Acute Postnatal Inflammation Alters Adult Microglial Responses to LPS that Are Sex-, Region- and Timing of Postnatal Inflammation-Dependent.

BACKGROUND: Adverse events in early life can have impact lasting into adulthood. We investigated the long-term effects of systemic inflammation during postnatal development on adult microglial responses to LPS in two CNS regions (cortex, cervical spinal cord) in male and female rats. METHODS: Inflammation was induced in Sprague-Dawley rats by lipopolysaccharide (LPS, 1 mg/kg) administered intraperitoneally during postnatal development at P7, P12 or P18. As adults (12 weeks of age), the rats received a second LPS dose (1 mg/kg). Control rats received saline. Microglia were isolated 3 hours post-LPS from the cortex and cervical spinal cord. Gene expression was assessed via qRT-PCR for pro-inflammatory (IL-6, iNOS, Ptgs2, C/EBPb, CD14, CXCL10), anti-inflammatory (CD68, Arg-1), and homeostatic genes (P2Y12, Tmemm119). CSF-1 and CX3CL1 mRNA was analyzed in microglia-free homogenates. RESULTS: Basal gene expression in adult microglia was largely unaffected by early life LPS. Changes in adult microglial pro-inflammatory genes in response to LPS were either unchanged or attenuated in rats exposed to LPS during postnatal development. Ptgs2, C/EBPb, CXCL10 and Arg-1 were the genes most affected, with expression levels significantly downregulated vs control rats without postnatal LPS exposure. Cortical microglia were affected more by postnatal inflammation than spinal microglia, and males were more impacted than females. Overall, inflammatory challenge at P18 had the greatest effect on adult microglial gene expression, whereas challenge at P7 had less impact. Microglial homeostatic genes were unaffected by postnatal LPS. CONCLUSIONS: Long-lasting effects of postnatal inflammation on adult microglia depend on the timing of postnatal inflammation, CNS region and sex.

Examining the role of social vulnerability, neighborhood characteristics, and geospatial patterns of firearm-related injuries and clinical outcomes in Milwaukee county.

BACKGROUND: Previous work has shown socioenvironmental factors can influence firearm injury. Milwaukee County, Wisconsin is a diverse midwestern county with historic disinvestment in marginalized communities yielding stark segregation along racial and ethnic lines. It is also one of the many U.S. counties burdened by surging firearm injuries. The differences among communities within Milwaukee County provides a unique opportunity to explore the intersection of socioenvironmental factors that may affect clinical outcomes and geospatial patterns of firearm injury. METHODS: The trauma registry from the regional adult level 1 trauma center was queried for patients who sustained a firearm-related injury from 2015 to 2022 (N = 2402). The Social Vulnerability Index (SVI) ranking was derived using patient residence addresses to evaluate its association with traumatic injury clinical outcomes (i.e., in-hospital mortality, length of hospital stay, ICU or ventilator treatment, or injury severity score) and risk screening results for alcohol use disorder (AUD), posttraumatic stress disorder (PTSD), and depression. We evaluated hotspots of firearm injury density over time for patient residences and injury locations and distances between locations. A spatially lagged regression model tested the association between firearm injury density and SVI domains, alcohol outlet types, and park coverage. RESULTS: Most firearm injury patients were younger, male, racial or ethnic minorities from disadvantaged neighborhoods (SVI total; M = 0.86, SD = 0.15). SVI was not associated with any clinical outcomes. Of those screened, 12.9% screened positive for AUD and 44.5% screened at risk for PTSD, depression, or both. Hotspot analysis indicated consistent concentrations of firearm injury density. There were no differences in clinical outcomes between those injured inside or outside the home. Census tracts with lower socioeconomic status, greater off-premises and lower on-premises alcohol outlet density were associated with greater firearm injury density. CONCLUSIONS: In Milwaukee County, firearm injury patients are injured in and often return to the same disadvantaged neighborhoods that may hamper recovery. Results replicate and expand previous work and implicate specific socioenvironmental factors for intervention and prevention of firearm injury.

Antihypertensive Medications and Risk of Melanoma and Keratinocyte Carcinomas: A Systematic Review and Meta-Analysis.

Some antihypertensive medications are photosensitizing. The implications for skin cancer risk remain unclear because results from prior studies are inconsistent and as new evidence is published. We performed a systematic review and meta-analysis to evaluate the association between antihypertensives and common skin cancers (cutaneous squamous cell carcinoma, basal cell carcinoma, and melanoma) and to evaluate dose-response relationships. Forty-four articles met inclusion criteria, and 42 could be meta analyzed. Increased risks were seen for basal cell carcinoma with calcium channel blockers (relative risk [RR] = 1.17, 95% confidence interval [CI] = 1.11-1.22), diuretics (RR = 1.06, 95% CI = 1.03-1.10), and thiazides (RR = 1.10, 95% CI = 1.04-1.16); for squamous cell carcinoma with calcium channel blockers (RR = 1.08, 95% CI = 1.01-1.14), diuretics (RR = 1.29, 95% CI = 1.17-1.43), and thiazides (RR = 1.36, 95% CI = 1.15-1.61); and for melanoma in angiotensin-converting enzyme inhibitors (RR = 1.09, 95% CI = 1.03-1.14), calcium channel blockers (RR = 1.08, 95% CI = 1.03-1.12), and thiazides (RR = 1.09, 95% CI = 1.02-1.17). The quality of evidence was low or very low. We observed evidence for dose-response for thiazides with basal cell carcinoma; angiotensin-converting enzyme inhibitors, diuretics, and thiazides with squamous cell carcinoma; and angiotensin-converting enzyme inhibitors, diuretics, and thiazides with melanoma. Our meta-analysis supports a potential causal association between some antihypertensives, particularly diuretics, and skin cancer risk.

Toward personalized skin cancer care: multiple skin cancer development in five cohorts.

Importance: Many patients will develop more than one skin cancer, however most research to date has examined only case status. Objective: Describe the frequency and timing of the treatment of multiple skin cancers in individual patients over time. Design: Longitudinal claims and electronic health record-based cohort study. Setting: Vanderbilt University Medical Center database called the Synthetic Derivative, VA, Medicare, Optum Clinformatics® Data Mart Database, IBM Marketscan. Participants: All patients with a Current Procedural Terminology code for the surgical management of a skin cancer in each of five cohorts. Exposures: None. Main Outcomes and Measures: The number of CPT codes for skin cancer treatment in each individual occurring on the same day as an ICD code for skin cancer over time. Results: Our cohort included 5,508,374 patients and 13,102,123 total skin cancers treated. Conclusions and Relevance: Nearly half of patients treated for skin cancer were treated for more than one skin cancer. Patients who have not developed a second skin cancer by 2 years after the first are unlikely to develop multiple skin cancers within the following 5 years. Better data formatting will allow for improved granularity in identifying individuals at high risk for multiple skin cancers and those unlikely to benefit from continued annual surveillance. Resource planning should take into account not just the number of skin cancer cases, but the individual burden of disease.

Open Resources for Biology Education (ORBE): a resource collection.

In undergraduate life sciences education, open educational resources (OERs) increase accessibility and retention for students, reduce costs, and save instructors time and effort. Despite increasing awareness and utilization of these resources, OERs are not centrally located, and many undergraduate instructors describe challenges in locating relevant materials for use in their classes. To address this challenge, we have designed a resource collection (referred to as Open Resources for Biology Education, ORBE) with 89 unique resources that are primarily relevant to undergraduate life sciences education. To identify the resources in ORBE, we asked undergraduate life sciences instructors to list what OERs they use in their teaching and curated their responses. Here, we summarize the contents of the ORBE and describe how educators can use this resource as a tool to identify suitable materials to use in their classroom context. By highlighting the breadth of unique resources openly available for undergraduate biology education, we intend for the ORBE to increase instructors' awareness and use of OERs.

A cross-sectional survey of the mental health of midwives in Ontario, Canada: Burnout, depression, anxiety, stress, and associated factors.

PROBLEM: Burnout and the psychological co-morbidities stress, anxiety and depression have a significant impact on healthcare providers, including midwives. These conditions impact the quality of care provided to women, and midwives' ability to remain in the profession. BACKGROUND: There is growing concern regarding the retention of maternity care providers in Canada, particularly midwives. Nationally, 33% of Canadian midwives are seriously considering leaving practice; impacts of the profession on work-life-balance and mental health being commonly cited reasons. Burnout has been shown to contribute to workplace attrition, but little is known concerning burnout among Canadian midwives. AIM: To assess levels of stress, anxiety, depression, and burnout among midwives in Ontario, Canada and potential factors associated with these conditions. METHODS: A cross-sectional survey of Ontario midwives incorporating a series of well-validated tools including the Copenhagen Burnout Inventory and the Depression, Anxiety and Stress Scale. FINDINGS: Between February 5, and April 14, 2021, 275 Ontario midwives completed the survey. More than 50% of respondents reported depression, anxiety, stress, and burnout. Factors associated with poor mental health outcomes included having less than 10-years practice experience, identifying as a midwife with a disability, the inability to work off-call, and having taken a prior mental health leave. DISCUSSION & CONCLUSION: A significant proportion of Ontario midwives are experiencing high levels of stress, anxiety, depression, and burnout, which should be a serious concern for the profession, its leaders, and regulators. Investment in strategies aimed at retaining midwives that address underlying factors leading to attrition should be prioritized.

Thermotherapy has Sexually Dimorphic Responses in APP/PS1 Mice.

A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimer's disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30°C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30°C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-ß (Aß)42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy with potential nonpharmacological management for some individuals with AD, and provides further evidence for the necessity of adopting personalized patient care.

Five Key Articles on Curriculum Development for Graduate Medical Educators.

Background Curriculum development is an essential domain for medical educators, yet specific training in this area is inconsistent. With competing demands for educators' time, a succinct resource for best practice is needed. Objective To create a curated list of the most essential articles on curriculum development to guide education scholars in graduate medical education. Methods We used a modified Delphi method, a systematic consensus strategy to increase content validity, to achieve consensus on the most essential curriculum development articles. We convened a panel of 8 experts from the United States in curricular development, with diverse career stages, institutions, gender, and specialty. We conducted a literature search across PubMed and Google Scholar with keywords, such as "curriculum development" and "curricular design," to identify relevant articles focusing on a general overview or approach to curriculum development. Articles were reviewed across 3 iterative Delphi rounds to narrow down those that should be included in a list of the most essential articles on curriculum development. Results Our literature search yielded 1708 articles, 90 of which were selected for full-text review, and 26 of which were identified as appropriate for the modified Delphi process. We had a 100% response rate for each Delphi round. The panelists narrowed the articles to a final list of 5 articles, with 4 focusing on the development of new curriculum and 1 on curriculum renewal. Conclusions We developed a curated list of 5 essential articles on curriculum development that is broadly applicable to graduate medical educators.

Plumage microorganism communities of tidal marsh sparrows.

Microorganism communities can shape host phenotype evolution but are often comprised of thousands of taxa with varied impact on hosts. Identification of taxa influencing host evolution relies on first describing microorganism communities and acquisition routes. Keratinolytic (keratin-degrading) microorganisms are hypothesized to be abundant in saltmarsh sediments and to contribute to plumage evolution in saltmarsh-adapted sparrows. Metabarcoding was used to describe plumage bacterial (16S rRNA) and fungal (ITS) communities in three sparrow species endemic to North America's Atlantic coast saltmarshes. Results describe limited within-species variability and moderate host species-level patterns in microorganism diversity and community composition. A small percentage of overall microorganism diversity was comprised of potentially keratinolytic microorganisms, warranting further functional studies. Distinctions between plumage and saltmarsh sediment bacteria, but not fungal, communities were detected, suggesting multiple bacterial acquisition routes and/or vertebrate host specialization. This research lays groundwork for future testing of causal links between microorganisms and avian host evolution.

Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APP NL-F/NL-F Mice.

Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer's disease (AD). The APP NL-F/NL-F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APP NL-F/NL-F mice. Thus, four month old male and female APP NL-F/NL-F mice were treated monthly with vehicle, 5 mg/kg Dasatinib + 50 mg/kg Quercetin, or 100 mg/kg Fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + Quercetin treatment in female APP NL-F/NL-F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-ß (Aß) 42 and senescence associated-ß-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APP NL-F/NL-F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.

The role of neurosteroids in posttraumatic stress disorder and alcohol use disorder: A review of 10 years of clinical literature and treatment implications.

Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.

Faculty Entrustment and Resident Entrustability.

Importance: As the surgical education paradigm transitions to entrustable professional activities, a better understanding of the factors associated with resident entrustability are needed. Previous work has demonstrated intraoperative faculty entrustment to be associated with resident entrustability. However, larger studies are needed to understand if this association is present across various surgical training programs. Objective: To assess intraoperative faculty-resident behaviors and determine if faculty entrustment is associated with resident entrustability across 4 university-based surgical training programs. Design, Setting, and Participants: This cross-sectional study was conducted at 4 university-based surgical training programs from October 2018 to May 2022. OpTrust, a validated tool designed to assess both intraoperative faculty entrustment and resident entrustability behaviors independently, was used to assess faculty-resident interactions. A total of 94 faculty and 129 residents were observed. Purposeful sampling was used to create variation in type of operation performed, case difficulty, faculty-resident pairings, faculty experience, and resident training level. Main Outcomes and Measures: Observed resident entrustability scores (scale 1-4, with 4 indicating full entrustability) were compared with reported measures (faculty level, case difficulty, resident postgraduate year [PGY], resident gender, observation month) and observed faculty entrustment scores (scale 1-4, with 4 indicating full entrustment). Path analysis was used to explore direct and indirect effects of the predictors. Associations between resident entrustability and faculty entrustment scores were assessed by pairwise Pearson correlation coefficients. Results: A total of 338 cases were observed. Cases observed were evenly distributed by faculty experience (1-5 years' experience: 67 [20.9%]; 6-14 years' experience: 186 [58%]; ≥15 years' experience: 67 [20.9%]), resident PGY (PGY 1: 28 [8%]; PGY 2: 74 [22%]; PGY 3: 64 [19%]; PGY 4: 40 [12%]; PGY 5: 97 [29%]; ≥PGY 6: 36 [11%]), and resident gender (female: 183 [54%]; male: 154 [46%]). At the univariate level, PGY (mean [SD] resident entrustability score range, 1.44 [0.46] for PGY 1 to 3.24 [0.65] for PGY 6; F = 38.92; P < .001) and faculty entrustment (2.55 [0.86]; R2 = 0.94; P < .001) were significantly associated with resident entrustablity. Path analysis demonstrated that faculty entrustment was associated with resident entrustability and that the association of PGY with resident entrustability was mediated by faculty entrustment at all 4 institutions. Conclusions and Relevance: Faculty entrustment remained associated with resident entrustability across various surgical training programs. These findings suggest that efforts to develop faculty entrustment behaviors may enhance intraoperative teaching and resident progression by promoting resident entrustability.

Stressed and Depressed: Prevalence of Anxiety and/or Depression in Physician Assistant Students.

INTRODUCTION: This research highlights the prevalence of anxiety and/or depression among physician assistant (PA) students compared with the general population. It is believed that the results of this study will encourage graduate programs to place a stronger emphasis on the mental health of students and create a more positive learning environment. METHODS: An original survey was created using questions from Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, and several original questions. The survey was distributed using a SurveyMonkey link to directors of all accredited US PA programs. Program directors were asked to distribute the survey to their students. The survey remained open for 6 weeks, after which a cross-sectional statistical analysis was performed to compare the results with national anxiety and depression data in the United States. RESULTS: There is a statistically significant increase in the rate of occurrence of anxiety and/or depression among PA students compared with the general population. According to survey results, 84.4% of respondents experienced feelings of anxiety and 80.9% experienced feelings of depression while enrolled in PA school. Physician assistant students found the greatest need for anxiety and depression treatment during the didactic portion of their program. DISCUSSION: When compared with the national population, the level of anxiety in PA students was found to be 65.3% higher and the levels of depression in PA students to be 72.5% higher. These results should encourage PA programs and health care providers to take action regarding the mental health of future providers.

The effect of potassium supplementation and concomitant medications on potassium homeostasis for hospitalized patients.

PURPOSE: Hospitalized patients receive potassium (K+) supplementation for hypokalemia, with clinicians often estimating a rise in serum K+ levels of 0.1 mEq/L per 10 mEq delivered. However, there is limited evidence to support this expectation. Patients also concomitantly take medications that may alter K+ levels, and it is not known to what degree these may impact interventions to correct K+ levels via supplementation. The objective of this study was to identify the impact of oral and/or intravenous K+ supplementation on serum K+ levels, including the influence of selected concomitant medications, in adult hospitalized patients. METHODS: A single-center, retrospective descriptive study of adult hospitalized patients receiving K+ supplementation at a tertiary hospital between 2021 and 2022 was conducted. Patients were included if they received at least one dose of potassium chloride while admitted to the general medicine ward. The primary outcome was the daily median change in serum K+, normalized per 10 mEq of supplementation administered. The secondary outcome was the impact of selected concomitant medication use on supplement-induced changes in serum K+. RESULTS: A total of 800 patients and 1,291 daily episodes of K+ supplementation were evaluated. The sample was approximately 53% women, was 78% white, and had a median age of 68 years. The overall daily median change in serum K+ level was 0.05 mEq/L per 10 mEq of supplementation delivered. Patients received a median of 40 mEq of supplementation per day, primarily via the oral route (80.6%). Among the concomitant medications assessed, loop diuretics significantly dampened the impact of K+ supplementation. CONCLUSION: Supplementation of K+ in non-critically ill hospitalized patients is variable and dependent on concomitant medication use.

Keratinocyte Carcinoma Incidence by Race and Ethnicity in Older Adults With Medicare Coverage.

This cohort study examines raw and age-adjusted differences in the incidence of keratinocyte carcinoma among Medicare beneficiaries by race and ethnicity.

Assessment of Gray Matter Microstructure and Synaptic Density in Alzheimer's Disease: A Multimodal Imaging Study With DTI and SV2A PET.

OBJECTIVE: Multimodal imaging techniques have furthered our understanding of how different aspects of Alzheimer's disease (AD) pathology relate to one another. Diffusion tensor imaging (DTI) measures such as mean diffusivity (MD) may be a surrogate measure of the changes in gray matter structure associated with AD. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has been used to quantify synaptic loss, which is the major pathological correlate of cognitive impairment in AD. In this study, we investigated the relationship between gray matter microstructure and synaptic density. METHODS: DTI was used to measure MD and [11C]UCB-J PET to measure synaptic density in 33 amyloid-positive participants with AD and 17 amyloid-negative cognitively normal (CN) participants aged 50-83. Univariate regression analyses were used to assess the association between synaptic density and MD in both the AD and CN groups. RESULTS: Hippocampal MD was inversely associated with hippocampal synaptic density in participants with AD (r = -0.55, p <0.001, df = 31) but not CN (r = 0.13, p = 0.62, df = 15). Exploratory analyses across other regions known to be affected in AD suggested widespread inverse associations between synaptic density and MD in the AD group. CONCLUSION: In the setting of AD, an increase in gray matter MD is inversely associated with synaptic density. These co-occurring changes may suggest a link between synaptic loss and gray matter microstructural changes in AD. Imaging studies of gray matter microstructure and synaptic density may allow important insights into AD-related neuropathology.