Faculty Bibliography

For femoral reconstruction in revision total hip arthroplasty (rTHA), cementless, diaphyseal engaging femoral components are the most commonly-used implants. At present, there are no reviews that directly compare the design features of these implants. We performed a manual review of the designs of commercially available diaphyseal engaging femoral stems. We compiled and compared the design features of these implants. Clinical outcomes of modular and monoblock stems were also compared. We identified five modular and four monoblock stems in the manual review of commercial companies manufacturing these stems. Distal stem taper varied from 2° to 3.5°, and the number of splines varied from 8 to 16. The stems varied in their stem lengths, offsets, and surface finish. Although there are no clinically significant differences in the restoration of leg length between monoblock compared to modular stems. The modular stems appear to perform slightly better with respect to subsidence and restoration of leg length. A source of concern for modular stems are mechanical implant failures that occur almost exclusively at modular junctions. Current evidence does not support any difference in dislocation rate, intraoperative or postoperative fracture, aseptic loosening, re-revision rates, or clinical outcomes between monoblock and modular stems. With the knowledge of the distinct features of implants, surgeons must make choices associated with specific design characteristics that could be pivotal to the success of the operation. Our understanding of design differences will help us minimize chances of failure and choose patient-specific implants that will lead to a high rate of success.

VEXAS syndrome is a severe adult-onset autoinflammatory disease caused by somatic mutations in the UBA1 gene, disrupting cytoplasmic ubiquitin-activating enzyme E1 function in hematopoietic progenitors. Its pathogenesis remains poorly understood, particularly the mechanisms by which UBA1 mutations disrupt myeloid cell function in the context of inflammatory stimuli. Here, we combine a genetically engineered THP-1 monocytic model with ex vivo analyses of blood and tissue samples from VEXAS patients to investigate the consequences of the canonical UBA1M41V mutation. We show that UBA1-mutated monocytes exhibit TNF-α-induced cell death, characterized by RIPK1 phosphorylation, and MLKL- and caspase-8-mediated cell death. Importantly, we extend these findings to patient-derived CD14⁺ sorted cells, confirming that these cells undergo aberrant apoptotic and necroptotic cell death. Mechanistically, activation of these cell death pathways appears to be promoted by defective NF-κB-dependent transcriptional responses and reduced cFLIP(L) expression following TNF-α stimulation. UBA1-mutated monocytes also display blunted cytokine responses to Toll-like receptor (TLR) agonists despite preserved TLR expression, linked to an impaired NF-κB response. UBA1M41V-derived macrophages exhibit a pro-inflammatory transcriptional profile with increased chemokine secretion that promotes monocyte recruitment. In addition, these UBA1-mutated macrophages display impaired efferocytosis due to lysosomal dysfunction. Together, these findings reveal a pathogenic axis in VEXAS syndrome linking UBA1 loss of function and defective ubiquitination to RIPK1-mediated inflammatory cell death, impaired antimicrobial signaling, and defective resolution mechanisms. Our study provides novel mechanistic insights into the myeloid dysfunction underlying inflammation and cytopenia in VEXAS and supports the therapeutic targeting of inflammatory cell death pathways.

Improving long-term protective immunity elicited by prime-boost vaccinations requires a deeper understanding of the immunologic outcomes of different vaccine platforms. Given the variety of platforms used to develop vaccines against SARS-CoV-2, we reasoned that SARS-CoV-2 offered an opportunity to compare vaccine platforms in humans. We used flow cytometry and single-cell transcriptomics to explore the B cell response to different homologous and heterologous vaccine regimens. We found that an adenovirus vector prime followed by a messenger RNA (mRNA) vaccine boost showed the greatest short-term B cell expansion and preferentially elicited an activated atypical B cell subset that was associated with antibody binding titers against spike protein. In contrast, an mRNA primary series followed by homologous boost induced a different activated B cell subset with more proliferative potential and high frequencies of a long-lived resting memory subset. Moreover, immunoglobulin A (IgA)-expressing memory B cells had more somatic hypermutations than the predominant IgG-expressing B cell population. This heterogeneity in vaccine-elicited B cell responses underscores the potential of tailoring vaccine regimens that combine different platforms to achieve potent and durable protection against infectious diseases.

UNLABELLED:Despite the vast promise of abrupt wavefront engineering within subwavelength thickness, most optical metasurfaces are still bound to bulky and rigid substrates. Recently, metasurfaces in suspended membranes (MISMs) have attracted increasing attention due to their unique flexible, conformal properties and their ability to minimize undesired substrate effects. Most importantly, the MISM platform enables metasurface transfer and integration with non-conventional substrates and electronic/photonic devices. By summarizing multiple approaches to create MISMs with a variety of membrane and sacrificial layer materials and configurations, we demonstrate the Omni-Purpose Transfer and Integration of Metasurfaces in Suspended Membranes (OPTIMISM), overcoming the existing limitations on metasurface geometries or materials. It is particularly suitable for metasurface integration on optical fiber tips to form meta-optic probes for broad applications, including biomedical and endoscopic imaging and sensing. Considering the various configurations of membrane dielectric environment in integrated MISM devices, we performed a systematic investigation to demonstrate the strong influence of the surrounding refractive index on ultrathin metasurface design based on both conventional forward design (library search) and inverse design strategy (evolutionary algorithm). Our findings highlight the advantage of the inverse design strategy leveraging meta-atom non-local interactions, and the great potential of the MISM platform for universal and scalable metasurface transfer and integration. SUPPLEMENTARY INFORMATION/UNASSIGNED:The online version contains supplementary material available at 10.1007/s44275-026-00041-y.

BACKGROUND & AIMS/UNASSIGNED:Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in patients with metabolic dysfunction-associated steatohepatitis (MASH). No therapy targets both diseases simultaneously, and a roadblock for discovering new treatments is the lack of animal models that recapitulate both diseases, especially in females. METHODS/UNASSIGNED:mice (n = 8-13) were fed a western diet (WD), modified choline-deficient high-fat diet (mCDHFD), or modified MASH-inducing diet (mMASHD) containing equivalent physiological levels of cholesterol. Comprehensive multiomics including metabolomics, lipidomics, and transcriptomics, alongside histopathological and biochemical analyses, were integrated to characterize concurrent MASH and atherosclerosis. Transcriptomics was validated in other mouse models and integrated with human data (n = 79). RESULTS/UNASSIGNED:0.04). Lipidomic analyses revealed dysregulated polyunsaturated fatty acid, steryl ester, and dihexosylceramide metabolism. Integration of mouse and human transcriptomes revealed similarities in metabolic and proinflammatory/proatherogenic pathways. CONCLUSION/UNASSIGNED:This sex-based multiomics analysis establishes a murine model of concurrent MASH and atherosclerosis, reveals sex-specific dietary responses, and identifies metabolic and transcriptional pathways with potential utility as biomarkers and therapeutic targets. IMPACT AND IMPLICATIONS/UNASSIGNED:mice, we found that different diets containing equivalent physiological levels of cholesterol induce sex-specific responses, with a modified choline-deficient high-fat diet effectively modeling both diseases in both sexes, while a western diet is effective only in males. Multiomics analyses identified key metabolic and inflammatory pathways linking MASH and atherosclerosis that mirror transcriptomic signatures found in humans, and highlight circulating cholesterol, CCL2, and sphinganine as potential biomarkers. These findings establish a translational model and reveal sex-specific metabolic pathways that will advance our understanding of the shared pathophysiology of MASH and atherosclerosis, and facilitate the development of dual therapeutic approaches, addressing an urgent unmet clinical need.

INTRODUCTION/BACKGROUND:Though brain fog is common in Long-coronavirus disease 2019 (Long-COVID), the incidence of mild cognitive impairment (MCI) is unknown. METHODS:In an observational cohort study, recovered COVID-positive, Long-COVID, and COVID-negative subjects underwent blinded evaluation using National Alzheimer's Coordinating Center (NACC) and National Institute on Aging (NIA) -Alzheimer's Association diagnostic criteria for dementia and MCI. The cumulative incidence of MCI was calculated for each group, and the hazard of MCI was compared between groups. RESULTS:Among 260 subjects, the cumulative incidence of MCI over 4.4 years was higher with Long-COVID (27%) versus recovered-COVID (5%) or COVID-negative status (1%). There was a higher hazard of MCI for patients with Long-COVID compared to those without (hazard ratio [HR] 3.93, 95% confidence interval [CI] 1.86-8.31, p < 0.001), and specifically for the Alzheimer's disease (AD) -related MCI subtype (HR 3.20, 95% confidence interval [CI] 1.14-9.00, p = 0.027). DISCUSSION/CONCLUSIONS:The cumulative incidence and adjusted hazard of MCI (and specifically AD-related MCI) at 4.4 years was significantly higher among Long-COVID patients compared to recovered-COVID and COVID-negative controls.

Durable left ventricular assist devices (dLVAD) remain a lifesaving therapy in patients with stage D heart failure that is refractory to conventional medical therapies. Owing to improvements in technology and patient outcomes, the number of patients supported with dLVADs has increased over the past decade. Despite this growing population, there are few resources for cardiovascular intensivists that integrate epidemiology, diagnostic workup and multidisciplinary medical management of acute emergencies in patients supported with dLVADs.

Mental health conditions are a major public health concern in the African region, where women experience a high prevalence of maternal mental health conditions and limited access to adequate care. This issue is particularly severe among women living with HIV (WLHIV), who face a heightened risk of depression and anxiety. Despite the well-documented association between male partner-related factors and maternal/child health outcomes, their impact on perinatal mental health from the perspective of women is not well understood. We conducted semi-structured interviews and focus group discussions with women affected by HIV. Thematic analysis revealed common sources of mental distress they experienced. Relationship with male partners was identified as an area needing further interrogation to better understand how gender inequities exacerbate maternal mental health outcomes. Male partners emerged as the most significant source of stress for postpartum women, often due to relationship instability, inadequate financial support, and in some cases, verbal or physical abuse. Additionally, women noticed signs of mental health challenges in their male partners, such as anger and chronic stress, and observed that these men often lacked support to address these issues. Other sources of stress included pregnancy-related changes, fear of acquiring HIV among those on HIV PrEP (Pre-Exposure prophylaxis) and fear of transmitting HIV to their babies among those living with HIV. Strategies for coping with perinatal mental health challenges included praying, singing, listening to music, taking walks, social interaction, and participating in church or community-based support groups. Recognizing the significant influence men have on women's mental health and the interconnectedness of men's stress and women's mental well-being, family-oriented mental health programs could be instrumental in improving perinatal mental health.

Calcineurin inhibitors, particularly tacrolimus, have been a fundamental immunosuppressive treatment in solid organ transplantation for over four decades, helping prevent organ rejection in transplant recipients. Tacrolimus has also proven effective in treating several autoimmune diseases. Despite its effectiveness, the use of tacrolimus has been characterized by challenges related to its narrow therapeutic index-particularly in kidney transplantation-necessitating frequent blood monitoring and dose adjustments. In recent years, improved extended-release formulations have made strides in reducing toxic effects, such as neurotoxicity and nephrotoxicity, and enhancing medication adherence. However, there remains considerable room for improvement, which has the potential to ameliorate long-term graft outcomes and decrease the burden of pill intake, especially for vulnerable patient populations. Recent advances enabling very-extended oral drug delivery present potential opportunities to optimize the peak-trough effects of tacrolimus-based immunosuppression, while also benefitting from the synergy of drug compounding and minimizing pill burden. In this article, we review the history of tacrolimus as a cornerstone of immunosuppression in kidney transplantation, the iterative improvements in outcomes and patient quality-of-life enabled by increasingly extended-release formulations, and the potential outlook for very-extended release formulations in the future.