (HF) symptoms and prognosis. METHODS: Patients with symptomatic HF with any left ventricular ejection fraction (LVEF) were randomized 1:1 to transcatheter shunt implantation versus a placebo procedure, stratified by reduced (≤40%) versus preserved (>40%) LVEF. The primary safety outcome was a composite of device-related or procedure-related major adverse cardiovascular or neurological events at 30 days compared with a prespecified performance goal of 11%. The primary effectiveness outcome was the hierarchical composite ranking of all-cause death, cardiac transplantation or left ventricular assist device implantation, HF hospitalization, outpatient worsening HF events, and change in quality of life from baseline measured by the Kansas City Cardiomyopathy Questionnaire overall summary score through maximum 2-year follow-up, assessed when the last enrolled patient reached 1-year follow-up, expressed as the win ratio. Prespecified hypothesis-generating analyses were performed on patients with reduced and preserved LVEF. RESULTS: Between October 24, 2018, and October 19, 2022, 508 patients were randomized at 94 sites in 11 countries to interatrial shunt treatment (n=250) or a placebo procedure (n=258). Median (25th and 75th percentiles) age was 73.0 years (66.0, 79.0), and 189 patients (37.2%) were women. Median LVEF was reduced (≤40%) in 206 patients (40.6%) and preserved (>40%) in 302 patients (59.4%). No primary safety events occurred after shunt implantation (upper 97.5% confidence limit, 1.5%; P<0.0001). There was no difference in the 2-year primary effectiveness outcome between the shunt and placebo procedure groups (win ratio, 0.86 [95% CI, 0.61-1.22]; P=0.20). However, patients with reduced LVEF had fewer adverse cardiovascular events with shunt treatment versus placebo (annualized rate 49.0% versus 88.6%; relative risk, 0.55 [95% CI, 0.42-0.73]; P<0.0001), whereas patients with preserved LVEF had more cardiovascular events with shunt treatment (annualized rate 60.2% versus 35.9%; relative risk, 1.68 [95% CI, 1.29-2.19]; P=0.0001; Pinteraction<0.0001). There were no between-group differences in change in Kansas City Cardiomyopathy Questionnaire overall summary score during follow-up in all patients or in those with reduced or preserved LVEF. CONCLUSIONS: Transcatheter interatrial shunt implantation was safe but did not improve outcomes in patients with HF. However, the results from a prespecified exploratory analysis in stratified randomized groups suggest that shunt implantation is beneficial in patients with reduced LVEF and harmful in patients with preserved LVEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03499236.

Geriatric femur fractures: Index fracture pattern is associated with the risk of subsequent peri-implant fracture.

Introduction: Following an index femoral fragility fracture, patients are at risk of a subsequent peri-implant fracture. Management of these injuries are further complicated by patient factors and multi-institutional care. This study quantifies such events and compare rate of identification between in-system and out-of-system patients. Methods: A retrospective chart review of index operative femoral fragility fractures at a level I trauma center from January 1, 2005 to January 1, 2018 identified 840 patients with twenty-two subsequent peri-implant fractures. Kaplan Meier survival analyses assessed associations between patient and injury characteristics with the subsequent fracture while accounting for differential follow-up. Cumulative incidence curves were reported, and Cox regression analyses estimated hazard ratios for statistically significant associations. In-system and out-of-system patients were compared with absolute rate of identifying subsequent fracture and follow-up time. Results: Cumulative incidence of subsequent fracture was 2.1 % at 2 years, 3.4 % at 4 years, and 4.6 % at 6 years. The index fracture pattern (intertrochanteric vs other) was associated with a cumulative incidence of subsequent peri-implant fracture (0.8 % at 2 years, 1.4 % at 4 years, and 2.7 % at 6 years for intertrochanteric fractures vs 3.4 % at 2 years, 5.3 % at 4 years, and 6.4 % at 6 years for non-intertrochanteric fractures), p = 0.029. Follow-up was shorter for out-of-system patients (median 6 versus 28 months, p < 0.001), and only 1 of 348 out-of-system patients (0.3 %) vs. 21 of 492 in-system patients (4.3 %) were diagnosed with a subsequent peri-implant fracture (p < 0.001). There was no association of subsequent peri-implant fracture with patient demographics or comorbidity burden. Conclusion: Cumulative incidence of subsequent peri-implant fracture was higher for non-intertrochanteric (femoral neck, shaft and distal femur) fractures than intertrochanteric fractures. Out-of-system patients had shorter follow-up and were less likely to be diagnosed with a subsequent peri-implant fracture, indicating ascertainment bias and underscoring the importance of accounting for loss to follow-up. Level of evidence: Therapeutic Level III.

Fitness factors impacting survival of a subsurface bacterium in contaminated groundwater.

Many factors contribute to the ability of a microbial species to persist when encountering complexly contaminated environments including time of exposure, the nature and concentration of contaminants, availability of nutritional resources, and possession of a combination of appropriate molecular mechanisms needed for survival. Herein we sought to identify genes that are most important for survival of Gram-negative Enterobacteriaceae in contaminated groundwater environments containing high concentrations of nitrate and metals using the metal-tolerant Oak Ridge Reservation (ORR) isolate, Pantoea sp. MT58 (MT58). Survival fitness experiments in which a randomly barcoded transposon insertion (RB-TnSeq) library of MT58 was exposed directly to contaminated ORR groundwater samples from across a nitrate and mixed metal contamination plume were used to identify genes important for survival with increasing exposure times and concentrations of contaminants, and availability of a carbon source. Genes involved in controlling and using carbon, encoding transcriptional regulators, and related to Gram-negative outer membrane processes were among those found to be important for survival in contaminated ORR groundwater. A comparative genomics analysis of 75 Pantoea genus strains allowed us to further separate the survival determinants into core and non-core genes in the Pantoea pangenome, revealing insights into the survival of subsurface microorganisms during contaminant plume intrusion.

The pro-inflammatory cytokines IL-1ß and IL-6 promote upregulation of the ST6GAL1 sialyltransferase in pancreatic cancer cells.

The ST6GAL1 sialyltransferase is overexpressed in multiple cancers including pancreatic ductal adenocarcinoma (PDAC). ST6GAL1 adds an α2-6-linked sialic acid to N-glycosylated membrane receptors, which consequently modulates receptor structure and function. While many studies have investigated the effects of ST6GAL1 on cell phenotype, there is a dearth of knowledge regarding mechanisms that regulate ST6GAL1 expression. In the current study, we evaluated the regulation of ST6GAL1 by two pro-inflammatory cytokines, IL-1ß and IL-6, that are abundant within the PDAC tumor microenvironment. Cytokine activity was monitored using the Suit-2 PDAC cell line and two Suit-2-derived metastatic subclones, S2-013 and S2-LM7AA. For all three cell models, treatment with IL-1ß or IL-6 increased the expression of ST6GAL1 protein and mRNA. Specifically, IL-1ß and IL-6 induced expression of the ST6GAL1 YZ mRNA isoform, which is driven by the P3 promoter. The ST6GAL1 H and X isoforms were not detected. Promoter reporter assays confirmed that IL-1ß and IL-6 activated transcription from the P3 promoter. We then examined downstream signaling mechanisms. IL-1ß is known to signal through the NFκB transcription factor, whereas IL-6 signals through the STAT3 transcription factor. CUT&RUN experiments revealed that IL-1ß promoted the binding of NFκB to the ST6GAL1 P3 promoter, and IL-6 induced the binding of STAT3 to the P3 promoter. Finally, we determined that inhibitors of NFκB and STAT3 blocked the upregulation of ST6GAL1 stimulated by IL-1ß and IL-6, respectively. Together, these results highlight a novel molecular pathway by which cytokines within the tumor microenvironment stimulate the upregulation of ST6GAL1 in PDAC cells.

Intraoperative fluid management in adult spinal deformity surgery: variation analysis and association with outcomes.

PURPOSE: To evaluate the variability in intraoperative fluid management during adult spinal deformity (ASD) surgery, and analyze the association with complications, intensive care unit (ICU) requirement, and length of hospital stay (LOS). METHODS: Multicenter comparative cohort study. Patients ≥ 18 years old and with ASD were included. Intraoperative intravenous (IV) fluid data were collected including: crystalloids, colloids, crystalloid/colloid ratio (C/C), total IV fluid (tIVF, ml), normalized total IV fluid (nIVF, ml/kg/h), input/output ratio (IOR), input-output difference (IOD), and normalized input-output difference (nIOD, ml/kg/h). Data from different centers were compared for variability analysis, and fluid parameters were analyzed for possible associations with the outcomes. RESULTS: Seven hundred ninety-eight patients with a median age of 65.2 were included. Among different surgical centers, tIVF, nIVF, and C/C showed significant variation (p < 0.001 for each) with differences of 4.8-fold, 3.7-fold, and 4.9-fold, respectively. Two hundred ninety-two (36.6%) patients experienced at least one in-hospital complication, and ninety-two (11.5%) were IV fluid related. Univariate analysis showed significant relations for: LOS and tIVF (ρ = 0.221, p < 0.001), IOD (ρ = 0.115, p = 0.001) and IOR (ρ = -0.138, p < 0.001); IV fluid-related complications and tIVF (p = 0.049); ICU stay and tIVF, nIVF, IOD and nIOD (p < 0.001 each); extended ICU stay and tIVF (p < 0.001), nIVF (p = 0.010) and IOD (p < 0.001). Multivariate analysis controlling for confounders showed significant relations for: LOS and tIVF (p < 0.001) and nIVF (p = 0.003); ICU stay and IOR (p = 0.002), extended ICU stay and tIVF (p = 0.004). CONCLUSION: Significant variability and lack of standardization in intraoperative IV fluid management exists between different surgical centers. Excessive fluid administration was found to be correlated with negative outcomes. LEVEL OF EVIDENCE: III.