New threats from an old foe: Evaluating the risk to the blood supply due to increasing incidence and endemicity of leprosy in the United States.

Leprosy (i.e., Hansen's disease) is a chronic disease secondary to infection with either Mycobacterium leprae or M. lepromatosis. While the incidence of this disease is decreasing across the world, there is mounting evidence that it might be increasing, and becoming endemic, in the United States. Leprosy was once considered a potential threat to the blood supply, and while this threat has not borne out, it is worth revisiting the available data to assess whether it may pose a threat in the future. Herein, we discuss the evidence for and against the potential for transfusion-transmission of leprosy, and highlight future areas of research to further elucidate this possibility.

COVID-19 as a chronic stressor and the importance of individual identity: A data-driven look at academic productivity during the pandemic.

The COVID-19 pandemic impacted personal and professional life. For academics, research, teaching, and service tasks were upended and we all had to navigate the altered landscape. However, some individuals faced a disproportionate burden, particularly academics with minoritized identities or those who were early career, were caregivers, or had intersecting identities. As comparative endocrinologists, we determine how aspects of individual and species-level variation influence response to, recovery from, and resilience in the face of stressors. Here, we flip that framework and apply an integrative biological lens to the impact of the COVID-19 chronic stressor on our endocrine community. We address how the pandemic altered impact factors of academia (e.g., scholarly products) and relatedly, how factors of impact (e.g., sex, gender, race, career stage, caregiver status, etc.) altered the way in which individuals could respond. We predict the pandemic will have long-term impacts on the population dynamics, composition, and landscape of our academic ecosystem. Impact factors of research, namely journal submissions, were altered by COVID-19, and women authors saw a big dip. We discuss this broadly and then report General and Comparative Endocrinology (GCE) manuscript submission and acceptance status by gender and geographic region from 2019 to 2023. We also summarize how the pandemic impacted individuals with different axes of identity, how academic institutions have responded, compile proposed solutions, and conclude with a discussion on what we can all do to (re)build the academy in an equitable way. At GCE, the first author positions had gender parity, but men outnumbered women at the corresponding author position. Region of manuscript origin mattered for submission and acceptance rates, and women authors from Asia and the Middle East were the most heavily impacted by the pandemic. The number of manuscripts submitted dropped after year 1 of the pandemic and has not yet recovered. Thus, COVID-19 was a chronic stressor for the GCE community.

Assessment of glucocorticoids, sex steroids, and innate immunity in wild red-eared slider turtles (Trachemys scripta elegans).

When access to resources is limited, organisms must shift energy investment among physiological processes to survive, reproduce, and respond to unpredictable events. The shifting of these limited resources among processes may result in physiological tradeoffs, often mediated by glucocorticoids. We assessed relationships among the physiological processes of immunity, reproduction, and the stress response in wild adult red-eared slider turtles (Trachemys scripta elegans). Red-eared sliders exhibit a multi-clutching reproductive strategy that requires high energetic investment in reproduction at the beginning of the nesting season in females. Males mate in spring and undergo spermatogenesis and mating in late summer/early fall. We expected to observe tradeoffs when investment toward reproductive processes was particularly demanding. To test this, we subjected 123 individuals to a standardized acute stressor and collected blood to measure innate immunocompetence and circulating steroid hormone concentrations. Tradeoffs between female reproduction and immunocompetence occurred early in the nesting season. This high reproductive investment was evident by heightened circulating progesterone and reduced baseline innate immunity. Corticosterone (CORT) was also high during this period, indicating a role in facilitating allocation of energy. Tradeoffs were not as evident in males, though males upregulated innate immune function, baseline CORT, and testosterone prior to fall spermatogenesis and mating. Throughout the entire sampling period, both males and females increased CORT and immunocompetence following the acute standardized stressor. Taken together, we concluded that reproduction requires shifts in energy allocation in during the highest reproductive period for females but all individuals in this population remain able to respond to the standardized stressor even during increased reproductive investment. These findings reinforce the continuing evidence that physiological relationships are context-dependent and resource demands are dynamic across the reproductive season.

Investigating relationships among stress, reproduction, and immunity in three species of watersnake.

Energy is a finite resource required for all physiological processes and must be allocated efficiently among essential activities to ensure fitness and survival. During the active season, adult organisms are expected to prioritize investment in reproduction over other energetically expensive processes, such as responding to immunological challenges. Furthermore, when encountering a stressor, the balance between reproduction and immunity might be disrupted in order to fuel the stress response. Because of the distinct differences in life histories across species, watersnakes provide a unique group of study in which to examine these tradeoffs. Over a two-year period, we captured three watersnake species throughout Northeast Arkansas. Animals were subjected to restraint stress and blood samples were collected throughout the acute stress response. Blood samples were used to assess innate immunity and steroid hormone concentrations. We found the peak in corticosterone concentration is season-specific, potentially because energetic reserves fluctuate with reproductive activities. We also found body condition was positively related to acute stress and negatively related to immunity. Watersnakes evidently prioritize reproduction over immunity, especially during the energetically intensive process of vitellogenesis. Energetic tradeoffs between reproduction, immunity, and the stress response are complex, and this study contributes to our understanding of energetic shifts in free-living organisms in the context of stress.

Emerging therapeutics in the management of connective tissue disease. Part II: Dermatomyositis and scleroderma.

The management of connective tissue diseases is dramatically evolving with the advent of biologics and novel oral systemic therapeutics. Despite involvement in the care of these complex patients, there is a knowledge gap in the field of dermatology regarding these emerging agents. The second article in this continuing medical education series discusses new and emerging therapeutics for dermatomyositis and scleroderma that target cells, intracellular signaling pathways, and cytokines.

Efficacy of Platinum Rechallenge in Metastatic Urothelial Carcinoma After Previous Platinum-Based Chemotherapy for Metastatic Disease.

BACKGROUND: Fit patients with metastatic urothelial carcinoma (mUC) receive first-line platinum-based combination chemotherapy (fPBC) as standard of care and may receive additional later-line chemotherapy after progression. Our study compares outcomes with subsequent platinum-based chemotherapy (sPBC) versus subsequent non-platinum-based chemotherapy (sNPBC). MATERIALS AND METHODS: Patients from 27 international centers in the Retrospective International Study of Cancers of the Urothelium (RISC) who received fPBC for mUC and at least two cycles of subsequent chemotherapy were included in this study. A multivariable Cox proportional hazards model compared overall survival (OS) and progression-free survival (PFS). RESULTS: One hundred thirty-five patients received sPBC and 161 received sNPBC. Baseline characteristics were similar between groups, except patients who received sPBC had higher baseline hemoglobin, higher disease control rate with fPBC, and longer time since fPBC. OS was superior in the sPBC group (median 7.9 vs 5.5 months) in a model adjusting for comorbidity burden, performance status, liver metastases, number of fPBC cycles received, best response to fPBC, and time since fPBC (hazard ratio, 0.72; 95% confidence interval, 0.53-0.98; p = .035). There was no difference in PFS. More patients in the sPBC group achieved disease control than in the sNPBC group (57.4% vs 44.8%; p = .041). Factors associated with achieving disease control in the sPBC group but not the sNPBC group included longer time since fPBC, achieving disease control with fPBC, and absence of liver metastases. CONCLUSION: After receiving fPBC for mUC, patients who received sPBC had better OS and disease control. This may help inform the choice of subsequent chemotherapy in patients with mUC. IMPLICATIONS FOR PRACTICE: Patients with progressive metastatic urothelial carcinoma after first-line platinum-based combination chemotherapy may now receive immuno-oncology agents, erdafitinib, enfortumab vedotin, or sacituzumab govitecan-hziy; however, those ineligible for these later-line therapies or who progress after receiving them may be considered for subsequent chemotherapy. In this retrospective study of 296 patients, survival outcomes and disease control rates were better in those receiving subsequent platinum-based rechallenge compared with non-platinum-based chemotherapy, suggesting that patients should receive platinum rechallenge if clinically able. Disease control with platinum rechallenge was more likely with prior first-line platinum having achieved disease control, longer time since first-line platinum, and absence of liver metastases.

Phase 1 clinical trial of losmapimod in facioscapulohumeral dystrophy: Safety, tolerability, pharmacokinetics, and target engagement.

AIMS: Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD). METHODS: This study included Part A: 10 healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B: 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7.5 mg (n = 6) or 15 mg (n = 6); and Part C: FSHD subjects received open-label losmapimod 15 mg (n = 5) twice daily for 14 days. Biopsies were performed in FSHD subjects at baseline and Day 14 in magnetic resonance imaging-normal appearing (Part B) and affected muscle identified by abnormal short-tau inversion recovery sequence + (Part C). PK and TE, based on pHSP27:total HSP27, were assessed in muscle and sorbitol-stimulated blood. RESULTS: PK profiles were similar between healthy volunteers and FSHD subjects, with mean Cmax and AUC0-12 for 15 mg in FSHD subjects (Part B) of 85.0 ± 16.7 ng*h/mL and 410 ± 50.3 ng*h/mL, respectively. Part B and Part C PK results were similar, and 7.5 mg results were approximately dose proportional to 15 mg results. Dose-dependent concentrations in muscle (42.1 ± 10.5 ng/g [7.5 mg] to 97.2 ± 22.4 ng/g [15 mg]) were observed, with plasma-to-muscle ratio from ~0.67 to ~1 at estimated tmax of 3.5 hours postdose. TE was observed in blood and muscle. Adverse events (AEs) were mild and self-limited. CONCLUSION: Losmapimod was well tolerated, with no serious AEs. Dose-dependent PK and TE were observed. This study supports advancing losmapimod into Phase 2 trials in FSHD. CLINICAL TRIAL REGISTRATION: Clinical trial identifier ToetsingOnline: NL68539.056.18 Nederlands Trials Register NL8000.

Measuring adrenal and reproductive hormones in hair from Southern Beaufort Sea polar bears (Ursus maritimus).

Polar bears (Ursus maritimus) use sea ice to access marine mammal prey. In Alaska's Southern Beaufort Sea, the declining availability of sea ice habitat in summer and fall has reduced opportunities for polar bears to routinely hunt on the ice for seals, their primary prey. This reduced access to prey may result in physiological stress with subsequent potential consequences to reproductive function (physiological changes that accompany reproduction), which can be measured via reproductive hormones. Hormone concentrations in hair can be used as a minimally invasive alternative to serum concentrations, which must come from animal captures. Hair samples also provide a long-term average measurement of hormone concentrations that is not influenced by short-term fluctuations like that of serum. The aim of this study was (1) to determine if a radioimmunoassay could be used to measure adrenal and reproductive hormones in polar bear hair, and (2) to determine what the relationship is between these hormones and other reproductive, condition, and demographic parameters of polar bears. We successfully validated this method for cortisol, progesterone, estradiol, and testosterone through the analysis of hair and serum of 141 free-ranging polar bears. We found that while hair cannot be used to estimate serum hormone concentrations during the breeding season, hormone concentrations in hair can be used to measure reproductive function in polar bears. Further, our findings support trends in previous studies measuring hormone concentrations in serum. We found that adrenal and some reproductive hormones were positively correlated in hair samples of females. Associations between hormone concentrations in hair and serum did not vary relative to reproductive status of adult females. Serum testosterone increased throughout the breeding season for adult males and was significantly associated with body mass index (BMI). Our research supports the use of hair as a measure of reproductive function in polar bears and allows us to monitor the future effects of climate change on polar bear physiology.

Simultaneous occurrence of idiopathic trachyonychia in dizygotic twins.

Trachyonychia (or twenty-nail dystrophy) is an uncommon chronic disorder manifesting as thin, flattened, brittle nails with excessive longitudinal ridging and loss of luster creating a "sandpaper-like" texture that most commonly presents spontaneously in childhood as an isolated phenomenon; however, it has been historically associated with numerous dermatoses. Rarely, trachyonychia has been reported to occur in families, suggesting a potential hereditary predisposition. We report trachyonychia occurring simultaneously in dizygotic twins, further supporting a possible underlying genetic basis of this idiopathic nail disorder.

p38α Regulates Expression of DUX4 in a Model of Facioscapulohumeral Muscular Dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the loss of repression at the D4Z4 locus leading to aberrant double homeobox 4 (DUX4) expression in skeletal muscle. Activation of this early embryonic transcription factor results in the expression of its target genes causing muscle fiber death. Although progress toward understanding the signals driving DUX4 expression has been made, the factors and pathways involved in the transcriptional activation of this gene remain largely unknown. Here, we describe the identification and characterization of p38α as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent, and specific inhibitors of p38α/ß, we show a robust reduction of DUX4 expression, activity, and cell death across patient-derived FSHD1 and FSHD2 lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38α/ß inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38α/ß inhibitors as effective therapeutics to treat FSHD at its root cause. SIGNIFICANCE STATEMENT: Using patient-derived facioscapulohumeral muscular dystrophy (FSHD) myotubes, we characterize the pharmacological relationships between p38α/ß inhibition, double homeobox 4 (DUX4) expression, its downstream transcriptional program, and muscle cell death. p38α/ß inhibition results in potent and specific DUX4 downregulation across multiple genotypes without significant effects in the process of myogenesis in vitro. These findings highlight the potential of p38α/ß inhibitors for the treatment of FSHD, a condition that today has no approved therapies.

Investigating the relationship between corticosterone and glucose in a reptile.

The glucocorticoid hormone corticosterone (CORT) has classically been used in ecophysiological studies as a proxy for stress and energy mobilization, but rarely are CORT and the energy metabolites themselves concurrently measured. To examine CORT's role in mobilizing glucose in a wild reptile, we conducted two studies. The first study measured natural baseline and stress-induced blood-borne CORT and glucose levels in snakes during spring emergence and again when snakes return to the denning sites in autumn. The second study manipulated the hypothalamic-pituitary-adrenal (HPA) axis in male snakes in the autumn by taking a baseline blood sample, then subjecting individuals to one of five treatments (no injection, saline, CORT, adrenocorticotropin hormone and metyrapone). Subsequent samples were taken at 30 and 60 min. In both studies, we found that glucose levels do increase with acute stress, but that the relationship was not directly related to CORT elevation. In the second study, we found that none of the HPA axis manipulations directly affected blood glucose levels, further indicating that CORT may play a complex but not direct role in glucose mobilization in snakes. This study highlights the need for testing mechanisms in wild organisms by combining in situ observations with manipulative studies.

Synthesis of functionalized derivatives of the gamma-secretase modulator BMS-932481 and identification of its major metabolite.

In an effort to improve physical properties by introducing polar functionality into the bicyclic pyrimidine gamma-secretase modulator (GSM) clinical candidate BMS-932481, we prepared several oxidative products of BMS-932481. Among the analogs that were prepared, the C-5 alcohol 3 was identified as the predominant metabolite of BMS-932481 found in rat and human liver microsomes. Alcohol 3 was determined to be chemically unstable, leading to the hypothesis that 3 may lead to the production of reactive species both in vitro and in vivo.

Discovery of new indole-based acylsulfonamide Nav1.7 inhibitors.

Screening of 100 acylsulfonamides from the Bristol-Myers Squibb compound collection identified the C3-cyclohexyl indole 6 as a potent Nav1.7 inhibitor. Replacement of the C2 furanyl ring of 6 with a heteroaryl moiety or truncation of this group led to the identification of 4 analogs with hNav1.7 IC50 values under 50 nM. Fluorine substitution of the truncated compound 12 led to 34 with improved potency and isoform selectivity. The inverted indole 36 also maintained good activity. Both 34 and 36 exhibited favorable CYP inhibition profiles, good membrane permeability and a low efflux ratio and, therefore, represent new leads in the search for potent and selective Nav1.7 inhibitors to treat pain.

Discovery of morpholine-based aryl sulfonamides as Nav1.7 inhibitors.

Replacement of the piperidine ring in the lead benzenesulfonamide Nav1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Nav1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Nav1.7 inhibitors. This report describes the synthesis and SAR of these analogs.

A sex-dependent change in behavioral temperature regulation in African house snakes (Lamprophis fuliginosus) challenged with different pathogens.

Behavioral fever in reptiles is often considered an adaptive response used to eliminate pathogens, yet empirical data showing the wide-spread use of this response is mixed. This behavioral change can be beneficial by enhancing the host's immune response and increasing the animal's chance of survival, but it can also be detrimental in terms of host energetic requirements and enzymatic performance. Thus, we examined whether captive-bred African house snakes (Lamprophis fuliginosus) employed behavioral fever in response to pathogen stimulus. Twenty-one African house snakes were injected separately with three different strains of ultraviolet (UV) light-killed bacteria (Escherichia coli, Staphylococcus aureus, Salmonella enterica). We found an increased variance of hourly cloacal temperatures following exposure to pathogens in male but not female house snakes. We did not, however, find a significant febrile response to pathogen exposure as measured via mean cloacal temperature. This research adds critical information to the field of reptilian physiology as this field remains understudied. Reptilian immune function and its relationship with thermal biology is ever more pertinent as new challenges arise, such as novel pathogens and changing climate.

Preclinical Characterization of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder.

(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 µM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.

Endocrine-reproductive-immune interactions in female and male Galápagos marine iguanas.

Endocrine-immune interactions are variable across species and contexts making it difficult to discern consistent patterns. There is a paucity of data in non-model systems making these relationships even more nebulous, particularly in reptiles. In the present study, we have completed a more comprehensive test of the relationship among steroid hormones and ecologically relevant immune measures. We tested the relationship between baseline and stress-induced levels of sex and adrenal steroid hormones and standard ecoimmunological metrics in both female and male Galápagos marine iguanas (Amblyrhynchus cristatus). We found significant associations between adrenal activity and immunity, whereby females that mounted greater corticosterone responses to stress had lower basal and stress-induced immunity (i.e., bactericidal ability). Males showed the opposite relationship, suggesting sex-specific immunomodulatory actions of corticosterone. In both sexes, we observed a stress-induced increase in corticosterone, and in females a stress-induced increase in bactericidal ability. Consistent with other taxa, we also found that baseline corticosterone and testosterone in males was inversely related to baseline bactericidal ability. However, in females, we found a positive relationship between both testosterone and progesterone and bactericidal ability. Multivariate analysis did not discern any further endocrine-immune relationships, suggesting that interactions between adrenal, sex steroid hormones, and the immune system may not be direct and instead may be responding to other common stimuli, (i.e., reproductive status, energy). Taken together, these data illustrate significant endocrine-immune interactions that are highly dependent on sex and the stress state of the animal.

Discovery of non-zwitterionic aryl sulfonamides as Nav1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation.

Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons.