Influence of test paradigm on loading dynamics during proximal femur fracture tests simulating sideways falls.

Fall-related hip fractures are a serious public health issue in older adults. As most mechanistic hip fracture risk prediction models incorporate tissue tolerance, test methods that can accurately characterize the fracture force of the femur (and factors that influence it) are imperative. While bone possesses viscoelastic properties, experimental characterization of rate-dependencies has been inconsistent in the whole-femur literature. The goal of this study was to investigate the influence of experimental paradigm on loading rate and fracture force (both means and variability) during mechanical tests simulating lateral fall loadings on the proximal femur. Six pairs of matched femurs were split randomly between two test paradigms: a 'lower rate' materials testing system (MTS) with a constant displacement rate of 60 mm/s, and a hip impact test system (HIT) comprised of a custom-built vertical drop tower utilizing an impact velocity of 4 m/s. The loading rate was 88-fold higher for the HIT (mean (SD) = 2465.49 (807.38) kN/s) compared to the MTS (27.78 (10.03) kN/s) paradigm. However, no difference in fracture force was observed between test paradigms (mean (SD) = 4096.4 (1272.6) N for HIT, and 3641.3 (1285.8) N for MTS). Within-paradigm variability was not significantly different across paradigms for either loading rate or fracture force (coefficients of variation ranging from 0.311 to 0.361). Within each test paradigm, significant positive relationships were observed between loading rate and fracture force (HIT adjusted R2 = 0.833, p = 0.007; MTS adjusted R2 = 0.983, p < 0.0001). Overall, this study provides evidence that energy-based impact simulators can be a valid method to measure femoral bone strength in the context of fall-related hip fractures. This study motivates future research to characterize potential non-linear relationships between loading rate and fracture threshold at both macro and microscales.

Multi-scale signaling and tumor evolution in high-grade gliomas.

Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.

Lower or higher oxygenation targets in the intensive care unit: an individual patient data meta-analysis.

PURPOSE: Optimal oxygenation targets for patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are not clearly defined due to substantial variability in design of previous trials. This study aimed to perform a pre-specified individual patient data meta-analysis of the Handling Oxygenation Targets in the ICU (HOT-ICU) and the Handling Oxygenation Targets in coronavirus disease 2019 (COVID-19) (HOT-COVID) trials to compare targeting a partial pressure of arterial oxygen (PaO2) of 8-12 kPa in adult ICU patients, assessing both benefits and harms. METHODS: We assessed 90-day all-cause mortality and days alive without life support in 90 days using a generalised mixed model. Heterogeneity of treatment effects (HTE) was evaluated in 14 subgroups, and results graded using the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN). RESULTS: At 90 days, mortality was 40.4% (724/1792) in the 8 kPa group and 40.9% (733/1793) in the 12 kPa group (risk ratio, 0.99; 95% confidence interval [CI] 0.92-1.07; P = 0.80). No difference was observed in number of days alive without life support. Subgroup analyses indicated more days alive without life support in COVID-19 patients targeting 8 kPa (P = 0.04) (moderate credibility), and lower mortality (P = 0.03) and more days alive without life support (P = 0.02) in cancer-patients targeting 12 kPa (low credibility). CONCLUSION: This study reported no overall differences comparing a PaO2 target of 8-12 kPa on mortality or days alive without life support in 90 days. Subgroup analyses suggested HTE in patients with COVID-19 (moderate credibility) and cancer (low credibility).

A cross-sectional assessment of injection of "salts" and HIV transmission-related behaviours among a cohort of people who inject drugs in Kyrgyzstan.

INTRODUCTION: Despite the increasing availability of new psychoactive substances (hereafter referred to as "salts") in Eastern Europe and Central Asia, there is a dearth of epidemiological data on the relationship between injecting "salts" and HIV risk behaviours. This is particularly relevant in settings where injection drug use accounts for a substantial proportion of the HIV burden, such as in Kyrgyzstan, a former Soviet Republic. This study assessed whether injecting "salts" is associated with sexual and injection-related HIV risk behaviours among people who inject drugs in Kyrgyzstan. METHODS: The Kyrgyzstan InterSectional Stigma Study is a cohort of people who inject drugs in Kyrgyzstan's capital of Bishkek and the surrounding rural administrative division of Chuy Oblast. We conducted a cross-sectional analysis using survey data collected from cohort participants between July and November 2021, which included information on injection drug use (including "salts") and HIV risk behaviours. To minimize confounding by measured covariates, we used inverse-probability-weighted logistic and Poisson regression models to estimate associations between recent "salt" injection and HIV risk behaviours. RESULTS: Of 181 participants included in the analysis (80.7% men, 19.3% women), the mean age was 40.1 years (standard deviation [SD] = 8.8), and 22% (n = 39) reported that they had injected "salts" in the past 6 months. Among people who injected "salts," 72% (n = 28) were men, and most were ethnically Russian 59% (n = 23), with a mean age of 34.6 (SD = 9.6). Injecting "salts" was significantly associated with a greater number of injections per day (adjusted relative risk [aRR] = 1.59, 95% confidence interval [CI] = 1.30-1.95) but lower odds of using syringe service programmes in the past 6 months (adjusted odds ratio [aOR] = 0.20, 95% CI = 0.12-0.32). Injecting "salts" was also significantly associated with lower odds of condomless sex in the past 6 months (aOR = 0.42, 95% CI = 0.24-0.76) and greater odds of having ever heard of pre-exposure prophylaxis (aOR = 4.80, 95% CI = 2.61-8.83). CONCLUSIONS: (PWID) people who inject drugs who inject "salts" are a potentially emergent group with increased HIV acquisition risk in Kyrgyzstan. Targeted outreach bundled with comprehensive harm reduction and pre-exposure prophylaxis services are needed to prevent transmission of HIV and other blood-borne viruses.

Shared functional specialization in transformer-based language models and the human brain.

When processing language, the brain is thought to deploy specialized computations to construct meaning from complex linguistic structures. Recently, artificial neural networks based on the Transformer architecture have revolutionized the field of natural language processing. Transformers integrate contextual information across words via structured circuit computations. Prior work has focused on the internal representations ("embeddings") generated by these circuits. In this paper, we instead analyze the circuit computations directly: we deconstruct these computations into the functionally-specialized "transformations" that integrate contextual information across words. Using functional MRI data acquired while participants listened to naturalistic stories, we first verify that the transformations account for considerable variance in brain activity across the cortical language network. We then demonstrate that the emergent computations performed by individual, functionally-specialized "attention heads" differentially predict brain activity in specific cortical regions. These heads fall along gradients corresponding to different layers and context lengths in a low-dimensional cortical space.

A training goal-oriented categorization model of high-intensity interval training.

There are various categorization models of high-intensity interval training (HIIT) in the literature that need to be more consistent in definition, terminology, and concept completeness. In this review, we present a training goal-oriented categorization model of HIIT, aiming to find the best possible consensus among the various defined types of HIIT. This categorization concludes with six different types of HIIT derived from the literature, based on the interaction of interval duration, interval intensity and interval:recovery ratio. We discuss the science behind the defined types of HIIT and shed light on the possible effects of the various types of HIIT on aerobic, anaerobic, and neuromuscular systems and possible transfer effects into competition performance. We highlight various research gaps, discrepancies in findings and not yet proved know-how based on a lack of randomized controlled training studies, especially in well-trained to elite athlete cohorts. Our HIIT "toolbox" approach is designed to guide goal-oriented training. It is intended to lay the groundwork for future systematic reviews and serves as foundation for meta-analyses.

Cost-Effectiveness of Plasma Microbial Cell-Free DNA Sequencing When Added to Usual Care Diagnostic Testing for Immunocompromised Host Pneumonia.

INTRODUCTION: Immunocompromised host pneumonia (ICHP) is an important cause of morbidity and mortality, yet usual care (UC) diagnostic tests often fail to identify an infectious etiology. A US-based, multicenter study (PICKUP) among ICHP patients with hematological malignancies, including hematological cell transplant recipients, showed that plasma microbial cell-free DNA (mcfDNA) sequencing provided significant additive diagnostic value. AIM: The objective of this study was to perform a cost-effectiveness analysis (CEA) of adding mcfDNA sequencing to UC diagnostic testing for hospitalized ICHP patients. METHODS: A semi-Markov model was utilized from the US third-party payer's perspective such that only direct costs were included, using a lifetime time horizon with discount rates of 3% for costs and benefits. Three comparators were considered: (1) All UC, which included non-invasive (NI) and invasive testing and early bronchoscopy; (2) All UC & mcfDNA; and (3) NI UC & mcfDNA & conditional UC Bronch (later bronchoscopy if the initial tests are negative). The model considered whether a probable causative infectious etiology was identified and if the patient received appropriate antimicrobial treatment through expert adjudication, and if the patient died in-hospital. The primary endpoints were total costs, life-years (LYs), equal value life-years (evLYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio per QALY. Extensive scenario and probabilistic sensitivity analyses (PSA) were conducted. RESULTS: At a price of $2000 (2023 USD) for the plasma mcfDNA, All UC & mcfDNA was more costly ($165,247 vs $153,642) but more effective (13.39 vs 12.47 LYs gained; 10.20 vs 9.42 evLYs gained; 10.11 vs 9.42 QALYs gained) compared to All UC alone, giving a cost/QALY of $16,761. NI UC & mcfDNA & conditional UC Bronch was also more costly ($162,655 vs $153,642) and more effective (13.19 vs 12.47 LYs gained; 9.96 vs 9.42 evLYs gained; 9.96 vs 9.42 QALYs gained) compared to All UC alone, with a cost/QALY of $16,729. The PSA showed that above a willingness-to-pay threshold of $50,000/QALY, All UC & mcfDNA was the preferred scenario on cost-effectiveness grounds (as it provides the most QALYs gained). Further scenario analyses found that All UC & mcfDNA always improved patient outcomes but was not cost saving, even when the price of mcfDNA was set to $0. CONCLUSIONS: Based on the evidence available at the time of this analysis, this CEA suggests that mcfDNA may be cost-effective when added to All UC, as well as in a scenario using conditional bronchoscopy when NI testing fails to identify a probable infectious etiology for ICHP. Adding mcfDNA testing to UC diagnostic testing should allow more patients to receive appropriate therapy earlier and improve patient outcomes.

Corrigendum: ACE2 knockout hinders SARS-CoV-2 propagation in iPS cell-derived airway and alveolar epithelial cells.

[This corrects the article DOI: 10.3389/fcell.2023.1290876.].

Statistical Coupling Analysis Predicts Correlated Motions in Dihydrofolate Reductase.

The role of dynamics in enzymatic function is a highly debated topic. Dihydrofolate reductase (DHFR), due to its universality and the depth with which it has been studied, is a model system in this debate. Myriad previous works have identified networks of residues in positions near to and remote from the active site that are involved in dynamics and others that are important for catalysis. For example, specific mutations on the Met20 loop in E. coli DHFR (N23PP/S148A) are known to disrupt millisecond-timescale motions and reduce catalytic activity. However, how and if networks of dynamically coupled residues influence the evolution of DHFR is still an unanswered question. In this study, we first identify, by statistical coupling analysis and molecular dynamic simulations, a network of coevolving residues, which possess increased correlated motions. We then go on to show that allosteric communication in this network is selectively knocked down in N23PP/S148A mutant E. coli DHFR. Finally, we identify two sites in the human DHFR sector which may accommodate the Met20 loop double proline mutation while preserving dynamics. These findings strongly implicate protein dynamics as a driving force for evolution.

Same-visit hepatitis C testing and treatment to accelerate cure among people who inject drugs (the QuickStart Study): a cluster randomised cross-over trial protocol.

INTRODUCTION: Despite universal access to government-funded direct-acting antivirals (DAAs) in 2016, the rate of hepatitis C treatment uptake in Australia has declined substantially. Most hepatitis C is related to injecting drug use; reducing the hepatitis C burden among people who inject drugs (PWID) is, therefore, paramount to reach hepatitis C elimination targets. Increasing DAA uptake by PWID is important for interrupting transmission and reducing incidence, as well as reducing morbidity and mortality and improving quality of life of PWID and meeting Australia's hepatitis C elimination targets. METHODS AND ANALYSIS: A cluster randomised cross-over trial will be conducted with three intervention arms and a control arm. Arm A will receive rapid hepatitis C virus (HCV) antibody testing; arm B will receive rapid HCV antibody and rapid RNA testing; arm C will receive rapid HCV antibody testing and same-day treatment initiation for HCV antibody-positive participants; the control arm will receive standard of care. The primary outcomes will be (a) the proportion of participants with HCV commencing treatment and (b) the proportion of participants with HCV achieving cure. Analyses will be conducted on an intention-to-treat basis with mixed-effects logistic regression models. ETHICS AND DISSEMINATION: The study has been approved by the Alfred Ethics Committee (number HREC/64731/Alfred-2020-217547). Each participant will provide written informed consent. Reportable adverse events will be reported to the reviewing ethics committee. The findings will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05016609. TRIAL PROGRESSION: The study commenced recruitment on 9 March 2022 and is expected to complete recruitment in December 2024.

Quantitative Measurement of Rate of Targeted Protein Degradation.

Targeted protein degradation (TPD) is a therapeutic approach that leverages the cell's natural machinery to degrade targets instead of inhibiting them. This is accomplished by using mono- or bifunctional small molecules designed to induce the proximity of target proteins and E3 ubiquitin ligases, leading to ubiquitination and subsequent proteasome-dependent degradation of the target. One of the most significant attributes of the TPD approach is its proposed catalytic mechanism of action, which permits substoichiometric exposure to achieve the desired pharmacological effects. However, apart from one in vitro study, studies supporting the catalytic mechanism of degraders are largely inferred based on potency. A more comprehensive understanding of the degrader catalytic mechanism of action can help aspects of compound development. To address this knowledge gap, we developed a workflow for the quantitative measurement of the catalytic rate of degraders in cells. Comparing a selective and promiscuous BTK degrader, we demonstrate that both compounds function as efficient catalysts of BTK degradation, with the promiscuous degrader exhibiting faster rates due to its ability to induce more favorable ternary complexes. By leveraging computational modeling, we show that the catalytic rate is highly dynamic as the target is depleted from cells. Further investigation of the promiscuous kinase degrader revealed that the catalytic rate is a better predictor of optimal degrader activity toward a specific target compared to degradation magnitude alone. In summary, we present a versatile method for mapping the catalytic activity of any degrader for TPD in cells.

Glucagon resistance in individuals with obesity and hepatic steatosis can be measured using the GLUSENTIC test and index.

Increased plasma levels of glucagon (hyperglucagonaemia) promote diabetes development but is also observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This may reflect hepatic glucagon resistance towards amino acid catabolism. A clinical test for measuring glucagon resistance has not been validated. We evaluated our glucagon sensitivity (GLUSENTIC) test, consisting of two study days: a glucagon injection and measurements of plasma amino acids, and an infusion of mixed amino acids and subsequent calculation of the GLUSENTIC index (primary outcome measure) from measurements of glucagon and amino acids. To distinguish glucagon-dependent from insulin-dependent actions on amino acid metabolism, we also studied patients with type 1 diabetes (T1D). The delta-decline in total amino acids was 49% lower in MASLD following exogenous glucagon (p=0.01), and the calculated GLUSENTIC index was 34% lower in MASLD (p<0.0001), but not T1D (p>0.99). In contrast, glucagon-induced glucose increments were similar in controls and MASLD (p=0.41). The GLUSENTIC test and index may be used to measure glucagon resistance in individuals with obesity and MASLD.

Assessing thresholds of resistance prevalence at which empiric treatment of gonorrhea should change among men who have sex with men in the US: A cost-effectiveness analysis.

BACKGROUND: Since common diagnostic tests for gonorrhea do not provide information about susceptibility to antibiotics, treatment of gonorrhea remains empiric. Antibiotics used for empiric therapy are usually changed once resistance prevalence exceeds a certain threshold (e.g., 5%). A low switch threshold is intended to increase the probability that an infection is successfully treated with the first-line antibiotic, but it could also increase the pace at which recommendations are switched to newer antibiotics. Little is known about the impact of changing the switch threshold on the incidence of gonorrhea, the rate of treatment failure, and the overall cost and quality-adjusted life-years (QALYs) associated with gonorrhea. METHODS AND FINDINGS: We developed a transmission model of gonococcal infection with multiple resistant strains to project gonorrhea-associated costs and loss in QALYs under different switch thresholds among men who have sex with men (MSM) in the United States. We accounted for the costs and disutilities associated with symptoms, diagnosis, treatment, and sequelae, and combined costs and QALYs in a measure of net health benefit (NHB). Our results suggest that under a scenario where 3 antibiotics are available over the next 50 years (2 suitable for the first-line therapy of gonorrhea and 1 suitable only for the retreatment of resistant infections), changing the switch threshold between 1% and 10% does not meaningfully impact the annual number of gonorrhea cases, total costs, or total QALY losses associated with gonorrhea. However, if a new antibiotic is to become available in the future, choosing a lower switch threshold could improve the population NHB. If in addition, drug-susceptibility testing (DST) is available to inform retreatment regimens after unsuccessful first-line therapy, setting the switch threshold at 1% to 2% is expected to maximize the population NHB. A limitation of our study is that our analysis only focuses on the MSM population and does not consider the influence of interventions such as vaccine and common use of rapid drugs susceptibility tests to inform first-line therapy. CONCLUSIONS: Changing the switch threshold for first-line antibiotics may not substantially change the health and financial outcomes associated with gonorrhea. However, the switch threshold could be reduced when newer antibiotics are expected to become available soon or when in addition to future novel antibiotics, DST is also available to inform retreatment regimens.

TrkA + sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression.

Bone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multi-omics analyses of human OS bone samples and human dorsal root ganglia neurons further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. In order to curb tumor-associated axonal ingrowth, we next leveraged FDA-approved bupivacaine liposomes leading to significant reductions in sarcoma growth, vascularity, as well as alleviation of pain. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition appears to disrupt calcitonin receptor signaling (CALCR) and VEGF signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of osteosarcoma represent a novel adjunctive therapy to improve clinical outcomes and survival.

Word Forms Reflect Trade-Offs Between Speaker Effort and Robust Listener Recognition.

How do cognitive pressures shape the lexicons of natural languages? Here, we reframe George Kingsley Zipf's proposed "law of abbreviation" within a more general framework that relates it to cognitive pressures that affect speakers and listeners. In this new framework, speakers' drive to reduce effort (Zipf's proposal) is counteracted by the need for low-frequency words to have word forms that are sufficiently distinctive to allow for accurate recognition by listeners. To support this framework, we replicate and extend recent work using the prevalence of subword phonemic sequences (phonotactic probability) to measure speakers' production effort in place of Zipf's measure of length. Across languages and corpora, phonotactic probability is more strongly correlated with word frequency than word length. We also show this measure of ease of speech production (phonotactic probability) is strongly correlated with a measure of perceptual difficulty that indexes the degree of competition from alternative interpretations in word recognition. This is consistent with the claim that there must be trade-offs between these two factors, and is inconsistent with a recent proposal that phonotactic probability facilitates both perception and production. To our knowledge, this is the first work to offer an explanation why long, phonotactically improbable word forms remain in the lexicons of natural languages.

Racial and Ethnic Variations in Patients Undergoing Mitral and Tricuspid Valve Surgery.

INTRODUCTION: Prior investigations assessing the impact of race/ethnicity on outcomes after mitral valve (MV) surgery have reported conflicting findings. This analysis aimed to examine the association between race/ethnicity and operative presentation and outcomes of patients undergoing MV and tricuspid valve (TV) surgery. METHODS: We retrospectively analyzed 5984 patients (2730 female, median age 63 y) who underwent MV (n = 4,534, 76%), TV (n = 474, 8%) or both MV and TV (n = 976, 16%) surgery in a statewide collaborative from 2012 to 2021. The influence of race/ethnicity on preoperative characteristics, MV and TV repair rates, and postoperative outcomes was assessed for White (n = 4,244, 71%), Black (n = 1,271, 21%), Hispanic (n = 144, 2%), Asian (n = 171, 3%), and mixed/other race (n = 154, 3%) patients. RESULTS: Black patients, compared to White patients, had higher Society of Thoracic Surgeons predicted risk of morbidity/mortality (24.5% versus 13.1%; P < 0.001) and more comorbid conditions. Compared to White patients, Black and Hispanic patients were less likely to undergo an elective procedure (White 71%, Black 55%, Hispanic 58%; P < 0.001). Degenerative MV disease was more prevalent in White patients (White 62%, Black 41%, Hispanic 43%, Asian 51%, mixed/other 45%; P < 0.05), while rheumatic disease was more prevalent in non-White patients (Asian 28%, Hispanic 26%, mixed/other 25%, Black 17%, White 10%;P < 0.05). After multivariable adjustment, repair rates and adverse postoperative outcomes, including mortality, did not differ by racial/ethnic group. CONCLUSIONS: Patient race/ethnicity is associated with a higher burden of comorbidities at operative presentation and MV disease etiology. Strategies to improve early detection of valvular heart disease and timely referral for surgery may improve outcomes.

Evaluating Knee Recovery Beyond Patient Reports: A Comparative Study of Smart Implantable Device-Derived Gait Metrics Versus Patient-Reported Outcome Measures in Total Knee Arthroplasty.

BACKGROUND: Total Knee Arthroplasty (TKA) is frequently performed for advanced osteoarthritis, with patient-reported outcome measures (PROMs) traditionally reporting on efficacy. These subjective evaluations, although useful, may inaccurately reflect post-TKA activity levels. With technological advancements, smart implantable devices (SIDs) offer objective, real-time gait metrics, potentially providing a more accurate postoperative recovery assessment. This study compares these objective metrics with PROMs to evaluate TKA success more effectively. METHODS: We conducted a retrospective cohort study with 88 participants undergoing TKA using a SID. Eligible patients were aged 18 years or older and had advanced osteoarthritis. We excluded those who had bilateral TKAs, joint infections, or neuromuscular disease. The SID system collected daily gait metrics, including step count, distance traveled, walking speed, stride length, cadence, and functional knee range of motion. The PROMs, including Knee Injury and Osteoarthritis Outcome Score-Joint Replacement, Veterans Rand 12 Physical Component Summary, and Veterans Rand 12 Mental Component Summary, were analyzed against SID gait metrics. Among the 88 patients, 80 provided continuous data over 12 weeks. RESULTS: All gait metrics, except stride length, significantly increased at the 12-week point (P < .05). The PROMs also significantly improved postoperatively (P < .05). Initial low positive correlations between 12-week PROMs and SID metrics decreased after adjusting for demographic variables, leaving only weak correlations between the Veterans Rand 12 Physical Component Summary and Knee Injury and Osteoarthritis Outcome Score-Joint Replacement with functional knee range of motion (r = 0.389, P = .002; r = 0.311, P = .014, respectively), and Veterans Rand 12 Mental Component Summary with step count (r = 0.406, P = .001) and distance traveled (r = 0.376, P = .003). CONCLUSIONS: This study indicates that both PROMs and SID gait metrics show significant improvements post-TKA, though they correlate weakly with each other, suggesting a possible discrepancy between perceived recovery and actual functional improvement. The SID gait metrics might provide a valuable addition to traditional PROMs by offering an objective representation of physical capabilities unaffected by patient compliance or subjective perceptions of recovery. Further research is needed to validate these findings in larger populations and to explore whether integrating SID metrics can enhance long-term functional outcomes.

Solvent concentration at 50% protein unfolding may reform enzyme stability ranking and process window identification.

As water miscible organic co-solvents are often required for enzyme reactions to improve e.g., the solubility of the substrate in the aqueous medium, an enzyme is required which displays high stability in the presence of this co-solvent. Consequently, it is of utmost importance to identify the most suitable enzyme or the appropriate reaction conditions. Until now, the melting temperature is used in general as a measure for stability of enzymes. The experiments here show, that the melting temperature does not correlate to the activity observed in the presence of the solvent. As an alternative parameter, the concentration of the co-solvent at the point of 50% protein unfolding at a specific temperature T in short c U 50 T is introduced. Analyzing a set of ene reductases, c U 50 T is shown to indicate the concentration of the co-solvent where also the activity of the enzyme drops fastest. Comparing possible rankings of enzymes according to melting temperature and c U 50 T reveals a clearly diverging outcome also depending on the specific solvent used. Additionally, plots of c U 50 versus temperature enable a fast identification of possible reaction windows to deduce tolerated solvent concentrations and temperature.

High-risk subgroups were not identified to benefit from thromboprophylaxis after hospitalization for COVID-19.

Background: The Accelerating COVID-19 Therapeutic Interventions and Vaccines-4c (ACTIV-4c) trial investigated prophylactic apixaban for 30 days following hospitalization for COVID-19. The overall incidence of early postdischarge death or thromboembolism was low, and the trial was closed early. Objectives: To identify a high-risk patient population who might benefit from postdischarge thromboprophylaxis through subgroup analyses stratified by age, race/ethnicity, obesity, D-dimer elevation, World Health Organization score, and modified International Medical Prevention Registry on Venous Thromboembolism score on 30-day composite outcome of all-cause death, arterial thromboembolism (ATE), and venous thromboembolism (VTE). Methods: Cumulative incidences of all-cause death, ATE, and VTE within 30 days were described for each subgroup. Time to death, ATE, or VTE by 30 days was analyzed using Cox proportional hazard models with interaction testing for each subgroup. Results: Among 1217 patients randomized to apixaban or placebo group, 32% were >60 years old. Modified International Medical Prevention Registry on Venous Thromboembolism score was ≥4 in 2% and 2 or 3 with an elevated D-dimer in an additional 9% of participants. The overall incidence of the primary endpoint was 2.13% in the apixaban group and 2.31% in the placebo group. At day 30, similar rates of the primary endpoint occurred within subgroups, except for participants aged >60 years. No benefit of thromboprophylaxis was seen in any subgroup. Conclusion: The combined incidence of 30-day death, ATE, and VTE was low in patients who survived COVID-19 hospitalization, except in patients over age 60 years. Due to the limited number of events, the findings remain inconclusive; nonetheless, the study did not identify a high-risk subgroup that would derive benefits from extended thromboprophylaxis.