Faculty Bibliography

BACKGROUND:It is unknown whether there is a general factor that accounts for the propensity for both physical and mental conditions in different age groups and how it is associated with lifestyle and well-being. METHODS:factor, lifestyles, and well-being was further explored. RESULTS:factor scores significantly correlated with lifestyle and well-being, suggesting healthier lifestyles were associated with a reduced likelihood of physical and mental health comorbidities, which in turn improved well-being. CONCLUSIONS:Contrary to the traditional dichotomy between mental and physical conditions, our study showed a general factor underlying the comorbidity across mental and physical diseases, related to lifestyle and well-being. Our results inform the conceptualization of mental and physical illness as well as future research assessing risk and pathways of disease transmission, intervention, and prevention. Our results also provide a strong rationale for a systematic screening for mental disorders in individuals with physical conditions and vice versa, and for integrated services addressing multimorbidity.

After stroke, upper extremity (UE) motor recovery may be mediated in part by transcallosal projections between hemispheres. The interhemispheric competition model posits that transcallosal inhibition (TI) from the contralesional hemisphere is abnormally strengthened following stroke and interferes with motor recovery. This model has recently been questioned. In this longitudinal study, we aimed to definitively confirm or refute a maladaptive role of contralesional TI in subacute motor recovery. We assessed 30 mild-to-moderately impaired subjects over the six months following ischemic stroke. We tracked contralesional TI and motor functions in the proximal and distal segments of the paretic UE. We used transcranial magnetic stimulation to examine the ipsilateral silent period (iSP) in an arm and hand muscle. We used quantitative and clinical testing to examine deficits in muscle strength, motor control, and individuation; UE segmental impairment; and UE activity limitation. We assessed the relationships of contralesional TI to motor functions in the subacute period. Despite recovery of most motor functions in the proximal and distal UE, contralesional TI was largely static and unrelated to recovery of any motor function. There were inconsistent associations between stronger TI, less hand impairment, and less activity limitation in the subacute period overall. We found no compelling evidence to suggest a maladaptive role of contralesional TI in UE motor recovery in mild-to-moderately impaired stroke subjects. The scattered associations between stronger TI and better levels of paretic UE function suggest a potential supportive role rather than a limiting one. These findings challenge the validity of the interhemispheric competition model in the subacute recovery period, and prompt reconsideration of neuromodulatory strategies that subacutely target contralesional TI.

Amyotrophic lateral sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this heterogeneity, large-scale genomics studies revealed that ALS postmortem samples can be grouped into a small number of subtypes, defined by transcriptomic signatures of mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or TDP-43 pathology and associated transposable elements (ALS-TE). In this study, we present a deep ALS neural net classifier (DANCer) for ALS molecular subtypes. Applying DANCer to an expanded cohort from the NYGC ALS Consortium highlights two subtypes that strongly correlate with disease duration: ALS-TE in cortex and ALS-Glia in spinal cord. Finally, single-nucleus transcriptomes demonstrate that ALS subtypes are recapitulated in neurons and glia, with both ALS-wide and subtype-specific alterations in all cell types. In summary, ALS molecular subtypes represent a combination of cellular and pathological features that correlate with clinical features of ALS.

BACKGROUND:No empirical data support the 54-58mm external diameter of intravaginal rings (rings) currently available and in development for contraception and other indications. Understanding how external diameter affects preference, adherence, and acceptability is critical for optimizing future product development. OBJECTIVES/OBJECTIVE:Our primary objectives were to determine which of three non-medicated rings of differing external diameters was preferred and yielded the highest adherence. Secondary objectives were comparing acceptability, patterns of adherence, and safety of the three rings. STUDY DESIGN/METHODS:In an open-label, three-way crossover trial, healthy, HIV-uninfected, monogamous, sexually active, non-pregnant,18-40-year-old cisgender women and their male partners in Atlanta, GA and the Bronx, NY were randomly assigned to the sequence of using three non-medicated silicone rings (46mm, 56mm, 66mm external diameters)continuously for approximately 30 days each (90 days total; November 2021-December 2022). We tested whether end of study preference for any of the three rings was greater than 0.33 (binomial proportion, exact test). We used mixed-effect regression models with random intercepts by participant to compare adherence (ring never out for longer than 30 minutes in 24 hours); and probability of removals (including reasons for removal), expulsions, and the ring being out of the vagina all day, per ring, per day of use with the 56mm ring as the reference group; and to compare scores on a novel 19-item acceptability scale with items related to ease and experience of use, and impact on sex. RESULTS:23/24 women completed the study (median age 26.7 years [SD 3.78]). Most were college graduates (92%), White (63%), non-Hispanic (79%), single (79%), and nulliparous (92%). At study end, 59% preferred the smallest (46mm) ring versus 18% each for the 56mm and 66mm rings (p=0.0045). The proportion of participants who were adherent did not differ significantly by ring (46mm, 78%; 56mm, 75%; 66mm, 59%; p=0.30), however, odds of expulsion were higher for the 46mm (OR 5.72, 95% CI: 1.25-26.1) and 66mm (OR 25.9, 95% CI: 6.11-109) rings than the 56mm ring. The 66mm ring also had greater odds of being out (removal or expulsion, any length of time) than the 56mm ring (OR 6.50, 95% CI 3.46-12.2). Mean acceptability scale scores were identical (4.54/5) for the 46mm and 56mm (smallest and medium) rings and significantly higher than the largest, 66mm ring (3.94/5; p<0.001). CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Although the 46mm ring was preferred by more women and had higher rates of adherence compared to the other two rings, the 56mm ring was rated as equally acceptable with significantly fewer reports of expulsions/removals compared to the other two rings. These data confirm that the current 54-58mm diameter of vaginal rings on the market and in development is acceptable and performs well. Future studies should explore the effect of other mechanical attributes, such as compressibility, on preference, adherence, and acceptability, as well as investigating ring characteristics in other populations.

Aging populations worldwide face an increasing burden of age-related chronic conditions, necessitating a deeper understanding of the underlying mechanisms. Purine metabolism has emerged as a crucial player in the pathophysiology of aging, affecting various tissues and organs. Dysregulation of purine metabolism, particularly alterations in extracellular adenosine levels and adenosine receptor signaling, contributes to age-related musculoskeletal problems, cardiovascular diseases, inflammation, and impaired immune responses. Changes in purine metabolism are associated with diminished tissue repair and regeneration, altered bone density, and impaired muscle regeneration. Mechanistically, age-related alterations in purine metabolism involve reductions in extracellular adenosine production, impaired autocrine signaling, and dysregulated expression of CD73 and CD39. Targeting adenosine receptors, such as A_2A and A_2B receptors, emerges as a promising therapeutic approach to mitigate age-related conditions, including sarcopenia, obesity, osteoarthritis, and impaired wound healing. Since we cannot reverse time, understanding the intricate molecular interplay between purine metabolism and aging-related pathologies holds significant potential for developing novel therapeutic strategies to improve the health and quality of life of aging populations. In this review, we compile the findings related to purine metabolism during aging in several tissues and organs and provide insights into how these signals can be manipulated to circumvent the deleterious effects of the passage of time on our body.

OBJECTIVE:We analyzed the long-term safety and effectiveness of fenfluramine (FFA) in patients with Dravet syndrome (DS) in an open-label extension (OLE) study after participating in randomized controlled trials (RCTs) or commencing FFA de novo as adults. METHODS:Patients with DS who participated in one of three RCTs or were 19 to 35 years of age and started FFA de novo were included. Key endpoints were: incidence of treatment-emergent adverse events (TEAEs) in the safety population, and median percentage change in monthly convulsive seizure frequency (MCSF) from the RCT baseline to end of study (EOS) in the modified intent-to-treat (mITT) population. Post hoc analyses compared effectiveness in patients on concomitant stiripentol (STP) vs those not taking STP, and assessed safety (TEAEs) and effectiveness (Clinical Global Impression-Improvement [CGI-I] scale ratings) in patients enrolled as adults. RESULTS:A total of 374 patients, including 45 adults, received ≥1 FFA dose. Median FFA exposure was 824 days (range, 7-1280). TEAEs occurring in ≥10% of patients were pyrexia, nasopharyngitis, decreased appetite, seizure, decreased blood glucose, diarrhea, abnormal echocardiography (only physiologic regurgitation), upper respiratory tract infection, influenza, vomiting, and ear infection; no valvular heart disease or pulmonary arterial hypertension was observed over the OLE. In the mITT population (n = 324), median percentage change in MCSF from baseline to EOS was -66.8% (p < .001). The post hoc analyses of MCSF change from baseline to EOS in patients on concomitant STP (n = 75) was -36.2% vs -71.6% in those not on concomitant STP (n = 234) (p < .0001). In adult patients, 29 of 41 (70.7%) and 29 of 42 patients (69.1%) demonstrated clinically meaningful improvement on CGI-I at last visit as rated by caregivers and investigators, respectively. SIGNIFICANCE/CONCLUSIONS:Our OLE study of FFA in patients with DS confirmed previous positive findings and extended the exposure up to 3.5 years. No new or unexpected safety signals were observed and FFA demonstrated sustained and clinically meaningful reduction in MCSF.

Microsporidia are divergent fungal pathogens that employ a unique harpoon-like apparatus called the polar tube (PT) to invade host cells. The long PT is fired out of the microsporidian spore over the course of just a few hundred milliseconds. Once fired, the PT is thought to pierce the plasma membrane of a target cell and act as a conduit for the transfer of the parasite into the host cell, which initiates infection. The PT architecture and its association with neighboring organelles within the parasite cell remain poorly understood. Here, we use cryoelectron tomography to investigate the structural cell biology of the PT in dormant spores from the human-infecting microsporidian species, Encephalitozoon intestinalis. Segmentation and subtomogram averaging of the PT reveal at least four layers: two protein-based layers surrounded by a membrane layer and filled with a dense core. Regularly spaced protein filaments form the structural skeleton of the PT. Combining cryoelectron tomography with cellular modeling, we propose a model for the three-dimensional organization of the polaroplast, an organelle that surrounds the PT and is continuous with the outermost, membranous layer of the PT. Our results reveal the ultrastructure of the microsporidian invasion apparatus in situ, laying the foundation for understanding infection mechanisms.

BACKGROUND:EUS-guided gastroenterostomy (EUS-GE) is a minimally invasive therapy for the management of gastric outlet obstruction (GOO). EUS-GE has demonstrated excellent short-term efficacy without the risks of surgical bypass. However, there is limited data on follow-up outcomes. In this study, we collected 6-month follow-up data on patients who underwent EUS-GE for benign and malignant etiologies, to aim to show the shift in paradigm in their management algorithm. METHODS:This was a retrospective multicenter study across 7 international centers of consecutive patients undergoing EUS-GE over a 4-year period who were entered in a dedicated registry. Demographic characteristics, procedure-related information, and follow-up data were collected. Primary outcome was the 6-month data on clinical resolution of GOO. RESULTS:Ninety-one patients were included (71 malignant and 20 benign cases). Technical success was 99% due to high expertise and volume. Clinical success at 48 hours was 97% (88/90) with an average procedure time of 47 minutes and length of stay of 5.86 days. At 3 months, 87 (95.6%) patients had achieved clinical resolution. At 6 months, 48 (53%) subjects were alive, 40 (44%) were deceased, 3 were lost to follow-up (3.3%) and 1 (1%) had a recurrence of GOO. Clinical success at 6 months follow-up was 98% (47/48). CONCLUSIONS:The majority of patients with GOO who undergo EUS-GE showed clinical resolution at 6-month follow-up. Patients with malignant etiology are appropriately palliated during their life span. Further prospective studies are necessary to obtain long-term data regarding EUS-GE for benign etiologies.

BACKGROUND:People experiencing homelessness (PEH) with opioid use disorder (OUD) are at high risk of overdose yet less likely to enroll and stay engaged in standard-of-care treatment for OUD, opioid agonist medication for OUD (MOUD), particularly methadone treatment. Engaging this group in treatment is a public health priority, yet little is known about the experiences of PEH enrolled in MOUD. We sought to understand the housing experiences and perspectives of PEH engaged in methadone treatment using mixed quantitative and qualitative methods. METHODS:We recruited individuals with past or present experiences of homelessness who were engaged in methadone treatment at a low-barrier opioid treatment program (OTP) in Connecticut between December 2022 and May 2023. Participants completed surveys about their demographics, resource needs, and housing and healthcare experiences. One-to-one qualitative interviews using a semi-structured interview guide queried participants' experiences with homelessness. Descriptive statistics summarize study variables using Python. The interviews were transcribed and analyzed using thematic analysis. RESULTS:Of 50 participants (19 women, 31 men, mean age 44 years), 80 % reported experiencing homelessness for over a year. Participants reported experiencing a mean of 56.6 months without permanent, stable housing and a mean of 2.4 periods of homelessness in the past 3 years. Thematic analysis yielded three primary themes that described the intersectional identity of an individual with OUD and experiencing homelessness: 1) Challenges created by homelessness (e.g., transportation barriers limiting access to the OTP); 2) Personal barriers to exiting homelessness (e.g., struggling with continued substance use); and 3) Structural barriers to exiting homelessness (e.g., difficulty navigating the housing system). CONCLUSIONS:PEH enrolled in methadone treatment face substantial barriers related to their OUD and housing status as well as many structural, social, and health-related vulnerabilities. Future efforts to address these vulnerabilities in clinical settings may enhance treatment engagement and should be examined to potentially attenuate the very high risk of overdose that PEH face. Challenges created by homelessness, personal barriers to exiting homelessness, and structural barriers to exiting homelessness are potential targets for methadone treatment programs to better tailor treatment and improve engagement and outcomes.