Faculty Bibliography

VEXAS syndrome is characterized by high glucocorticoid (GC) requirements and frequent relapses during tapering, yet dose-response relationships remain poorly defined. We conducted a pilot study to assess the feasibility of granular longitudinal treatment-line reconstruction and to explore GC dose-response patterns associated with disease activity and flare risk. In this retrospective single-center study, we reconstructed detailed treatment trajectories of patients with VEXAS syndrome. Disease courses were segmented into treatment-line periods defined by any therapeutic modification, including GC dose changes. For each period, GC dose, concomitant therapies, and clinical activity were recorded. Associations between GC dose and disease activity were analyzed using multivariable models adjusting for concomitant treatments. Twelve patients were included, representing 315 treatment-line periods over a mean follow-up of 45 months. Mean annual GC exposure was 3.27 ± 2.26 g per patient. Higher GC dose (continuous variable) was independently associated with lower odds of clinical activity (aOR 0.91 per mg increase [95% CI 0.88-0.94], p < 0.001). Exploratory threshold analyses suggested increased flare risk below approximately 15 mg/day (or 0.2 mg/kg/day), with a lower-risk plateau above 20 mg/day. The increased flare risk below 15 mg/day remained significant after adjustment for concomitant therapies (HR 0.24 [95% CI 0.11-0.54], p = 0.001). Organ-specific analyses suggested heterogeneous glucocorticoid sensitivity, with higher doses appearing required for lung involvement and lower doses appearing sufficient for fever, skin, and joint manifestations. This pilot study demonstrates the feasibility of detailed treatment-line reconstruction in VEXAS syndrome and identifies GC dose-response trends. These preliminary findings provide planning parameters for a future adequately powered study aimed at validating dose thresholds and refining tapering strategies in VEXAS.

The guest editors introduce the Biomedical Optics Express feature issue "Optics and the Brain." This issue highlights a range of important neuroscientific questions and clinical needs, and illustrates novel optical methodologies being developed to address them by this research community.

BACKGROUND/UNASSIGNED:Heart failure is an increasingly common comorbidity among people with HIV infection, complicating care and heightening the vulnerability of this population to social adversity (SA). However, the impact of different SA domains on outcomes in this population remains poorly understood. METHODS/UNASSIGNED:We analyzed data on people with HIV infection and heart failure from the NYC 4H (NYC Health + Hospitals HIV-Heart Failure) cohort. Baseline multidimensional SA was assessed by licensed clinical social workers using standardized evaluations and grouped into 5 domains: economic hardship, health care access barriers, neighborhood or built environment instability, social support challenge, and psychobehavioral instability. We used multivariable adjusted Cox models to estimate hazard ratios (HRs) of all-cause, cardiovascular, and infection-related mortality and logistic regression to estimate odds ratios of 6-month rehospitalization risk. RESULTS/UNASSIGNED:Among 1044 participants (62.9% male; mean age, 61.6 years), 601 (58%) reported at least 1 SA: economic hardship (n=130), limited health care access (n=155), unstable housing (n=129), social support challenge (n=179), or psychobehavioral instability (n=438). Over a mean follow-up of 3.8 years, exposure to any SA was associated with higher all-cause mortality (HR, 4.32 [95% CI, 3.03-6.14]), cardiovascular mortality (HR, 4.05 [95% CI, 2.17-6.83]), and infection-related mortality (HR, 2.37 [95% CI, 1.23-4.56]). Social support challenge (HR, 2.19 [95% CI, 1.35-3.55]) and psychobehavioral instability (HR, 1.96 [95% CI, 1.24-3.11]) were associated with higher cardiovascular mortality. Economic hardship (HR, 2.40 [95% CI, 1.22-4.70]) and social support challenge (HR, 3.09 [95% CI, 1.75-5.48]) were associated with higher infection-related mortality. Compared with patients without SA, those with environmental instability, psychobehavioral instability, or social support challenges had a 73% (adjusted odds ratio, 1.73 [95% CI, 1.15-2.06]), 75% (adjusted odds ratio, 1.75 [95% CI, 1.31-2.35]), and 44% (adjusted odds ratio, 1.44 [95% CI, 1.00-2.06]) higher risk of rehospitalization within 6 months, respectively. CONCLUSIONS/UNASSIGNED:SA was significantly associated with mortality and rehospitalization among people with HIV infection and heart failure, with domain-specific pathways influencing specific outcomes. Multidimensional assessment of SA may offer a framework for domain-specific risk stratification in people with HIV infection and heart failure.

Amplitude-modulation (AM) is critical for the perception of complex sounds, and transformations in AM encoding may underlie primate-specific aspects of complex sound perception. The nonhuman primate (NHP) model provides an opportunity to understand what circuit mechanisms generate hierarchical and interhemispheric transformations of AM encoding in different circuits across the cortical hierarchy. To address this, here we report the encoding of AM signals as a function of cortical layer and hemisphere in primary area A1 and the tertiary parabelt (PB) area of five NHPs. We presented AM noise and click trains to awake NHPs while recording from linear array multielectrodes spanning cortical layers. A1 typically encoded all AM frequencies (1.6-200 Hz) with high (> 90%) classification accuracy, while the PB encoded lower (~1.6-25 Hz) frequencies. The laminar gradient observed in A1 (Granular > Infragranular > Supragranular) was inverted in PB (Supragranular > Infragranular > Granular), consistent with differences in thalamocortical input. Both areas displayed enhanced AM encoding in the left hemisphere, restricted to the supragranular layers. These results represent the first analysis of AM encoding in the PB, in which we identify circuits differing in their temporal sensitivity across the hierarchy, and suggest local supragranular neuronal populations contribute to hemispheric specialization.

The heat shock protein 70 (Hsp70) family consists of ATP-driven molecular chaperones essential for maintaining protein homeostasis (proteostasis) across all cell types, however, modulation of chaperone activity by small molecules remains challenging. In bacteria, a major Hsp70 called DnaK represents a putative antibacterial target, as it plays essential roles in growth, antibiotic resistance, and stress response. While Hsp70 inhibitors are in development as potential cancer and neurodegenerative disease treatments in humans, we lack generalizable methods to target Hsp70s across species. Here, we address how peptidomimetic scaffolds designed to inhibit proteases, exemplified by the drug telaprevir, interact with two different bacterial DnaKs to disrupt chaperone function. We perform extensive structure-function studies of telaprevir analogs against DnaK to inform the design of synthetic unnatural peptide sequences with a range of inhibitory potencies. X-ray crystallography analysis of telaprevir and several synthetic peptidomimetics reveal interactions with DnaK's substrate binding domain via ligand side chain recognition reminiscent of that observed in protease active sites, but in two orientations. These co-complexes inspire the synthesis of shorter peptidomimetics capable of allosterically inhibiting DnaK's ATPase activity. Overall, this work demonstrates that chemical scaffolds devised for protease inhibition may be modified to disrupt Hsp70 chaperone activities.

INTRODUCTION/BACKGROUND:Moral injury is the psychological distress resulting from actions, or the lack thereof, which violate one's moral or ethical code. There is a notable gap in literature exploring moral injury among substance use disorder (SUD) treatment and community service providers. Despite the lack of literature describing moral injury among the SUD workforce, moral injury was discussed extensively during meetings of the Community Representative Council (CIRCL) of the National Drug Abuse Treatment Clinical Trials Network (CTN), which engages community members within the CTN Nodes to understand perspectives of people with lived/living experience and those providing substance use services. METHODS:In response to this consistently raised topic, this commentary reviews the literature on moral injury related to the SUD workforce, as well as the perspectives of CIRCL members on the unique and persistent challenges faced by SUD treatment and community services providers. RESULTS:Members of CIRCL in the SUD treatment and community provider workforce consistently described experiencing morally injurious events, including acts of commission and omission, bearing witness, and observing betrayal from those in power. While some experiences are akin to those experienced by providers in other healthcare settings, some were unique to front-line SUD treatment and community services providers. These experiences caused intense experiences of guilt, isolation, and hopelessness, sometimes contributing to turnover. CONCLUSIONS:Addressing moral injury among the SUD provider workforce may require unique mitigation and prevention strategies, potentially involving structural changes at the organizational, social, and policy levels that support the SUD treatment and community service workforce, ultimately improving not just the wellbeing of providers and patients, but the wellbeing of our communities.

Young adults with hip pathology present a therapeutic challenge requiring careful consideration of treatment options that will affect decades of future function. Historically, the orthopedic community has maintained a strong preservation bias, often pursuing multiple preservation attempts before considering arthroplasty because of concerns about implant longevity. This narrative review critically examines current evidence regarding hip preservation surgery and total hip arthroplasty in young adults to inform evidence-based decision making. The literature reveals that successful hip preservation requires a narrow therapeutic window defined by preserved articular cartilage, accurate structural diagnosis, and appropriate patient selection. Clinical and imaging predictors, including joint space narrowing below 2 mm, Tönnis grade 2 or higher osteoarthritis, bipolar chondral damage, and mechanical symptoms, reliably identify patients unlikely to benefit from preservation. Concurrently, advances in bearing surfaces-particularly highly cross-linked polyethylene and ceramics-have dramatically improved arthroplasty outcomes, with contemporary data demonstrating 10-year survivorship exceeding 90% in patients younger than 55 years. Modern total hip arthroplasty delivers consistent pain relief and functional improvement that often exceeds preservation outcomes in appropriately indicated patients. This review proposes a decision-making framework emphasizing that treatment selection should be guided by objective disease characteristics rather than age-based algorithms, optimizing long-term outcomes while minimizing unnecessary morbidity.

Bioconjugation reactions are indispensable for probing biomolecules in their native environments. Photoactivatable bioconjugation offers spatiotemporal control; however, current methods face significant limitations, including the requirement for noncanonical functional groups, cytotoxic heavy-metal catalysts, and high-energy UV or visible light (λ < 800 nm), which restrict tissue penetration and increase phototoxicity risks. In response, we introduce TagC-RED, a Retro-Ene type sigmatropic rearrangement of Diazonium compounds for Cysteine-specific bioconjugation activated by infrared light (λ > 1000 nm). TagC-RED is quantitative, rapid, and catalyst-free, with deep tissue penetration, enabling robust labeling intracellularly and in vivo. Mechanistic studies and DFT calculations show that TagC-RED activates through the formation of an electron donor-acceptor (EDA) complex that enables IR irradiation and undergoes a stepwise retro-ene reaction. TagC-RED holds significant potential as a platform for in vivo chemical biology and diagnostic innovation.

Childhood is a period of peak developmental plasticity, involving drastic changes in the maturation of the neural circuitry underlying fear learning. Disruption and atypical development of fear learning are candidate mechanisms underlying child psychopathology. While there is a lack of understanding behind the maturation of fear learning systems in humans, rodent studies in this area delineate the normative development of fear learning systems early in life, and the effects of early threatening and fearful experiences on this developmental trajectory. Here, we review the rodent literature on developmental fear learning, as well as human studies that show translational convergence in typical development and children exposed to early life threat. We identify several gaps in research, including the role that caregivers play in regulating fear learning at different developmental stages and the intergenerational transmission of learned fear. Finally, we provide recommendations on how to address these gaps in a way that would improve our developmental frameworks of fear learning.