A brave new framework for glioma drug development.

Patients with brain tumours are motivated to participate in clinical trials involving repeat tissue sampling. Normalising the use of neoadjuvant and staged surgical trials necessitates collaboration among patients, regulatory agencies, and researchers. Initial and repetitive tissue sampling plays a crucial role in enhancing our understanding of resistance mechanisms and vulnerabilities in brain tumour therapy. Standardising biopsy techniques and ensuring technical uniformity across institutions are vital for effective interinstitutional collaboration. Although liquid biopsy technologies hold promise, they are not yet ready to replace tissue analysis. Clear communication about the risks and benefits of biopsies is essential, particularly regarding potential postoperative deficits. Changes in mindset and neurosurgical culture are imperative to achieve much needed breakthroughs in the development of new, effective therapies for brain tumours.

Socioeconomic inequity in the utilization of healthcare among people with eating disorders in Australia.

BACKGROUND: Little is known about socioeconomic equity in access to healthcare among people with eating disorders in Australia. This study aims to measure the extent of inequity in eating disorder-related healthcare utilization, analyze trends, and explore the sources of inequalities using New South Wales (NSW) administrative linked health data for 2005 to 2020. METHODS: Socioeconomic inequities were measured using concentration index approach, and decomposition analysis was conducted to explain the factors accounting for inequality. Healthcare utilization included: public inpatient admissions, private inpatient admissions, visits to public mental health outpatient clinics and emergency department visits, with three different measures (probability of visit, total and conditional number of visits) for each outcome. RESULTS: Private hospital admissions due to eating disorders were concentrated among individuals from higher socioeconomic status (SES) from 2005 to 2020. There was no significant inequity in the probability of public hospital admissions for the same period. Public outpatient visits were utilized more by people from lower SES from 2008 to 2020. Emergency department visits were equitable, but more utilized by those from lower SES in 2020. CONCLUSIONS: Public hospital and emergency department services were equitably used by people with eating disorders in NSW, but individuals from high SES were more likely to be admitted to private hospitals for eating disorder care. Use of public hospital outpatient services was higher for those from lower SES. These findings can assist policymakers in understanding the equity of the healthcare system and developing programs to improve fairness in eating disorder-related healthcare in NSW.

Embracing a different outlook: Strengths and goals of individuals currently in treatment for anorexia nervosa.

PURPOSE: Developing personal goals beyond weight and shape, and promoting the agency to pursue those goals, could aid in treatment and recovery from anorexia nervosa (AN). This research explores the strengths, interests and goals of individuals currently receiving treatment for AN and evaluates how treatment services are supporting them to work towards personal goals across all areas of everyday life. METHOD: A total of 58 community-dwelling adults currently receiving treatment for anorexia nervosa at any stage of recovery completed the Client Assessment of Strengths, Interests and Goals Self-Report (CASIG-SR). Participants reported their goals for accommodation, work and study, interpersonal relationships, recreational activities, spirituality, religion or life purpose, physical health and mental health, and the personal strengths and supports needed to achieve those goals. Concordance scores were calculated between importance of personal goals and level of support from current services regarding these goals. RESULTS: Themes identified across goals, strengths and supports were Connection, Independence & Confidence, Meaning & Self: The Real Me, and Stability & Balance. Work and study goals and strengths were identified strongly. The key support needed was stability from the current treatment team to provide a stable base for change. Concordance scores indicate support provided for personal goals was less than the importance of the goal to the individual. CONCLUSION: Results suggest goals for everyday living are critical to recovery in anorexia nervosa. Specific clinical considerations to increase motivation and hope are increased access to peer support, a focus on increasing positive affect, supporting safe exercise and promoting outdoor experiences and connection with nature. LEVEL III: Evidence obtained from well-designed cohort or case-control analytic studies.

Maternal supplementation of egg yolk modulates brain functional organization and functional outcomes of offspring.

Maternal nutrition during the perinatal stage is critical to offspring brain development. Egg yolks are a balanced and nutrient-dense food that is rich in bioactive components crucial to optimal neurodevelopment early in life. Egg consumption is often recommended to pregnant women to enhance both maternal and fetal health. We hypothesized that maternal intake of egg yolk from late gestation and throughout lactation would enhance functional organization and cognitive developmental outcomes in offspring using a pig model. Sows were fed a control diet (n = 6) or a diet containing egg yolks (n = 5, 350 mg egg yolk powder/kg BW/day, equivalent to ∼3 eggs/day for humans) from late gestation through lactation. At weaning, piglet offspring (n = 2/sow, total n = 22) underwent structural magnetic resonance imaging (MRI) and resting-state-functional MRI. Piglets underwent novel object recognition testing to assess hippocampal-dependent learning and memory. Functional MRI results demonstrated that egg yolk significantly increased functional activation in the executive network (p = 0.0343) and cerebellar network (p = 0.0253) in piglets when compared to control. Diffusion tensor imaging analysis showed that perinatal intake of egg yolks significantly increased white matter fiber length in the hippocampus (p = 0.0363) and cerebellum (p = 0.0287) in piglet offspring compared to control piglets. Furthermore, piglets from egg yolk-fed sows spent significantly more proportional frequency exploring the novel object than the familiar object in novel object recognition testing (p = 0.0370). The findings from this study support egg yolk-altered activation of specific brain networks may be associated with functional cognitive outcomes in weaning piglets.

A community-academic partnership to develop an implementation support package for overdose prevention in permanent supportive housing.

INTRODUCTION: The overdose crisis in the U.S. disproportionately impacts people experiencing homelessness. Permanent supportive housing (PSH) - permanent, affordable housing with voluntary support services - is an effective, evidence-based intervention to address homelessness. However, overdose risk remains high even after entering PSH for individual and structural reasons. In this study, we aimed to refine a set of evidence-based overdose prevention practices (EBPs) and an associated implementation support package for PSH settings using focus groups with PSH tenants, frontline staff, and leaders. METHODS: Our community-academic team identified an initial set of overdose EBPs applicable for PSH through research, public health guidance, and a needs assessment. We adapted these practices based on feedback from focus groups with PSH leaders, staff, and tenants. Focus groups followed semi-structured interview guides developed using the EPIS (Exploration, Preparation, Implementation, Sustainment) framework constructs of inner context, outer context, and bridging factors related to overdose prevention and response. RESULTS: We conducted 16 focus groups with 40 unique participants (14 PSH tenants, 15 PSH staff, 11 PSH leaders); focus groups were held in two iterative rounds and individuals could participate in one or both rounds. Participants were diverse in gender, race, and ethnicity. Focus group participants were enthusiastic about the proposed EBPs and implementation strategies, while contributing unique insights and concrete suggestions to improve upon them. The implementation support package contains an iteratively refined PSH Overdose Prevention (POP) Toolkit with 20 EBPs surrounding overdose prevention and response, harm reduction, and support for substance use treatment and additional core implementation strategies including practice facilitation, tenant-staff champion teams, and learning collaboratives. CONCLUSIONS: This manuscript describes how robust community-academic partnerships and input from people with lived experience as tenants and staff in PSH informed adaptation of evidence-based overdose prevention approaches and implementation strategies to improve their fit for PSH settings. This effort can inform similar efforts nationally in other settings serving highly marginalized populations. We are currently conducting a randomized trial of the refined overdose prevention implementation support package in PSH.

Trigeminal Herpes Zoster With Mucosal Involvement in a Patient on Prophylactic Valacyclovir: An Uncommon Presentation.

This case report details a unique presentation of trigeminal herpes zoster with mucosal involvement in a 72-year-old female undergoing prophylactic valacyclovir treatment for suspected herpes labialis. The patient initially presented for a routine skin examination. Despite the absence of clinical evidence of herpes labialis, she was prescribed prophylactic valacyclovir. Three days later, the patient developed a unilateral rash, gingival darkening, and severe ipsilateral tooth pain. An examination revealed a crusted erythematous rash along the mandibular division of the left trigeminal nerve and a darkening of the gums. Diagnosed with trigeminal herpes zoster, she was treated with valacyclovir and a prednisone taper. A follow-up showed the resolution of the skin and gingival lesions, though herpetic neuralgia persisted. This case underscores the complexity and potential atypical presentations of herpes zoster, even under prophylactic antiviral therapy. It highlights the importance of considering herpes zoster in differential diagnoses, especially in patients presenting with unilateral dermatological and mucosal symptoms.

The Essentials: Upskilling a National Health Workforce in the Identification and Treatment of Eating Disorders.

OBJECTIVE: Health practitioners report limited skills and lack of confidence in managing and treating people with eating disorders. The purpose of this study was to evaluate the national rollout of comprehensive basic training in identification, assessment, treatment, and management of people with eating disorders to clinicians. METHODS: The Essentials: Training Clinicians in Eating Disorders is a core competency eLearning program. As part of a nation-wide multidisciplinary workforce training strategy, 7500 course places were provided free of charge to public and private health care professionals across all jurisdictions of Australia between January 2020 and March 2022. RESULTS: A total of 7370 health professionals enrolled during the study period. All learning outcomes showed improvement with large effect (Cohen's d = 1.2-2), with the largest improvements for self-reported knowledge of requirements for working with children and adolescents. Effects did not depend on years of working with eating disorders suggesting that the training was beneficial across levels of experience. Those who started with very low knowledge of eating disorders or higher willingness to treat eating disorders were most likely to complete the course. Most participants reported that the course was relevant to their clinical practice, that they expected their clinical practices to change, and that they would recommend the course to other health professionals. DISCUSSION: The strategy to provide government-funded core competency training in eating disorder care to healthcare professionals met key objectives by reaching health professionals eligible to provide government-rebated services in public and private settings across all jurisdictions including regional and remote areas.

Preparedness of Practicing Nurses in the Care of Sexual and Gender Diverse People in the United States: A Scoping Review.

BACKGROUND: Sexual and gender diverse (SGD) people in the United States (US) experience health inequities due to societal stigma and marginalisation. The nursing workforce must provide evidence-based affirming, inclusive and culturally responsive care for SGD people to meet individual and community health needs and eliminate disparities. AIMS: The purpose of this scoping review was to synthesise what is known about (1) nurses' knowledge, skills and attitudes related to caring for SGD people in the US and (2) the existence, development and evaluation of SGD-related educational offerings available to practicing nurses in the US to develop the knowledge and skills needed to promote the health and wellbeing of SGD individuals, families and communities. METHODS: This review followed the scoping review methodology and PRISMA for Scoping Reviews (PRISMA-ScR). DATA SOURCES: In conjunction with a health librarian, an electronic literature search was conducted using PubMed, LGBT Health, CINAHL, ERIC and Health Source-Nursing. RESULTS: Thirty-two studies were included in this review, including quantitative and qualitative studies that sought to understand the knowledge, attitudes and clinical experiences of nurses related to the care of SGD people; studies that tested educational interventions and studies that identified educational barriers and facilitators. Major gaps in education, practice and research, as well as methodological limitations of existing studies, were noted. CONCLUSION: Nurses would benefit from expanded access to effective standardised foundational SGD-related health continuing education to help prepare them to care for diverse patient populations. Equity, inclusivity and dignity are key values of the nursing profession. It is imperative that nurses have the knowledge and skills to apply these values consistently in day-to-day professional practice across populations and settings. IMPACT: There is an urgent need to develop standardised, easily accessible evidence-based educational content to address nurses' knowledge of and attitudes towards caring for SGD people. REPORTING METHOD: This study adhered to the PRISMA-ScR reporting guidelines. PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public contribution to this study.

Anion Exchange and Lateral Heterostructure Formation in Ferromagnetic PEA2Cr(Cl,Br)4 Two-Dimensional Perovskites.

Postsynthetic vapor-phase anion exchange in the ferromagnetic two-dimensional (2D) hybrid metal-halide perovskite, PEA2CrCl4 (PEA+ = phenethylammonium), is reported. Anion exchange using vaporous trimethylsilyl bromide (TMS-Br) is shown to drive complete conversion of solution-processed PEA2CrCl4 polycrystalline thin films to PEA2CrBr4. Low-temperature magnetic circular dichroism spectroscopy indicates ferromagnetic ordering in these PEA2CrCl4 and PEA2CrBr4 films. Via partial anion exchange of exfoliated flakes of PEA2CrCl4 single crystals, we demonstrate that it is possible to generate abrupt lateral PEA2CrCl4/PEA2CrBr4 magneto-heterointerfaces. Kinetic studies reveal that lateral heterostructure formation is dictated by rapid edge-site halide exchange followed by slower intralayer bromide diffusion, and there is negligible interlayer (3D) bromide or TMS-Br diffusion. The importance of the bulky PEA+ interlayer cation in suppressing 3D diffusion is highlighted by parallel anion-exchange experiments on MA2CrCl4 (MA+ = methylammonium), which instead show 3D exchange. Comparison of anion-exchange reactions in PEA2CrCl4, PEA2MnCl4, and PEA2PbCl4 shows that 2D bromide diffusion is slowest in PEA2CrCl4, attributed to the antiferrodistortive ordering found in this composition. In addition to demonstrating both postsynthetic composition control and heterostructure formation in ferromagnetic Cr-based 2D perovskites for the first time, these results also advance our fundamental understanding of ion-exchange processes in this relatively unexplored family of 2D perovskites, broadening opportunities for investigation and control of novel spin effects in low-dimensional metal-halide perovskites.

The discovery and structural basis of two distinct state-dependent inhibitors of BamA.

BamA is the central component of the essential ß-barrel assembly machine (BAM), a conserved multi-subunit complex that dynamically inserts and folds ß-barrel proteins into the outer membrane of Gram-negative bacteria. Despite recent advances in our mechanistic and structural understanding of BamA, there are few potent and selective tool molecules that can bind to and modulate BamA activity. Here, we explored in vitro selection methods and different BamA/BAM protein formulations to discover peptide macrocycles that kill Escherichia coli by targeting extreme conformational states of BamA. Our studies show that Peptide Targeting BamA-1 (PTB1) targets an extracellular divalent cation-dependent binding site and locks BamA into a closed lateral gate conformation. By contrast, PTB2 targets a luminal binding site and traps BamA into an open lateral gate conformation. Our results will inform future antibiotic discovery efforts targeting BamA and provide a template to prospectively discover modulators of other dynamic integral membrane proteins.

Observed Changes in the Distribution of Colon Cancer Metastasis: A National Cancer Database Review and Institutional Experience.

BACKGROUND: The University of Louisville has observed a near 70% drop in resectable/borderline resectable metastatic colorectal cancer in the past 5 years. The aim of this study was to evaluate the distribution of colon cancer metastasis at diagnosis and at recurrence. PATIENTS AND METHODS: Stage was defined by the American joint committee on cancer (AJCC) eighth edition. Institutional review board approval was granted for post hoc review of stage II and III patients with colon cancer from the University of Louisville prospective hepatic database from 2002 to 2023, as well as for the National cancer database (NCDB) Participant user file (PUF) 2021. The Surveillance epidemiology and end-results (SEER) 22 database was also utilized to corroborate the findings in the NCDB. RESULTS: Between 2018 and 2021 pathological M1a decreased annually (51.9-46.3%), while M1c increased year-over-year (26.6-32.4%) and M1b stayed relatively the same (21.4-21.3%). These differences were significant on chi-squared analysis with a p value of < 0.001. Univariate analysis of the post hoc review between 2017 and 2020 revealed significant differences between stage 4a and 4c in terms of race (p value 0.018), carcinoembryonic antigen (CEA) at diagnosis (p value 0.037), CEA at recurrence (p value 0.012), presence of liver metastasis (p value 0.003), and referral pattern (p value 0.014). Multivariate analysis identified stage 4b as an independent predictor for hepatic metastasis (odds ratio; OR 4.69, p value 0.011). CONCLUSIONS: A significant change in the distribution of colon cancer metastases has occurred at an institutional and national level over the past 3-5 years. Interdisciplinary treatment strategies will have to be modified accordingly.

Case Report: Asymmetric Visual Field Progression in Melanoma-Associated Retinopathy Heralding Recurrent Malignancy.

PURPOSE: To report a case of asymmetric melanoma-associated retinopathy (MAR) associated with metastatic melanoma which was thought to be in remission for 6 years. Identification of MAR led to the discovery of recurrent malignancy. METHOD: A man in his 60s presented with monocular visual disturbances with a large relative afferent pupillary defect, rapidly progressing visual field defect and otherwise normal eye examination. Initial work-up for retrobulbar optic neuropathy was inconclusive. After a few months, similar symptoms developed in his fellow eye and a full-field electroretinogram revealed a reduced b:a wave ratio suspicious for MAR. RESULTS: Visual field defects were present in both eyes at initial examination, but the visual field of one eye progressed rapidly while the fellow eye did not develop symptoms or progress until roughly 3 months later. Visual field defects and symptoms improved following resection of the lymph node with active metastatic disease and serum plasmapheresis. CONCLUSION: This report highlights a case of MAR with asymmetric objective findings and progression of visual field defects. It also demonstrates the success of plasmapheresis, in combination with treating recurrent metastatic disease, in improving visual function.

DNA methylation age acceleration is associated with incident cognitive impairment in the Health and Retirement Study.

Background: DNA methylation clocks have emerged as promising biomarkers for cognitive impairment and dementia. Longitudinal studies exploring the link between DNA methylation clocks and cognitive decline have been constrained by limited sample sizes and a lack of diversity. Objective: Our study aimed to investigate the longitudinal associations between DNA methylation clocks and incident cognitive impairment using a larger sample size encompassing a US nationally representative sample from the Health and Retirement Study. Methods: We measured DNA methylation age acceleration in 2016 by comparing the residuals of DNA methylation clocks, including GrimAge, against chronological age. Cognitive decline was determined by the change in Langa-Weir cognition status from 2016 to 2018. Using multivariable logistic regression, we evaluated the link between DNA methylation age acceleration and cognitive decline, adjusting for cell-type proportions, demographic, and health factors. We also conducted an inverse probability weighting analysis to address potential selection bias from varying loss-to-follow-up rates. Results: The analytic sample (N=2,713) at baseline had an average of 68 years old, and during the two years of follow-up, 12% experienced cognitive decline. Participants who experienced cognitive decline during follow-up had higher baseline GrimAge (mean = 1.2 years) acceleration compared to those who maintained normal cognitive function (mean = -0.8 years, p < 0.001). A one-year increase in GrimAge acceleration was associated with 1.05 times higher adjusted and survey-weighted odds of cognitive decline during follow-up (95% CI: 1.01-1.10). This association was consistent after accounting for loss-to-follow-up (OR = 1.07, 95% CI: 1.04-1.11). Conclusion: Our study offers insights into DNA methylation age acceleration associated with cognitive decline, suggesting avenues for improved prevention, diagnosis, and treatment.

DNA methylation signatures of prenatal socioeconomic position associated with 36-month language outcomes.

BACKGROUND: Socioeconomic position (SEP), which reflects one's position in society and access to resources, is strongly tied to neurodevelopment and is associated with epigenetic changes. AIM: This study examined whether DNA methylation signatures of prenatal SEP, measured in birth samples, are associated with child neurodevelopmental outcomes at 36 months of age. METHODS: Prenatal SEP DNA methylation scores were derived using 97 placenta and 127 cord blood biospecimens in the Early Autism Risk Longitudinal Investigation cohort. Participants completed the Mullen Scales of Early Learning (MSEL) and Vineland Adaptive Behavior Scales (VABS) at 36 months of age. Generalized regression analyses, adjusting for maternal age and race, were performed to test the association between SEP methylation score, for each birth biospecimen type, and MSEL and VABS scores. RESULTS: Significant associations were observed between placenta SEP methylation score and MSEL Expressive Language outcomes (beta = -2.7, p = 0.046, 95 % CI [- 5.43, -0.05]) and Receptive Language outcomes (beta = -2.5, p = 0.037, 95 % CI [-4.82, -0.16]). In cord blood, methylation-SEP scores were significantly associated with Receptive Language outcomes (beta = -2.0, p = 0.037, 95 % CI [-3.85, -0.12]). No significant associations were observed with VABS scores. CONCLUSION: Our results confirm associations between prenatal SEP and early childhood language development using a novel empiric DNA methylation measure of exposure.

Epigenetic age acceleration is associated with occupational exposures, sex, and survival in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is linked to ageing and genetic and environmental risk factors, yet underlying mechanisms are incompletely understood. We aimed to evaluate epigenetic age acceleration (EAA), i.e., DNA methylation (DNAm) age acceleration, and its association with ALS case status and survival. METHODS: In this study, we included 428 ALS and 288 control samples collected between 2011 and 2021. We calculated EAA using the GrimAge residual method from ALS and control blood samples and grouped participants with ALS into three ageing groups (fast, normal, slow). We associated EAA with ALS case status and survival, stratified by sex, and correlated it with environmental and biological factors through occupational exposure assessments, immune cell proportions, and transcriptome changes. FINDINGS: Participants with ALS had higher average EAA by 1.80 ± 0.30 years (p < 0.0001) versus controls. Participants with ALS in the fast ageing group had a hazard ratio of 1.52 (95% confidence interval 1.16-2.00, p = 0.0028) referenced to the normal ageing group. In males, this hazard ratio was 1.55 (95% confidence interval 1.11-2.17, p = 0.010), and EAA was positively correlated with high-risk occupational exposures including particulate matter (adj.p < 0.0001) and metals (adj.p = 0.0087). Also, in male participants with ALS, EAA was positively correlated with neutrophil proportions and was negatively correlated with CD4+ T cell proportions. Pathways dysregulated in participants with ALS with fast ageing included spliceosome, nucleocytoplasmic transport, axon guidance, and interferons. INTERPRETATION: EAA was associated with ALS case status and, at least in males, with shorter survival after diagnosis. The effect of EAA on ALS was partially explained by occupational exposures and immune cell proportions in a sex-dependent manner. These findings highlight the complex interactions of ageing and exposures in ALS. FUNDING: NIH, CDC/National ALS Registry, ALS Association, Dr. Randall Whitcomb Fund for ALS Genetics, Peter Clark Fund for ALS Research, Sinai Medical Staff Foundation, Scott L. Pranger ALS Clinic Fund, NeuroNetwork Therapeutic Discovery Fund, NeuroNetwork for Emerging Therapies.

The Relationship Between Big Five Personality Traits and Sleep Patterns: A Systematic Review.

Sleep, an intrinsic aspect of human life, is experienced by individuals differently which may be influenced by personality traits and characteristics. Exploring how these traits influence behaviors and sleep routines could be used to inform more personalized and effective interventions to promote better sleep. Our objective was to summarize the existing literature on the relationship between personality traits and sleep patterns through a systematic review. An abstract and keyword search was conducted in PsycINFO, Cochrane and PubMed, collecting relevant literature, published between January 1980 and June 2024. A total of 1713 records were found, of which 18 studies were analyzed in the descriptive synthesis. Relevant studies covered populations in 11 different countries, Australia, China, Estonia, Finland, Germany, Italy, Japan, Poland, Turkey, the United Kingdom, and the United States, comprising a total of 58,812 subjects. All studies reported an association between a sleep pattern with at least one of the Big Five personality traits (agreeableness, conscientiousness, extraversion, neuroticism, openness to experience). Ten studies found associations between personality and sleep quality, all of which reported a link between neuroticism and sleep quality (effect sizes 0.183-0.40). Five studies found an association between conscientiousness and morningness (effect sizes 0.16-0.35). Other sleep patterns linked to personality traits included sleep duration, nightmare frequency and distress, sleep deficiency, sleep continuity, insomnia severity and sleep problems, sleep hygiene, sleep latency and daytime sleepiness. This novel systematic review confirms that sleep and personality traits are related, suggesting that those traits should be considered when trying to understand or change one's sleep behavior.

Pulmonary surfactant and prostaglandin E2 in airway smooth muscle relaxation of human and male guinea pigs.

Pulmonary surfactant serves as a barrier to respiratory epithelium but can also regulate airway smooth muscle (ASM) tone. Surfactant (SF) relaxes contracted ASM, similar to ß2-agonists, anticholinergics, nitric oxide, and prostanoids. The exact mechanism of surfactant relaxation and whether surfactant relaxes hyperresponsive ASM remains unknown. Based on previous research, relaxation requires an intact epithelium and prostanoid synthesis. We sought to examine the mechanisms by which surfactant causes ASM relaxation. Organ bath measurements of isometric tension of ASM of guinea pigs in response to exogenous surfactant revealed that surfactant reduces tension of healthy and hyperresponsive tracheal tissue. The relaxant effect of surfactant was reduced if prostanoid synthesis was inhibited and/or if prostaglandin E2-related EP2 receptors were antagonized. Atomic force microscopy revealed that human ASM cells stiffen during contraction and soften during relaxation. Surfactant softened ASM cells, similarly to the known bronchodilator prostaglandin E2 (PGE2) and the cell softening was abolished when EP4 receptors for PGE2 were antagonized. Elevated levels of PGE2 were found in cultures of normal human bronchial epithelial cells exposed to pulmonary surfactant. We conclude that prostaglandin E2 and its EP2 and EP4 receptors are likely involved in the relaxant effect of pulmonary surfactant in airways.

No Replication of Alzheimer's Disease Genetics as a Moderator of Combat Exposure's Association with PTSD risk in 138,592 Combat Veterans.

Large-scale cohort and epidemiological studies suggest that posttraumatic stress disorder (PTSD) confers risk for late-onset Alzheimer's disease (AD) and related dementias (ADRD); however, the basis for this association remains unclear. Several prior studies of military Veterans have reported that carriers of the apolipoprotein E (APOE) ε4 gene variant are at heightened risk for the development of PTSD following combat exposure, suggesting that PTSD and ADRD may share some genetic risk. This cohort study was designed to further examine the hypothesis that ADRD genetic risk also confers risk for PTSD. To do so, we examined APOE ε4 and ε2 genotypes, an AD polygenic risk score (PRS), and other Veteran-relevant risk factors for PTSD in age-stratified groups of individuals of European (n = 123,372) and African (n = 15,220) ancestry in the US Department of Veterans Affairs' Million Veteran Program. Analyses revealed no significant main effect associations between the APOE ε4 (or ε2) genotype or the AD PRS on PTSD severity or diagnosis. There were also no significant interactions between measures of AD genetic risk and either combat exposure severity or history of head injury in association with PTSD in any age group. We conclude that the association between PTSD and the primary ADRD genetic risk factor, APOE ε4, that was reported previously was not replicable in the largest relevant dataset in the world. Thus, the epidemiological association between PTSD and ADRD is not likely to be driven by the major genetic factors underlying ADRD risk.

MK-5475, an inhaled soluble guanylate cyclase stimulator, for treatment of pulmonary arterial hypertension: the INSIGNIA-PAH study.

BACKGROUND: MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation. METHODS: The phase 2 INSIGNIA-PAH (NCT04732221) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32 µg, 100 µg or 380 µg via dry powder inhalation for 12 weeks. OBJECTIVES: The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH. RESULTS: 168 participants were randomised to placebo (n=41), MK-5475 32 µg (n=42), 100 µg (n=44), and 380 µg (n=41). Median age was 51 years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were -9.2% (95% CI -21.3%, 2.9%; p=0.068) with 32 µg, -22.0% (95% CI -33.7%, -10.3%; p<0.001) with 100 µg, and -19.9% (95% CI -33.4%, -6.4%; p=0.002) with 380 µg MK-5475. No treatment differences versus placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100 µg. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100 µg). CONCLUSIONS: In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect.

"What Else Could It Be?" A Scoping Review of Questions for Patients to Ask Throughout the Diagnostic Process.

BACKGROUND: Diagnostic errors are a global patient safety challenge. Over 75% of diagnostic errors in ambulatory care result from breakdowns in patient-clinician communication. Encouraging patients to speak up and ask questions has been recommended as one strategy to mitigate these failures. OBJECTIVES: The goal of the scoping review was to identify, summarize, and thematically map questions patients are recommended to ask during ambulatory encounters along the diagnostic process. This is the first step in a larger study to co-design a patient-facing question prompt list for patients to use throughout the diagnostic process. METHODS: Medline and Google Scholar were searched to identify question lists in the peer-reviewed literature. Organizational websites and a search engine were searched to identify question lists in the gray literature. Articles and resources were screened for eligibility and data were abstracted. Interrater reliability (K = 0.875) was achieved. RESULTS: A total of 5509 questions from 235 resources met inclusion criteria. Most questions (n = 4243, 77.02%) were found in the gray literature. Question lists included an average of 23.44 questions. Questions were most commonly coded along the diagnostic process categories of treatment (2434 questions from 250 resources), communication of the diagnosis (1160 questions, 204 resources), and outcomes (766 questions, 172 resources). CONCLUSIONS: Despite recommendations for patients to ask questions, most question prompt lists focus on later stages of the diagnostic process such as communication of the diagnosis, treatment, and outcomes. Further research is needed to identify and prioritize diagnostic-related questions from the patient perspective and to develop simple, usable guidance on question-asking to improve patient safety across the diagnostic continuum.