Technology in Total Knee Arthroplasty in 2023.

Over the past few decades, instrumentation and techniques for total knee arthroplasty (TKA) have evolved from conventional manual tools to a wide range of technologies, including calibrated guides for accurate bone cuts and alignment, smart tools, dynamic intraoperative sensors for soft-tissue balancing, patient-specific guides, computer navigation, and robotics. This review is intended to provide an overview of the latest advancements in TKA technology, address potential challenges and solutions related to the application of these technologies, and explore their limitations.

Deep learning classification of pediatric spinal radiographs for use in large scale imaging registries.

PURPOSE: The purpose of this study is to develop and apply an algorithm that automatically classifies spine radiographs of pediatric scoliosis patients. METHODS: Anterior-posterior (AP) and lateral spine radiographs were extracted from the institutional picture archive for patients with scoliosis. Overall, there were 7777 AP images and 5621 lateral images. Radiographs were manually classified into ten categories: two preoperative and three postoperative categories each for AP and lateral images. The images were split into training, validation, and testing sets (70:15:15 proportional split). A deep learning classifier using the EfficientNet B6 architecture was trained on the spine training set. Hyperparameters and model architecture were tuned against the performance of the models in the validation set. RESULTS: The trained classifiers had an overall accuracy on the test set of 1.00 on 1166 AP images and 1.00 on 843 lateral images. Precision ranged from 0.98 to 1.00 in the AP images, and from 0.91 to 1.00 on the lateral images. Lower performance was observed on classes with fewer than 100 images in the dataset. Final performance metrics were calculated on the assigned test set, including accuracy, precision, recall, and F1 score (the harmonic mean of precision and recall). CONCLUSIONS: A deep learning convolutional neural network classifier was trained to a high degree of accuracy to distinguish between 10 categories pre- and postoperative spine radiographs of patients with scoliosis. Observed performance was higher in more prevalent categories. These models represent an important step in developing an automatic system for data ingestion into large, labeled imaging registries.

Cohesin-mediated 3D contacts tune enhancer-promoter regulation.

Enhancers are key drivers of gene regulation thought to act via 3D physical interactions with the promoters of their target genes. However, genome-wide depletions of architectural proteins such as cohesin result in only limited changes in gene expression, despite a loss of contact domains and loops. Consequently, the role of cohesin and 3D contacts in enhancer function remains debated. Here, we developed CRISPRi of regulatory elements upon degron operation (CRUDO), a novel approach to measure how changes in contact frequency impact enhancer effects on target genes by perturbing enhancers with CRISPRi and measuring gene expression in the presence or absence of cohesin. We systematically perturbed all 1,039 candidate enhancers near five cohesin-dependent genes and identified 34 enhancer-gene regulatory interactions. Of 26 regulatory interactions with sufficient statistical power to evaluate cohesin dependence, 18 show cohesin-dependent effects. A decrease in enhancer-promoter contact frequency upon removal of cohesin is frequently accompanied by a decrease in the regulatory effect of the enhancer on gene expression, consistent with a contact-based model for enhancer function. However, changes in contact frequency and regulatory effects on gene expression vary as a function of distance, with distal enhancers (e.g., >50Kb) experiencing much larger changes than proximal ones (e.g., <50Kb). Because most enhancers are located close to their target genes, these observations can explain how only a small subset of genes - those with strong distal enhancers - are sensitive to cohesin. Together, our results illuminate how 3D contacts, influenced by both cohesin and genomic distance, tune enhancer effects on gene expression.

SMCHD1 activates the expression of genes required for the expansion of human myoblasts.

SMCHD1 is an epigenetic regulatory protein known to modulate the targeted repression of large chromatin domains. Diminished SMCHD1 function in muscle fibers causes Facioscapulohumeral Muscular Dystrophy (FSHD2) through derepression of the D4Z4 chromatin domain, an event which permits the aberrant expression of the disease-causing gene DUX4. Given that SMCHD1 plays a broader role in establishing the cellular epigenome, we examined whether loss of SMCHD1 function might affect muscle homeostasis through additional mechanisms. Here we show that acute depletion of SMCHD1 results in a DUX4-independent defect in myoblast proliferation. Genomic and transcriptomic experiments determined that SMCHD1 associates with enhancers of genes controlling cell cycle to activate their expression. Amongst these cell cycle regulatory genes, we identified LAP2 as a key target of SMCHD1 required for the expansion of myoblasts, where the ectopic expression of LAP2 rescues the proliferation defect of SMCHD1-depleted cells. Thus, the epigenetic regulator SMCHD1 can play the role of a transcriptional co-activator for maintaining the expression of genes required for muscle progenitor expansion. This DUX4-independent role for SMCHD1 in myoblasts suggests that the pathology of FSHD2 may be a consequence of defective muscle regeneration in addition to the muscle wasting caused by spurious DUX4 expression.

Validation of predictive performance models for supersonic gas-jet nozzles at the Laboratory for Laser Energetics.

We present results characterizing the neutral-density distributions produced by the supersonic nozzles used in experiments on the OMEGA-60 and OMEGA-EP laser systems at the University of Rochester's Laboratory for Laser Energetics (LLE). Axisymmetric Fluent® simulations using LLE nozzle specifications capture the viscous effects, gas expansion, and shock waves that complicate flow predictions for offsets above the nozzle exit. These simulations show good agreement with neutral-density measurements obtained using a four-wave shearing interferometer. An analytical form is given for the plateau length. Fits to simulation data for boundary layer thickness, mean plateau density, and density ramps are given as functions of nozzle offset and nozzle backing pressure for a number of nozzles and gases.

Hot beverage consumption in the African Esophageal Cancer Corridor: A community-based thermal exposure measurement study across the lifespan.

"Very hot beverage" (>65°C) consumption is an IARC probable carcinogen and may contribute to the African esophageal cancer burden. We conducted community cross-sectional exposure studies of hot beverage consumption in Kenya and Malawi during 2018-2019, aiming to: (i) implement a detailed measurement protocol incorporating three measurements of sip temperature and volume so as to predict each sip's intra-esophageal liquid temperature (IELT); (ii) examine variations by seasonality, drinking venue and age, including children. 246 participants were included, of whom 236 had drink measurements (52 children and 183 adults). Among adults, mean (SD) temperatures at first sip were 67 (9) and 68 (7) °C in Kenya and Malawi respectively, i.e. 58 and almost 70 % of first sips were > 65 °C. In both countries, adults exhibited a protective habit of smaller sips at higher temperatures (mean 11 mL at first sip), whereas the larger middle sip (20 mL) had the highest IELT (45 °C). The highest temperatures were observed in men and for drinks taken in social settings, whereas we did not detect seasonality or associations with other esophageal cancer risk factors. Measurements were difficult to make for 20 % (8/43) of Kenyan children whose drink was cooled by pouring between cups ('poesha'). Where poesha was not practiced, IELTs were lower in children (especially < 10 years) than in adults, owing to a mean of 8 °C cooler first sip temperature, however 20 % of first sips were > 65 °C. If very hot beverage consumption is an esophageal carcinogen, lowering sip temperatures and volumes in East Africa would form important prevention avenues.

Immunogenicity and Safety Following 1 Dose of AS01E-Adjuvanted Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults: A Phase 3 Trial.

BACKGROUND: The recently approved AS01E-adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine for older adults (RSVPreF3 OA) demonstrated high efficacy against RSV-related disease in ≥60-year-olds. METHODS: This ongoing phase 3 study in ≥60-year-olds evaluates immune persistence until 3 years after RSVPreF3 OA vaccination. Here, we describe interim results on humoral and cell-mediated immunogenicity, reactogenicity, and safety until 1 year post-dose 1. RESULTS: In total, 1653 participants were vaccinated. One month post-dose 1, neutralization titers increased 10.5-fold (RSV-A) and 7.8-fold (RSV-B) vs pre-dose 1. Titers then declined to levels 4.4-fold (RSV-A) and 3.5-fold (RSV-B) above pre-dose 1 at month 6 and remained 3.1-fold (RSV-A) and 2.3-fold (RSV-B) above pre-dose 1 levels after 1 year. RSVPreF3-binding immunoglobulin G levels and CD4+ T-cell frequencies showed similar kinetics. Solicited administration-site and systemic adverse events (mostly mild to moderate and transient) were reported by 62.2% and 49.5% of participants. Serious adverse events were reported by 3.9% of participants within 6 months post-dose 1; 1 case was considered vaccine related. CONCLUSIONS: One RSVPreF3 OA dose elicited cell-mediated and RSV-A- and RSV-B-specific humoral immune responses that declined over time but remained above pre-dose 1 levels for at least 1 year. The vaccine was well tolerated with an acceptable safety profile. Clinical Trials Registration. NCT04732871 (ClinicalTrials.gov).

Respiratory syncytial virus (RSV) is a major cause of illness and hospitalization in older adults. An RSV vaccine for older adults developed by GSK was recently approved. The vaccine was well tolerated and provided protection against RSV disease in adults aged ≥60 years during at least 1 RSV season. In this ongoing study, we are evaluating the magnitude and durability of the immune response, as well as vaccine safety, until 3 years after vaccination of adults aged ≥60 years from 5 countries. Here, we report the results of an interim analysis until 1 year after vaccination with 1 dose. In total, 1653 participants were vaccinated. We found that the vaccine induced a strong immune response that was evident 1 month after vaccination, after which it declined but persisted for at least 1 year. Study participants most often reported pain at the injection site, muscle pain, tiredness, and headache as adverse reactions, which were mostly mild to moderate and of short duration. One serious adverse reaction was considered related to the vaccine. The long-term immune response that was observed in this study is consistent with the vaccine providing protection during at least 1 RSV season.

Representativeness of Patients With Lung Cancer in an Integrated Health Care Delivery System.

INTRODUCTION: Observational research is important for understanding the real-world benefits of advancements in lung cancer care. Integrated health care systems, such as Kaiser Permanente Northern California, have extensive electronic health records suitable for such research, but the generalizability of their populations is often questioned. METHODS: Leveraging data from the California Cancer Registry, the authors compared distributions of demographic and clinical characteristics, in addition to neighborhood and environmental conditions, between patients diagnosed with lung cancer from 2015 through 2019 at Kaiser Permanente Northern California, National Cancer Institute-designated cancer centers (NCICCs), and all other non-NCICC hospitals within the same catchment area. RESULTS: Of 20,178 included patients, 30% were from Kaiser Permanente Northern California, 8% from NCICCs, and 62% from other non-NCICC hospitals. Compared to NCICC patients, Kaiser Permanente Northern California patients were more similar to other non-NCICC patients on most characteristics. Compared to other non-NCICC patients, Kaiser Permanente Northern California patients were slightly older, more likely to be female, and less likely to be Hispanic or Asian/Pacific Islander and to reside in lower socioeconomic status (SES) neighborhoods. In contrast, NCICC patients were younger, less likely to be female or from non-Asian/Pacific Islander minoritized racial groups, and more likely to present with early-stage disease and adenocarcinoma and to reside in neighborhoods with higher SES and lower air pollution than Kaiser Permanente Northern California or other non-NCICC patients. DISCUSSION: Patients from Kaiser Permanente Northern California, compared to NCICCs, are more broadly representative of the underlying patient population with lung cancer. CONCLUSION: Research using electronic health record data from integrated health care systems can contribute generalizable real-world evidence to benchmark and improve lung cancer care.

Mechanisms of action of microbicides commonly used in infection prevention and control.

SUMMARYUnderstanding how commonly used chemical microbicides affect pathogenic microorganisms is important for formulation of microbicides. This review focuses on the mechanism(s) of action of chemical microbicides commonly used in infection prevention and control. Contrary to the typical site-specific mode of action of antibiotics, microbicides often act via multiple targets, causing rapid and irreversible damage to microbes. In the case of viruses, the envelope or protein capsid is usually the primary structural target, resulting in loss of envelope integrity or denaturation of proteins in the capsid, causing loss of the receptor-binding domain for host cell receptors, and/or breakdown of other viral proteins or nucleic acids. However, for certain virucidal microbicides, the nucleic acid may be a significant site of action. The region of primary damage to the protein or nucleic acid is site-specific and may vary with the virus type. Due to their greater complexity and metabolism, bacteria and fungi offer more targets. The rapid and irreversible damage to microbes may result from solubilization of lipid components and denaturation of enzymes involved in the transport of nutrients. Formulation of microbicidal actives that attack multiple sites on microbes, or control of the pH, addition of preservatives or potentiators, and so on, can increase the spectrum of action against pathogens and reduce both the concentrations and times needed to achieve microbicidal activity against the target pathogens.

HbA1c variability associated with dementia risk in people with type 2 diabetes.

INTRODUCTION: Although poor glycemic control is associated with dementia, it is unknown if variability in glycemic control, even in those with optimal glycosylated hemoglobin A1c (HbA1c) levels, increases dementia risk. METHODS: Among 171,964 people with type 2 diabetes, we evaluated the hazard of dementia association with long-term HbA1c variability using five operationalizations, including standard deviation (SD), adjusting for demographics and comorbidities. RESULTS: The mean baseline age was 61 years (48% women). Greater HbA1c SD was associated with greater dementia hazard (adjusted hazard ratio = 1.15 [95% confidence interval: 1.12, 1.17]). In stratified analyses, higher HbA1c SD quintiles were associated with greater dementia hazard among those with a mean HbA1c < 6% (P = 0.0004) or 6% to 8% (P < 0.0001) but not among those with mean HbA1c ≥ 8% (P = 0.42). DISCUSSION: Greater HbA1c variability is associated with greater dementia risk, even among those with HbA1c concentrations at ideal clinical targets. These findings add to the importance and clinical impact of recommendations to minimize glycemic variability. HIGHLIGHTS: We observed a cohort of 171,964 people with type 2 diabetes (mean age 61 years). This cohort was based in Northern California between 1996 and 2018. We examined the association between glycosylated hemoglobin A1c (HbA1c) variability and dementia risk. Greater HbA1c variability was associated with greater dementia hazard. This was most evident among those with normal-low mean HbA1c concentrations.

Systemic Osteoporosis and Osteopenia Among Periprosthetic Fractures After Total Hip Arthroplasty.

BACKGROUND: Most periprosthetic fractures following total hip arthroplasty (THA) are fragility fractures that qualify patients for osteoporosis diagnoses. However, it remains unknown how many patients were diagnosed who had osteoporosis before injury or received the proper evaluation, diagnosis, and treatment after injury. METHODS: We identified 171 Vancouver B2 (109) and B3 (62) periprosthetic femur fractures treated with a modular fluted tapered stem from 2000 to 2018 at 1 institution. The mean patient age was 75 years (range, 35 to 94), 50% were women, and the mean body mass index was 29 (range, 17 to 60). We identified patients who had osteoporosis or osteopenia diagnoses, a fracture risk assessment tool (FRAX), bone mineral density (BMD) testing, an endocrinology consult, and osteoporosis medications. Age-appropriate BMD testing was defined as no later than 1 year after the recommended ages of 65 (women) or 70 years (men). The mean follow-up was 11 years (range, 4 to 21). RESULTS: Falls from standing height caused 94% of fractures and thus, by definition, qualified as osteoporosis-defining events. The prevalence of osteoporosis diagnosis increased from 20% before periprosthetic fracture to 39% after (P < .001). The prevalence of osteopenia diagnosis increased from 13% before the fracture to 24% after (P < .001). The prevalence of either diagnosis increased from 24% before fracture to 44% after (P < .001). No patients had documented FRAX scores before fracture, and only 2% had scores after. The prevalence of BMD testing was 21% before fracture and 22% after (P = .88). By the end of the final follow-up, only 16% had received age-appropriate BMD testing. The proportion of patients who had endocrinology consults increased from 6% before the fracture to 25% after (P < .001). The proportion on bisphosphonate therapy was 19% before fracture and 25% after (P = .08). CONCLUSIONS: Although most periprosthetic fractures following THA are fragility fractures that qualify patients for osteoporosis diagnoses, there remain major gaps in diagnosis, screening, endocrinology follow-up, and treatment. Like nonarthroplasty fragility fractures, a systematic approach is needed after periprosthetic fractures. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Stereoselective Access to Diverse Alkaloid-Like Scaffolds via an Oxidation/Double-Mannich Reaction Sequence.

Sequential oxidative cleavage and double-Mannich reactions enable the stereoselective conversion of simple norbornenes into complex alkaloid-like structures. The products undergo a wide range of derivatization reactions, including regioselective enol triflate formation/cross-coupling sequences and highly efficient conversion to an unusual tricyclic 8,5,5-fused lactam. Overall, the process represents a formal one-atom aza-ring expansion with concomitant bridging annulation, making it of interest for the broader derivatization of alkene feedstocks.

Gene-environment interactions within a precision environmental health framework.

Understanding the complex interplay of genetic and environmental factors in disease etiology and the role of gene-environment interactions (GEIs) across human development stages is important. We review the state of GEI research, including challenges in measuring environmental factors and advantages of GEI analysis in understanding disease mechanisms. We discuss the evolution of GEI studies from candidate gene-environment studies to genome-wide interaction studies (GWISs) and the role of multi-omics in mediating GEI effects. We review advancements in GEI analysis methods and the importance of large-scale datasets. We also address the translation of GEI findings into precision environmental health (PEH), showcasing real-world applications in healthcare and disease prevention. Additionally, we highlight societal considerations in GEI research, including environmental justice, the return of results to participants, and data privacy. Overall, we underscore the significance of GEI for disease prediction and prevention and advocate for integrating the exposome into PEH omics studies.

Exploring Anesthesia Provider Preferences for Precision Feedback: Preference Elicitation Study.

Background: Health care professionals must learn continuously as a core part of their work. As the rate of knowledge production in biomedicine increases, better support for health care professionals' continuous learning is needed. In health systems, feedback is pervasive and is widely considered to be essential for learning that drives improvement. Clinical quality dashboards are one widely deployed approach to delivering feedback, but engagement with these systems is commonly low, reflecting a limited understanding of how to improve the effectiveness of feedback about health care. When coaches and facilitators deliver feedback for improving performance, they aim to be responsive to the recipient's motivations, information needs, and preferences. However, such functionality is largely missing from dashboards and feedback reports. Precision feedback is the delivery of high-value, motivating performance information that is prioritized based on its motivational potential for a specific recipient, including their needs and preferences. Anesthesia care offers a clinical domain with high-quality performance data and an abundance of evidence-based quality metrics. Objective: The objective of this study is to explore anesthesia provider preferences for precision feedback. Methods: We developed a test set of precision feedback messages with balanced characteristics across 4 performance scenarios. We created an experimental design to expose participants to contrasting message versions. We recruited anesthesia providers and elicited their preferences through analysis of the content of preferred messages. Participants additionally rated their perceived benefit of preferred messages to clinical practice on a 5-point Likert scale. Results: We elicited preferences and feedback message benefit ratings from 35 participants. Preferences were diverse across participants but largely consistent within participants. Participants' preferences were consistent for message temporality (α=.85) and display format (α=.80). Ratings of participants' perceived benefit to clinical practice of preferred messages were high (mean rating 4.27, SD 0.77). Conclusions: Health care professionals exhibited diverse yet internally consistent preferences for precision feedback across a set of performance scenarios, while also giving messages high ratings of perceived benefit. A "one-size-fits-most approach" to performance feedback delivery would not appear to satisfy these preferences. Precision feedback systems may hold potential to improve support for health care professionals' continuous learning by accommodating feedback preferences.

Relative contribution of COVID-19 vaccination and SARS-CoV-2 infection to population-level seroprevalence of SARS-CoV-2 spike antibodies in a large integrated health system.

BACKGROUND: Understanding the relative contributions of SARS-CoV-2 infection-induced and vaccine-induced seroprevalence is key to measuring overall population-level seroprevalence and help guide policy decisions. METHODS: Using a series of six population-based cross-sectional surveys conducted among persons aged ≥7 years in a large health system with over 4.5 million members between May 2021 and April 2022, we combined data from the electronic health record (EHR), an electronic survey and SARS-CoV-2 spike antibody binding assay, to assess the relative contributions of infection and vaccination to population-level SARS-CoV-2 seroprevalence. EHR and survey data were incorporated to determine spike antibody positivity due to SARS-CoV-2 infection and COVID-19 vaccination. We used sampling and non-response weighting to create population-level estimates. RESULTS: We enrolled 4,319 persons over six recruitment waves. SARS-CoV-2 spike antibody seroprevalence increased from 83.3% (CI 77.0-88.9) in May 2021 to 93.5% (CI 89.5-97.5) in April 2022. By April 2022, 68.5% (CI 61.9-74.3) of the population was seropositive from COVID-19 vaccination only, 13.9% (10.7-17.9) from COVID-19 vaccination and prior diagnosed SARS-CoV-2 infection, 8.2% (CI 4.5-14.5) from prior diagnosed SARS-CoV-2 infection only and 2.9% (CI 1.1-7.6) from prior undiagnosed SARS-CoV-2 infection only. We found high agreement (≥97%) between EHR and survey data for ascertaining COVID-19 vaccination and SARS-CoV-2 infection status. CONCLUSIONS: By April 2022, 93.5% of persons had detectable SARS-CoV-2 spike antibody, predominantly from COVID-19 vaccination. In this highly vaccinated population and over 18 months into the pandemic, SARS-CoV-2 infection without COVID-19 vaccination was a small contributor to overall population-level seroprevalence.

Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease.

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples.

Ten simple rules to make computable knowledge shareable and reusable.

Computable biomedical knowledge (CBK) is: "the result of an analytic and/or deliberative process about human health, or affecting human health, that is explicit, and therefore can be represented and reasned upon using logic, formal standards, and mathematical approaches." Representing biomedical knowledge in a machine-interpretable, computable form increases its ability to be discovered, accessed, understood, and deployed. Computable knowledge artifacts can greatly advance the potential for implementation, reproducibility, or extension of the knowledge by users, who may include practitioners, researchers, and learners. Enriching computable knowledge artifacts may help facilitate reuse and translation into practice. Following the examples of 10 Simple Rules papers for scientific code, software, and applications, we present 10 Simple Rules intended to make shared computable knowledge artifacts more useful and reusable. These rules are mainly for researchers and their teams who have decided that sharing their computable knowledge is important, who wish to go beyond simply describing results, algorithms, or models via traditional publication pathways, and who want to both make their research findings more accessible, and to help others use their computable knowledge. These rules are roughly organized into 3 categories: planning, engineering, and documentation. Finally, while many of the following examples are of computable knowledge in biomedical domains, these rules are generalizable to computable knowledge in any research domain.

The Influence of Dietary Isothiocyanates on the Effectiveness of Mitomycin C and Bacillus Calmette-Guérin in Treating Nonmuscle-Invasive Bladder Cancer.

PURPOSE: Nonmuscle-invasive bladder cancer (NMIBC) has high recurrence rates and is often treated with mitomycin C (MMC) and bacillus Calmette-Guérin (BCG). Their efficacy relies on phase 2 enzyme metabolism and immune response activation, respectively. Dietary isothiocyanates, phytochemicals in cruciferous vegetables, are phase 2 enzyme inducers and immunomodulators, and may impact treatment outcomes. We investigated the modifying effects of cruciferous vegetable and isothiocyanate intake on recurrence risk following MMC or BCG treatment. MATERIALS AND METHODS: Self-reported cruciferous vegetable intake, estimated isothiocyanate intake, and urinary isothiocyanate metabolites were collected from 1158 patients with incident NMIBC in the prospective Be-Well Study. Hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazards regression models for risk of first recurrences, and random effects Cox shared frailty models for multiple recurrences. RESULTS: Over median follow-up of 23 months, 343 (30%) recurrences occurred. Receipt of MMC and BCG was associated with decreased risks of first recurrence (MMC: HR = 0.58; 95% CI: 0.46-0.73; BCG: HR = 0.66; 95% CI: 0.49-0.88) and multiple recurrences (MMC: HR = 0.55; 95% CI: 0.44-0.68; BCG: HR = 0.72; 95% CI: 0.55-0.95). Patients receiving BCG and having high intake (>2.4 servings/mo), but not low intake, of raw cruciferous vegetables had reduced risk of recurrence (HR: 0.56; 95% CI: 0.36-0.86; P for interaction = .02) and multiple recurrences (HR: 0.51; 95% CI: 0.34-0.77; P for interaction < .001). The inverse association between MMC receipt and recurrence risk was not modified. CONCLUSIONS: For NMIBC patients who receive induction BCG, increasing consumption of raw cruciferous vegetables could be a promising strategy to attenuate recurrence risk.

Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosis.

BACKGROUND & AIMS: Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated survodutide in people with cirrhosis. METHODS: This multinational, non-randomized, open-label, phase 1 clinical trial initially evaluated a single subcutaneous (s.c.) dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently, people with overweight/obesity with or without cirrhosis and Child-Pugh class A or B received once-weekly s.c. doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored. RESULTS: In the single-dose cohorts (n = 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared with healthy individuals (90% confidence intervals for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment. CONCLUSIONS: Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis. Clinical trial number; ClinicalTrials.gov identifier: NCT05296733. IMPACT AND IMPLICATIONS: Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted.

Can step count be used to identify older adults with high sedentary time and low moderate-to-vigorous physical activity?

INTRODUCTION: Combined high sedentary time (ST) and low moderate-to-vigorous physical activity (MVPA) has been associated with adverse cardiovascular events. However, accurately assessing ST and MVPA in older adults is challenging in clinical practice. PURPOSE: To investigate whether step count can identify older adults with unhealthier movement behavior (high ST/low MVPA) and poorer cardiometabolic profile. METHODS: Cross-sectional study (n = 258; 66 ± 5 years). Step count, ST, and MVPA were assessed by hip accelerometry during 7 days. The cardiometabolic profile was assessed using a continuous metabolic syndrome score (cMetS), including blood pressure, HDL-cholesterol, triglycerides, fasting glucose, and waist circumference. Receiving operating curve analysis was used to test the performance of step count in identifying older adults with unhealthier movement behavior (highest tertile of ST/lowest tertile of MVPA). Healthier movement behavior was defined as lowest tertile of ST/highest tertile of MVPA, with neutral representing the remaining combinations of ST/MVPA. RESULTS: A total of 40 participants (15.5%) were identified with unhealthier movement behavior (ST ≥ 11.4 h/day and MVPA ≤ 10 min/day). They spent ~73% and 0.4% of waking hours in ST and MVPA, respectively. Step count identified those with unhealthier movement behavior (area under the curve 0.892, 0.850-0.934; cutoff: ≤5263 steps/day; sensitivity/specificity: 83%/81%). This group showed a higher cMetS compared with neutral (ß = .25, p = .028) and healthier movement behavior groups (ß = .41, p = .008). CONCLUSION: Daily step count appears to be a practical, simple metric for identifying community-dwelling older adults with concomitant high ST and low MVPA, indicative of unhealthier movement behavior, who have a poorer cardiometabolic profile.