Insula Dynorphin and Kappa Opioid Receptor Systems Regulate Alcohol Drinking in a Sex-Specific Manner in Mice.

Alcohol use disorder is complex and multifaceted, involving the coordination of multiple signaling systems across numerous brain regions. Previous work has indicated that both the insular cortex and dynorphin (DYN)/kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit components on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knock-out strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased the overall intake of and preference for alcohol in male and female mice. This effect was specific to alcohol in male mice, as DYN deletion did not impact sucrose intake. Further, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA in male mice only. Alcohol consumption was not affected by insula KOR knockout in either sex. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPNs) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPNs. Combined, our findings suggest there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR microcircuitry.SIGNIFICANCE STATEMENT The insular cortex is a complex region that serves as an integratory hub for sensory inputs. In our previous work, we identified a microcircuit in the insula that signals through the kappa opioid receptor (KOR) and its endogenous ligand dynorphin (DYN). Both the insula and DYN/KOR systems have been implicated in excessive alcohol use and alcohol use disorder (AUD). Here, we use converging approaches to determine how insula DYN/KOR microcircuit components contribute to escalated alcohol consumption. Our findings show that insula DYN/KOR systems regulate distinct phases of alcohol consumption in a sex-specific manner, which may contribute to the progression to AUD.

Pancreatic Transdifferentiation Using ß-Cell Transcription Factors for Type 1 Diabetes Treatment.

Type 1 diabetes is a chronic illness in which the native beta (ß)-cell population responsible for insulin release has been the subject of autoimmune destruction. This condition requires patients to frequently measure their blood glucose concentration and administer multiple daily exogenous insulin injections accordingly. Current treatments fail to effectively treat the disease without significant side effects, and this has led to the exploration of different approaches for its treatment. Gene therapy and the use of viral vectors has been explored extensively and has been successful in treating a range of diseases. The use of viral vectors to deliver ß-cell transcription factors has been researched in the context of type 1 diabetes to induce the pancreatic transdifferentiation of cells to replace the ß-cell population destroyed in patients. Studies have used various combinations of pancreatic and ß-cell transcription factors in order to induce pancreatic transdifferentiation and have achieved varying levels of success. This review will outline why pancreatic transcription factors have been utilised and how their application can allow the development of insulin-producing cells from non ß-cells and potentially act as a cure for type 1 diabetes.

Real World Impact of Remdesivir and Dexamethasone on Clinical Outcomes of Severe Coronavirus Disease 2019 in a Community Hospital.

BACKGROUND: Evidence has emerged showing potential benefit of Remdesivir and dexamethasone in severe coronavirus disease 2019 (COVID-19) but results from large randomized control trials are conflicting. While initial data for dexamethasone indicated a mortality benefit, the impact of Remdesivir was best demonstrated in decreased time to recovery. Despite extensive disease burden throughout the world efficacy data of individual interventions is lacking in part due to extensive concurrent use of confounding investigational therapeutics. MATERIALS AND METHODS: We performed a retrospective analysis of the impact of Remdesivir and dexamethasone on real-world outcomes in severe COVID-19. All patients admitted to our community hospital between March 2020 and December 31, 2020 were included, and all patients admitted before national guidelines endorsed Remdesivir and dexamethasone outside of clinical trials were treated with only supportive care and used as historical controls. No other investigational therapeutics were utilized. This study was reviewed and approved by the Fort Belvoir Community Hospital IRB. RESULTS: 58 hospitalized patients met criteria for severe COVID-19 as confirmed by RT-PCR, and 14 (25%) were used as historical controls. Baseline demographics and overall mortality rate (7.1%) did not significantly differ between the groups. The median length of stay was 7 days and 6 days in the historical control group and interventional group, respectively (P = 0.55). CONCLUSIONS: We did not observe an appreciable impact on the duration of hospitalization when Remdesivir and dexamethasone were added to supportive care in a community hospital. This study was not sufficiently powered to detect the previously described mortality benefit of dexamethasone.

Active Duty Service Members, Primary Managers, and Administrators' Perspectives on a Novel Sleep Telehealth Management Platform in the U.S. Military Healthcare System.

INTRODUCTION: Sleep disorders are common in the military, and there is a gross shortage of sleep specialists in the military health system. The purposes of the present study were to (1) understand perceptions and expectations surrounding sleep telehealth approaches and (2) solicit feedback to optimize and refine a proposed novel sleep telehealth management platform. To accomplish these objectives, we investigated the perceptions, expectations, and preferences of active duty service members (ADSMs) with sleep disorders, primary care managers (PCMs), and administrative stakeholders regarding sleep telehealth management. MATERIALS AND METHODS: Using convenience sampling, we conducted five focus groups with 26 ADSMs and 11 individual interviews with PCMs from two military treatment facilities in the U.S National Capital Region and 11 individual interviews with administrative sleep stakeholders (9 military and 2 civilian). RESULTS: Active duty service members, PCMs, and administrative stakeholders provided insight regarding expectations for sleep telehealth as well as suggestions to optimize the novel sleep telehealth platform. In terms of outcomes, ADSMs expected sleep telehealth to improve sleep and convenience. Primary care managers expected improved sleep and other comorbidities, enhanced operational readiness, and reduced mortalities among their patients. Administrators expected increased access to care, optimized utilization of health services, realized cost savings, reduced accidents and errors, and improved military performance. In terms of the platform, for ADSMs, desired characteristics included delivery of timely clinical reports, improved patient-provider communication, and enhanced continuity of care. For PCMs and administrators,an ideal sleep telehealth solution will improve the diagnosis and triage of sleep patients, save PCM time, be easy to use, and integrate with the electronic health record system. CONCLUSION: The proposed sleep telehealth platform appealed to nearly all participants as a significant force multiplier to enhance sleep disorder management in the military. Stakeholders offered valuable recommendations to optimize the platform to ensure its successful real-world implementation.

Clinical Outcomes of Coronavirus Disease 2019 With Evidence-based Supportive Care.

Calls for adherence to evidence-based medicine have emerged during the initial wave of the COVID-19 pandemic but reports of outcomes are lacking. This retrospective study of an institutional cohort including 135 patients with confirmed COVID-19 demonstrates positive outcomes when organizational standards of care consist of evidence-based supportive therapies.

Diagnostic accuracy of a new COVID-19 antigen test obtained by mid-turbinate swab.

Context: At the mid-point of the COVID-19 pandemic, polymerase chain reaction (PCR) testing for SARS-CoV-2 was difficult to obtain and took several days to return a result. Our health system wished to explore the use of the Quidel Sofia™ antigen test to diagnose COVID-19 in our primary care clinics, but the test was approved for emergency use authorization by the US Food and Drug Administration with only 250 test subjects. In addition, because it was important to avoid aerosol generating procedures in primary care clinics, it was necessary to test the diagnostic performance of the antigen test using mid-turbinate (MT) swabs rather than the approved nasopharyngeal (NP) swab technique. Objective: To assess the diagnostic test characteristics of a SARS-CoV-2 antigen test performed using mid-turbinate nasal swabs compared with the presumed reference standard PCR test by NP swab. Study Design: Prospective cohort study. Setting or Dataset: Outpatient. Population studied: Adults with symptoms consistent with mild-moderate COVID-19. We attempted to recruit 800 subjects to provide statistical assurance that the test sensitivity was at least 90%. Intervention/Instrument: After informed consent, subjects underwent MT nasal swab for antigen testing followed by NP swabbing for PCR testing. Outcome Measures: Sensitivity, specificity, positive and negative predictive values, and likelihood ratios, all with associated 95% confidence intervals. Results: Due to recruitment difficulty (subject reluctance and staffing issues at the testing centers), we recruited only 117 subjects. Sensitivity was 0.750 (95% CI 0.566, 0.885), and specificity was 0.988 (95% CI 0.936, 1.000). Positive Predictive Value was 0.960 (95% CI 0.796, 0.999) and Negative Predictive Value was 0.913 (95% CI 0.836, 0.962). The likelihood ratio for a positive test was 63.75 (95% CI 8.99, 451.97) and the likelihood ratio for a negative test was 0.25 (95% CI 0.14, 0.46). Conclusions: This antigen test for SARS-CoV-2 was of reasonable clinical utility in a low prevalence environment but concerns about the actual prevalence of COVID-19 and the ramifications of false negatives limited its use. Difficulty recruiting subjects and the resultant delay in the results made it impossible to implement this antigen testing in primary care practices, but it is hoped that these data will contribute to the accumulation of evidence about diagnostic testing for COVID-19.

Engaging Stakeholders to Optimize Sleep Disorders' Management in the U.S. Military: A Qualitative Analysis.

INTRODUCTION: Sleep disorders' are highly prevalent among U.S. active duty service members (ADSMs) and present well-documented challenges to military health, safety, and performance. In addition to increased need for sleep medicine services, a major barrier to effective sleep management has been a lack of alignment among patients, health providers, and economic-decision-makers. To address this gap in knowledge, the purpose of the present study was to engage diverse stakeholders vested in improving sleep disorders' management in the military. MATERIALS AND METHODS: We elicited feedback from ADSMs with sleep disorders (five focus group discussion, n = 26) and primary care managers (PCMs) (11 individual semi-structured interview) in two military treatment facilities (MTFs) in the National Capitol Region, in addition to national level military and civilian administrative stakeholders (11 individual semi-structured interview) about their experiences with sleep disorders' management in U.S. MTFs, including facilitators and barriers for reaching a definitive sleep diagnosis, convenience and effectiveness of sleep treatments, and key desired outcomes from interventions designed to address effectively sleep disorders in the U.S. military health care system (MHS). Recordings from focus groups and semi-structured interviews were transcribed verbatim and analyzed using QSR International's NVivo 12 software using inductive thematic analysis. The study was approved by Walter Reed National Military Medical Center Department of Research Programs. RESULTS: Active duty service members with sleep disorders often fail to recognize their need for professional sleep management. Whereas PCMs identified themselves as first-line providers for sleep disorders in the military, patients lacked confidence that PCMs can make accurate diagnoses and deliver effective sleep treatments. Active duty service members cited needs for expeditious treatment, educational support and care coordination, and support for obtaining sleep treatments during deployment. Challenges that PCMs identified for effective management include insufficient time during routine care visits, delays in scheduling testing procedures, and limited number of sleep specialists. Primary care managers suggested offering evidence-based telehealth tools and enhanced care coordination between PCMs and specialists; standardized medical education, materials, and tools; patient preparation before appointments; self-administered patient education; and including behavioral sleep specialists as part of the sleep management team. For administrative stakeholders, key outcomes of enhanced sleep management included (1) improved resource allocation and cost savings, and (2) improved ADSM safety, productivity, and combat effectiveness. CONCLUSION: Current military sleep management practices are neither satisfactory nor maximally effective. Our findings suggest that solving the military sleep problem will require sustained effort and ongoing collaboration from ADSM patients, providers, and health systems leaders. Important potential roles for telehealth and technology were identified. Future research should seek to enhance implementation of sleep management best practices to improve outcomes for patients, providers, MHS, and the military as a whole.

The kappa opioid receptor modulates GABA neuron excitability and synaptic transmission in midbrainprojections from the insular cortex.

As an integrative hub, the insular cortex (IC) translates external cues into interoceptive states that generate complex physiological, affective, and behavioral responses. However, the precise circuit and signaling mechanisms in the IC that modulate these processes are unknown. Here, we describe a midbrain-projecting microcircuit in the medial aspect of the agranular IC that signals through the Gαi/o-coupled kappa opioid receptor (KOR) and its endogenous ligand dynorphin (Dyn). Within this microcircuit, Dyn is robustly expressed in layer 2/3, while KOR is localized to deep layer 5, which sends a long-range projection to the substantia nigra (SN). Using ex vivo electrophysiology, we evaluated the functional impact of KOR signaling in layer 5 of the IC. We found that bath application of dynorphin decreased GABA release and increased glutamate release on IC-SN neurons, but did not alter their excitability. Conversely, dynorphin decreased the excitability of GABA neurons without altering synaptic transmission. Pretreatment with the KOR antagonist nor-BNI blocked the effects of dynorphin in IC-SN neurons and GABA neurons, indicating that the changes in synaptic transmission and excitability were selectively mediated through KOR. Selective inhibition of IC GABA neurons using a KOR-derived DREADD recapitulated these effects. This work provides insight into IC microcircuitry and indicates that Dyn/KOR signaling may act to directly reduce activity of layer 5 GABA neurons. In turn, KOR-driven inhibition of GABA promotes disinhibition of IC-SN neurons, which can modulate downstream circuits. Our findings present a potential mechanism whereby chronic upregulation of IC Dyn/KOR signaling can lead to altered subcortical function and downstream activity.