The Emergence of Bromazolam in Jefferson County AL. A Case Series.

Postmortem toxicology is an ever-changing landscape presenting challenges for toxicologists and medical examiners. Trends can vary for certain benzodiazepines. While diazepam use tends to remain constant, alprazolam and clonazepam ebb and flow depending on prescription trends and street popularity. Novel benzodiazepines like etizolam vary in casework depending on legal restrictions and black-market availability. In May 2022, the first case of the designer benzodiazepine, bromazolam, was detected in Jefferson County Coroner/Medical Examiner's Office (JCCMEO) casework. Between then and December of 2023, an additional nine cases have been observed. Bromazolam, is the brominated analog of the low dose benzodiazepine alprazolam and is likely similar in potency. As bromazolam is a potent benzodiazepine, low concentrations of this novel drug are likely to contribute to CNS depression in opioid overdose cases. We present ten cases in which bromazolam was detected in postmortem samples at the University of Alabama at Birmingham (UAB) toxicology laboratory. The decedents ranged in age from 20 to 41 years of age. Most of the decedents were White (n = 8; 80%) and male (n = 7; 70%). Bromazolam concentrations ranged from 21 to 3,220 ng/mL (mean 401 ng/mL). All but one case were polydrug and all deaths were related to drug toxicity. Fentanyl was detected in 8 of the 10 decedents, with concentrations ranging from <2.5 to 97 ng/mL (mean 30 ng/mL). Additional drugs detected were methamphetamine, ethanol, oxycodone, methadone, cocaine, amphetamine, morphine, and diphenhydramine. While all manners of death were ruled as accidental, bromazolam was included in the cause of death statements in nine of the ten cases. Capturing important emerging drug trends on the death certificate is critical to help inform public health and medical colleagues for preventive measures and treatment in the continued drug epidemic.

Alcohol use is associated with intracranial hemorrhage in older emergency department head trauma patients.

Objectives: Falls are common in adults aged 65 years and older and are the leading cause of traumatic brain injuries in this age group. Alcohol use may increase the risk of falls as well as the severity of resultant injuries. The aim of this study was to examine the association between self-reported alcohol use and the prevalence of intracranial hemorrhage (ICH) in this patient group. Methods: This was a secondary analysis of the Geriatric Head Trauma Short Term Outcomes Project (GREAT STOP), a study of older adults with blunt head trauma from a fall. We determined the characteristics of every fall event, including patient demographics and medical history, and clinical signs and symptoms related to head trauma. Self-reported alcohol use was categorized as none, occasionally, weekly, or daily. We defined ICH as any acute ICH detected by computed tomography scan. We evaluated the association between alcohol use frequency and ICH, adjusted for patient factors and head injury risk factors. Results: Of 3128 study participants, 18.2% (n = 567) reported alcohol use: 10.3% with occasional use, 1.9% with weekly use, and 6.0% with daily use. ICH was more common in patients who used alcohol (20.5%, 22.0%, and 25.1% for occasional, weekly, and daily alcohol users, respectively, vs. 12.0% for non-users, p < 0.001). The frequency of alcohol use was independently associated with ICH, adjusted for patient and head injury risk factors. The adjusted odds ratios (with 95% confidence intervals) for occasional, weekly, and daily alcohol users increased from 2.0 (1.5‒2.8) to 2.1 (1.1‒4.1) and 2.5 (1.7‒3.6), respectively, and showed the characteristics of dose‒response effect. Conclusions: Alcohol use in older adult emergency department patients with head trauma is relatively common. Self-reported alcohol use appears to be associated with a higher risk of ICH in a dose-dependent fashion. Fall prevention strategies may need to consider alcohol mitigation as a modifiable risk factor.

A data-driven approach to identifying PFAS water sampling priorities in Colorado, United States.

BACKGROUND: Per and polyfluoroalkyl substances (PFAS), a class of environmentally and biologically persistent chemicals, have been used across many industries since the middle of the 20th century. Some PFAS have been linked to adverse health effects. OBJECTIVE: Our objective was to incorporate known and potential PFAS sources, physical characteristics of the environment, and existing PFAS water sampling results into a PFAS risk prediction map that may be used to develop a PFAS water sampling prioritization plan for the Colorado Department of Public Health and Environment (CDPHE). METHODS: We used random forest classification to develop a predictive surface of potential groundwater contamination from two PFAS, perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). The model predicted PFAS risk at locations without sampling data into one of three risk categories after being "trained" with existing PFAS water sampling data. We used prediction results, variable importance ranking, and population characteristics to develop recommendations for sampling prioritization. RESULTS: Sensitivity and precision ranged from 58% to 90% in the final models, depending on the risk category. The model and prioritization approach identified private wells in specific census blocks, as well as schools, mobile home parks, and public water systems that rely on groundwater as priority sampling locations. We also identified data gaps including areas of the state with limited sampling and potential source types that need further investigation. IMPACT STATEMENT: This work uses random forest classification to predict the risk of groundwater contamination from two per- and polyfluoroalkyl substances (PFAS) across the state of Colorado, United States. We developed the prediction model using data on known and potential PFAS sources and physical characteristics of the environment, and "trained" the model using existing PFAS water sampling results. This data-driven approach identifies opportunities for PFAS water sampling prioritization as well as information gaps that, if filled, could improve model predictions. This work provides decision-makers information to effectively use limited resources towards protection of populations most susceptible to the impacts of PFAS exposure.

Adolescent alcohol exposure alters age-related progression of behavioral and neurotrophic dysfunction in the TgF344-AD model in a sex-specific manner.

Alzheimer's Disease (AD) and heavy alcohol use are widely prevalent and lead to brain pathology. Both alcohol-related brain damage (ABRD) and AD result in cholinergic dysfunction, reductions in hippocampal neurogenesis, and the emergence of hippocampal-dependent cognitive impairments. It is still unknown how ARBD caused during a critical developmental timepoint, such as adolescence, interacts with AD-related pathologies to accelerate disease progression later in life. The current study utilized a longitudinal design to characterize behavioral and pathological changes in a transgenic rat model of AD (TgF344-AD) following adolescent intermittent ethanol (AIE) exposure. We found that AIE accelerates cognitive decline associated with AD transgenes in female rats at 6 months of age, and male AD-rats are impaired on spatial navigation by 3-months with no additional deficits due to AIE exposure. Protein levels of various AD-pathological markers were analyzed in the dorsal and ventral hippocampus of male and female rats. The data suggests that AIE-induced alterations of the tropomyosin-related kinase A receptor (TrkA) / p75 neurotrophin receptor (p75NTR) ratio creates a brain that is vulnerable to age- and AD-related pathologies, which leads to an acceleration of cognitive decline, particularly in female rats.

Medical Chart Review to Explore Suicidal and Self-Harm Thoughts and Behavior Among Psychiatric Inpatients.

Suicide and self-harm events are elevated in psychiatric inpatient populations. In this study, health data were retrospectively collected from the medical records of 183 patients (97 civil and 86 forensic) who had resided in, or been admitted to, a public psychiatric hospital in Saskatchewan, Canada from April 1 to December 31, 2021. Descriptive and inferential analyses were conducted to estimate prevalence and correlates of (non-fatal) suicide and self-harm events, including recent and lifetime occurrences, according to patients' health information. Nearly two-thirds (62%) of patients had any record of non-fatal suicide or self-harm events, including a lifetime history of self-harm (42%) and suicidal behavior (37%) as well as recent self-harm (24%) and suicidal (31%) thoughts or behaviors. Forensic patients were significantly more likely to have a record of suicide and self-harm events. This study emphasizes the need for further research into the course of suicidality and self-harm in psychiatric inpatients.

A systematic review and meta-analysis of loss-of-control eating in relation to cardiometabolic health components and inflammatory markers.

INTRODUCTION: Loss-of-control (LOC) eating, or the subjective experience of being unable to stop eating, is a hallmark feature of binge-eating episodes, which are also characterized by consuming an unusually large amount of food. However, regardless of the size of eating episode, LOC-eating may be a risk factor for adverse health outcomes. This systematic review and meta-analysis comprehensively examine the relationship of LOC-eating with cardiometabolic health components and inflammatory markers. METHODS: Search procedures were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines in six electronic databases. Studies of adult or youth samples published in English from the year 2000 onward were included. Given heterogeneity in age groups and adjustment for body mass index across studies, these factors were included as meta-regression moderators. RESULTS: Fifty-eight studies were identified through the literature search. Among individuals with (versus without) LOC-eating, relative risk ratios provided evidence of a greater relative risk for metabolic syndrome, hypertension, and dyslipidemia; standardized mean differences also provided evidence of higher waist circumference and impaired levels of fasting plasma glucose, high-density lipoprotein (HDL)-cholesterol, and triglycerides, but not blood pressure. Age group did not impact cardiometabolic health components. Body mass index differences moderated the effect on waist circumference. A narrative review of inflammatory markers revealed mixed findings linking inflammatory markers to LOC-eating. DISCUSSION: Overall, evidence for the relationship between LOC-eating and impaired cardiometabolic health underscores LOC-eating as an important early intervention target for prevention of serious adverse health outcomes.

Differences in Self-Reported Stress Versus. Hair and Nail Cortisol Among Adolescent and Young Adult Males.

BACKGROUND: Chronic stress causes harmful physiologic responses that yield increased inflammation and subsequent health conditions. Stress is an important measure among minoritized populations who face social situations that predispose risk to developing mental health problems. Hair and fingernail cortisol have been studied as retrospective measures of chronic stress and to demonstrate biological response to social situations. OBJECTIVES: The objective of this study was to compare the Perceived Stress Scale (PSS) with hair and nail cortisol concentrations and assess the risk factors associated with stress levels among heterosexual and sexual and gender-minoritized adolescent males. METHODS: We recruited a cohort of adolescents who were assigned male sex at birth. Approximately half of our cohort consisted of sexual and gender-minoritized people, and half consisted of heterosexual cisgender males. Participants provided hair and nail samples and completed a survey that included demographic and hair hygiene questions, and the PSS. Hair and nail samples were processed in a lab and survey results were analyzed descriptively. RESULTS: Several samples were not provided or received, and some survey data was missing. Hair and nail cortisol values were significantly correlated. There was no significant relationship between the PSS and hair and nail cortisol values. No significant differences were found between the heterosexual and sexual minoritized groups. Black participants reported lower perceived stress scores compared to White participants. Participants whose gender was non-binary or genderqueer had higher hair cortisol values compared to those who identified as male. Older participants had higher hair cortisol values compared to younger participants. DISCUSSION: Previous researchers have similarly found no correlation between self-report stress scales and cortisol values, increased stress experience among non-binary or genderqueer individuals compared to cisgender individuals, and a positive correlation between aging and stress. Yet, our finding that Black participants reported lower stress levels than White participants is unexpected. Our study demonstrates a high correlation between hair and nail cortisol values, suggeting the potential to interchange these markers as needed.

ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.

Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.

Periconceptional Dietary Quality and Metabolic Syndrome at 3 Years Postpartum.

BACKGROUND: The period around pregnancy is a critical window in the primordial prevention of cardiovascular disease, but little is known about the role of dietary patterns in cardiometabolic health. Our objective was to determine the association between alignment of periconceptional diet with the 2020 to 2025 Dietary Guidelines for Americans and the risk of metabolic syndrome. METHODS AND RESULTS: We used data from the Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-Be Heart Health Study, a pregnancy cohort study that followed pregnant participants to a median of 3 years postpartum (n=4423). Usual dietary intake in the 3 months around conception was estimated from a Food Frequency Questionnaire. Alignment with the Dietary Guidelines was measured using the Healthy Eating Index-2020, where higher scores represent greater alignment. Postpartum metabolic syndrome was defined using the American Heart Association/National Heart, Lung, and Blood Institute guideline. The prevalence of metabolic syndrome at 3 years postpartum was 20%. After adjusting for confounders, the prevalence of metabolic syndrome was flat up to a periconceptional Healthy Eating Index-2020 total score of ≈60, and then declined steeply as scores increased. Compared with a Healthy Eating Index-2020 score of 60, having scores of 70, 80, and 90 were associated with 2, 4, and 7 fewer cases of metabolic syndrome per 100 individuals, respectively (prevalence differences: -0.02 [95% CI, -0.03, 0]; -0.04 [-0.08, -0.1]; -0.07 [-0.13, -0.02]). CONCLUSIONS: Dietary interventions around conception and systems-level changes to support high diet quality may be important for improving postpartum cardiometabolic health, and helping to reverse or slow the decline in women's cardiometabolic health.

Qualitative evaluation of a package of implementation strategies codesigned to support the introduction of multiple micronutrient supplementation (MMS) for pregnant women in Bamako, Mali.

Mali national policy recommends that women take iron and folic acid supplements (IFA) from the time of the first antenatal care (ANC) visit, throughout pregnancy and during the first 3 months after delivery. In 2020, the World Health Organization (WHO) updated their ANC guidelines to recommend the United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) formulation of multiple micronutrient supplements (MMS) in the context of rigorous research, including implementation research. In Bamako, Mali, a codesign process was used to tailor antenatal care MMS packaging and counselling materials aimed at optimizing delivery and uptake of and adherence to MMS. This paper presents the codesign process along with the results of a post-intervention qualitative assessment to evaluate the behaviour change intervention. At the conclusion of the intervention, we conducted semistructured qualitative interviews with 24 women who had received the intervention and six pharmacy managers from the six health centres participating in the study. We conducted two focus groups with midwives who had delivered the intervention and two group discussions with family members of women who had received the intervention. Respondent perspectives reveal an easy experience transitioning from previously used IFA. Women and providers concur that the intervention counselling materials and visual aids were instrumental in influencing the perceived benefit and uptake of MMS. Family members play an influential role in pregnant women's decision-making regarding MMS uptake. MMS and the associated implementation strategies developed through the codesign process were found to be a highly acceptable intervention.

Pandemic-associated pernio harbors footprints of an abortive SARS-CoV-2 infection.

Elevated pernio incidence was observed during the COVID-19 pandemic. This prospective study enrolled subjects with pandemic-associated pernio in Wisconsin and Switzerland. Because pernio is a cutaneous manifestation of the interferonopathies, and type I interferon (IFN-I) immunity is critical to COVID-19 recovery, we tested the hypothesis that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated IFN-I signaling might underlie some pernio cases. Tissue-level IFN-I activity and plasmacytoid dendritic cell infiltrates were demonstrated in 100% of the Wisconsin cases. Across both cohorts, sparse SARS-CoV-2 RNA was captured in 25% (6/22) of biopsies, all with high inflammation. Affected patients lacked adaptive immunity to SARS-CoV-2. A hamster model of intranasal SARS-CoV-2 infection was used as a proof-of-principle experiment: RNA was detected in lungs and toes with IFN-I activity at both the sites, while replicating virus was found only in the lung. These data support a viral trigger for some pernio cases, where sustained local IFN-I activity can be triggered in the absence of seroconversion.

Maternal history of childhood maltreatment and pregnancy weight outcomes.

BACKGROUND: Childhood maltreatment is associated with elevated adult weight. It is unclear whether this association extends to pregnancy, a critical window for the development of obesity. METHODS: We examined associations of childhood maltreatment histories with pre-pregnancy BMI and gestational weight gain among women who had participated for >20 years in a longitudinal cohort.At age 26-35 participants reported childhood maltreatment (physical, sexual, and emotional abuse; emotional neglect) and, 5 years later, about pre-pregnancy weight and gestational weight gain for previous pregnancies (n=656). Modified Poisson regression models were used to estimate associations of maltreatment history with pre-pregnancy BMI and gestational weight gain z-scores, adjusting for sociodemographics. We used Multivariate Imputation by Chained Equations to adjust outcome measures for misclassification using data from an internal validation study. RESULTS: Before misclassification adjustment, results indicated a higher risk of pre-pregnancy BMI ≥30 kg/m2 in women with certain types of maltreatment (e.g., emotional abuse RR=2.4; 95% CI: 1.5, 3.7) compared with women without that maltreatment type. After misclassification adjustment, estimates were attenuated but still modestly elevated (e.g., emotional abuse RR=1.7; 95% CI: 1.1, 2.7). Misclassification-adjusted estimates for maltreatment associations with gestational weight gain z-scores were close to the null and imprecise. CONCLUSIONS: Findings suggest an association of maltreatment with pre-pregnancy BMI ≥30 kg/m2 but not with high gestational weight gain. Results suggest a potential need for equitable interventions that can support all women, including those with maltreatment histories, as they enter pregnancy.

Practice-Based Implementation Network: Behavioral Health Technician Optimization Pilot Lessons Learned.

INTRODUCTION: Between June 2021 and December 2022, the Practice-Based Implementation (PBI) Network conducted a pilot to study the optimization of behavioral health technicians (BHTs) within military behavioral health (BH) care system specialty BH clinics. Behavioral health technicians are paraprofessionals found in all branches of the military, and with training across a variety of clinic functions. Behavioral health technicians support BH specialty providers in many clinic functions (i.e., administrative, case management, clinical, and outreach). The primary aim of the BHT optimization pilot was to increase BHTs' involvement in clinical care. MATERIALS AND METHODS: Four military BH outpatient clinics participated in the BHT optimization pilot. Participants from the 4 clinics included 12 BHTs, 3 providers, 3 internal facilitators, and 3 dual-role providers/internal facilitators. The pilot asked each clinic to assess their BHT utilization needs, and then barriers and facilitators to BHT optimization were addressed by creating site-specific BHT optimization plans. RESULTS: The degree to which clinic optimization of BHTs impacts provider workload, clinic capability or capacity, and patient access to evidence-based care could not be determined during the BHT optimization pilot. However, individualized clinic BHT optimization plans and strategies appeared to be feasible and acceptable methods for military health system BH clinics to optimize BHTs' clinical skills. Lessons learned from this pilot included that: (1) clinics should consider establishing and maintaining action plans with specific, actionable goals for use of BHTs, and (2) BHT supervision, training, and clinic processes supporting optimization should be prioritized despite time constraints. CONCLUSION: Overall, individualized clinic BHT optimization plans and strategies appear to be feasible and acceptable methods for military health system BH clinics to optimize BHTs' clinical skills.

CRISPR-Cas inhibits plasmid transfer and immunizes bacteria against antibiotic resistance acquisition in manure.

The horizontal transfer of antibiotic resistance genes among bacteria is a pressing global issue. The bacterial defense system clustered regularly interspaced short palindromic repeats (CRISPR)-Cas acts as a barrier to the spread of antibiotic resistance plasmids, and CRISPR-Cas-based antimicrobials can be effective to selectively deplete antibiotic-resistant bacteria. While significant surveillance efforts monitor the spread of antibiotic-resistant bacteria in the clinical context, a major, often overlooked aspect of the issue is resistance emergence in agriculture. Farm animals are commonly treated with antibiotics, and antibiotic resistance in agriculture is on the rise. Yet, CRISPR-Cas efficacy has not been investigated in this setting. Here, we evaluate the prevalence of CRISPR-Cas in agricultural Enterococcus faecalis strains and its antiplasmid efficacy in an agricultural niche: manure. Analyzing 1,986 E. faecalis genomes from human and animal hosts, we show that the prevalence of CRISPR-Cas subtypes is similar between clinical and agricultural E. faecalis strains. Using plasmid conjugation assays, we found that CRISPR-Cas is a significant barrier against resistance plasmid transfer in manure. Finally, we used a CRISPR-based antimicrobial approach to cure resistant E. faecalis of erythromycin resistance, but this was limited by delivery efficiency of the CRISPR antimicrobial in manure. However, immunization of bacteria against resistance gene acquisition in manure was highly effective. Together, our results show that E. faecalis CRISPR-Cas is prevalent and effective in an agricultural setting and has the potential to be utilized for depleting antibiotic-resistant populations. Our work has broad implications for tackling antibiotic resistance in the increasingly relevant agricultural setting, in line with a One Health approach.IMPORTANCEAntibiotic resistance is a growing global health crisis in human and veterinary medicine. Previous work has shown technologies based on CRISPR-Cas-a bacterial defense system-to be effective in tackling antibiotic resistance. Here we test if CRISPR-Cas is present and effective in agricultural niches, specifically in the ubiquitously present bacterium, Enterococcus faecalis. We show that CRISPR-Cas is both prevalent and functional in manure and has the potential to be used to specifically kill bacteria carrying antibiotic resistance genes. This study demonstrates the utility of CRISPR-Cas-based strategies for control of antibiotic resistance in agricultural settings.

Microvascular remodeling after autologous stem cell transplant in an overlap of systemic sclerosis and systemic lupus erythematosus: A case report.

Microvascular remodeling and capillary repopulation can occur after autologous hematopoietic stem cell transplant (HSCT) in patients with systemic sclerosis and systemic lupus erythematosus (SLE). We aim to report evidence for microvascular remodeling after autologous HSCT as observed by nailfold videocapillaroscopy (NVC). We describe a rare occurrence of features consistent with systemic sclerosis and SLE in a 33-year-old female with a complex clinical course refractory to conventional treatments, ultimately requiring autologous HSCT. We performed NVC before and after HSCT using optical video and light microscopy. At the microvascular level, morphologic changes in the capillary vascular bed were observed after HSCT. Pretransplant damage in capillary structure was noted as evidenced on NVC with architectural loss, ramifications, capillary drop, and decreased density. Posttransplant NVC revealed an increase in capillary density with evidence of microvascular remodeling. Further studies on the clinical use and impact of microvascular remodeling on disease progression are needed and looking into the application of NVC scoring to assess clinical response would be meaningful.

Reliability of CT Enterography for Describing Fibrostenosing Crohn Disease.

Background Standardized methods to measure and describe Crohn disease strictures at CT enterography are needed to guide clinical decision making and for use in therapeutic studies. Purpose To assess the reliability of CT enterography features to describe Crohn disease strictures and their correlation with stricture severity. Materials and Methods A retrospective study was conducted in 43 adult patients with symptomatic terminal ileal Crohn disease strictures who underwent standard-of-care CT enterography at a tertiary care center at the Cleveland Clinic between January 2008 and August 2016. After training on standardized definitions, four abdominal radiologists blinded to all patient information assessed imaging features (seven continuous measurements and nine observations) of the most distal ileal stricture in two separate sessions (separated by ≥2 weeks) in random order. Features with an interrater intraclass correlation coefficient (ICC) of 0.41 or greater (ie, moderate reliability or better) were considered reliable. Univariable and multivariable linear regression analysis identified reliable features associated with a visual analog scale of overall stricture severity. Significant reliable features were assessed as components of a CT enterography-based model to quantitate stricture severity. Results Examinations in 43 patients (mean age, 52 years ± 16 [SD]; 23 female) were evaluated. Five continuous measurements and six observations demonstrated at least moderate interrater reliability (interrater ICC range, 0.42 [95% CI: 0.25, 0.57] to 0.80 [95% CI: 0.67, 0.88]). Of these, 10 were univariably associated with stricture severity, and three continuous measurements-stricture length (interrater ICC, 0.64 [95% CI: 0.42, 0.81]), maximal associated small bowel dilation (interrater ICC, 0.80 [95% CI: 0.67, 0.88]), and maximal stricture wall thickness (interrater ICC, 0.50 [95% CI: 0.34, 0.62])-were independently associated (P value range, <.001 to .003) with stricture severity in a multivariable model. These three measurements were used to derive a well-calibrated (optimism-adjusted calibration slope = 1.00) quantitative model of stricture severity. Conclusion Standardized CT enterography measurements and observations can reliably describe terminal ileal Crohn disease strictures. Stricture length, maximal associated small bowel dilation, and maximal stricture wall thickness are correlated with stricture severity. © RSNA, 2024 Supplemental material is available for this article. See also the article by Rieder et al in this issue. See also the editorial by Galgano and Summerlin in this issue.

LSDDEP2: study protocol for a randomised, double-dummy, triple-blind, active placebo-controlled, parallel groups trial of LSD microdosing in patients with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) poses a significant global health burden with available treatments limited by inconsistent efficacy and notable side effects. Classic psychedelics, including lysergic acid diethylamide (LSD), have garnered attention for their potential in treating psychiatric disorders. Microdosing, the repeated consumption of sub-hallucinogenic doses of psychedelics, has emerged as a self-treatment approach for depression within lay communities. Building upon preliminary evidence and the successful completion of an open-label pilot trial of microdosing LSD for depression (LSDDEP1), this protocol outlines a phase 2b randomised controlled trial (LSDDEP2). The main objective of LSDDEP2 is to assess the modification of depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), following a regimen of LSD microdoses versus placebo. METHODS: This is a randomised, double-dummy, triple-blind, active placebo-controlled, parallel groups trial of LSD microdosing in patients meeting DSM-5 criteria for major depressive disorder. Participants will undergo an 8-week LSD microdosing regimen using the titratable MB-22001 formulation taking two doses a week. All doses will be self-administered at home and will be titratable from 4 to 20 µg based on subjective perception and tolerability. In addition to depression symptoms, outcome will include psychiatric and personality inventories, sleep and activity tracking, electroencephalography (EEG), blood biomarkers, semi-structured interviews, and safety (e.g. adverse event, laboratory exam) measures. DISCUSSION: This study will be the first randomised controlled trial to administer controlled microdoses of LSD for treatment of MDD in participants' naturalistic environment. The measures included are designed to assess the drug's safety, mechanism, and treatment efficacy over placebo in this population. The results of this study will be important for assessing the viability of psychedelic microdosing as an additional treatment option and for informing the direction of future clinical trials. TRIAL REGISTRATION: ANZCTR, ACTRN12624000128594. Prospectively Registered on 13 February 2024.

First report of leaf spot caused by Paramyrothecium roridum on Coffea arabica in Hawai'i, USA.

During the 2022-2023 season, the harvested coffee crop in Hawai'i (Coffea arabica) was valued at $57.1 million (USDA NASS 2023). In September 2022, coffee leaf samples with foliar leaf spots affecting the Kona Typica variety were collected from Honaunau, Hawai'i, incidence <10%. The symptoms were circular, necrotic leaf spots with yellow margins, which merged, resulting in complete leaf blade coverage and subsequent leaf drop. Sporodochia were present on the abaxial leaf surface. Symptomatic leaf tissue was disinfected in 10% bleach solution for 60 seconds and chlorotic leaf tissue from the spot margins were excised and placed onto water agar and potato dextrose agar (PDA; Difco, USA). After a 7-day incubation period, pure cultures with white aerial mycelium having sporodochia arranged in concentric rings with olivaceous to black conidial masses were isolated. The conidia were aseptate, hyaline, smooth, cylindrical with rounded ends, measuring 5.1 to 6.8 µm long and 1.7 to 2.3 µm wide (n=50). Based on symptomology and cultural/morphological characteristics (Huaman-Pilco et al. 2023; Lombard et al. 2016; Pelayo-Sanchez et al. 2017), the isolates were initially identified as Paramyrothecium roridum (Tode) L. Lombard & Crous, comb. nov. (syn. Myrothecium roridum Tode). Fungal identification of isolate P22-81-2 was further confirmed using BLAST analysis of bulk sequenced PCR products of the ribosomal DNA internal transcribed spacer (ITS) region (White et al. 1990), ß-tubulin (ßtub), RNA polymerase II (RPB2), and calmodulin genes (Lombard et al., 2016; Huaman-Pilco et al., 2023). The gene sequences (GenBank accession nos. PP211198, PQ192517-19) were >98.4% identical to the P. roridum type specimen (CBS 357.89). A multilocus maximum likelihood phylogenetic analysis incorporating sequence data from previous relevant studies (Lombard et al., 2016; Pinruan et al. 2022) confirmed species identification. To prove pathogenicity, four, 26-month-old Kona Typica variety seedlings were foliar inoculated with a 1 X 106 conidia/ml suspension using a perfume atomizer. An additional four plants were inoculated in a similar manner with sterile water which served as controls. All plants were sprayed to drip on both the upper and lower leaf surfaces and incubated in a clear plastic bag to keep the humidity levels between 90 to 100% for 48 hours at 24°C. After 48 hours, the plants were removed from the bags, placed on a greenhouse bench, and observed weekly for symptom development. Within seven days light brown sunken spots had developed on all inoculated plants. The spots continued to enlarge having a dark distinct margin, light tan center, chlorotic halo, and formed concentric rings, which were identical to the original diseased samples. Leaf spots were not present on any of the control plants. The test was conducted twice. A fungus was consistently reisolated from the leaf spot margins of inoculated plants and morphologically (PDA) and molecularly (ITS, ßtub, RPB2, calmodulin) identified as P. roridum, thus fulfilling Koch's Postulates. To the best of our knowledge, this is the first report of P. roridum causing leafspots on C. arabica plants in Hawai'i. This pathogen has been reported on coffee in other parts of the world including Colombia, Costa Rica, Guatemala, Puerto Rico, and Mexico (USDA Fungus-Host Database). Under the right conditions, P. roridum has the potential to cause leafspots and defoliation resulting in economic losses for coffee growers in Hawai'i.

The RNA-binding protein EIF4A3 promotes axon development by direct control of the cytoskeleton.

The exon junction complex (EJC), nucleated by EIF4A3, is indispensable for mRNA fate and function throughout eukaryotes. We discover that EIF4A3 directly controls microtubules, independent of RNA, which is critical for neural wiring. While neuronal survival in the developing mouse cerebral cortex depends upon an intact EJC, axonal tract development requires only Eif4a3. Using human cortical organoids, we show that EIF4A3 disease mutations also impair neuronal growth, highlighting conserved functions relevant for neurodevelopmental pathology. Live imaging of growing neurons shows that EIF4A3 is essential for microtubule dynamics. Employing biochemistry and competition experiments, we demonstrate that EIF4A3 directly binds to microtubules, mutually exclusive of the EJC. Finally, in vitro reconstitution assays and rescue experiments demonstrate that EIF4A3 is sufficient to promote microtubule polymerization and that EIF4A3-microtubule association is a major contributor to axon growth. This reveals a fundamental mechanism by which neurons re-utilize core gene expression machinery to directly control the cytoskeleton.

Impact of aspirin dose according to race in secondary prevention of atherosclerotic cardiovascular disease: a secondary analysis of the ADAPTABLE randomised controlled trial.

OBJECTIVES: To evaluate whether the effectiveness and safety of low (81 mg daily) versus high-dose (325 mg daily) aspirin is consistent across races among patients with established atherosclerotic cardiovascular disease (ASCVD). DESIGN: A secondary analysis of the randomised controlled trial ADAPTABLE was performed. SETTING: The study was conducted in 40 centres and one health plan participating in the National Patient-Centred Clinical Research Network (PCORnet) in the USA. PARTICIPANTS: Among 15 076 participants with established ASCVD, 14 096 had self-reported race available and were included in the analysis. Participants were divided according to self-reported race as Black (n=1311, 9.3%), White (n=11 990, 85.1%) or other race (n=795, 5.6%). INTERVENTIONS: Participants were randomised to open-label daily aspirin doses of 81 mg versus 325 mg in a 1:1 ratio for a median of 26.2 months. PRIMARY AND SECONDARY OUTCOMES MEASURES: The primary effectiveness endpoint was a composite of death from any cause, hospitalisation for myocardial infarction or hospitalisation for stroke. The primary safety endpoint was hospitalisation for bleeding requiring blood product transfusion. RESULTS: Estimated cumulative incidence of the primary effectiveness endpoint at median follow-up with the 81 mg and the 325 mg daily doses were 6.70% and 7.12% in White participants (adjusted HR: 1.00 [95% CI: 0.88 to 1.15]); 12.27% and 10.69% in Black participants (adjusted HR: 1.40 [95% CI: 1.02 to 1.93]); and 6.88% and 7.69% in other participants (adjusted HR: 0.86 [95% CI: 0.54 to 1.39]) (p-interaction=0.12), respectively. There was no significant interaction between self-reported race and assigned aspirin dose regarding the secondary effectiveness and the primary safety endpoints. CONCLUSION: Race is not an effect modifier on the impact of aspirin dosing on effectiveness and safety in patients with established ASCVD. In clinical practice, treatment decisions regarding aspirin dose in secondary prevention of ASCVD should not be influenced by race. TRIAL REGISTRATION NUMBER: NCT02697916.