Androgen aggravates aortic aneurysms via suppressing PD-1 in mice.

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and fatality rate in men than women. However, the mechanism by which androgen mediates aortic aneurysms is largely unknown. Herein, we found that male mice, not female mice, developed aortic aneurysms when exposed to aldosterone and high salt (Aldo-salt). We revealed that androgen and androgen receptors (AR) were crucial for this sexually dimorphic response to Aldo-salt. We identified programmed cell death protein 1 (PD-1), an immune checkpoint, as a key link between androgen and aortic aneurysms. We demonstrated that administration of anti-PD-1 Ab and adoptive PD-1 deficient T cell transfer reinstated Aldo-salt-induced aortic aneurysms in orchiectomized mice, and genetic deletion of PD-1 exacerbated aortic aneurysms induced by high-fat diet and angiotensin II (Ang II) in non-orchiectomized mice. Mechanistically, we discovered that AR bound to the PD-1 promoter to suppress its expression in the spleen. Thus, our study unveils a mechanism by which androgen aggravates aortic aneurysms by suppressing PD-1 expression in T cells. Moreover, our study suggests that some cancer patients might benefit from screenings for aortic aneurysms during immune checkpoint therapy.

Investigating in VigiBase over 6000 cases of pneumonia in clozapine-treated patients in the context of the literature: focus on high lethality and the association with aspiration pneumonia.

BACKGROUND: The literature associates clozapine with pneumonia/aspiration pneumonia. RESEARCH DESIGN AND METHODS: The international pharmacovigilance database (VigiBase™) uses the information component (IC) as statistical signal. VigiBase clozapine reports were analyzed for pneumonia/aspiration pneumonia from introduction to 10 May 2023. RESULTS: There were 6392 cases of all types of pneumonia (5572 cases of pneumonia, 775 of aspiration pneumonia, and 45 combined). The IC was 3.52 for aspiration pneumonia, introduced as a VigiBase label in 2003, and 1.91 for pneumonia. Patients were reclassified as 3628 with no signs of aspiration and 1533 with signs. Signs of aspiration were strongly associated with some co-medications: olanzapine, odds ratio (OR) = 23.8, 95% confidence interval (CI), 14.9-38.0; risperidone OR = 18.6, CI, 11.4-30.4; valproic acid, OR = 5.5, CI, 4.5-6.6; and benzodiazepines OR = 5.5, CI, 4.5-6.6. In 2415 cases with completed data, fatal outcomes made up 45% (signs of aspiration made no difference), but there was wide variability from 0% (females <45 years of age; duration ≤30 days) to 76% (males >64 years of age; duration >1 year). During the first week, pneumonia was associated with 1) very high titration doses, 2) very small doses in Parkinson's disease, and 3) Japan vs other countries. CONCLUSIONS: In clozapine-treated patients: 1) at least 30% of pneumonia cases may be aspiration pneumonia, 2) stopping some co-medications may decrease the risk of aspiration pneumonia, 3) average lethality in pneumonia was 45% but may be around 75% in geriatric patients with long-term treatment, and 4) safer titrations may sometimes require 5-mg tablets.

How many mislabelled samples go unidentified? Results of a pilot study to determine the occult mislabelled sample rate.

BACKGROUND: Specimens with incorrect patient information are both a critical safety error and difficult to identify. Estimates of sample mislabelling rely on subjective identification of mislabelling, with the possibility that not all mislabelled samples are being caught. METHODS: We determined the blood type of two or more complete blood count specimens with the same patient label and assessed for discrepancies. We additionally determined the rate of identified sample mislabelling for the study period. RESULTS: We found a rate of 3.17 per 1000 discrepancies over the study period. These discrepancies most likely represent occult, or unidentified, mislabelled samples. In contrast, the rate of identified sample mislabelling was 1.15 per 1000. CONCLUSIONS: This study suggests that specimens identified as, or known to be, mislabelled represent only a fraction of those mislabelled. These findings are currently being confirmed in our laboratory and are likely generalisable to other institutions.

Periodontal inflammatory and microbial profiles in healthy young African Americans and Caucasians.

AIM: This study aimed to compare microbial and inflammatory profiles in periodontally/systemically healthy African American (AA) and Caucasian (C) individuals. MATERIALS AND METHODS: Thirty-seven C and 46 AA aged from 5 to 25 years were evaluated regarding periodontal disease, caries, microbial subgingival profile via 16-s sequencing, as well as salivary and gingival crevicular fluid (GCF) inflammatory profile via multiplex assay. RESULTS: Greater probing depth percentage was detected in AA (p = .0075), while a higher percentage of caries index (p = .0069) and decayed, missing, filled teeth (DMFT) index (p = .0089) was observed in C, after adjusting for number of teeth, sex and age. Salivary levels of IL-6, IL-8 and TNFα were higher for C, whereas GCF levels of eotaxin, IL-12p40, IL-12p70, IL-2 and MIP-1α were higher in AA (p < .05). Different microbial profiles were observed between the races (p = .02). AA presented higher abundance of periodontopathogens (such as Tanerella forsythia, Treponema denticola, Filifactor alocis, among others), and C presented more caries-associated bacteria (such as Streptococcus mutans and Prevotella species). Bacillaceae and Lactobacillus species were associated with higher DMFT index, whereas Fusobacterium and Tanerella species with periodontal disease parameters. CONCLUSIONS: A different inflammatory and bacterial profile was observed between healthy AA and C, which may predispose these races to higher susceptibility to specific oral diseases.

Scratch Descriptive epidemiologic study of billiards-related injuries.

The purpose of this descriptive epidemiological study is to identify billiards-related injuries that presented to the United States emergency departments from 2000 to 2020. This is a study using secondary data from emergency departments from 2000 to 2020 and presented with billiards-related injuries. No applicable intervention, but the main outcome measure was a description of injuries sustained due to participation in billiards. Billiards-related injury was captured by the National Electronic Injury Surveillance System - All Injury Program database. We extracted information on age, gender, injury, and disposition. A collective total of 78,524 (n = 1214) estimated patients, had emergency department visits after incurring billiards-related injuries as a sample. The mean age was 24.9 years. Most injuries occurred in males, 54,915 (n = 851, 69.9%). More injuries appeared to be soft-tissue contusions and abrasions, 19,000 (24.2%, n = 280), followed by lacerations, 17,520 (22.3%, n = 269). The most common cause of injury was being struck by a ball or cue, 39,705 (51.1%, n = 643). While the majority of injured patients were discharged home after evaluation, 2527 (3.2%, n = 45) of them required hospitalization. While a small number of billiards-related injuries presented to the emergency department in comparison to other sports-related injuries, some required more intensive treatment or hospitalization.

Evaluating the impact of pre-diagnostic use of statins and testosterone replacement therapy on mortality outcomes in older men with hormone-related cancers: Surveillance, Epidemiology, and End Results-Medicare 2007-2015.

BACKGROUND: The link between the pre-diagnostic use of statins and testosterone replacement therapy and their impact on hormone-related cancers, prostate cancer, colorectal cancer, and male breast cancer survival remains a topic of controversy. Further, there is a knowledge gap concerning the joint effects of statins and testosterone replacement therapy on hormone-related cancer survival outcomes. OBJECTIVE: To examine the independent and joint effects of pre-diagnostic use of statins and testosterone replacement therapy on the risk of all-cause and cause-specific mortality among older men diagnosed with hormone-related cancers, including prostate cancer, colorectal cancer, and male breast cancer. METHODS: In 41,707 men (≥65 years) of Surveillance, Epidemiology, and End Results-Medicare 2007-2015, we identified 31,097 prostate cancer, 10,315 colorectal cancer, and 295 male breast cancer cases. Pre-diagnostic prescription of statins and testosterone replacement therapy was ascertained and categorized into four groups (Neither users, statins alone, testosterone replacement therapy alone, and Dual users). Multivariable-adjusted Cox proportional hazards and competing-risks (Fine-Gray subdistribution hazard) models were conducted. RESULTS: No significant associations were found in Cox-proportional hazard models for hormone-related cancers. However, in the Fine-Gray competing risk models among high-grade hormone-related cancers, statins alone had an 11% reduced risk of hormone-related cancer-specific death (hazard ratio: 0.89; 95% confidence interval: 0.81-0.99; p 0.0451). In the prostate cancer cohort with both statistical models, the use of testosterone replacement therapy alone had a 24% lower risk of all-cause death (hazard ratio: 0.76; 95% confidence interval: 0.59-0.97; p 0.0325) and a 57% lower risk of prostate cancer-specific death (hazard ratio: 0.43; 95% confidence interval: 0.24-0.75; p 0.0029). Similar inverse associations were found among aggressive prostate cancer cases with testosterone replacement therapy alone and statins alone. No significant associations were found in the colorectal cancer and male breast cancer sub-groups. CONCLUSION: Pre-diagnostic use of statins and testosterone replacement therapy showed a survival benefit with reduced mortality in high-grade hormone-related cancer patients (only statins) and aggressive prostate cancer patients in both statistical models. Findings of testosterone replacement therapy use in aggressive prostate cancer settings could facilitate clinical trials. Further studies with extended follow-up periods are needed to substantiate these findings.

Comparative effectiveness of pelvic floor muscle training, mirabegron, and trospium among older women with urgency urinary incontinence and high fall risk: a feasibility randomized clinical study.

BACKGROUND: Untreated, urgency urinary incontinence (UUI) and overactive bladder (OAB) can precipitate a vicious cycle of decreasing physical activity, social isolation, fear of falling, and falls. Structured behavioral interventions and medications are common initial treatment options, but they elicit their effects through very different mechanisms of action that may influence fall-related outcomes differently. This study will determine the feasibility of conducting a comparative effectiveness, three-arm, mixed methods, randomized clinical trial of a behaviorally based pelvic floor muscle training (PFMT) intervention versus two recent drug options in older women with UUI or OAB who are also at increased risk of falling. METHODS: Forty-eight women 60 years and older with UUI or OAB who screen positive for increased fall risk will be recruited through the urogynacology and pelvic health clinics of our university health system. Participants will be randomly assigned to one of three 12-week treatment arms: (1) a course of behavioral and pelvic floor muscle training (PFMT) provided by physical therapists; (2) the beta-3 agonist, mirabegron; and (3) the antimuscarinic, trospium chloride. Study feasibility will be established through objective metrics of evaluability, adherence to the interventions, and attrition. We will also assess relevant measures of OAB symptom severity, quality of life, physical activity, incident falls, and concern about falling. DISCUSSION: The proposed research seeks to ultimately determine if linkages between reduction in UI symptoms through treatment also reduce the risk of falling in this patient population. TRIAL REGISTRATION: NCT05880862. Registered on 30 May 2023.

Association of sleep duration and quality with serum testosterone concentrations among men and women: NHANES 2011-2016.

BACKGROUND: The association between testosterone concentrations and sleep duration is poorly understood. OBJECTIVE: To evaluate the association between sleep duration and quality with serum testosterone concentrations and its variation by sex and age. METHODS: Data were analyzed for 8748 men and women (≥20 years old) who participated in the cycles of the National Health and Nutrition Examination Survey 2011-2016, a cross-sectional study. Total testosterone (ng/dL) was measured and categorized (low, moderate, and high) based on established cut-offs for men and its tertile distribution among women. Sleep duration was classified as ≤6, 7-8, and ≥9 h. Sleep quality was classified as poor or good based on the frequency of trouble falling or staying asleep or sleeping too much. Weighted multivariable adjusted and multinomial logistic regression models were conducted to assess these associations. RESULTS: The association between sleep duration and testosterone concentrations, varied according to sex and age. Sleep deprivation (≤6 h) was associated with high testosterone (odds ratio = 3.62; 95% confidence interval: 1.37, 9.53) among young men (20-40 years old); meanwhile, middle-aged men (41-64 years old) who reported more sleep duration had low testosterone (odds ratio = 2.03; 95% confidence interval: 1.10, 3.73). A J-shaped association between sleep duration and low testosterone (odds ratio≤6 h  = 1.57; 95% confidence interval: 1.10, 2.27; odds ratio≥9  h  = 2.06; 95% confidence interval: 1.18, 3.59) was observed in women aged 41-64 years. We did not find any association with sleep quality. CONCLUSION: The association of sleep duration with serum testosterone concentrations varies with sex and age group. Prospective studies are warranted to confirm these sex and age group differences.

Association of serum testosterone with chronic obstructive pulmonary disease (COPD) in a nationally representative sample of White, Black, and Hispanic men.

BACKGROUND: The association between total testosterone (T) and chronic obstructive pulmonary disease (COPD), remains poorly understood. We aim to investigate this association and how it varies by smoking status, body fatness, and race/ethnicity in a nationally representative sample of American men. METHODS: Data included a full sample (NHANES 1988-1991, 1999-2004, 2011-2012) and subset sample (excluding 2011-2012, no estradiol and SHBG levels available) of 2748 and 906 men (≥20 years), respectively. COPD was measured by self-report or spirometry test. Total T (ng/mL) was measured among men who participated in a morning examination session. Weighted multivariable-adjusted logistic regression models were conducted. RESULTS: Low T was positively associated with self-reported COPD in the full sample (OR = 2.10, 95% CI = 1.18-3.74, Ptrend = 0.010), and when stratified by current smokers and body fatness. When examined across race and ethnicity strata, this association persisted among White men (OR = 2.50, 95% CI = 1.30-4.79, Ptrend = 0.002) but not among Hispanic or Black men. In the subset sample, low T was positively associated with self-reported COPD (OR = 1.42, 95% CI, 0.57,3.55, Ptrend = 0.04), including among smokers and White men, but not body fatness. No significant associations were observed with COPD defined with spirometry plus self-report. CONCLUSION: Low levels of T were associated with an increased prevalence of self-reported COPD in the full and subset samples. Similar associations were observed after stratifying by smoking status, body fatness, and race/ethnicity in the full sample and subset sample. Prospective studies are warranted to confirm these significant associations among understudied and underserved populations.

Factors that impact initiation of pain management agreements for patients on chronic opioid therapy.

OBJECTIVE: This analysis seeks to understand variables within our institution that impact pain management agreement (PMA) utilization for chronic noncancer pain (CNCP). DESIGN: Retrospective chart review. SETTING: Public academic medical center. PATIENTS: Adults prescribed an opioid for CNCP between July 2020 and October 2020. MAIN OUTCOME MEASURE: We assessed the association between patient demographics, prescription factors, and prescriber factors with the presence of a PMA. Unadjusted rates and chi-square tests were generated for each predictor. Additionally, we performed two multivariable logistic regressions: one including all variables and another utilizing a stepwise forward variable selection process to further understand the relationships between predictors and the presence of a PMA. RESULTS: 49.7 percent of patients who received an opioid for CNCP had a PMA on file. One significant predictor of the presence of PMA was prescriber specialty with anesthesia/pain medicine, demonstrating 88 percent compliance. Compared to anesthesia/pain medicine, patients receiving opioids from internal medicine had an odds ratio (OR) of 0.155 (95 percent confidence interval (CI), 0.109-0.220), while patients receiving opioids from family medicine had an OR of 0.122 (95 percent CI, 0.090-0.167). Additionally, patients who received schedule II opioids (as opposed to schedule III/IV opioids), patients with multiple opioid fills in 3 months, middle aged patients, and Black patients were more likely to have a PMA. CONCLUSIONS: Compliance with PMA within our institution was only 49 percent despite an existing state law mandating use. Our analysis suggests quality improvement interventions should target patients on schedule III/IV opioids who receive their prescriptions from primary care providers.

Effect of statins and testosterone replacement therapy on incident cardiovascular disease among male hormone-related cancer survivors.

Purpose: Statins and testosterone replacement therapy (TTh) have been previously linked with prostate, colorectal and male breast cancer (hereinafter we will refer as hormone related cancers [HRCa]), and cardiovascular disease (CVD). However, there is a poor understanding about the combined association of statins and TTh with incident CVD among HRCa survivors and a matched cancer-free cohort. Methods: We identified 44,330 men of whom 22,165 were previously diagnosed with HRCa, and 22,165 were age-and index-matched cancer-free in SEER-Medicare 2007-2015. Pre-diagnostic prescription of statins and TTh prior to CVD development was ascertained for this analysis in the two matched cohorts. Weighted multivariable-adjusted conditional logistic regression models were used to evaluate the independent and combined associations of statins and TTh with CVD. Results: We found that use of statins (OR = 0.51, 95% CI: 0.46-0.55) and TTh (OR = 0.81, 95% CI: 0.67-0.97) were each independently inversely associated with incident CVD in the overall sample. TTh plus statins was also inversely associated with CVD. Associations were similar in the matched cancer-free cohort. Among HRCa survivors, only statins and combination of TTh plus statins (OR = 0.60, 95% CI: 0.44-0.98) were inversely associated with CVD, but the independent use of TTh was not associated with CVD. Conclusion: In general, pre-diagnostic use of statins and TTh, prior to CVD development, independently or in combination, were inversely associated with CVD in the overall, cancer-free population, and among HRCa survivors (mainly combination). Independent effects and combination of statins and TTh remained to be confirmed with specific CVD outcomes among HRCa survivors.

Body Mass Index Effect on Minimally Invasive Ventral Hernia Repair: A Systematic Review and Meta-analysis.

PURPOSE: Obesity is one of the most important risk factors for complications after ventral hernia repair (VHR), and minimally invasive (MIS) techniques are preferred in obese patients as they minimize wound complications. It is common practice to attempt weight loss to achieve a specific body mass index (BMI) goal; however, patients are often unable to reach it and fail to become surgical candidates. Therefore, we aim to perform a meta-analysis of studies comparing outcomes of obese and nonobese patients undergoing laparoscopic or robotic VHR. PATIENTS AND METHODS: A literature search of PubMed, Scopus, and Cochrane Library databases was performed to identify studies comparing obese and nonobese patients undergoing MIS VHR. Postoperative outcomes were assessed by means of pooled analysis and meta-analysis. Statistical analysis was performed using RevMan 5.4. Heterogeneity was assessed with I2 statistics. RESULTS: A total of 6483 studies were screened and 26 were thoroughly reviewed. Eleven studies and 3199 patients were included in the meta-analysis. BMI >40 kg/m 2 cutoff analysis included 5 studies and 1533 patients; no differences in hernia recurrence [odds ratios (OR): 1.64; 95% CI: 0.57-4.68; P = 0.36; I2 = 47%), seroma, hematoma, and surgical site infection (SSI) rates were noted. BMI >35 kg/m 2 cutoff analysis included 5 studies and 1403 patients; no differences in hernia recurrence (OR: 1.24; 95% CI: 0.71-2.16; P = 0.58; I2 = 0%), seroma, hematoma, and SSI rates were noted. BMI >30 kg/m 2 cutoff analysis included 4 studies and 385 patients; no differences in hernia recurrence (OR: 2.07; 95% CI: 0.5-8.54; P = 0.32; I2 = 0%), seroma, hematoma, and SSI rates were noted. CONCLUSION: Patients with high BMI undergoing MIS VHR have similar hernia recurrence, seroma, hematoma, and SSI rates compared with patients with lower BMI. Further prospective studies with long-term follow-up and patient-reported outcomes are required to establish optimal management in obese patients undergoing VHR.

Keyhole Versus Sugarbaker Mesh Configuration in Parastomal Hernia Repair: A Systematic Review and Meta-analysis.

BACKGROUND: Parastomal hernia repairs (PHRs) are often complex and challenging, even for experienced abdominal wall surgeons. Although the ideal therapeutic option in the setting of a parastomal hernia is to restore intestinal continuity, this is often not feasible, and numerous techniques have been described for PHR. Current guidelines recommend using mesh for elective PHR, but there is a scarcity of evidence comparing different PHR techniques. We aimed to report a meta-analysis comparing the outcomes of the "Sugarbaker" and "Keyhole" mesh configuration in PHR. METHODS: A literature search of PubMed, Embase, Scopus, and Cochrane Library databases was performed to identify studies comparing Sugarbaker and Keyhole mesh configuration in PHR. Postoperative outcomes were assessed by means of pooled analysis and meta-analysis. Statistical analysis was performed using RevMan 5.4. Heterogeneity was assessed with I2 statistics. RESULTS: A total of 3247 studies were screened, and 27 were fully reviewed. Ten studies and 632 patients were included in the meta-analysis. Three hundred five patients (48.3%) with Keyhole and 327 patients (51.7%) with Sugarbaker mesh configuration. Four hundred thirty-three patients (68.5%) underwent laparoscopic PHR with intraperitoneal onlay mesh. Sugarbaker mesh configuration was associated with lower hernia recurrence compared with Keyhole (odds ratio: 0.39; 95% CI: 0.19-0.83; P = 0.01; I2 = 46%). No differences were seen in overall complications, reoperations, stoma outlet obstruction, mesh infection, and postoperative bleeding. CONCLUSION: PHR with Sugarbaker mesh configuration is associated with decreased hernia recurrence compared with Keyhole and had similar rates of overall complications, reoperations, stoma outlet obstruction, mesh infection, and postoperative bleeding.

Differential Susceptibility of Aedes aegypti and Aedes albopictus Mosquitoes to Infection by Mayaro Virus Strains.

Mayaro virus (MAYV) is an arthropod-borne virus (arbovirus) belonging to the family Togaviridae, genus Alphavirus. In recent years, the geographic distribution of MAYV may have expanded north from South and Central America into the Caribbean Islands. Although Haemagogus janthinomys is considered the main vector for MAYV, the virus has also been isolated from other mosquitoes, including Aedes aegypti, a widespread species that serves as the main vector for highly epidemic viruses. Given the possible expansion and outbreaks of MAYV in Latin America, it is possible that MAYV might be adapting to be efficiently transmitted by urban vectors. Therefore, to investigate this possibility, we evaluated the vector competence of Ae. aegypti and Ae. albopictus mosquitoes to transmit MAYV isolated during a year of low or high MAYV transmission. Adult Ae. aegypti and Ae. albopictus were orally infected with the MAYV strains, and the infection, dissemination, and transmission rates were calculated to evaluate their vector competence. Overall, we found higher infection, dissemination, and transmission rates in both Ae. aegypti and Ae. albopictus mosquitoes infected with the strain isolated during a MAYV outbreak, whereas low/no transmission was detected with the strain isolated during a year of low MAYV activity. Our results confirmed that both Ae. aegypti and Ae. albopictus are competent vectors for the emergent MAYV. Our data suggest that strains isolated during MAYV outbreaks might be better fit to infect and be transmitted by urban vectors, raising serious concern about the epidemic potential of MAYV.

Use of weight loss medications in relation with prostate, colorectal and male breast cancers among older men: SEER-Medicare 2007-2015.

BACKGROUND: The association of weight loss medications with prostate (PCa), colorectal (CRC) or male breast cancers, including assessment of these cancers combined (HRCs, hormone-associated cancers) remain poorly understood. Testosterone replacement therapy (TTh) is reported to be inversely associated with obesity, PCa and CRC, but it is unclear whether TTh modifies the association of weight loss medications with HRCs. METHODS: In 49,038 men (≥ 65 years) of SEER-Medicare, we identified 15,471 men diagnosed with PCa, 4836 with CRC, and 141 with male breast cancers. Pre-diagnostic prescription of weight loss medications and TTh was ascertained for this analysis. Weighted multivariable-adjusted conditional logistic and Cox proportional hazards (mortality) models were conducted. RESULTS: We found an inverse association between use of weight loss medications and incident PCa (OR 0.59, 95% CI 0.57-0.62), CRC (OR 0.86, 95% CI 0.80-0.92), and HRCs (OR 0.65, 95% CI 0.62-0.68). Similar associations were observed for advanced stage at diagnosis of PCa and CRC. Effects of weight loss medications on PCa and HRC remained significant irrespective of the use of TTh but were only suggestive with CRC with positive TTh use. No associations were observed with male breast cancer and HRCs mortality. CONCLUSION: Pre-diagnostic use of weight loss medications reduced the incidence of PCa, CRC, and HRCs. These associations persisted in the same direction irrespective of the history of TTh use. Future studies are needed to confirm these findings and to identify underlying biological mechanisms of weight loss medications and TTh on the risk of cancer.

Respiratory aspiration during treatment with clozapine and other antipsychotics: a literature search and a pharmacovigilance study in vigibase.

INTRODUCTION: Antipsychotics (APs), during treatment or overdose, may be associated with respiratory aspiration. AREAS COVERED: A PubMed search on 30 September 2022, provided 3 cases of respiratory aspiration during clozapine therapy and 1 case during an AP overdose. VigiBase records of respiratory aspiration associated with APs from inception until 5 September 2021, were reviewed. VigiBase, the World Health Organization's global pharmacovigilance database, uses a statistical signal for associations called the information component (IC). EXPERT OPINION: The ICs (and IC025) were 2.1 (and 2.0) for APs, 3.2 (and 3.0) for clozapine, 2.6 (and 2.4) for quetiapine, and 2.5 (and 2.2) for olanzapine. Cases of respiratory aspiration associated with APs included: 137 overdose/suicide cases (64 fatal) and 609 cases during treatment (385 fatal) including 333 taking clozapine (238 fatal). In logistic regression models of fatal outcomes, the odds ratios, OR, and (95% confidence intervals, CI) of significant independent variables were: a) 2.3-2.6 for clozapine in 3 samples of AP treatment of varying size, b) 1.9 (CI 1.0 to 3.5) for geriatric age in 284 patients on clozapine treatment, and c) 1.8 (CI 1.1-3.2) for antidepressant co-medication in 276 patients on non-clozapine APs. Multiple AP pharmacological mechanisms may explain respiratory aspiration.

Label-Free Imaging and Histo-Optical Evaluation of Head and Neck Cancers with Multiphoton Autofluorescence Microscopy.

Depth-resolved label-free optical imaging by the method of multiphoton autofluorescence microscopy (MPAM) may offer new ways to examine cellular and extracellular atypia associated with epithelial squamous cell carcinoma (SCC). MPAM was evaluated for its ability to identify cellular and microstructural atypia in head and neck tissues from resected discarded tumor tissue. Three-dimensional image volumes were obtained from tissues from the floor of the mouth, tongue, and larynx, and were then processed for histology. MPAM micrographs were evaluated for qualitative metrics of cell atypia and quantitative measures associated with nuclear pleomorphism. Statistical analyses correlated MPAM endpoints with histological grade from each imaged site. Cellular overcrowding, discohesion, anisonucleosis, and multinucleated cells, as observed through MPAM, were found to be statistically associated with dysplasia and SCC grading, but not in histologically benign regions. A quantitative measure of the coefficient of variance in nuclear size in SCC and dysplasia was statistically elevated above histologically benign regions. MPAM also allowed for the identification of cellular heterogeneity across transitional areas and other features, such as inflammatory infiltrates. In the future, MPAM could be evaluated for the non-invasive detection of neoplasia, possibly as an adjunct to traditional conventional examination and biopsy.

Androgen aggravates aortic aneurysms via suppressing PD-1 in mice.

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and mortality rate in men than women. However, the molecular mechanism by which androgen mediates aortic aneurysms is largely unknown. Here, we report that male but not female mice develop aortic aneurysms in response to aldosterone and high salt (Aldo-salt). We demonstrate that both androgen and androgen receptors (AR) are crucial for the sexually dimorphic response to Aldo-salt. We identify T cells expressing programmed cell death protein 1 (PD-1), an immune checkpoint molecule important in immunity and cancer immunotherapy, as a key link between androgen and aortic aneurysms. We show that intraperitoneal injection of anti-PD-1 antibody reinstates Aldo-salt-induced aortic aneurysms in orchiectomized mice. Mechanistically, we demonstrate that AR binds to the PD-1 promoter to suppress its expression in the spleen. Hence, our study reveals an important but unexplored mechanism by which androgen contributes to aortic aneurysms by suppressing PD-1 expression in T cells. Our study also suggests that cancer patients predisposed to the risk factors of aortic aneurysms may be advised to screen for aortic aneurysms during immune checkpoint therapy.

Evaluation of molnupiravir (EIDD-2801) efficacy against SARS-CoV-2 in the rhesus macaque model.

Molnupiravir (EIDD-2801) is a prodrug of a ribonucleoside analogue that is currently being used under a US FDA emergency use authorization for the treatment of mild to moderate COVID-19. We evaluated molnupiravir for efficacy as an oral treatment in the rhesus macaque model of SARS-CoV-2 infection. Twenty non-human primates (NHPs) were challenged with SARS-CoV-2 and treated with 75 mg/kg (n = 8) or 250 mg/kg (n = 8) of molnupiravir twice daily by oral gavage for 7 days. The NHPs were observed for 14 days post-challenge and monitored for clinical signs of disease. After challenge, all groups showed a trend toward increased respiration rates. Treatment with molnupiravir significantly reduced viral RNA levels in bronchoalveolar lavage (BAL) samples at Days 7 and 10. Considering the mild to moderate nature of SARS-CoV-2 infection in the rhesus macaque model, this study highlights the importance of monitoring the viral load in the lung as an indicator of pharmaceutical efficacy for COVID-19 treatments. Additionally, this study provides evidence of the efficacy of molnupiravir which supplements the current ongoing clinical trials of this drug.

Increased Seroprevalence of Typhus Group Rickettsiosis, Galveston County, Texas, USA.

Whether increases in typhus group rickettsiosis in Galveston County, Texas, USA, are caused by increased recognition or true reemergence is unclear. We conducted a serosurvey that demonstrated Rickettsia typhi antibodies increased from 1.2% in 2013 to 7.8% in 2021 (p<0.001). These findings support pathogen reemergence rather than enhanced recognition alone.