Disease heterogeneity and molecular classification of inflammatory palmoplantar diseases.

BACKGROUND: Palmoplantar pustulosis (PPP) is an inflammatory disease characterized by relapsing eruptions of neutrophil-filled, sterile pustules on the palms and soles that can be clinically difficult to differentiate from non-pustular palmoplantar psoriasis (palmPP) and dyshidrotic palmoplantar eczema (DPE). OBJECTIVE: To identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis. METHODS: We performed bulk RNA sequencing of lesional PPP (n=33), palmPP (n=5), and DPE (n=28) samples, as well as 5 healthy non-acral and 10 healthy acral skin samples. RESULTS: Acral skin shows a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared with healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of pro-inflammatory cytokines (TNF, IL36), chemokines, and T cell-associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the three disease states. These identified putative key upstream immunological switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity. CONCLUSION: We demonstrate the molecular overlap between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment, yet highlighting the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases.

ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults: A Randomized Clinical Trial.

Importance: Older adults with lower intake and tissue levels of long-chain ω-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6) have more brain white matter lesions (WMLs), an association suggesting that small-vessel ischemic disease, a major contributor to the development of dementia, including Alzheimer disease, may be preventable through ω-3 treatment. Objective: To determine whether ω-3 treatment reduces WML accumulation in older adults without dementia harboring WMLs and with suboptimal ω-3 status. Design, Setting, and Participants: This quadruple-blinded, placebo-controlled, randomized clinical trial with treatment stratification by apolipoprotein E ε4 allele (APOE*E4) carrier status used linear mixed-effects models to estimate mean annual change between groups. The study was conducted at Oregon Health & Science University, a major academic medical center in the Pacific Northwest, from May 2014 to final participant visit in September 2019. Data analysis concluded in July 2022. Participants were adults without dementia aged 75 years and older with WMLs greater than or equal to 5 cm3 and plasma ω-3 PUFA less than 5.5 weight percentage of total. Intervention: Three-year treatment with 1.65 g of ω-3 PUFA (975 mg of EPA and 650 mg of DHA) vs a soybean oil placebo matched for taste, smell, and appearance. Main Outcomes and Measures: The primary outcome was annual WML progression measured using magnetic resonance imaging. Secondary outcomes included diffusion tensor imaging of fractional anisotropy (DTI-FA), representing neuronal integrity breakdown. Results: A total of 102 participants (62 women [60.8%]; mean age, 81 years [range, 75-96 years]) were equally randomized, 51 per treatment group. Although the ω-3 group had less annual WML accumulation than the placebo group, the difference was not statistically significant (1.19 cm3 [95% CI, 0.64-1.74 cm3] vs 1.34 cm3 [95% CI, 0.80-1.88 cm3]; P = .30). Similarly, the ω-3 group had less annual DTI-FA decline than the placebo group, but the difference was not statistically significant (-0.0014 mm2/s [95% CI, -0.0027 to 0.0002 mm2/s] vs -0.0027 mm2/s [95% CI, -0.0041 to -0.0014 mm2/s]; P = .07). Among APOE*E4 carriers, the annual DTI-FA decline was significantly lower in the group treated with ω-3 than the placebo group (-0.0016 mm2/s [95% CI, -0.0032 to 0.0020 mm2/s] vs -0.0047 mm2/s [95% CI, -0.0067 to -0.0025 mm2/s]; P = .04). Adverse events were similar between treatment groups. Conclusions and Relevance: In this 3-year randomized clinical trial, ω-3 treatment was safe and well-tolerated but failed to reach significant reductions in WML accumulation or neuronal integrity breakdown among all participants, which may be attributable to sample size limitations. However, neuronal integrity breakdown was reduced by ω-3 treatment in APOE*E4 carriers, suggesting that this treatment may be beneficial for this specific group. Trial Registration: ClinicalTrials.gov Identifier: NCT01953705.

Delayed Burr Hole Evacuation Compared With Acute Craniotomy for Acute Subdural Hematoma in Older Patients With Low-Energy Trauma.

Background Acute subdural hematomas commonly require emergent surgical decompression by craniotomy. There is currently limited research on alternative surgical strategies in the elderly population. This study investigates delayed surgical intervention for stable patients with low-energy trauma presenting with acute subdural hematomas. Methodology In this retrospective chart review, 45 patients over the age of 55 presenting with acute subdural hematomas with a Glasgow Coma Scale score greater than or equal to 13 in the setting of low-energy trauma were selected. Additionally, included patients had a maximal hematoma thickness of >10 mm and/or a midline shift size of >5 mm per the current Brain Trauma Foundations guidelines for surgical intervention of subdural hematomas. The study was performed at a large tertiary care center, with records being examined from 1995 to 2020. Comparison groups were immediate craniotomy (within 24 hours) or delayed burr hole (minimum of 48 hours passing since the initial presentation). Primary outcomes included minor complications, major complications, any complications, and any complications with mortality excluded. There was no significant difference in mortality between the two cohorts. Results The immediate craniotomy group consisted of 16 patients, while the delayed burr hole group consisted of 29 patients. The results demonstrated a statistically significant increase in the incidence of any complication including mortality (relative risk (RR) = 3.17, 95% confidence interval (CI) = 1.71-5.88, p < 0.0001), major complications (RR = 2.33, 95% CI = 1.07-5.07, p = 0.031), and minor complications (RR = 2.42, 95% CI = 1.02-5.74, p = 0.041) in the immediate craniotomy group compared to the delayed burr hole group. Conclusions Our study demonstrates the decreased risk of major and minor complications for delayed burr hole evacuation in stable patients >55 years old presenting with low-energy trauma and subdural hematoma. The results suggest that for this population of patients, it appears to be beneficial to delay surgery if the patient's clinical situation allows.

Relationship between fraction of exhaled nitric oxide and peripheral eosinophilia in asthma.

BACKGROUND: Achieving disease control is the goal of asthma management. Serum or sputum eosinophil counts have been known traditional means of assessing eosinophilic airway inflammation in asthma, which is vital in predicting response to corticosteroid therapy which ultimately promotes control of the disease. Evidence suggests that fraction of exhaled nitric oxide (FeNO) may be a more useful non-invasive surrogate biomarker for the assessment of eosinophilic airway inflammation and could help with the timely adjustment of inhaled corticosteroid therapy in the uncontrolled asthma patient. The relationship between FeNO and other markers of airway inflammation has been variable in literature, with limited data in sub-Saharan Africa where FeNO testing is very sparse. We sought to define the relationship between FeNO levels, serum eosinophil counts, spirometry measures and symptom control among asthma patients. MATERIALS AND METHODS: The study was conducted at the Asthma Clinic of a large tertiary hospital. This study included 82 patients with physician-diagnosed asthma being regularly managed at the clinic. All participants were taken through the asthma control test (ACT), had FeNO and spirometry measurements taken according to the American Thoracic Society (ATS) guidelines. Blood samples were obtained from all participants for serum eosinophil counts. Correlation coefficient was used to ascertain the relationship between FeNO levels and serum eosinophil counts, ACT scores, and spirometry measurements. Logistic regression was used to examine the association between high FeNO and abnormal FEV1 percentage predicted (<80%) with adjustments for age, sex, and BMI. RESULTS: A total of 82 patients with asthma were included in the study, with higher prevalence of females (72%). Majority (40.2%) of the patients were found in the 60 and above age category. The median FeNO level and ACT score was 42.00 (26.00-52.50) parts per billion (ppb) and 20.0 (18-23) respectively. The median serum eosinophil counts was 0.25(0.90-0.38) × 109/L. The median FeNO levels were significantly higher in patients with partly and very poorly controlled asthma than in the well-controlled group (p < 0.001). A total of 47(57%) of the patients were classified as having well controlled asthma and 35 (42%) uncontrolled. FeNO correlated with serum eosinophil counts (r = 0.450, p < 0.001), ACT (r = -0.648, p < 0.001), and FEV1 percentage predicted (r = -0.353, p = 0.001). High FeNO (>50 ppb) was associated with an over fivefold increased risk of having an abnormal FEV1 percentage predicted. CONCLUSION: FeNO levels significantly correlated with the ACT scores, serum eosinophil counts and FEV1% predicted among the asthma patients who were on inhaled corticosteroid therapy. High FeNO was significantly associated with abnormal FEV1 percentage predicted. We suggest that the point of care assessment of FeNO is a reliable marker of eosinophilic inflammation in our cohort of patients and together with 'ACT scores' in our asthma clinics could increase asthma control rates.

Online Search Interest in Gynecologists After the Release of the Film Barbie.

This cross-sectional study evaluates whether the film Barbie was associated with increased public interest in gynecologic care in the US after its release.

Evaluation of Local Prescribing Patterns and Antimicrobial Resistance in Women With Acute Pyelonephritis Caused by E. coli.

BACKGROUND: Owing to increasing local Escherichia coli resistance and current guidelines for the treatment of acute pyelonephritis (APN) over 14 years old, an evaluation of local prescribing patterns is warranted. OBJECTIVE: The purpose of this study was to evaluate local prescribing patterns and appropriateness of antibiotics in acute uncomplicated APN. METHODS: This is a retrospective cohort study of female patients aged 18 to 89 years diagnosed with APN and positive urine culture growing E. coli. Exclusion criteria included pregnancy, immunocompromised status, and complicated urinary tract infections. Outcomes included antibiotic appropriateness and its effects on hospital admission, hospital length of stay, and 30-day readmission. RESULTS: Between 2017 and 2022, 308 female patients were diagnosed with APN and had positive urine cultures, with 104 seen only in the emergency department (ED) and 109 admitted to the hospital. Patients seen in the ED had a significant increase in E. coli resistance to discharge antibiotics (12.5% vs 2.8%, P = 0.0070). In those patients discharged on antibiotics resistant to E. coli, significantly more patients returned to the ED in 30 days (31.3% vs 10.7%, P = 0.0155). CONCLUSION AND RELEVANCE: Patients seen only in the ED were more likely to have resistant organisms to discharge antibiotics compared with those admitted to the hospital. Patients discharged on antibiotics resistant to E. coli had a 3-fold increase in returning to the ED within 30 days regardless of admitted location. Follow-up of all cultures should be performed, and patients resistant to discharge antibiotics should be contacted and antibiotic regimens changed.

Inducible pluripotent stem cells to study human mast cell trajectories.

Mast cells (MCs) are derived from CD34+ hematopoietic progenitors, consist of different subtypes and are involved in several inflammatory conditions. However, our understanding of human MC developmental trajectories and subtypes have been limited by a scarcity of suitable cellular model systems. Herein, we developed an in vitro model of human MC differentiation from induced pluripotent stem cells (iPSC) to study human MC differentiation trajectories. Flow cytometry characterization of hemopoietic cells derived from the myeloid cells-forming complex (MCFC) revealed an initial increase in Lin- CD34+ hematopoietic progenitors within Weeks 1-3, followed by an increase in CD34- CD45RA- SSCLow and SSChigh hematopoietic cells. The Lin- CD34+ hematopoietic progenitors consisted of SSClow CD45RA- CD123± c-Kit+ FcERI+ population that was ß7-integrinhigh CD203c+ and ß7-integrinhigh CD203c- cells consistent with CMPFceRI+ cells. Flow cytometry and cytologic analyses of the CD34- Lin- (SSClow) population revealed hypogranular cell populations, predominantly characterized by CD45RA- CD123± c-Kit+ FcERI- ß7-integrinlow and CD45RA- CD123± c-Kit- FcERI+ ß7-integrinMid cells. Analyses of hypergranular SSChigh cells identified Lin- CD34- CD45RA- c-Kit+ FceRI- and Lin- CD34- CD45RA- c-Kit+ FceRI+ cells. scRNA seq analysis of the cells harvested at week 4 of the MCFC culture revealed the presence of monocyte and granulocyte progenitors (n = 547 cells, 26.7 %), Erythrocyte / unknown (n = 85, 4.1 %), neutrophils / myelocytes (n = 211 cells, 10.2 %), Mast cell progenitor 1 (n = 599, 29.1 %), Mast cell progenitor 2 (n = 152, 7.4 %), Committed Mast cell precursor (n = 113, 5.5 %), and mast cells (n = 353, 17.1 %). In silico analyses of the MC precursor and mature MC populations revealed transcriptionally distinct MC precursor subtype and mature MC states (CMA1+ and CMA1- subtypes). Culturing MC precursor populations in MC maturation media (mast cell media II) led to homogenous mature MC populations as evidenced by high expression of high affinity IgE receptor, metachromatic granules, presence of MC granule proteins (Tryptase and Chymase) and activation following substance P stimulation and FceRI crosslinking. This human iPSC-based approach generates MC precursors and phenotypically mature and functional MC populations. This system will be a useful model to generate human MC populations and broaden our understanding of MC biology and transcriptional regulation of MC differentiation trajectories.

Pervasive conservation of intron number and other genetic elements revealed by a chromosome-level genomic assembly of the hyper-polymorphic nematode Caenorhabditis brenneri.

With within-species genetic diversity estimates that span the gambit of that seen across the entirety of animals, the Caenorhabditis genus of nematodes holds unique potential to provide insights into how population size and reproductive strategies influence gene and genome organization and evolution. Our study focuses on Caenorhabditis brenneri, currently known as one of the most genetically diverse nematodes within its genus and metazoan phyla. Here, we present a high-quality gapless genome assembly and annotation for C. brenneri, revealing a common nematode chromosome arrangement characterized by gene-dense central regions and repeat rich peripheral parts. Comparison of C. brenneri with other nematodes from the 'Elegans' group revealed conserved macrosynteny but a lack of microsynteny, characterized by frequent rearrangements and low correlation iof orthogroup sizes, indicative of high rates of gene turnover. We also assessed genome organization within corresponding syntenic blocks in selfing and outcrossing species, affirming that selfing species predominantly experience loss of both genes and intergenic DNA. Comparison of gene structures revealed strikingly small number of shared introns across species, yet consistent distributions of intron number and length, regardless of population size or reproductive mode, suggesting that their evolutionary dynamics are primarily reflective of functional constraints. Our study provides valuable insights into genome evolution and expands the nematode genome resources with the highly genetically diverse C. brenneri, facilitating research into various aspects of nematode biology and evolutionary processes.

Explaining inequity in knowledge, attitude, and services related to HIV/AIDS: a systematic review.

BACKGROUND: Equitable service provision and coverage are important responses to end the threat of the HIV/AIDS pandemic. Understanding inequity supports policies and programmes to deliver tailored interventions. There is continuous evidence generation on inequity in HIV/AIDS services. However, there was a lack of evidence on the global picture of inequity in behavioural and biomedical services related to HIV/AIDS. This systematic review assessed inequities in knowledge, attitude, HIV testing, and ART coverage across individual-level social groups and multiple (dis)advantage categories. METHODS: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, with a PROSPERO registration number CRD42024521247. The risk of bias was assessed by using Hoy et al's and Joanna Brigg's quality appraisal checklists for cross-sectional quantitative and qualitative studies, respectively. The search date was from inception to the final database search date (May 29, 2023). The included articles were either quantitative or qualitative studies. We used mixed-methods approach to analyse the data from the review articles. Quantitative descriptive analysis was conducted to estimate frequency of articles published from different countries around the world. Qualitative content analysis of the findings from the original studies was conducted using the PROGRESS plus framework which stands for: place of residence, occupation or employment status, gender, religion, education status, socioeconomic status, and social capital. RESULTS: Out of 6,029 articles that were accessed and screened, only 72 articles met the inclusion criteria. More articles on HIV-related equity in knowledge, attitude, testing, and ART were published in developed countries than in developing countries. Individuals from higher-income households had better knowledge about HIV/AIDS. Unfavourable attitudes towards people living with HIV and HIV/AIDS-associated stigma were common among women. HIV/AIDS service coverage (HIV testing or ART coverage) was higher among richer and urban residents. HIV/AIDS-associated stigma and lower levels of knowledge about HIV/AIDS were observed among multiple disadvantageous groups due to the intersection of two or more identities. CONCLUSIONS: The current review revealed that there have been disparities in HIV/AIDS services between social classes. Ending service disparity towards the global threat of HIV/AIDS demands tailored interventions based on socially disadvantaged groups (e.g., poor, rural dwellers, and women) and intersectional determinants. There is a need to understand the deep-rooted causes of inequity and the challenges that an equity-oriented system faces over time. More studies on inequity are needed, including intersectional inequity, which has been rarely studied in developing countries.

Adolescent oral oxycodone self-administration disrupts neurobehavioral and neurocognitive development.

Nonmedical use of prescription opioids peaks during late adolescence, a developmental period associated with the maturation of higher-order cognitive processes. To date, however, how chronic adolescent oxycodone (OXY) self-administration alters neurobehavioral (i.e., locomotion, startle reactivity) and/or neurocognitive (i.e., preattentive processes, intrasession habituation, stimulus-reinforcement learning, sustained attention) function has not yet been systematically evaluated. Hence, the rationale was built for establishing the dose-dependency of adolescent OXY self-administration on the trajectory of neurobehavioral and neurocognitive development. From postnatal day (PD) 35 to PD 105, an age in rats that corresponds to the adolescent and young adult period in humans, male and female F344/N rats received access to either oral OXY (0, 2, 5, or 10 mg/kg) or water under a two-bottle choice experimental paradigm. Independent of biological sex or dose, rodents voluntarily escalated their OXY intake across ten weeks. A longitudinal experimental design revealed prominent OXY-induced impairments in neurobehavioral development, characterized by dose-dependent increases in locomotion and sex-dependent increases in startle reactivity. Systematic manipulation of the interstimulus interval in prepulse inhibition supports an OXY-induced impairment in preattentive processes. Despite the long-term cessation of OXY intake, rodents with a history of chronic adolescent oral OXY self-administration exhibited deficits in sustained attention; albeit no alterations in stimulus-reinforcement learning were observed. Taken together, adolescent oral OXY self-administration induces selective long-term alterations in neurobehavioral and neurocognitive development enjoining the implementation of safer prescribing guidelines for this population.

Baseline levels and longitudinal changes in plasma Aß42/40 among Black and white individuals.

Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with C2N Diagnostics' PrecivityAD test for Aß42 and Aß40. Compared to white individuals, Black individuals had higher average plasma Aß42/40 levels at baseline, consistent with a lower average level of amyloid pathology. Interestingly, this difference resulted from lower average levels of plasma Aß40 in Black participants. Despite the differences, Black and white individuals had similar longitudinal rates of change in Aß42/40, consistent with a similar rate of amyloid accumulation. Our results agree with multiple recent studies demonstrating a lower prevalence of amyloid pathology in Black individuals, and additionally suggest that amyloid accumulates consistently across both groups.

The Spaghetti Sign: Nerve Root Redundancy in Lumbar Spinal Stenosis.

OBJECTIVE: Redundant nerve roots (RNR) seen in conjunction with lumbar spinal stenosis (LSS) are well-described radiographic findings. Several studies suggest their presence may be a negative prognostic indicator of postoperative outcome. Our hypothesis was that severe RNR (informally known as the Spaghetti Sign; SS) can serve as a reliable marker of LSS that would benefit from surgical decompression. We sought to evaluate a grading scale for RNR, characterize the association with stenosis, and investigate the clinical implications of RNR. METHODS: We conducted a retrospective chart review of 72 patients who underwent lumbar spine surgery from 2016 to 2018 at one institution. Preoperative T2 MRI scans were graded by three reviewers for severity of stenosis (0-4), severity of RNR (0-3), and rostral versus caudal RNR. Spaghetti Sign (SS) was defined as RNR score ≥2 (clear-cut or marked nerve root irregularity). Pre- and post-operative Oswestry Disability Index (ODI) scores were analyzed by stenosis and RNR severity. RESULTS: Seventy-one (98%) patients had severe stenosis (score ≥3) and twenty-five (35%) had a SS. SS was 100% specific for high grade stenosis. If patients had a SS, it was more likely rostral (p = 0.02). Post-operative ODI scores improved significantly, but there were no differences related to RNR score, presence of SS or stenosis severity. CONCLUSION: The study demonstrated that there is a significant association between SS and severe LSS and that presence of RNR is not a negative prognostic indicator for postoperative outcomes.

Design and validation of a patient-specific stereotactic frame for transcranial ultrasound therapy.

Transcranial focused ultrasound (tFUS) procedures such as neuromodulation and blood brain barrier opening require precise focus placement within the brain. MRI is currently the most reliable tool for focus localization but can be prohibitive for procedures requiring recurrent therapies. We designed, fabricated, and characterized a patient-specific, 3D-printed, stereotactic frame for repeated tFUS therapy. The frame is compact with minimal footprint, can be removed and re-secured between treatments while maintaining sub-mm accuracy and will allow for precise and repeatable transcranial FUS treatment without the need for MR-guidance following the initial calibration scan. Focus localization and repeatability were assessed via MR-thermometry and MR-ARFI on an ex vivo skull-phantom and in vivo non-human primates (NHP), respectively. Focal localization, registration, steering, and re-steering were accomplished during the initial MRI calibration scan session. Keeping steering coordinates fixed in subsequent therapy and imaging sessions, we found good agreement between steered foci and intended target, with target registration error of 1.2 ± 0.3 (n = 4, ex vivo) and 1.0 ± 0.5 (n = 3, in vivo) mm. Focus position (steered and non-steered) was consistent, with sub-mm variation in each dimension between studies. Our 3D-printed, patient-specific stereotactic frame can reliably position and orient the ultrasound transducer for repeated targeting of brain regions using a single MR-based calibration. The compact frame allows for high-precision tFUS to be carried out outside the magnet, and could help reduce the cost of tFUS treatments where repeated application of an ultrasound focus is required with high precision.

In Pursuit of Optimal Outcomes: A Framework for Quality Standards in Immune Effector Cell Therapy.

Immune Effector Cell (IEC) therapy represents a transformative advancement in oncology, leveraging the immune system to combat various malignancies. This manuscript outlines a comprehensive framework for establishing and maintaining quality standards in IEC therapy amidst rapid scientific and clinical advancements. We emphasize the integration of structured process measures, robust quality assurance, and meticulous outcome evaluation to ensure treatment efficacy and safety. Key components include multidisciplinary expertise, stringent accreditation protocols, and advanced data management systems, which facilitate standardized reporting and continual innovation. The collaborative effort among stakeholders-ranging from patients and healthcare providers to regulatory bodies-is crucial in delivering high-quality IEC therapies. This framework aims to enhance patient outcomes and cement the role of IEC therapy as a cornerstone of modern oncology, promoting continuous improvement and adherence to high standards across the therapeutic spectrum.

Pre-Pandemic Landscape of the Oklahoma Public Health Workforce: A Case Study From the Region 6 Training Needs Assessment Survey, 2019.

CONTEXT: The COVID-19 pandemic highlighted the need for a well-trained public health workforce prior to the public health crisis. Public health training centers regularly assess workforce needs and their pre-pandemic data play vital roles in guiding public health workforce development beyond the crisis. PROGRAM: In 2019, Oklahoma partners of the Region 6 South Central Public Health Training Center (R6SCPHTC) co-conducted an online survey of the public health workforce located in the Health Resources & Services Administration Region 6. IMPLEMENTATION: Between March and April, the R6SCPHTC collected 503 surveys, including 201 surveys from Oklahoma. Questions inquired about demographic and workforce characteristics, work contexts, training needs and interests, training access and logistics, and knowledge of R6SCPHTC online resources. EVALUATION: Key findings included that two-thirds of the pre-pandemic Oklahoma public health workforce consisted of employees age 40 or older with few holding public health or medical degrees. The majority of respondents worked for health departments and Tribes, and almost half were frontline workers. Although at least half of the participants interested in training on public health activities and topics were familiar with them, confidence in their abilities related to these activities and topics was expressed by less than half. Qualitative data provided details on training needs addressed quantitatively and described new training areas. Survey participants expressed interest in diverse training delivery methods and technological devices. Most respondents were not familiar with the free trainings available through the R6SCPHTC. DISCUSSION: Similar to the regional and national public health workforce, Oklahoma's workforce needed training and support already before COVID-19. Time and resources need to be invested into the current and future workforce. While addressing priority public health skills and topics remains important, training on current and emerging topics is needed. Providing accessible trainings with expanded content will prepare Oklahoma's public health workforce for the future.

Alcohol and substance use in older adults with treatment-resistant depression.

INTRODUCTION: Alcohol and substance use are increasing in older adults, many of whom have depression, and treatment in this context may be more hazardous. We assessed alcohol and other substance use patterns in older adults with treatment-resistant depression (TRD). We examined patient characteristics associated with higher alcohol consumption and examined the moderating effect of alcohol on the association between clinical variables and falls during antidepressant treatment. METHODS: This secondary and exploratory analysis used baseline clinical data and data on falls during treatment from a large randomized antidepressant trial in older adults with TRD (the OPTIMUM trial). Multivariable ordinal logistic regression was used to identify variables associated with higher alcohol use. An interaction model was used to evaluate the moderating effect of alcohol on falls during treatment. RESULTS: Of 687 participants, 51% acknowledged using alcohol: 10% were hazardous drinkers (AUDIT-10 score ≥5) and 41% were low-risk drinkers (score 1-4). Benzodiazepine use was seen in 24% of all participants and in 21% of drinkers. Use of other substances (mostly cannabis) was associated with alcohol consumption: it was seen in 5%, 9%, and 15% of abstainers, low-risk drinkers, and hazardous drinkers, respectively. Unexpectedly, use of other substances predicted increased risk of falls during antidepressant treatment only in abstainers. CONCLUSIONS: One-half of older adults with TRD in this study acknowledged using alcohol. Use of alcohol concurrent with benzodiazepine and other substances was common. Risks-such as falls-of using alcohol and other substances during antidepressant treatment needs further study.

Equity in HIV/AIDS services requires optimization of mainstreaming sectors in Ethiopia.

BACKGROUND: Mainstreaming HIV and AIDS across sectors is crucial to close the disparities in service provision and coverage. However, evidence has shown that certain social groups are left behind in receiving HIV/AIDS services. The objective of this study was twofold: to understand the reasons behind the existing inequities and to explore challenges of equity in HIV/AIDS services in the Amhara region of Ethiopia. METHODS: Twenty-two adults (aged 26-57 years) from eighteen sectors that are mainstreaming HIV and AIDS were purposefully selected until the point of saturation and participated in a semi-structured in-depth interview conducted between January 20 and February 17, 2023. Interviewees were asked to describe their mainstreaming experiences in equitable HIV/AIDS services, reflect on the challenges and barriers that impede equitable service provision, or explain the reasons behind the existence of inequity in HIV/AIDS services. The interviews were audio recorded, transcribed, translated, and iteratively analysed, with early analysis informing subsequent interviews. An inductive-reflexive thematic analysis was conducted, whereby themes and subthemes were identified, and the relationships between subthemes and patterns were critically reviewed. RESULTS: The challenges to equitable HIV/AIDS service provision were grouped into eight thematic areas: (1) changing contexts that shifts public and government attention to emerging diseases, war and political instability, and poverty; (2) leadership-related, such as the lack of supervision and monitoring, not politicising HIV/AIDS (not providing political attention to HIV/AIDS) and weak intersectoral collaboration; (3) financial constraints due to a random budgeting and contract interruption with non-governmental organisations (NGOs); (4) lack of resources due to scarcity and unfair distribution; (5) inadequate skilled personnel due to inadequate numbers and lack of continuous professional and career development; (6) lack of equity-related evidence-based tools and guidelines; (7) inadequate understanding of equity due to lack of training and misunderstanding, and lack of access to equity-oriented tools and guidelines; and (8) cultural norms, values, and perceptions. CONCLUSIONS: This study identified critical challenges faced in the equitable HIV/AIDS services provision. To achieve equity in HIV/AIDS services, mainstreaming sectors need to invest in mechanisms to sustain services in emergency situations; identify effective leaders to maintain collaboration, monitoring, and evaluation; institutionalise responsive budgeting and establish alternative funds to maintain non-governmental organisations initiatives; provide continuous up-to-date training and create a common evidence-sharing platform; implement proper recruitment, education, and professional development of HIV/AIDS focal persons; and promote and practice culturally safe care. It is, therefore, essential to optimise sectors that are mainstreaming HIV/AIDS and incorporate equity considerations in their strategic plans and working guidelines.

δ-containing GABA A receptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex.

In medial prefrontal cortex (mPFC), fast-spiking parvalbumin (PV) interneurons regulate excitability and microcircuit oscillatory activity important for cognition. Although PV interneurons inhibit pyramidal neurons, they themselves express δ subunits of GABAA receptors important for slow inhibition. However, the specific contribution of δ-containing GABAA receptors to the function of PV interneurons in mPFC is unclear. We explored cellular, synaptic, and local-circuit activity in PV interneurons and pyramidal neurons in mouse mPFC after selectively deleting δ subunits in PV interneurons (cKO mice). In current-clamp recordings, cKO PV interneurons exhibited a higher frequency of action potentials and higher input resistance than wild type (WT) PV interneurons. Picrotoxin increased firing and GABA decreased firing in WT PV interneurons but not in cKO PV interneurons. The δ-preferring agonist THIP reduced spontaneous inhibitory postsynaptic currents in WT pyramidal neurons but not in cKO pyramidal neurons. In WT slices, depolarizing the network with 400 nM kainate increased firing of pyramidal neurons but had little effect on PV interneuron firing. By contrast, in cKO slices kainate recruited PV interneurons at the expense of pyramidal neurons. At the population level, kainate induced broadband increases in local field potentials in WT but not cKO slices. These results on cells and the network can be understood through increased excitability of cKO PV interneurons. In summary, our study demonstrates that δ-containing GABAA receptors in mPFC PV interneurons play a crucial role in regulating their excitability and the phasic inhibition of pyramidal neurons, elucidating intricate mechanisms governing cortical circuitry. Significance statement: By selectively deleting δ-containing GABAA receptors in PV interneurons, we demonstrate the importance of these receptors on PV interneuron excitability, synaptic inhibition of pyramidal neurons, and circuit function.

Neurosteroids mediate and modulate the effects of pro-inflammatory stimulation and toll-like receptors on hippocampal plasticity and learning.

Pro-inflammatory changes contribute to multiple neuropsychiatric illnesses. Understanding how these changes are involved in illnesses and identifying strategies to alter inflammatory responses offer paths to potentially novel treatments. We previously found that acute pro-inflammatory stimulation with high (µg/ml) lipopolysaccharide (LPS) for 10-15 min dampens long-term potentiation (LTP) in the hippocampus and impairs learning. Effects of LPS involved non-canonical inflammasome signaling but were independent of toll-like receptor 4 (TLR4), a known LPS receptor. Low (ng/ml) LPS also inhibits LTP when administered for 2-4 h, and here we report that this LPS exposure requires TLR4. We also found that effects of low LPS on LTP involve the oxysterol, 25-hydroxycholesterol, akin to high LPS. Effects of high LPS on LTP are blocked by inhibiting synthesis of 5α-reduced neurosteroids, indicating that neurosteroids mediate LTP inhibition. 5α-Neurosteroids also have anti-inflammatory effects, and we found that exogenous allopregnanolone (AlloP), a key 5α-reduced steroid, prevented effects of low but not high LPS on LTP. We also found that activation of TLR2, TLR3 and TLR7 inhibited LTP and that AlloP prevented the effects of TLR2 and TLR7, but not TLR3. The enantiomer of AlloP, a steroid that has anti-inflammatory actions but low activity at GABAA receptors, prevented LTP inhibition by TLR2, TLR3 and TLR7. In vivo, both AlloP enantiomers prevented LPS-induced learning defects. These studies indicate that neurosteroids play complex roles in network effects of acute neuroinflammation and have potential importance for development of AlloP analogues as therapeutic agents.