Total Hip Arthroplasty in Patients Who Have Factor V Leiden: Elevated Risks Isolated to Venous Thromboembolism Events.

BACKGROUND: Total hip arthroplasty (THA) is a common procedure that requires consideration of preexisting comorbidities. Factor V Leiden (FVL), an inherited thrombophilia, is one such condition that predisposes patients to venous thromboembolism (VTE, deep vein thrombosis, and pulmonary embolism). The present study aimed to characterize the risks associated with FVL patients undergoing THA and evaluate the effect of VTE chemoprophylactic agents on these risks. METHODS: A total of 544,022 adult patients who underwent primary THA for osteoarthritis indications between 2010 and October 2021 were identified in an administrative claims database. Of these, FVL was identified in 1,138 (0.21%). Patients who had and did not have FVL were matched at a 1:4 ratio (1,131 with FVL and 4,519 without FVL) based on age, sex, and Elixhauser comorbidity index. Univariable and multivariable analyses were assessed for 90-day complications. Implant survival at 5 years was assessed and compared with log-rank tests. The relative use of different chemoprophylactic agents, including aspirin, warfarin, heparin, or direct oral anticoagulant (DOAC), was assessed. Bleeding events and VTE were compared for those prescribed either aspirin or warfarin, heparin, or DOAC. A Bonferroni correction was applied. RESULTS: On multivariable analysis, FVL patients were found to have increased odds of 90-day deep vein thrombosis (odds ratio (OR) = 9.20), pulmonary embolism (OR = 6.89), and aggregated severe and all adverse events (OR = 4.74 and 1.98, respectively), but not elevated risk of other perioperative adverse events or 5-year reoperations. More potent chemoprophylactic agents (warfarin, heparin, DOAC) reduced, but did not completely eliminate, the increased VTE risks (without increasing bleeding events). CONCLUSIONS: This study quantified the significantly elevated VTE risk associated with FVL patients undergoing THA. The lack of difference in other specific adverse events and 5-year reoperations is reassuring. Clearly, chemoprophylactic agents are important in this population and may need further attention.

Outcomes Following Total Hip Arthroplasty in Patients Who Have Von Willebrand Disease Depend on Postoperative Anticoagulation.

BACKGROUND: Von Willebrand disease (VWD) is the most common congenital bleeding disorder. This autosomal dominant condition arises from quantitative or qualitative defects of Von Willebrand factor. To our knowledge, this study leveraged a national database to characterize the largest VWD cohort of total hip arthroplasty (THA) patients to date, assessing 90-day postoperative adverse events and 5-year revision-free survival. METHODS: Adult patients who underwent primary THA for osteoarthritis were identified from January 2010 to October 2021 in a nationwide database. Patients who had and did not have VWD were matched (4:1) on age, sex, and Elixhauser Comorbidity Index and compared with multivariable logistic regression. Patients were then categorized based upon venous thromboembolism (VTE) chemoprophylaxis prescription patterns to compare bleeding and thrombotic adverse events. RESULTS: Of 544,851 THA patients, VWD was identified in 309 patients (0.06%). The matched cohorts contained 1,221 patients who did not have VWD and 306 patients who have VWD. On multivariable analysis, VWD patients had increased odds of 90-day VTE (odds ratio [OR] = 1.86) and hematoma (OR = 3.40) (P < .05 for all). No difference in 5-year revision-free survival was found. The VWD patients receiving aspirin or no prescriptions had greater odds of VTE (OR = 2.39, P = .048). Those on other chemoprophylaxis agents had greater odds of hematoma (OR = 4.84, P = .006). CONCLUSIONS: Patients with VWD undergoing THA had increased odds of 90-day VTE if using aspirin or no prescriptions, or hematoma if using other chemoprophylaxis. There is a delicate balancing act of clotting versus bleeding that must be considered in managing such patients, but it was reassuring that no difference in overall 5-year revision-free survival was found.

Safety and feasibility clinical trial of nucleus accumbens deep brain stimulation for treatment-refractory opioid use disorder.

OBJECTIVE: There were more than 107,000 drug overdose deaths in the US in 2021, the most ever recorded. Despite advances in behavioral and pharmacological treatments, over 50% of those receiving treatment for opioid use disorder (OUD) experience drug use recurrence (relapse). Given the prevalence of OUD and other substance use disorders (SUDs), the high rate of drug use recurrence, and the number of drug overdose deaths, novel treatment strategies are desperately needed. The objective of this study was to evaluate the safety and feasibility of deep brain stimulation (DBS) targeting the nucleus accumbens (NAc)/ventral capsule (VC) and potential impact on outcomes in individuals with treatment-refractory OUD. METHODS: A prospective, open-label, single-arm study was conducted among participants with longstanding treatment-refractory OUD (along with other co-occurring SUDs) who underwent DBS in the NAc/VC. The primary study endpoint was safety; secondary/exploratory outcomes included opioid and other substance use, substance craving, and emotional symptoms throughout follow-up and 18FDG-PET neuroimaging. RESULTS: Four male participants were enrolled and all tolerated DBS surgery well with no serious adverse events (AEs) and no device- or stimulation-related AEs. Two participants sustained complete substance abstinence for > 1150 and > 520 days, respectively, with significant post-DBS reductions in substance craving, anxiety, and depression. One participant experienced post-DBS drug use recurrences with reduced frequency and severity. The DBS system was explanted in one participant due to noncompliance with treatment requirements and the study protocol. 18FDG-PET neuroimaging revealed increased glucose metabolism in the frontal regions for the participants with sustained abstinence only. CONCLUSIONS: DBS of the NAc/VC was safe, feasible, and can potentially reduce substance use, craving, and emotional symptoms in those with treatment-refractory OUD. A randomized, sham-controlled trial in a larger cohort of patients is being initiated.

An experimental test of the evolutionary consequences of sympatry in Drosophila subquinaria.

Prezygotic isolation is often stronger between sympatric as opposed to allopatric taxa, but the underlying cause can be difficult to infer from comparative studies alone. Experimental evolution, where evolutionary responses to treatments manipulating the presence/absence of heterospecific individuals are tracked, can provide a powerful complementary approach. We used experimental evolution to investigate a naturally occurring pattern of reproductive character displacement in the mushroom-feeding fly, Drosophila subquinaria. In nature, female D. subquinaria from populations sympatric with the closely related Drosophila recens discriminate more strongly against heterospecific males than do females from allopatric populations. Starting with 16 replicate allopatric populations of D. subquinaria, we manipulated the presence/absence of D. recens during mating (experimental sympatry vs. control) and, when present, we allowed hybrids to live or kill them each generation. Across 12 generations, heterospecific offspring production from no-choice mating trials between D. subquinaria females and D. recens males declined in both experimental sympatry treatments relative to the control, suggesting increased sexual isolation. Male cuticular hydrocarbon profiles also evolved, but only in the hybrids killed treatment. Our results strongly imply that the existing reproductive character displacement in wild D. subquinaria populations was an evolutionary response to selection arising from secondary contact with D. recens.

De novo protein identification in mammalian sperm using in situ cryoelectron tomography and AlphaFold2 docking.

To understand the molecular mechanisms of cellular pathways, contemporary workflows typically require multiple techniques to identify proteins, track their localization, and determine their structures in vitro. Here, we combined cellular cryoelectron tomography (cryo-ET) and AlphaFold2 modeling to address these questions and understand how mammalian sperm are built in situ. Our cellular cryo-ET and subtomogram averaging provided 6.0-Å reconstructions of axonemal microtubule structures. The well-resolved tertiary structures allowed us to unbiasedly match sperm-specific densities with 21,615 AlphaFold2-predicted protein models of the mouse proteome. We identified Tektin 5, CCDC105, and SPACA9 as novel microtubule-associated proteins. These proteins form an extensive interaction network crosslinking the lumen of axonemal doublet microtubules, suggesting their roles in modulating the mechanical properties of the filaments. Indeed, Tekt5 -/- sperm possess more deformed flagella with 180° bends. Together, our studies presented a cellular visual proteomics workflow and shed light on the in vivo functions of Tektin 5.

Racial inequities and addiction research.

What accounts for variation across racial and ethnic groups in drug use and harms related to substance use? While explanatory mechanisms for racial and ethnic disparities include differential access to and use of health services, a myriad of other factors, including racism and historical trauma, contribute to drug-related disparities. Furthermore, the addiction scientific workforce, like the full biomedical research enterprise, lacks diversity. This deficit undercuts U.S. scientific leadership and is a major challenge for the field. To address these entrenched problems, the National Institute on Drug Abuse (NIDA) is prioritizing research on health disparities and supporting multiple efforts to enhance scientific workforce diversity. Studies on substance use trends and emerging threats must measure disparities and track progress in reducing disparities, but also acknowledge the limitations of race and ethnicity-based data. Researchers must take the bold step of proposing studies that elucidate causal mechanisms which have the potential to be ameliorated by novel policies and practices. Critically, the impact of racism on all aspects of the substance use trajectory must be assessed to better tailor prevention, harm reduction, treatment, and recovery-support interventions to the specific circumstances of those who need them. Particular attention should be given to people who are incarcerated, who are experiencing homelessness, and who have a history of adverse childhood experiences. Training the next generation of the addiction science workforce needs to address structural barriers to participation with partnerships between funders, such as NIDA, and grantee organizations.

National Institute on Drug Abuse (NIDA) research priorities to support the development of incentive-based treatments for substance use disorders.

The purpose of this commentary is to highlight current research priorities of National Institute on Drug Abuse (NIDA) Division of Therapeutics and Medical Consequences (DTMC) regarding the development and testing of incentive-based interventions for the treatment of substance use disorders (SUDs). This manuscript summarizes the NIH Stage Model for behavioral intervention development, briefly reviews existing research on incentive-based treatments for SUDs that falls within the scope of DTMC at NIDA and highlights the development of digital therapeutics-based incentive interventions as an exemplar and high priority area. We briefly review how digital therapeutics approaches may address some common limitations to dissemination of incentive-based interventions and highlight opportunities for integrating incentive-based approaches into pharmacotherapy efficacy trials. Finally, we mention several related funding opportunities for researchers interested in developing incentive-based approaches for SUD treatment. The overall goal of this commentary is to inform the research community of current NIDA priority areas for intervention development and funding.

The NIH Science of Behavior Change Program: Looking Toward the Future.

The National Institutes of Health established the Science of Behavior Change (SOBC) program to promote basic research on the initiation, personalization, and maintenance of health behavior change. The SOBC Resource and Coordinating Center now leads and supports activities to maximize the creativity, productivity, scientific rigor, and dissemination of the experimental medicine approach and experimental design resources. Here, we highlight those resources, including the Checklist for Investigating Mechanisms in Behavior-change Research (CLIMBR) guidelines introduced in this special section. We describe the ways in which SOBC can be applied across a range of domains and contexts, and end by considering ways to extend SOBC's perspective and reach, so as to best promote behavior change linked with health, quality of life, and well-being.

Mitochondrial uncouplers impair human sperm motility without altering ATP content†.

In human spermatozoa, the electrochemical potentials across the mitochondrial and plasma membranes are related to sperm functionality and fertility, but the exact role of each potential has yet to be clarified. Impairing sperm mitochondrial function has been considered as an approach to creating male or unisex contraceptives, but it has yet to be shown whether this approach would ultimately block the ability of sperm to reach or fertilize an egg. To investigate whether the mitochondrial and plasma membrane potentials are necessary for sperm fertility, human sperm were treated with two small-molecule mitochondrial uncouplers (niclosamide ethanolamine and BAM15) that depolarize membranes by inducing passive proton flow, and evaluated the effects on a variety of sperm physiological processes. BAM15 specifically uncoupled human sperm mitochondria while niclosamide ethanolamine induced proton current in the plasma membrane in addition to depolarizing the mitochondria. In addition, both compounds significantly decreased sperm progressive motility with niclosamide ethanolamine having a more robust effect. However, these uncouplers did not reduce sperm adenosine triphosphate (ATP) content or impair other physiological processes, suggesting that human sperm can rely on glycolysis for ATP production if mitochondria are impaired. Thus, systemically delivered contraceptives that target sperm mitochondria to reduce their ATP production would likely need to be paired with sperm-specific glycolysis inhibitors. However, since niclosamide ethanolamine impairs sperm motility through an ATP-independent mechanism, and niclosamide is FDA approved and not absorbed through mucosal membranes, it could be a useful ingredient in on-demand, vaginally applied contraceptives.

Mixtures of sediment chemical contaminants at freshwater sampling sites across Europe with different contaminant burdens.

Extended chemical analyses of fluvial sediments were undertaken to establish the key pollutant pressures and mixtures present across nine European Union inland waterways. A wide range of chemical components and physical parameters were investigated including substances from the EU Priority List and Watch List. The data set was examined for key indicator compounds, however it was found that a wide range of pollution pressures were present in the different sediments including organic hydrocarbons, metal(loid)s, nutrients, polycyclic aromatic hydrocarbon (PAH), polychlorinated biphenyl (PCB) compounds, perfluoroalkyl and polyfluoroalkyl substances and pesticides, some of which exceeded regulatory guidance at different sampling points. The presence of such a wide range of compounds underpins the complex chemical composition of sediments that have acted as sinks for many decades absorbing contaminants from urban, industrial and agricultural sources. This dataset has been used to describe average overall toxicity of the sediments sampled, a calculation which was based on key components identified by Principal Component Analysis (PCA) and for those that had existing freshwater sediment regulatory values. A total of 33 components were used including PCBs, PAHs, metal(iod)s and pesticides. This analysis reflected the contamination of each site, with most indicating some level of toxicity during the sampling period. Watch List chemicals triclosan (TCS) and diclofenac (DIC) were also investigated; levels were relatively low, typically 10-100's ng L-1, however they were present at all sampling sites. The dataset is available as a resource for future chemical, and toxicological, sediment analysis comparisons.

Locomotory Palp Function in Interstitial Annelids.

AbstractThe interstitial environment of marine sediments is a complex network of voids and pores that is inhabited by a diverse and abundant fauna. Animals living within these interstitial spaces show widespread functional adaptations to this environment and have developed many strategies for moving and navigating through small spaces. Interstitial annelids demonstrate a remarkable level of morphologic diversity, and some possess dexterous, filiform palps (tentacle-like appendages common across Annelida). The function(s) of these palps in interstitial spaces has not been closely examined, and we propose that they serve a sensory role in the navigation of interstitial spaces. We investigated the locomotory function of long, dexterous palps in three families of interstitial annelids to determine their role in interstitial navigation. We observed two species of protodrilids (Protodrilidae), Pharyngocirrus eroticus (Saccocirridae), and Protodorvillea recuperata (Dorvilleidae), as they moved through two transparent sand analogs: cyolite and glass beads. All four species of annelids consistently used their palps to probe the interstitial environment while locomoting, and the distance probed with their palps was greater than the distance traveled with their heads, indicating a sensory form of palp-based navigation. The functionality of palps as sensory organs in the interstitial environment raises interesting questions about interstitial navigation and how fauna without appendages map their surroundings. The discovery of this previously undocumented function was possible only through the direct observation of interstitial behavior and emphasizes the importance of developing new techniques to study these animals in more natural habitats.

Vi polysaccharide and conjugated vaccines afford similar early, IgM or IgG-independent control of infection but boosting with conjugated Vi vaccines sustains the efficacy of immune responses.

Introduction: Vaccination with Vi capsular polysaccharide (Vi-PS) or protein-Vi typhoid conjugate vaccine (TCV) can protect adults against Salmonella Typhi infections. TCVs offer better protection than Vi-PS in infants and may offer better protection in adults. Potential reasons for why TCV may be superior in adults are not fully understood. Methods and results: Here, we immunized wild-type (WT) mice and mice deficient in IgG or IgM with Vi-PS or TCVs (Vi conjugated to tetanus toxoid or CRM197) for up to seven months, with and without subsequent challenge with Vi-expressing Salmonella Typhimurium. Unexpectedly, IgM or IgG alone were similarly able to reduce bacterial burdens in tissues, and this was observed in response to conjugated or unconjugated Vi vaccines and was independent of antibody being of high affinity. Only in the longer-term after immunization (>5 months) were differences observed in tissue bacterial burdens of mice immunized with Vi-PS or TCV. These differences related to the maintenance of antibody responses at higher levels in mice boosted with TCV, with the rate of fall in IgG titres induced to Vi-PS being greater than for TCV. Discussion: Therefore, Vi-specific IgM or IgG are independently capable of protecting from infection and any superior protection from vaccination with TCV in adults may relate to responses being able to persist better rather than from differences in the antibody isotypes induced. These findings suggest that enhancing our understanding of how responses to vaccines are maintained may inform on how to maximize protection afforded by conjugate vaccines against encapsulated pathogens such as S. Typhi.

US National Institutes of Health Prioritization of SARS-CoV-2 Variants.

Since late 2020, SARS-CoV-2 variants have regularly emerged with competitive and phenotypic differences from previously circulating strains, sometimes with the potential to escape from immunity produced by prior exposure and infection. The Early Detection group is one of the constituent groups of the US National Institutes of Health National Institute of Allergy and Infectious Diseases SARS-CoV-2 Assessment of Viral Evolution program. The group uses bioinformatic methods to monitor the emergence, spread, and potential phenotypic properties of emerging and circulating strains to identify the most relevant variants for experimental groups within the program to phenotypically characterize. Since April 2021, the group has prioritized variants monthly. Prioritization successes include rapidly identifying most major variants of SARS-CoV-2 and providing experimental groups within the National Institutes of Health program easy access to regularly updated information on the recent evolution and epidemiology of SARS-CoV-2 that can be used to guide phenotypic investigations.

In situ cryo-electron tomography reveals the asymmetric architecture of mammalian sperm axonemes.

The flagella of mammalian sperm display non-planar, asymmetric beating, in contrast to the planar, symmetric beating of flagella from sea urchin sperm and unicellular organisms. The molecular basis of this difference is unclear. Here, we perform in situ cryo-electron tomography of mouse and human sperm, providing the highest-resolution structural information to date. Our subtomogram averages reveal mammalian sperm-specific protein complexes within the microtubules, the radial spokes and nexin-dynein regulatory complexes. The locations and structures of these complexes suggest potential roles in enhancing the mechanical strength of mammalian sperm axonemes and regulating dynein-based axonemal bending. Intriguingly, we find that each of the nine outer microtubule doublets is decorated with a distinct combination of sperm-specific complexes. We propose that this asymmetric distribution of proteins differentially regulates the sliding of each microtubule doublet and may underlie the asymmetric beating of mammalian sperm.

Advancing digital health equity: Directions for behavioral and social science research.

The field of digital health is evolving rapidly and encompasses a wide range of complex and changing technologies used to support individual and population health. The COVID-19 pandemic has augmented digital health expansion and significantly changed how digital health technologies are used. To ensure that these technologies do not create or exacerbate existing health disparities, a multi-pronged and comprehensive research approach is needed. In this commentary, we outline five recommendations for behavioral and social science researchers that are critical to promoting digital health equity. These recommendations include: (i) centering equity in research teams and theoretical approaches, (ii) focusing on issues of digital health literacy and engagement, (iii) using methods that elevate perspectives and needs of underserved populations, (iv) ensuring ethical approaches for collecting and using digital health data, and (v) developing strategies for integrating digital health tools within and across systems and settings. Taken together, these recommendations can help advance the science of digital health equity and justice.

The field of digital health is quickly growing and changing. Digital health technologies have the potential to increase access to health-related information and healthcare and improve wellbeing, but it is important that those technologies don't widen existing health disparities or create new ones. Behavioral and social science researchers have a key role to play in centering equity in their research teams and theoretical approaches, focusing on key barriers to access, uptake, and usage, studying digital health in ways that elevate the voices and needs of historically underserved groups, being thoughtful about how digital health data are collected and used, and making sure that digital health tools are designed to be used in real-world settings.

Topologically-imposed vacancies and mobile solid 3He on carbon nanotube.

Low dimensional fermionic quantum systems are exceptionally interesting because they reveal distinctive physical phenomena, including among others, topologically protected excitations, edge states, frustration, and fractionalization. Our aim was to confine 3He on a suspended carbon nanotube to form 2-dimensional Fermi-system. Here we report our measurements of the mechanical resonance of the nanotube with adsorbed sub-monolayer down to 10 mK. At intermediate coverages we have observed the famous 1/3 commensurate solid. However, at larger monolayer densities we have observed a quantum phase transition from 1/3 solid to an unknown, soft, and mobile solid phase. We interpret this mobile solid phase as a bosonic commensurate crystal consisting of helium dimers with topologically-induced zero-point vacancies which are delocalized at low temperatures. We thus demonstrate that 3He on a nanotube merges both fermionic and bosonic phenomena, with a quantum phase transition between fermionic solid 1/3 phase and the observed bosonic dimer solid.

Human sperm TMEM95 binds eggs and facilitates membrane fusion.

Tmem95 encodes a sperm acrosomal membrane protein, whose knockout has a male-specific sterility phenotype in mice. Tmem95 knockout murine sperm can bind to, but do not fuse with, eggs. How TMEM95 plays a role in membrane fusion of sperm and eggs has remained elusive. Here, we utilize a sperm penetration assay as a model system to investigate the function of human TMEM95. We show that human TMEM95 binds to hamster egg membranes, providing evidence for a TMEM95 receptor on eggs. Using X-ray crystallography, we reveal an evolutionarily conserved, positively charged region of TMEM95 as a putative receptor-binding surface. Amino acid substitutions within this region of TMEM95 ablate egg-binding activity. We identify monoclonal antibodies against TMEM95 that reduce the number of human sperm fused with hamster eggs in sperm penetration assays. Strikingly, these antibodies do not block binding of sperm to eggs. Taken together, these results provide strong evidence for a specific, receptor-mediated interaction of sperm TMEM95 with eggs and suggest that this interaction may have a role in facilitating membrane fusion during fertilization.

Methodological considerations in the open-plan office paradox: A systematic literature review.

BACKGROUND: Several recent reports conclude that open-plan offices negatively impact workers across a variety of outcome measures. This contrasts to a corporate trend to move from cellular to open-plan layouts, often justified by the same outcomes. Two explanations for this paradox are proposed: (1) the results are more complicated than critical reports suggest, and (2) methodological biases make open-plan layouts look more negative than they are. OBJECTIVE: To evaluate the proposed explanations using a systematic literature review. METHODS: Google Scholar was used to find original research on the relationship between office openness and worker outcomes. 89 articles were coded for the variables and methods they used, and conclusions about the relationship between layout and outcomes were evaluated. RESULTS: The proposed explanations were partly supported. The relationship between layout openness and worker outcomes depends on the variables considered and the methods used, and a small subset of methods was used far more often than others. That said, more research is needed to evaluate impact of open-plan offices on worker outcomes. CONCLUSIONS: The relationship between office openness and worker outcomes varies widely depending on how it is measured. Several promising areas for future research may help clarify this relationship.

Evidence of Large Recoil Velocity from a Black Hole Merger Signal.

The final black hole left behind after a binary black hole merger can attain a recoil velocity, or a "kick," reaching values up to 5000 km/s. This phenomenon has important implications for gravitational wave astronomy, black hole formation scenarios, testing general relativity, and galaxy evolution. We consider the gravitational wave signal from the binary black hole merger GW200129_065458 (henceforth referred to as GW200129), which has been shown to exhibit strong evidence of orbital precession. Using numerical relativity surrogate models, we constrain the kick velocity of GW200129 to v_{f}∼1542_{-1098}^{+747} km/s or v_{f}≳698 km/s (one-sided limit), at 90% credibility. This marks the first identification of a large kick velocity for an individual gravitational wave event. Given the kick velocity of GW200129, we estimate that there is a less than 0.48% (7.7%) probability that the remnant black hole after the merger would be retained by globular (nuclear star) clusters. Finally, we show that kick effects are not expected to cause biases in ringdown tests of general relativity for this event, although this may change in the future with improved detectors.