An update on drug-drug interactions in older adults living with human immunodeficiency virus (HIV).

INTRODUCTION: People with HIV are living longer due to advances in antiretroviral therapy. With improved life expectancy comes an increased lifetime risk of comorbid conditions - such as cardiovascular disease and cancer - and polypharmacy. Older adults, particularly those living with HIV, are more vulnerable to drug interactions and adverse effects, resulting in negative health outcomes. AREA COVERED: Antiretrovirals are involved in many potential drug interactions with medications used to treat common comorbidities and geriatric conditions in an aging population of people with HIV. We review the mechanisms and management of significant drug-drug interactions involving antiretroviral medications and non-antiretroviral medications commonly used among older people living with HIV. The management of these interactions may require dose adjustments, medication switches to alternatives, enhanced monitoring, and considerations of patient- and disease-specific factors. EXPERT OPINION: Clinicians managing comorbid conditions among older people with HIV must be particularly vigilant to side effect profiles, drug-drug interactions, pill burden, and cost when optimizing treatment. To support healthier aging among people living with HIV, there is a growing need for antiretroviral stewardship, multidisciplinary care models, and advances that promote insight into the correlations between an individual, their conditions, and their medications.

Assessing nutrition literacy and nutrition counseling proficiency following an interdisciplinary culinary medicine elective.

CONTEXT: Culinary medicine (CM) is a growing field of education that aims to bridge the gap between the clinical need for nutritional counseling and the lack of education on the topic. Healthcare professionals can aid in nutrition-related noncommunicable disease (NCD) prevention by improving a patient's dietary behavior. However, the presence of nutrition education in healthcare curricula is lacking. Early evidence indicates that CM could address this gap. OBJECTIVES: The objectives of this study are to determine if the provision of an interdisciplinary CM elective will improve student knowledge and confidence with counseling on nutrition and culinary principles, and to improve personal dietary habits of students. METHODS: This was a one-group pretest-posttest quasi-experimental design. First- and second-year osteopathic medical students (OMS) and nurse practitioner students were recruited to participate in a CM elective via email. Participants were excluded if they were not in good academic standing at their respective institutions. Twelve individuals (n=8 medical; n=4 nursing) were enrolled in the course. Participants completed pre- and postcourse surveys to determine changes in nutrition literacy (Nutrition Literacy Assessment Instrument [NLit42]), nutrition counseling proficiency (Nutrition Survey for Family Practitioners), and dietary quality (Automated Self-Administered 24-h dietary assessment tool; ASA24®). A two-sided, paired t test was conducted to determine changes in outcome variables. RESULTS: All 12 participants completed the precourse assessments, and 8 participants completed the postcourse assessments. Culinary activity attendance was 94.5 %. Participants exhibited a statistically significant increase in their overall nutrition literacy scores after completing the CM elective (p=0.006). Literacy subcategories indicated that the improvement came from the participant's ability to understand household measurements (p=0.005) better. Increases in self-reported proficiency were observed for participants' confidence to counsel on nutrition and prevention/wellness (p=0.02) and macronutrients in health and food safety (p=0.01). No statistically significant changes in the personal dietary pattern or quality were observed. CONCLUSIONS: The interdisciplinary CM elective improved nutrition literacy and some aspects of counseling proficiency. Although small shifts in dietary variables were observed, the elective did not statistically improve participants' dietary pattern. However, some changes that were observed may lead to clinically relevant outcomes if maintained long-term. These findings are encouraging. Implementing CM as an educational tool could improve healthcare practitioners' ability to understand and counsel patients on nutrition to prevent the nutrition-related NCDs.

Perspectives of gynecologic oncology fellowship training and preparedness for practice.

We aimed to examine the preparedness of recent gynecologic oncology fellowship graduates for independent practice.We conducted a web-based survey study using REDCap targeting Society of Gynecologic Oncology (SGO) members who graduated gynecologic oncology fellowship within the last six years. The survey included 52 items assessing fellowship training experiences, level of comfort in performing core gynecologic oncology surgical procedures and administering cancer-directed therapies. Questions also addressed factors driving participants' selection of fellowship programs, educational experience, research and preparedness for independent practice. A total of 296 participants were invited to complete the survey. Response rate was 42% with n = 124 completed surveys included for analysis. The highest ranked factor for fellowship selection was fit with program 36% (n = 45). Upon completing fellowship, most were uncomfortable performing ureteral conduit formation 84% (n = 103), ureteroneocystostomy 77% (n = 94), exenteration 68% (n = 83), splenectomy 67% (n = 83) and lower anterior resection 41% (n = 51). Most were comfortable managing intraoperative complications 85% (n = 104) and standard cancer staging procedures (range: 61%-99%). Majority were comfortable providing cancer directed therapies with chemotherapy 99% (n = 123), immunotherapy 84% (n = 104), and poly ADP-ribose polymerase (PARP) inhibitors 97% (n = 120). Upon completing fellowship, 77% (n = 95) report having mentorship that met their expectations during fellowship and 94% (n = 116) felt they were ready for independent practice. Majority of fellowship graduates were prepared for independent practice and felt comfortable performing routine surgical procedures and cancer directed treatment. However, most are not comfortable with ultra-radical gynecologic oncology procedures. Maximizing surgical opportunities during fellowship training and acquiring early career mentorship may help.

Targeting RAS-ERK pathway alterations with MEK inhibitors to improve chemosensitivity in high grade serous ovarian cancers.

OBJECTIVE: Assess if MEK inhibitor blockade of RAS-ERK pathway adaptive response in high grade serous ovarian cancers (HGSOC) improves platinum sensitivity. METHODS: Three HGSOC cell lines and three patient derived organoid (PDOs) samples from ascites of platinum resistant HGSOC patients were collected. Cell lines and PDOs were exposed to carboplatin and MEK inhibitors cobimetinib or trametinib. Cytotoxic effects of MEK inhibitors alone or combined with carboplatin were established. Western blots demonstrated RAS-ERK pathway blockage after MEK inhibitor treatment. RNA sequencing assessed gene expression after MEK inhibitor treatment. Cell line NF1 gene knockdown was performed with corresponding chemosensitivity levels. RESULTS: High carboplatin IC50 levels indicated platinum resistance in cell lines and PDOs. Cobimetinib induced cytotoxicity in cell lines and PDOs, while trametinib was less effective. Western blot confirmed MEK-ERK pathway blockage at minimal concentrations of MEK inhibitors in cell lines and PDOs. Phosphorylated-ERK levels of untreated cells indicated higher levels of RAS-ERK pathway activation in OVSAHO and OVCAR7 compared to OVCAR3. OVSAHO harbors a NF1 mutation and had highest levels of RAS-ERK activation. Cotreatment with carboplatin and MEK inhibitors showed varying synergistic cytotoxic effects at different combinations. Synergistic effect was most prominent in the OVSAHO carboplatin and cobimetinib combination. RNA sequencing identified downregulation of c-MYC and FOXM1 gene expression after MEK inhibitor treatment. NF1 gene knockdown showed an acquired increased IC50 compared to parental cells. CONCLUSION: MEK inhibitors block RAS-ERK pathways in platinum resistant HGSOC cells and PDOs. MEK inhibitors with carboplatin have select synergistic effects which may indicate a strategy to improve platinum sensitivity.

Interactions of metronidazole and chloramphenicol with myoglobin: Crystal structure of a Mb-acetamide product.

Nitroorganics present a general concern for a safe environment due to their health hazards. However, some nitroorganics such as metronidazole (Mtz) and chloramphenicol (CAM) also possess medicinal value. Mtz and CAM can undergo reductive bioactivation presumably via their nitroso derivatives. We show, using UV-vis spectroscopy, that sperm whale myoglobin (swMb) and its distal pocket mutants retaining H-bonding capacity react with Mtz in the presence of dithionite to generate products with spectra suggestive of the Fe-bound nitroso (Fe-RNO; λmax ~420 nm) forms. We have crystallized and solved the X-ray crystal structure of an H64Q swMb-acetamide compound to 1.76 Å resolution; formation of this compound results from the serendipitous crystallographic trapping, by the heme center, of acetamide from the reductive decomposition of Mtz. Only one of the swMb proteins, namely H64Q swMb with a relatively flexible Gln64 residue, reacted with CAM presumably due to the bulky nature of CAM that generally may restrict its access to the heme site.

How should the margin of stability during walking be expressed to account for body size?

When expressing the margin of stability as a distance, it does not directly estimate the perturbation magnitude needed to change stability states. Additionally, it is unknown how body size may influence this measure. Therefore, we propose other expressions of stability margins, including that of an impulse, a change in center of mass velocity, and a scaled, unitless impulse. The purpose of this study was to determine the influence of body size on these margin expressions using walking data from children and adults. We anticipated that margins expressed as an impulse would have strong correlations with body mass and height, as well as large between-group differences. We predicted that scaling this impulse value would result in small correlations and between-group effect sizes. We calculated each stability margin at minimum lateral values and in the anteroposterior directions at mid-swing and foot strike. In the lateral direction, margins expressed as an impulse had strong correlations with body size (r≥0.58, p<0.01) and large between-group differences (|d|≥1.07, p<0.01). The other expressions did not have strong positive correlations (|r|≤0.20) or large between-group effects (|d|≤0.44). In the anteroposterior directions, impulse margins had strong correlations with body size (|r|≥0.83, p<0.01) and large between-group differences (|d|≥1.74, p<0.01). The scaled, unitless impulse margin was the only variable that resulted in small, non-significant differences (|r|≤0.22, p≥0.24) as well as small between-group effect sizes (|d|≤0.46, p≥0.22). We propose expressing stability margins as an impulse. If scaling is needed, we encourage using the scaled, unitless impulse.

A participatory approach to designing and implementing an occupational health intervention for the nail salon community in the Greater Philadelphia region.

BACKGROUND: The nail salon industry in the US comprises mostly immigrant-owned, small mom-and-pop salons that employ primarily first-generation immigrant workers from Asia. Because of the cultural and language barriers, both owners and workers may not avail themselves of the occupational safety resources. We formed an academic-community partnership to co-design a feasibility study and multi-level occupational health intervention for Vietnamese-speaking salon owners, workers, and community-based organization. METHODS: The intervention for each salon included (i) 2-h in-person training covering chemical safety, infection control, musculoskeletal prevention, and workers' rights for both the owners and their employees, (ii) a tailored recommendation report for the owner, and (iii) check-ins with the owner during the 3-month follow-up. Community partner was trained to deliver the in-language training with technical assistance from the research team. Baseline and post-intervention individual data about health symptoms and behaviors, as well as personal chemical exposures were collected and analyzed. RESULTS: A total of 44 participants from 12 consented salons enrolled in the study. One salon dropped out at follow-up due to change of ownership. Analysis of the differences between post-and pre-intervention showed a tendency toward reduction in some self-reported symptoms in the respiratory system, skin, and eyes, neurotoxicity score, as well as chemical exposures. We could not rule out seasonality as an explanation for these trends. Increase in self-efficacy in some areas was observed post-intervention. CONCLUSIONS: Our study demonstrated a successful academic-community partnership to engage community members in the intervention study. While the intervention effects from this feasibility study should be interpreted with caution, our preliminary results indicated that our community-based intervention is a promising approach to reduce work-related exposures among Asian American nail salon workers.

Crystal structural investigations of heme protein derivatives resulting from reactions of aryl- and alkylhydroxylamines with human hemoglobin.

Phenylhydroxylamine (PhNHOH) and nitrosobenzene (PhNO) interact with human tetrameric hemoglobin (Hb) to form the nitrosobenzene adduct Hb(PhNO). These interactions also frequently lead to methemoglobin formation in red blood cells. We utilize UV-vis spectroscopy and X-ray crystallography to identify the primary and secondary products that form when PhNHOH and related alkylhydroxylamines (RNHOH; R = Me, t-Bu) react with human ferric Hb. We show that with MeNHOH, the primary product is Hb[α-FeIII(H2O)][ß-FeII(MeNO)], in which nitrosomethane is bound to the ß subunit but not the α subunit. Attempts to isolate a nitrosochloramphenicol (CAMNO) adduct resulted in our isolation of a Hb[α-FeII][ß-FeII-cySOx]{CAMNO} product (cySOx = oxidized cysteine) in which CAMNO was located outside of the protein in the solvent region between the ß2 and α2 subunits of the same tetramer. We also observed that the ßcys93 residue had been oxidized. In the case of t-BuNHOH, we demonstrate that the isolated product is the ß-hemichrome Hb[α-FeIII(H2O)][ß-FeIII(His)2]{t-BuNHOH}, in which the ß heme has slipped ∼4.4 Å towards the solvent exterior to accommodate the bis-His heme coordination. When PhNHOH is used, a similar ß-hemichrome Hb[α-FeIII(H2O)][ß-FeIII(His)2-cySOx]{PhNHOH} was obtained. Our results reveal, for the first time, the X-ray structural determination of a ß-hemichrome in a human Hb derivative. Our UV-vis and X-ray crystal structural result reveal that although Hb(PhNO) and Hb(RNO) complexes may form as primary products, attempted isolation of these products by crystallization may result in the structural determination of their secondary products which may contain ß-hemichromes en route to further protein degradation.

Insights into Nitrosoalkane Binding to Myoglobin Provided by Crystallography of Wild-Type and Distal Pocket Mutant Derivatives.

Nitrosoalkanes (R-N═O; R = alkyl) are biological intermediates that form from the oxidative metabolism of various amine (RNH2) drugs or from the reduction of nitroorganics (RNO2). RNO compounds bind to and inhibit various heme proteins. However, structural information on the resulting Fe-RNO moieties remains limited. We report the preparation of ferrous wild-type and H64A sw MbII-RNO derivatives (λmax 424 nm; R = Me, Et, Pr, iPr) from the reactions of MbIII-H2O with dithionite and nitroalkanes. The apparent extent of formation of the wt Mb derivatives followed the order MeNO > EtNO > PrNO > iPrNO, whereas the order was the opposite for the H64A derivatives. Ferricyanide oxidation of the MbII-RNO derivatives resulted in the formation of the ferric MbIII-H2O precursors with loss of the RNO ligands. X-ray crystal structures of the wt MbII-RNO derivatives at 1.76-2.0 Å resoln. revealed N-binding of RNO to Fe and the presence of H-bonding interactions between the nitroso O-atoms and distal pocket His64. The nitroso O-atoms pointed in the general direction of the protein exterior, and the hydrophobic R groups pointed toward the protein interior. X-ray crystal structures for the H64A mutant derivatives were determined at 1.74-1.80 Å resoln. An analysis of the distal pocket amino acid surface landscape provided an explanation for the differences in ligand orientations adopted by the EtNO and PrNO ligands in their wt and H64A structures. Our results provide a good baseline for the structural analysis of RNO binding to heme proteins possessing small distal pockets.

Time to completion of radiation treatment in locally advanced squamous cell carcinoma of the vulva and the impact on survival.

OBJECTIVE: To assess whether radiation completion within a planned timeframe in locally advanced squamous cell vulvar cancer impacts overall survival (OS). METHODS: The National Cancer Database from 2004 to 2017 was used to identify women ≥18 years old with stage II-IVA squamous cell vulvar cancer. We included women who received radiation alone (RT) or concurrent chemoradiation (CRT) for initial vulvar cancer treatment. Primary outcome was overall survival associated with time of delay in radiation completion. RESULTS: There were 2378 women identified (n = 856 RT and n = 1522 CRT). Median age was 67 (IQR 56-78), majority (88.35%) were white with advanced stage III or IVA (72.29%) disease. Median radiation dose was 5720 c-Gray (IQR 5040-6300). Radiation completion with delay ≥7 days resulted in reduction in survival compared to delay of <7 days (unadjusted HR 1.183 [95%CI: 1.066-1.313], p = 0.0016). When delays extended to ≥14 days compared to <14 days there was increased hazard of death (unadjusted HR: 1.263 [95%CI:1.126-1.416], p < 0.0001). Survival improved for patients with <7 versus ≥7 days delay whether treatment was with RT (median OS: 34.9 months versus 21.6 months, p < 0.01) or CRT (Median OS:58 months versus 41.3 months, p < 0.01). Stage IVA disease was associated with the greatest increase in hazard of death (HR 1.759 [95%CI 1.517-2.039], p < 0.0001) compared to stage II. CONCLUSION: Radiation completion with <7 days delay is associated with improved overall survival, independent of concurrent chemotherapy. This suggest that strategies to minimize delays in radiation are crucial in locally advanced vulvar cancer.

Reliability of Smartphone Accelerometers for Measuring Gait During Data Collection Over Zoom.

This study examined whether gait data could be reliably collected by homebound participants using iPhones under online supervision. Eighteen healthy young adults met with investigators through Zoom and installed an app to record acceleration from their iPhones' accelerometers. Half of the subjects walked normally; the other half walked while spelling words backward. During the gait tasks subjects recorded their anterior-posterior (AP), medial-lateral (ML), and vertical (V) accelerations. Data collection was repeated the following week. Seven maximum and minimum peak accelerations in the AP, ML, and vertical directions associated with events in gait were determined. Significant main effects of week and direction were observed for the first and second vertical acceleration measures. Cronbach alpha values were >0.60 for all acceleration measures, but the maximum and minimum AP accelerations that showed fair to good levels of consistency. The findings suggest gait data collected inside the home setting may be of clinical use.

Horizontal Transmission of Cytomegalovirus in a Rhesus Model Despite High-Level, Vaccine-Elicited Neutralizing Antibody and T-Cell Responses.

The development of a vaccine to prevent congenital human cytomegalovirus (HCMV) disease is a public health priority. We tested rhesus CMV (RhCMV) prototypes of HCMV vaccine candidates in a seronegative macaque oral challenge model. Immunogens included a recombinant pentameric complex (PC; gH/gL/pUL128/pUL130/pUL131A), a postfusion gB ectodomain, and a DNA plasmid that encodes pp65-2. Immunization with QS21-adjuvanted PC alone or with the other immunogens elicited neutralizing titers comparable to those elicited by RhCMV infection. Similarly, immunization with all 3 immunogens elicited pp65-specific cytotoxic T-cell responses comparable to those elicited by RhCMV infection. RhCMV readily infected immunized animals and was detected in saliva, blood, and urine after challenge in quantities similar to those in placebo-immunized animals. If HCMV evades vaccine-elicited immunity in humans as RhCMV evaded immunity in macaques, a HCMV vaccine must elicit immunity superior to, or different from, that elicited by the prototype RhCMV vaccine to block horizontal transmission.

Pathogenesis of Wild-Type-Like Rhesus Cytomegalovirus Strains following Oral Exposure of Immune-Competent Rhesus Macaques.

Rhesus cytomegalovirus (RhCMV) infection of rhesus macaques (Macaca mulatta) is a valuable nonhuman primate model of human CMV (HCMV) persistence and pathogenesis. In vivo studies predominantly use tissue culture-adapted variants of RhCMV that contain multiple genetic mutations compared to wild-type (WT) RhCMV. In many studies, animals have been inoculated by nonnatural routes (e.g., subcutaneous, intravenous) that do not recapitulate disease progression via the normative route of mucosal exposure. Accordingly, the natural history of RhCMV would be more accurately reproduced by infecting macaques with strains of RhCMV that reflect the WT genome using natural routes of mucosal transmission. Here, we tested two WT-like RhCMV strains, UCD52 and UCD59, and demonstrated that systemic infection and frequent, high-titer viral shedding in bodily fluids occurred following oral inoculation. RhCMV disseminated to a broad range of tissues, including the central nervous system and reproductive organs. Commonly infected tissues included the thymus, spleen, lymph nodes, kidneys, bladder, and salivary glands. Histological examination revealed prominent nodular hyperplasia in spleens and variable levels of lymphoid lymphofollicular hyperplasia in lymph nodes. One of six inoculated animals had limited viral dissemination and shedding, with commensurately weak antibody responses to RhCMV antigens. These data suggest that long-term RhCMV infection parameters might be restricted by local innate factors and/or de novo host immune responses in a minority of primary infections. Together, we have established an oral RhCMV infection model that mimics natural HCMV infection. The virological and immunological parameters characterized in this study will greatly inform HCMV vaccine designs for human immunization. IMPORTANCE Human cytomegalovirus (HCMV) is globally ubiquitous with high seroprevalence rates in all communities. HCMV infections can occur vertically following mother-to-fetus transmission across the placenta and horizontally following shedding of virus in bodily fluids in HCMV-infected hosts and subsequent exposure of susceptible individuals to virus-laden fluids. Intrauterine HCMV has long been recognized as an infectious threat to fetal growth and development. Since vertical HCMV infections occur following horizontal HCMV transmission to the pregnant mother, the nonhuman primate model of HCMV pathogenesis was used to characterize the virological and immunological parameters of infection following primary mucosal exposures to rhesus cytomegalovirus.

Effects of the hangover secret on mitigating hangover symptoms: A pilot study.

BACKGROUND: Due to the popularity of excessive alcohol consumption, there is an increasing need for hangover symptom remedies. Most commercially available hangover treatment products have not been tested for efficacy through clinical study. AIMS: The purpose of this pilot study was to characterize the activity of a commercially available hangover product, The Hangover Secret (THS). METHODS: This was a randomized, double-blinded, placebo-controlled, crossover pilot study. Healthy volunteers of 21- to 40-years-old were eligible for participation, and received either THS or placebo on two different occasions. Participants were given 43 mL of whiskey every twenty minutes for up to 3 hours to achieve a blood alcohol concentration (BrAC) ≥ 0.12%. Hangover severity was assessed using the Acute Hangover Scale (AHS) and Acute Hangover Severity Scale (AHSS) validated tools. RESULTS: Nine participants completed the study. AHS scores increased from baseline to 7 am by 4.11 ± 3.17 and 1.26 ± 2.29 for the placebo and active arms respectively (P = .16). AHS headache scores increased from baseline to 7 am by 2.44 ± 1.67 and 1.11 ± 1.17 for the placebo and active arms respectively (P = .06). AHSS scores increased from baseline to 7 am by 1.0 ± 1.05 and 0.41 ± 1.08, for the placebo and active arms respectively (P = .30). There was no significant difference between average BrAC at 7 am between the placebo and active arms. CONCLUSION: THS showed positive signals in the prevention of alcohol-induced hangover, especially headaches. The improvements with THS surpassed the minimum clinically important difference in overall AHS score and three individual AHS symptoms scores (hangover, headache, and thirsty). THS's reduction in AHS or AHSS scores did not reach statistical significance likely due to the small sample size. Larger studies with appropriate sample sizes are needed in light of these promising findings.

Hiding in plain sight: Shellfish-killing phytoplankton in Washington State.

Summer bivalve shellfish mortalities have been observed in Puget Sound for nearly a century and attempts to understand and mitigate these losses have been only partially successful. Likewise, the understanding of the environmental conditions triggering shellfish mortalities and successful strategies for their mitigation are incomplete. In the literature, phytoplankton have played only a cursory role in summer shellfish mortalities in Washington State because spawning stress and bacteria were thought to be the primary causes. In recent years, the occurrence of Protoceratium reticulatum (Claparede & Lachmann) Buetschli and Akashiwo sanguinea (Hirasaka) Hansen & Moestrup, have been documented by the SoundToxins research and monitoring partnership in increasing numbers and duration and have been associated with declining shellfish health or mortality at various sites in Puget Sound. Blooms of these species occur primarily in summer months and have been shown to cause mass mortalities of shellfish in the U.S. and other parts of the world. In 2016-2017, yessotoxins (YTX) were measured in several species of Puget Sound bivalve shellfish, with a maximum concentration of 2.20 mg/kg in blue mussels, a value below the regulatory limit of 3.75 mg/kg established by the European Union for human health protection but documented to cause shellfish mortalities in other locations around the world. In July 2019, a bloom of P. reticulatum coincided with a summer shellfish mortality event, involving a dramatic surfacing of stressed, gaping Manila clams, suggesting that YTX could be the cause. YTX concentrations in their tissues were measured at a maximum of 0.28 mg/kg and histology of these clams demonstrated damage to digestive glands. A culture of P. reticulatum, isolated from North Bay during this massive bloom and shellfish mortality event, showed YTX reaching 26.6 pg/cell, the highest recorded toxin quota measured in the U.S. to date. Concentrations of YTX in phytoplankton samples reached a maximum of 920 ng/L during a P. reticulatum bloom in Mystery Bay on 13 August 2019 when cell abundance reached 1.82 million cells/L. The highest cellular YTX quota during that bloom that lasted into September was 10.8 pg/cell on 3 Sept 2019. Shellfish producers in Washington State have also noted shellfish larvae mortalities due to A. sanguinea passing through filtration intake systems into hatchery facilities. Early warning of shellfish-killing harmful algal bloom (HAB) presence in Puget Sound, through partnerships such as SoundToxins, provides options for shellfish growers to mitigate their effects through early harvest, movement of shellstock to upland facilities, or enhanced filtration at aquaculture facilities.

GABAB-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice.

Some immune system cells express type A and/or type B γ-aminobutyric acid receptors (GABAA-Rs and/or GABAB-Rs). Treatment with GABA, which activates both GABAA-Rs and GABAB-Rs), and/or a GABAA-R-specific agonist inhibits disease progression in mouse models of type 1 diabetes (T1D), multiple sclerosis, rheumatoid arthritis, and COVID-19. Little is known about the clinical potential of specifically modulating GABAB-Rs. Here, we tested lesogaberan, a peripherally restricted GABAB-R agonist, as an interventive therapy in diabetic NOD mice. Lesogaberan treatment temporarily restored normoglycemia in most newly diabetic NOD mice. Combined treatment with a suboptimal dose of lesogaberan and proinsulin/alum immunization in newly diabetic NOD mice or a low-dose anti-CD3 in severely hyperglycemic NOD mice greatly increased T1D remission rates relative to each monotherapy. Mice receiving combined lesogaberan and anti-CD3 displayed improved glucose tolerance and, unlike mice that received anti-CD3 alone, had some islets with many insulin+ cells, suggesting that lesogaberan helped to rapidly inhibit ß-cell destruction. Hence, GABAB-R-specific agonists may provide adjunct therapies for T1D. Finally, the analysis of microarray and RNA-Seq databases suggested that the expression of GABAB-Rs and GABAA-Rs, as well as GABA production/secretion-related genes, may be a more common feature of immune cells than currently recognized.