Hershel Woody Williams VA Medical Center

BACKGROUND: Physicians play a critical role in healthcare delivery. With an aging US population, population growth, and a greater insured population following the Affordable Care Act (ACA), healthcare demand is growing at an unprecedented pace. This study is to examine current and future physician job surplus/shortage trends across the United States of America from 2017 to 2030. METHODS: Using projected changes in population size and age, the authors developed demand and supply models to forecast the physician shortage (difference between demand and supply) in each of the 50 states. Letter grades were then assigned based on projected physician shortage ratios (physician shortage per 100 000 people) to evaluate physician shortages and describe the changing physician workforce in each state. RESULTS: On the basis of current trends, the number of states receiving a grade of "D" or "F" for their physician shortage ratio will increase from 4 in 2017 to 23 by 2030, with a total national deficit of 139 160 physician jobs. By 2030, the West is forecasted to have the greatest physician shortage ratio (69 physician jobs per 100 000 people), while the Northeast will have a surplus of 50 jobs per 100 000 people. CONCLUSION: There will be physician workforce shortages throughout the country in 2030. Outcomes of this study provide a foundation to discuss effective and efficient ways to curb the worsening shortage over the coming decades and meet current and future population demands. Increased efforts to understand shortage dynamics are warranted.

Adolescence is a transitional stage marked by continued brain development. This period is accompanied by physical and neurochemical modifications in the shape and function of the hippocampus, prefrontal cortex, and other limbic system structures. Brain maturation during adolescence, which is typically governed by intrinsic factors, can be dramatically altered by environmental influences such as drugs and alcohol. Unlike many other addictive substances, binge drinking is very common and normative among teenagers and young adults. This repeated pattern of excessive alcohol consumption in adolescents has been shown to cause behavioral changes and neurocognitive impairments that include increased anxiety, risky decision-making, and learning deficits, which could lead to the development of alcohol use disorder (AUD). This manuscript highlights factors that lead to adolescent binge drinking, discusses maturational changes that occur in an adolescent's brain, and then evaluates the effect of adolescent alcohol consumption on brain structure, function, and neurocognitive abilities in both human studies and animal models. The impact of gender/sex and COVID-19 are briefly discussed. Understanding the factors that promote the onset of adolescent binge drinking and its undesirable consequences could serve as a catalyst for developing therapeutic agents that would decrease or eradicate the damaging effects of alcohol on an adolescent brain.

Dietary sodium intake and cardiovascular outcomes have a reported J-shaped curve relationship. This study analyzes the relationship between dietary sodium and sugar intake as a potential mechanism to explain this association. The authors examined cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2001-2016 where dietary sodium, carbohydrate, fat, cholesterol, and sugar intakes were assessed by 24-hour dietary recall and were standardized to a total daily intake of 2000 calories. Sodium intake was categorized into sodium quintiles (SQ) as follows: SQ1(0.06-2.6 g/d); SQ2(2.6-3.0 g/d); SQ3(3.0-3.4 g/d); SQ4(3.4-4.0 g/d); and SQ5(4.0-29.3 g/d). Simple and multivariate linear regression using SQ3 as reference were used to assess associations between daily sodium intake and the other nutrients. Our results showed that among 38 722 participants that met our study criteria, the mean age was 43.6 years (SD 16.8 years) and sex was equally distributed (48.8% male vs 51.2% female). Sugar intake went down across increasing SQs and was significantly higher in SQ1 (141.2 g/d) and SQ2 (118.6 g/d) and significantly lower in SQ4 (97.9 g/d) and SQ5 (85.6 g/d) compared to SQ3 (108.6 g/d; all P < .01). These same trends remained unchanged and significant in the fully adjusted multivariate model. In conclusion, NHANES study participants reporting low sodium intake on 24-hour dietary recall have a higher consumption of sugar. The negative impact of low sodium diet on cardiovascular health may be explained at least partially by the associated high sugar intake.

Adolescence is a developmental period that encompasses, but is not limited to, puberty and continues into early adulthood. During this period, maturation and refinement are observed across brain regions such as the prefrontal cortex (PFC), which is critical for cognitive function. Adolescence is also a time when excessive alcohol consumption in the form of binge drinking peaks, increasing the risk of long-term cognitive deficits and the risk of developing an alcohol use disorder later in life. Animal models have revealed that adolescent ethanol (EtOH) exposure results in protracted disruption of neuronal function and performance on PFC-dependent tasks that require higher-order decision-making. However, the role of astrocytes in EtOH-induced disruption of prefrontal cortex-dependent function has yet to be elucidated. Astrocytes have complex morphologies with an extensive network of peripheral astrocyte processes (PAPs) that ensheathe pre- and postsynaptic terminals to form the 'tripartite synapse.' At the tripartite synapse, astrocytes play several critical roles, including synaptic maintenance, dendritic spine maturation, and neurotransmitter clearance through proximity-dependent interactions. Here, we investigate the effects of adolescent binge EtOH exposure on astrocyte morphology, PAP-synaptic proximity, synaptic stabilization proteins, and dendritic spine morphology in subregions of the PFC that are important in the emergence of higher cognitive function. We found that adolescent binge EtOH exposure resulted in subregion specific changes in astrocyte morphology and astrocyte-neuronal interactions. While this did not correspond to a loss of astrocytes, synapses, or dendritic spines, there was a corresponding region-specific and EtOH-dependent shift in dendritic spine phenotype. Lastly, we found that changes in astrocyte-neuronal interactions were not a consequence of changes in the expression of key synaptic structural proteins neurexin, neuroligin 1, or neuroligin 3. These data demonstrate that adolescent EtOH exposure results in enduring effects on neuron-glia interactions that persist into adulthood in a subregion-specific PFC manner, suggesting selective vulnerability. Further work is necessary to understand the functional and behavioral implications.

Angiotensin-converting enzyme 2 (ACE2) has been an increasingly prevalent target for investigation since its discovery 20 years ago. The finding that it serves a counterregulatory function within the traditional renin-angiotensin system, implicating it in cardiometabolic health, has increased its clinical relevance. Focus on ACE2's role in cardiometabolic health has largely centered on its apparent functions in the context of obesity. Interest in ACE2 has become even greater with the discovery that it serves as the cell receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), opening up numerous mechanisms for deleterious effects of infection. The proliferation of ACE2 within the literature coupled with its dual role in SARS-CoV-2 infection and obesity necessitates review of the current understanding of ACE2's physiological, pathophysiological, and potential therapeutic functions. This review highlights the roles of ACE2 in cardiac dysfunction and obesity, with focus on epicardial adipose tissue, to reconcile the data in the context of SARS-CoV-2 infection.

Epicardial fat is a continuously growing target of investigation in cardiovascular diseases due to both its anatomical proximity to the heart and coronary circulation and its unique physiology among adipose depots. Previous reports have demonstrated that epicardial fat plays key roles in coronary artery disease, but the non-coding RNA and transcriptomic alterations of epicardial fat in coronary artery disease have not been investigated thoroughly. Micro- and lncRNA microarrays followed by GO-KEGG functional enrichment analysis demonstrated sex-dependent unique mi/lncRNAs altered in human epicardial fat in comparison to subcutaneous fat in both patients with and without coronary artery disease (IRB approved). Among the 14 differentially expressed microRNAs in epicardial fat between patients with and without coronary artery disease, the hsa-miR-320 family was the most highly represented. IPW lncRNA interacted with three of these differentially expressed miRNAs. Next-generation sequencing and pathway enrichment analysis identified six unique mRNAs-miRNA pairs. Pathway enrichment identified inflammation, adipogenesis, and cardiomyocyte apoptosis as the most represented functions altered by the mi/lncRNAs and atherosclerosis and myocardial infarction among the highest cardiovascular pathologies associated with them. Overall, the epicardial fat in patients with coronary artery disease has a unique mi/lncRNA profile which is sex-dependent and has potential implications for regulating cardiac function.

Astrocytes are a subtype of non-neuronal glial cells that reside in the central nervous system. Astrocytes have extensive peripheral astrocytic processes that ensheathe synapses to form the tripartite synapse. Through a multitude of pathways, astrocytes can influence synaptic development and structural maturation, respond to neuronal signals, and modulate synaptic transmission. Over the last decade, strong evidence has emerged demonstrating that astrocytes can influence behavioral outcomes in various animal models of cognition. However, the full extent of how astrocytes influence brain function is still being revealed. Astrocyte calcium (Ca 2+ ) signaling has emerged as an important driver of astrocyte-neuronal communication allowing intricate crosstalk through mechanisms that are still not fully understood. Here, we will review the field's current understanding of astrocyte Ca 2+ signaling and discuss the sophisticated state-of-the-art tools and approaches used to continue unraveling astrocytes' interesting role in brain function. Using the field of pre-clinical ethanol (EtOH) studies in the context of alcohol use disorder, we focus on how these novel approaches have helped to reveal an important role for astrocyte Ca 2+ function in regulating EtOH consumption and how astrocyte Ca 2+ dysfunction contributes to the cognitive deficits that emerge after EtOH exposure in a rodent model.

Adolescence is characterized as a period of increased social behavior, risk taking, and novelty seeking, partly due to ongoing maturation in critical brain areas and the hypothalamic-pituitary-adrenal (HPA) negative-feedback system. During this period there is heightened vulnerability to stress that can drive neuro-immune-endocrine remodeling, resulting in the emergence of maladaptive behaviors that increase susceptibility to alcohol and substance abuse. Here we used a rat model to investigate the impact of chronic adolescent unpredictable stress on a battery of behavioral measures to assess anxiety, novelty seeking, risk taking, depression, and voluntary ethanol consumption while determining whether the PPARγ agonist rosiglitazone can attenuate these effects. Adolescent female rats that experienced stress showed increased risk taking behavior and novelty seeking behavior with no change in ethanol consumption. The administration of rosiglitazone during stress induction attenuated stress-induced cortisol elevation, normalized risk taking behavior in a model anxiety, and attenuated novelty seeking in a task-specific manner. Depressive-like behavior was not impacted by adolescent unpredictable stress or the administration of rosiglitazone. The results from this study demonstrate that exposure to unpredictable stress during adolescence increases the prevalence of maladaptive behaviors that are known to increase susceptibility to alcohol and substance abuse, and that rosiglitazone may be an effective therapeutic to attenuate the emergence of select risk taking and novelty seeking behaviors in females.

Abstract Introduction: Penicillium species is rarely implicated in human infections yet can be a virulent pathogen in immunocompromised hosts. Invasive pulmonary infection reported cases are on the rise. We report a case of immunocompetent male with penicillium species pneumonia presented as obstructive airway disease. Case report:53-year-old male with medical history of nasal polyp, and acid reflux, follows in the pulmonary clinic for presumed cough variant asthma diagnosed 5 years ago. He works as part time mechanic, denies significant smoking or vaping history and no childhood asthma. He was treated with budesonide/formoterol and albuterol inhalers without much improvement. Symptoms negatively impacted daily activities requiring frequent short courses of prednisone. Mild-moderate obstruction noted on multiple pulmonary function tests. Immunoglobulin E level was 14 international unit/milliliter, normal eosinophil count, and negative skin allergy test, despite treatment with Dupilumab for approximately one year, he said he could not lough without coughing. A computed tomography showed bibasilar segmental atelectasis and 3-millimeter lung nodule. Bronchoscopy showed bronchus intermedium mild erythematous changes and thick lower lobe secretions, otherwise normal. Bronchoalveolar lavage (BAL) was only significant for penicillium species on culture results, he was treated with Micafungin for a total of 8 weeks, with complete resolution of his symptoms off all medications. Discussion: Penicillium species occur in a wide range of habitats, producing a diverse range of mycotoxins and enzymes, including penicillin. They play a major role in decomposition of organic materials and food manufacturing. They are a common allergens and can trigger asthma, One study reported an 80% increased risk of asthma in children who exposed to fungal species, penicillium is among the top 3. Clinically isolated penicillium is usually viewed as a contaminant which poses a diagnostic challenge especially in immunocompetent patients leading to a delayed diagnosis. Pulmonary invasion has been reported in lupus, diabetes, leukemia, and transplant recipients. It could present as localized granuloma, lobar pneumonia, or disseminated parenchymal infection. In contrast aspergillosis, penicillium species is not commonly considered in uncontrolled asthma. Our patient had cough and dyspnea symptoms impacting his activities without much improvement on maximum treatment, and evidence of obstructive airway disease of PFT. Now he is asymptomatic off all medications and leading a normal life. Conclusion: Positive penicillium species culture should be interpreted within the proper clinical settings and must not always be regarded as a contaminant. Fungal identification and drug sensitivity with prompt treatment positively impacts patient care and outcome.

ABSTRACT Introduction Adolescence is characterized as a transitional developmental period between childhood and adulthood that is associated with increased freedom and novel experiences that are frequently peer-influenced. Due to newfound independence, there is a higher prevalence of alcohol consumption, which is heightened by the rewarding effects of alcohol. However, the contributions of social interaction and sexual dimorphism to alcohol intake are not fully understood. Here we explore the use a novel self-administration ethanol (EtOH) vapor system to investigate the sexual dimorphic nature of socially facilitated ethanol exposure. Methods Adolescent and adult male and female Sprague-Dawley rats underwent a novel voluntary intermittent EtOH vapor paradigm. Nosepoke initiated self-administration vapor chambers administered 20mg/L of vaporized EtOH or air into the chamber following each nosepoke. Beginning on postnatal day 30 (PND30), during the onset of adolescence, or 70 (PND70), at the onset of adulthood, animals were placed in vapor chambers for 4hr every other day for 40 sessions. All animals underwent 10 sessions with their cagemate (social access) followed by 10 sessions in isolation (isolated access), a 10-day forced abstinence period, 10 sessions isolated access, and 10 sessions social access. Results These data reveal that despite low EtOH consumption across all groups, adolescent (PND30) and adult (PND70) female rats voluntarily self-administered more EtOH vapor per body weight than age-matched males, while male rats increased EtOH preference over sessions regardless of age. In addition, all rats regardless of sex or age voluntarily self-administered more EtOH vapor per body weight during the social access session than during the subsequent isolated access sessions. Conclusion These data demonstrate that under these experimental parameters, male and female rats regardless of age do not self-administer high quantities of EtOH vapor using this paradigm. Further work is required to determine whether the nose-poke EtOH vapor self-administration apparatus can be modified to promote high voluntary EtOH consumption that can be socially facilitated. These data demonstrate that with further investigation, the self-administration EtOH vapor system could be an effective alternative to other methods of voluntary EtOH administration to further our understanding of socially facilitated drinking.

The US is leading the world in terms of the number of deaths and cases due to COVID-19. After the end of the national lockdown, there has been a significant rise in both new cases and deaths associated with COVID-19—especially in the southern and western states. This study presents an interim report of each state (50 states, DC, and Puerto Rico), in terms of mortality rate (MR, the number of cumulative deaths per 100,000 population due to COVID-19 by July 15, 2020) and Case Rate Progression (CRP, the percent change in the number of cumulative cases per 100,000 population increased from May 31 to July 15, 2020). The study provided an A - F grade report card for each state when compared to one another. The results showed that the states that received F’s in MR are the following (starting from the worst): New Jersey, New York, Massachusetts, Connecticut, Washington DC, Rhode Island, and Louisiana. The following states received F’s in CRP (starting from the worst): Arizona, Florida, South Carolina, Texas, Idaho, Arkansas, Montana, Alaska, Nevada, and Oklahoma. A poor CRP grade reflects rampant increases in new COVID-19 cases, followed by resulting increases in hospitalization, health resource utilization, and mortality. Some prior high casualty states with MR grades of F (e.g. New York, New Jersey, and Connecticut) have maintained low new case counts and received A grades in CRP. They are exemplary in terms of COVID-19 state/region-wide response and public health efforts.

BACKGROUND: Industrial workers and active military personnel within combat roles face heightened risk for blast pressure wave traumatic brain injury (bTBI). Previous studies have shown that experiencing TBI is associated with increased alcohol (EtOH) consumption and illicit substance use. Notably, alcohol use typically begins during late adolescence or early adulthood, a period that precedes many TBI incidents; moreover, early-onset drinking is further associated with heightened risk of developing an alcohol use disorder (AUD) even in the absence of TBI. Adolescent binge drinking can induce lasting cognitive and astrocyte changes, impacting brain recovery and repair. However, the impact of adolescent drinking history on behavioral recovery after bTBI and its role in the subsequent escalation of alcohol consumption remain unexplored. Here, we used a mouse model to investigate how adolescent (PND28-42) and young adult (PND60-90) EtOH consumption affects behavioral outcomes following bTBI. We aim to determine whether the history of adolescent binge drinking contributes to bTBI-induced escalation in EtOH intake, preference, or worsened fear memory and anxiety. METHODS: Adolescent mice were subjected to drinking in the dark (DID) EtOH paradigm for 4 weeks, then randomly assigned to sham, mild-bTBI, or severe-bTBI. Behavioral testing was conducted, followed by a second DID. RESULTS: Both EtOH and bTBI independently induced hyperlocomotor activity in a sex-dependent manner. These findings reflect an increase in risk-taking rather than generalized anxiety. Importantly, a history of adolescent EtOH consumption synergistically worsened bTBI-induced impaired fear extinction in both sexes. Changes in EtOH preference post-bTBI are context-dependent, with male mice showing a significant decrease in preference following mild-bTBI and prior EtOH exposure, while females exhibited a trend toward increased preference post-bTBI, with significant increases in preference observed only when comparing pre- to post-bTBI drinking behavior. CONCLUSIONS: Both males and females exhibited vulnerability to the combined effects of adolescent EtOH consumption and bTBI on fear extinction, while female mice showed a unique vulnerability to the escalation in EtOH preference.

ABSTRACT Introduction Binge drinking is common among adolescents and young adults and is associated with an increased risk of developing alcohol use disorder (AUD) and long-term cognitive deficits. We analyzed RNA-seq data from male Sprague Dawley rats to identify candidate genes that may play a role in the acute and chronic changes in cognitive function during binge-like adolescent alcohol/EtOH exposure and after a period of abstinence. Methods At postnatal day (PND) 30, male rats received chronic intermittent EtOH across 16 days. RNA was extracted from hippocampal tissue and sequenced at two acute timepoints, PND 35 and PND 46, and after 24 days forced abstinence (PND 70). We processed RNA-seq data, compiled gene counts, and performed normalization and differential expression analysis (DESeq2). Gene set enrichment analysis was performed through the R package fgsea. Gene sets of the Molecular Signatures Database (MSigDB) collections were used to identify gene pathways that were dysregulated following EtOH exposure. We also evaluated overlapping gene pathways that were affected across all timepoints. Results Multiple gene pathway analyses revealed that EtOH has robust effects on neuroinflammation, cellular remodeling, sleep, and bioenergetics. Changes were heavily dependent on whether gene expression was assessed during acute EtOH exposure or after abstinence. Genes involved in sleep regulation were selectively impacted during the acute timepoints, whereas dysregulation of genes involved in bioenergetics were only impacted after abstinence. The most striking changes occurred in genes that regulate neuroinflammatory processes and cellular remodeling. Conclusion These data reveal acute and chronic effects of EtOH on multiple gene pathways that persist across analytic approaches and identify genes that have increased sensitivity to EtOH. These findings contribute to our understanding of the temporal effects of adolescent EtOH exposure and how gene pathway dysregulation contributes to the protracted emergence of neuronal remodeling in the hippocampus during a critical period of brain maturation.

The US has led the world with over 667,000 deaths due to COVID-19, partly fueled by the spread of the Delta Variant since the spring of 2021. The “Delta Surge” has especially impacted the southern states, despite the rolling out of three effective vaccines (Pfizer/BioNTech’s Comirnaty, Moderna, and Johnson & Johnson’s Jansen) since early 2021. This is an interim report of each state (50 states, Washington DC, and Puerto Rico), in terms of mortality rate (MR, the number of cumulative deaths per 100,000 population due to COVID-19 by July 27^th, 2021) and Case Rate Progression (CRP, the percent change in the number of cumulative cases per 100,000 population increased from June 1^st to August 1^st, 2021). The study provided an A-F grade report card for each state when compared to one another. The results showed that the states that received F’s in MR are the following (starting from the worst): New Jersey, New York, Massachusetts, Rhode Island, and Mississippi. The 3 states that received an A rating were (starting from the best): Hawaii, Vermont, and Alaska. The following states received F’s in CRP (starting from the worst): Louisiana, Arkansas, Florida, Missouri, Nevada, and Mississippi. A poor CRP grade reflects rampant increases in new COVID-19 cases, followed by resulting increases in hospitalization, health resource utilization, and mortality. It is critical that we as a nation remain vigilant to observe these lingering effects of COVID-19 by participating in public health efforts, continuing to vaccinate the public, and observing social distancing, healthy hygiene practices, and masking as per CDC guidance.

Coronary artery disease (CAD) is characterized by the buildup of atherosclerotic plaques within the coronary arteries, leading to serious complications. CAD affects 7.2% and 4.2% of males and females, respectively. Epicardial adipose tissue (EAT) interacts with the heart and vasculature, but its mechanistic role in CAD is not completely understood. A more comprehensive view of non‐coding RNA (ncRNA) expression in EAT is needed to better characterize its role in CAD. To conduct this characterization, in an IRB‐approved investigation, we isolated the microRNA (miRNA), long non‐coding RNA (lncRNA), and messenger RNA (mRNA) from the EAT and subcutaneous adipose tissue (SAT) of male and female CAD patients undergoing coronary artery bypass graft as well as from non‐CAD patients undergoing aortic valve replacement. Differential expression of these RNAs between tissues, disease status, and sex was determined using next generation sequencing (mRNA) and microarrays (miRNA and lncRNA). Functional and pathological associations of the differentially expressed RNAs were determined using Ingenuity Pathway Analysis, GO, KEGG, and TAM 2.0. DIANA‐LncBase was used to identify experimentally verified miRNA‐lncRNA interactions. NGS showed differential expression of mRNAs associated with cardiovascular function in EAT but not in SAT. miRNA microarray showed that ncRNA expression within the EAT of CAD patients is distinct from its expression in non‐CAD patients. 14 miRNAs were differentially expressed in EAT from patients with CAD compared to those without CAD. Similarly, lncRNA RT 2 PCR array showed a downregulation of three lncRNAs: IPW, TINCR, and linc00853, between the EAT of CAD compared to non‐CAD male patients but not in the EAT of female patients. DIANA‐LncBase showed high confidence pairings of IPW with three miRNAs that were upregulated in the EAT of patients with CAD: hsa‐miR‐24‐3p, hsa‐miR‐26b‐5p, and hsa‐29c‐3p. This suggests that IPW may serve as a ‘sponge’ for these three miRNAs in the EAT of patients without CAD, but its downregulation in CAD reduces that interaction. TAM 2.0 showed these three miRNAs to be associated with functional pathways such as vascular inflammation, apoptosis, adipogenesis, etc. Overall, these findings both reveal potential ncRNA biomarkers for CAD and elucidates possible pathological roles of EAT in CAD mediated by ncRNAs.

Abstract Adolescence is a window of heightened vulnerability to the neurotoxic effects of binge ethanol exposure. Adolescent intermittent ethanol (AIE) exposure has been shown to induce long-lasting cognitive and behavioral impairments in patients and rodent models that increase the risk of developing alcohol use disorder (AUD). Our previous work shows that these behavioral deficits coincide with persistent dysfunction of astrocytes. Here, we aim to understand how astrocyte-synaptic structural and functional crosstalk are disrupted following AIE to provide better mechanistic understanding of why behavioral impairments persist into adulthood. Male Sprague-Dawley rats received AIE, a variety of adeno-associated viruses encoding astrocyte-specific sensors, and fiber implantation in the dorsal hippocampal (dHipp) for in vivo photometry. A subset of rats received hM3D(Gq) to chemogenetically activate astrocytes. Following AIE and a forced abstinence period that allowed growth into adulthood, rats underwent assessment in the contextual fear conditioning (CFC) task with simultaneous fiber photometry recordings. By combining immunohistochemistry (IHC), Stimulated Emission Depletion (STED) microscopy, fiber photometry, chemogenetics, and slice physiology, we show that AIE induces structural and functional decoupling of astrocytes from synapses and astrocyte dysregulation that persists into adulthood. Remarkably, stimulating astrocytic calcium signaling via chemogenetic activation attenuates heightened fear responding and restores gliotransmitter availability. These findings highlight a critical role for astrocyte–synaptic crosstalk in regulating fear learning and underscore the untapped therapeutic potential of targeting astrocytes to improve behavioral outcomes following substance use.

Background: About 1 in 4 veterans have diabetes, and many also have chronic kidney disease (CKD).Empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, is approved for the treatment of diabetes.The purpose of this study was to evaluate the effectiveness of empagliflozin on hemoglobin A 1c (HbA 1c ) in patients with CKD.Methods: A retrospective chart review evaluated patients that had a type 2 diabetes diagnosis and stage 3 CKD prescribed empagliflozin for diabetes management between January 1, 2015, and October 1, 2022.Patient demographics, medication, HbA 1c levels, and other data were collected from a random sample of 100 patients from 1771 potential study subjects.Results: There was no statistically significant difference in changes in HbA 1c levels between those with stage 3 and stage 3b diabetes CKD who were taking empagliflozin (P = .51).Within each group, there were significant statistical differences in changes in HbA 1c for patients with stage 3a (P < .05)and stage 3b (P = .02).Patients with stage 3a had a reduction in HbA 1c of 0.65% and the stage 3b grow had a 0.48% reduction.There was a statistically significant weight change for patients in the stage 3a group (P < .05).Statistically significant differences were found in systolic (P = .003)and diastolic (P = .04)blood pressure for the stage 3a CKD group only.The most common adverse effects leading to discontinuation of empagliflozin were dizziness, increased incidence of urinary tract infections, and rash.Conclusions: Empagliflozin is a favorable option for reducing HbA 1c levels in patients with diabetes and CKD.

Abstract The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist to efficiently test for differences across subgroups in the thousands of multiple comparisons generated as part of a PheWAS. In this study, we developed an approach that maximizes the power to test for heterogeneous genotype–phenotype associations and applied this approach to an IL6R PheWAS among individuals of African (AFR) and European (EUR) ancestries. We identified 29 traits with differences in IL6R variant-phenotype associations, including a lower risk of type 2 diabetes in AFR (OR 0.96) vs EUR (OR 1.0, p-value for heterogeneity = 8.5 × 10 –3 ), and higher white blood cell count (p-value for heterogeneity = 8.5 × 10 –131 ). These data suggest a more salutary effect of IL6R blockade for T2D among individuals of AFR vs EUR ancestry and provide data to inform ongoing clinical trials targeting IL6 for an expanding number of conditions. Moreover, the method to test for heterogeneity of associations can be applied broadly to other large-scale genotype–phenotype screens in diverse populations.