Neuroimaging features of depression-frailty phenotype in older adults: a pilot study.

OBJECTIVE: Frailty and late-life depression (LLD) often coexist and share several structural brain changes. We aimed to study the joint effect LLD and frailty have on brain structure. DESIGN: Cross-sectional study. SETTING: Academic Health Center. PARTICIPANTS: Thirty-one participants (14 LLD+Frail and 17 Never-depressed+Robust). MEASUREMENT: LLD was diagnosed by a geriatric psychiatrist according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition for single episode or recurrent major depressive disorder without psychotic features. Frailty was assessed using the FRAIL scale (0-5), classifying subjects as robust (0), prefrail (1-2), and frail (3-5). Participants underwent T1-weighted magnetic resonance imaging in which covariance analysis of subcortical volumes and vertex-wise analysis of cortical thickness values were performed to access changes in grey matter. Participants also underwent diffusion tensor imaging in which tract-based spatial statistics was used with voxel-wise statistical analysis on fractional anisotropy and mean diffusion values to assess changes in white matter (WM). RESULTS: We found a significant difference in mean diffusion values (48,225 voxels; peak voxel: pFWER=0.005, MINI coord. (X,Y,Z) = -26,-11,27) between the LLD-Frail group and comparison group. The corresponding effect size (f=0.808) was large. CONCLUSION: We showed the LLD+Frailty group is associated with significant microstructural changes within WM tracts compared to Never-depressed+Robust individuals. Our findings indicate the possibility of a heightened neuroinflammatory burden as a potential mechanism underlying the co-occurrence of both conditions and the possibility of a depression-frailty phenotype in older adults.

Reserve and resilience in CKD: concept introduction and baseline results from the Physical REsilience Prediction in Advanced REnal Disease (PREPARED) study.

BACKGROUND: The purpose of this manuscript is to introduce reserve and resilience as novel concepts in chronic kidney disease (CKD) research and present baseline data from a unique prospective cohort study designed to characterize recovery from functional decline after a health event. METHODS: The Physical REsilience Prediction in Advanced REnal Disease (PREPARED) study recruited a national, prospective cohort of Veterans ≥70 years old with an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2, prior nephrology care, and at high risk for hospitalization. Electronic health record data were paired with telephone surveys. Self-reported measures of reserve included physical, psychological, and cognitive capacity and environmental resources. We calculated counts (frequencies) and medians (25th, 75th percentiles) for baseline measures of reserve. The study's longitudinal follow-up of physical function every 8 weeks or following an acute care encounter, which will be used to define resilience, is ongoing. RESULTS: Participants had a median (25th, 75th percentile) age of 76.3 (72.8, 81.4) years and eGFR of 23.4 (18.2, 28.8) ml/min/1.73 m2; 23.3% were Black, and 97.4% were male, 91.6% had hypertension, 67.4% had diabetes mellitus, 46.0% had coronary heart disease, and 39.8% had heart failure. Baseline measures of physical, psychological, and cognitive domains showed low reserve on average, but with wide ranges. CONCLUSIONS: Despite similar levels of kidney function, older adults participating in PREPARED had a wide range of measures of reserve in other health domains. Non-renal measures of reserve may be important indicators of capacity of CKD patients to recover after acute care encounters.

Feedback from health professionals in postgraduate medical education: Influence of interprofessional relationship, identity and power.

INTRODUCTION: Capitalising on direct workplace observations of residents by interprofessional team members might be an effective strategy to promote formative feedback in postgraduate medical education. To better understand how interprofessional feedback is conceived, delivered, received and used, we explored both feedback provider and receiver perceptions of workplace feedback. METHODS: We conducted 17 individual interviews with residents and eight focus groups with health professionals (HPs) (two nurses, two rehabilitation therapists, two pharmacists and two social workers), for a total of 61 participants. Using a constructivist grounded theory approach, data collection and analysis proceeded as an iterative process using constant comparison to identify and explore themes. RESULTS: Conceptualisations and content of feedback were dependent on whether the resident was perceived as a learner or a peer within the interprofessional relationship. Residents relied on interprofessional role understanding to determine how physician competencies align with HP roles. The perceived alignment was unique to each profession and influenced feedback credibility judgements. Residents prioritised feedback from physicians or within the Medical Expertise domain-a role that HPs felt was over-valued. Despite ideal opportunities for direct observation, operational enactment of feedback was influenced by power differentials between the professions. DISCUSSION: Our results illuminate HPs' conceptualisation of feedback for residents and the social constructs influencing how their feedback is disseminated. Professional identity and social categorisation added complexity to feedback acceptance and incorporation. To ensure that interprofessional feedback can achieve desired outcomes, education programmes should implement strategies to help mitigate intergroup bias and power imbalance.

Temporally and sex-specific effects of maternal perinatal stress on offspring cortical gyrification and mood in young adulthood.

Maternal stress during pregnancy and shortly thereafter is associated with altered offspring brain development that may increase risk of mood and anxiety disorders. Cortical gyrification is established during the prenatal period and the first 2 years of life and is altered in psychiatric disorders. Here, we sought to characterize the effects of perinatal stress exposure on offspring gyrification patterns and mood dysregulation in young adulthood. Participants included 85 young adults (56.5% women; 23-24 years) from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) with perinatal stress data across four distinct timepoints and structural MRI data from young adulthood. Perinatal stress exposure was measured as maternal stress during first and second half of pregnancy, first 6 months, and 6-18 months after birth. Cortical gyrification and mood dysregulation were quantified using local gyrification index (LGI), computed with Freesurfer, and the Profile of Mood States questionnaire, respectively. Perinatal stress predicted cortical gyrification in young adulthood, and its timing influenced location, direction, and sex-specificity of effects. In particular, whereas early prenatal stress was associated with sex-dependent medium-to-large effects in large temporal, parietal, and occipital regions (f2 = 0.19-0.38, p < .001), later perinatal stress was associated with sex-independent small-to-medium effects in smaller, more anterior regions (f2 = 0.10-0.19, p < .003). Moreover, in females, early prenatal stress predicted higher LGI in a large temporal region, which was further associated with mood disturbance in adulthood (r = 0.399, p = .006). These findings point out the long-term implications of perinatal stress exposure for cortical morphology and mood dysregulation.

A comparison of rheumatoid arthritis and systemic lupus erythematosus trial design: a commentary on ways to improve the number of positive trials in SLE.

OBJECTIVES: Recent systemic lupus erythematosus (SLE) randomised controlled trials (RCTs) were examined for potential design flaws and compared to rheumatoid arthritis (RA) RCT over the same time period to suggest modifications to SLE RCTs that could help improve the potential success rate of future SLE trials. METHODS: RA and SLE biologics RCTs published between 2005 and July 2013 were identified using PubMed. Inclusion criteria, study design, outcome measures, sample size calculations, patient baseline characteristics steroid use in the protocol and results were extracted and compared. RESULTS: All trials required active disease for enrolment. Twenty-two RA RCTs and eight SLE RCTs were included. All RA RCTs used either a partial or continuous measure of improvement. SLE RCTs used SLEDAI, BILAG, SLAM, SRI and BICLA. RA trials were larger (543 vs. 376 participants). Concomitant corticosteroid use was stable in 100% of RA trials while all SLE RCTs allowed dose tapering. RA trials were mostly in methotrexate or DMARD inadequate responders whereas SLE trials allowed for the presence or absence immunosuppressives within all trials. Sample sizes in RA were determined on a change in disease activity or proportion meeting a disease state. Positive trials were found in 100% of RA RCTs and 25% of SLE RCTs. CONCLUSIONS: The potential insensitivity of SLE disease activity indices to partial improvements may result in type II errors in SLE RCTs. Varying concomitant pharmacotherapy, especially corticosteroid use, in SLE may blunt observed treatment effects. Steroid tapering should be considered a trial outcome in isolation. More realistic sample size calculations are needed in SLE.

Delays in blood collection and drug toxicology results among crash-involved drivers arrested for impaired driving.

OBJECTIVE: The concentration of drugs in a driver's system can change between an impaired driving arrest or crash and the collection of a biological specimen for drug testing. Accordingly, delays in specimen collection can result in the loss of critical information that has the potential to affect impaired driving prosecution. The objectives of the study were: (1) to identify factors that influence the time between impaired-driving violations and specimen collections (time-to-collection) among crash-involved drivers, and (2) to consider how such delays affect measured concentrations of drugs, particularly with respect to common drug per se limits. METHOD: Study data included blood toxicology results and crash-related information from 8,923 drivers who were involved in crashes and arrested for impaired driving in Wisconsin between 2019 and 2021. Analyses examined how crash timing and severity influenced time-to-collection and the effects of delays in specimen collection on blood alcohol concentrations (BACs) and blood delta-9-tetrahydrocannabinol (THC) concentrations. RESULTS: The mean time-to-collection for the entire sample was 1.80 h. Crash severity had a significant effect on time-to-collection with crashes involving a fatality having the longest duration (M = 2.35 h) followed by injury crashes (M = 2.06 h) and noninjury crashes (M = 1.69 h). Time of day also affected time-to-collection; late night and early morning hours were associated with shorter durations. Both BAC (r = -0.11) and blood THC concentrations (r = -0.16) were significantly negatively correlated with time-to-collection. CONCLUSIONS: Crash severity and the time of day at which a crash occurs can result in delays in the collection of blood specimens after impaired driving arrests. Because drugs often continue to be metabolized and eliminated between arrest and biological specimen collection, measured concentrations may not represent the concentrations of drugs that were present at the time of driving. This has the potential to affect drug-impaired driving prosecution, particularly in jurisdictions whose laws specify per se impairment thresholds.

Neurodevelopmental signature of a transcriptome-based polygenic risk score for depression.

Disentangling the molecular underpinnings of major depressive disorder (MDD) is necessary for identifying new treatment and prevention targets. The functional impact of depression-related transcriptomic changes on the brain remains relatively unexplored. We recently developed a novel transcriptome-based polygenic risk score (tPRS) composed of genes transcriptionally altered in MDD. Here, we sought to investigate effects of tPRS on brain structure in a developmental cohort (Adolescent Brain Cognitive Development study; n = 5124; 2387 female) at baseline (9-10 years) and 2-year follow-up (11-12 years). We tested associations between tPRS and Freesurfer-derived measures of cortical thickness, cortical surface area, and subcortical volume. Across the whole sample, higher tPRS was significantly associated with thicker left posterior cingulate cortex at both baseline and 2-year follow-up. In females only, tPRS was associated with lower right hippocampal volume at baseline and 2-year follow-up, and lower right pallidal volume at baseline. Furthermore, regional subcortical volume significantly mediated an indirect effect of tPRS on depressive symptoms in females at both timepoints. Conversely, tPRS did not have significant effects on cortical surface area. These findings suggest the existence of a sex-specific neurodevelopmental signature associated with shifts towards a more depression-like brain transcriptome, and highlight novel pathways of developmentally mediated MDD risk.

Pharmacology of R-(-)-Methamphetamine in Humans: A Systematic Review of the Literature.

Methamphetamine exists as two stereoisomers: S-(+)-methamphetamine ((+)-MAMP) and R-(-)-methamphetamine ((-)-MAMP). The (+)-MAMP stereoisomer is a well-known central nervous system stimulant, available as a pharmaceutical and clandestine drug of abuse. However, the (-)-MAMP stereoisomer is less well understood despite commercial availability for over 30 years as an over-the-counter (OTC) nasal decongestant in the Vicks Vapor Inhaler (a product of Procter & Gamble). Recently, several generic versions have become available, decreasing the cost and increasing the availability of (-)-MAMP-containing nasal sprays to consumers. Despite widespread commercial availability and use in the United States, a paucity of literature exists on the pharmacology of (-)-MAMP in humans. This knowledge gap is problematic, given the difficulty in separating (-)-MAMP and (+)-MAMP isomers in laboratory assays for workplace drug testing, suspected impaired drivers, post-mortem investigations, and assessment of drug involvement in crimes. In response, this systematic review of the literature coalesces and summarizes available knowledge of (-)-MAMP pharmacology in humans. It was found that available knowledge relies heavily on urine drug and metabolite concentrations, systematic pharmacokinetics studies are lacking, and existing knowledge has been derived from a total of 99 unique participants. The impacts of highlighted gaps in the literature are discussed, focusing on forensic toxicology and law enforcement, and future research directions are suggested.

Brain structure and working memory adaptations associated with maturation and aging in mice.

Introduction: As the population skews toward older age, elucidating mechanisms underlying human brain aging becomes imperative. Structural MRI has facilitated non-invasive investigation of lifespan brain morphology changes, yet this domain remains uncharacterized in rodents despite increasing use as models of disordered human brain aging. Methods: Young (2m, n = 10), middle-age (10m, n = 10) and old (22m, n = 9) mice were utilized for maturational (young vs. middle-age) and aging-related (middle-age vs. old mice) comparisons. Regional brain volume was averaged across hemispheres and reduced to 32 brain regions. Pairwise group differences in regional volume were tested using general linear models, with total brain volume as a covariate. Sample-wide associations between regional brain volume and Y-maze performance were assessed using logistic regression, residualized for total brain volume. Both analyses corrected for multiple comparisons. Structural covariance networks were generated using the R package "igraph." Group differences in network centrality (degree), integration (mean distance), and segregation (transitivity, modularity) were tested across network densities (5-40%), using 5,000 (1,000 for degree) permutations with significance criteria of p < 0.05 at ≥5 consecutive density thresholds. Results: Widespread significant maturational changes in volume occurred in 18 brain regions, including considerable loss in isocortex regions and increases in brainstem regions and white matter tracts. The aging-related comparison yielded 6 significant changes in brain volume, including further loss in isocortex regions and increases in white matter tracts. No significant volume changes were observed across either comparison for subcortical regions. Additionally, smaller volume of the anterior cingulate area (χ2 = 2.325, pBH = 0.044) and larger volume of the hippocampal formation (χ2 = -2.180, pBH = 0.044) were associated with poorer cognitive performance. Maturational network comparisons yielded significant degree changes in 9 regions, but no aging-related changes, aligning with network stabilization trends in humans. Maturational decline in modularity occurred (24-29% density), mirroring human trends of decreased segregation in young adulthood, while mean distance and transitivity remained stable. Conclusion/Implications: These findings offer a foundational account of age effects on brain volume, structural brain networks, and working memory in mice, informing future work in facilitating translation between rodent models and human brain aging.

Suitability of SoToxa® Oral Fluid Screening Over Time: Re-Examination of Drugged Driving in Wisconsin.

Drug-impaired driver detection is a critical element of traffic safety. However, shifting drug use patterns over time and geography may limit the long-term reliability of assay-based screening tools. In this work, we compare qualitative results from the Abbott SoToxa® oral fluid (OF) screening device to Quantisal™ OF and whole blood. Our objective was to examine these three qualitative toxicological approaches, scope applicability of OF collection at the roadside, and compare them with a previous analysis of SoToxa® in Wisconsin. OF specimens were screened with the SoToxa® for six drugs or drug classes including amphetamine, benzodiazepines, cocaine, methamphetamine, opioids and tetrahydrocannabinol (THC). OF and blood specimens were collected from 106 participants. Quantisal™ OF and blood specimens were screened for drugs on ultra-performance liquid chromatography coupled to quadrupole time-of-flight high-resolution mass spectrometry (UPLC-QToF-HRMS) using a data-independent acquisition mode. UPLC-QToF-HRMS data were compared to comprehensive spectral libraries, and drugs were qualitatively identified. Drug Recognition Expert evaluations were performed, and face sheets submitted for 21 participants in this work. In general, the SoToxa® results were consistent with the combined qualitative results observed in Quantisal™ OF specimens and whole blood specimens. Limitations were uncovered for benzodiazepines, opioids and THC. The SoToxa® benzodiazepine assay has high cutoff concentrations for diazepam and clonazepam, limiting its sensitivity and positive predictive value when considering these drugs. SoToxa® opioid screening did not detect fentanyl, which is increasingly prevalent among drug users. Finally, ∆9-THC and its major metabolite 11-nor-9-carboxy-∆9-THC are lipophilic, limiting partitioning into OF. Despite these limitations, the SoToxa® instrument may be useful in assisting law enforcement with identifying individuals driving under the influence of drugs and establishing probable cause at roadside for making impaired driving arrests. Furthermore, Quantisal™ OF may be useful as screening specimens due to their ease of collection and results consistent with whole blood.

Comparison of Breath- and Blood-Alcohol Concentrations in a Controlled Drinking Study.

In this work, 114 volunteers were dosed with 80-proof liquor to produce peak blood-alcohol concentration (BAC) or breath-alcohol concentration (BrAC) of 0.040-0.080 g/100 mL blood or g/210 L breath. This was followed by a 30 minute deprivation period before simultaneous blood and breath samples were collected and the alcohol concentration quantified. BAC was determined by gas chromatography with flame ionization detection and BrAC by a dual-sensor Intox EC/IR II instrument. Paired Student t-tests showed that differences between paired blood- and breath-alcohol results differed significantly. Results from these two measurement methods are highly correlated and, on average, measured BAC was 11.3% greater than BrAC. There were 10 instances of BrAC being greater than the corresponding BAC, and the average difference between these two values was 0.0059 g/100 mL. Agreement plots of coupled BAC and BrAC revealed a mean bias of 0.00754 g/100 mL and 95% limits of agreement (LOA) at -0.00705 and 0.0221 g/100 mL. Once BrAC values were truncated to the hundredths place as required by Wisconsin state statute, only three participants had greater BrAC than corresponding BAC, with an average difference between these values of 0.008 g/100 mL. Agreement plots with truncated BrAC values gave a mean bias of 0.0120 g/100 mL and 95% LOA at -0.00344 and 0.0275 g/100 mL. Data showed that typically, blood samples had greater alcohol concentrations than corresponding breath values. Differences were exacerbated by Wisconsin's statutory requirement that reported breath alcohol measurements be truncated to the hundredths place, whereas blood has no corresponding mandate.

Prenatal stress and its association with amygdala-related structural covariance patterns in youth.

BACKGROUND: Prenatal stress influences brain development and mood disorder vulnerability. Brain structural covariance network (SCN) properties based on inter-regional volumetric correlations may reflect developmentally-mediated shared plasticity among regions. Childhood trauma is associated with amygdala-centric SCN reorganization patterns, however, the impact of prenatal stress on SCN properties remains unknown. METHODS: The study included participants from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) with archival prenatal stress data and structural MRI acquired in young adulthood (age 23-24). SCNs were constructed based on Freesurfer-extracted volumes of 7 subcortical and 34 cortical regions. We compared amygdala degree centrality, a measure of hubness, between those exposed to high vs. low (median split) prenatal stress, defined by maternal reports of stressful life events during the first (n = 93, 57% female) and second (n = 125, 54% female) half of pregnancy. Group differences were tested across network density thresholds (5-40%) using 10,000 permutations, with sex and intracranial volume as covariates, followed by sex-specific analyses. Finally, we sought to replicate our results in an independent all-male sample (n = 450, age 18-20) from the Avon Longitudinal Study of Parents and Children (ALSPAC). RESULTS: The high-stress during the first half of pregnancy ELSPAC group showed lower amygdala degree particularly in men, who demonstrated this difference at 10 consecutive thresholds, with no significant differences in global network properties. At the lowest significant density threshold, amygdala volume was positively correlated with hippocampus, putamen, rostral anterior and posterior cingulate, transverse temporal, and pericalcarine cortex in the low-stress (p(FDR) < 0.027), but not the high-stress (p(FDR) > 0.882) group. Although amygdala degree was nominally lower across thresholds in the high-stress ALSPAC group, these results were not significant. CONCLUSION: Unlike childhood trauma, prenatal stress may shift SCN towards a less amygdala-centric SCN pattern, particularly in men. These findings did not replicate in an all-male ALSPAC sample, possibly due to the sample's younger age and lower prenatal stress exposure.

Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals With Anorexia Nervosa: A Coordinated Analysis by the ENIGMA Eating Disorders Working Group.

BACKGROUND: The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and dependencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data. METHODS: We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251). RESULTS: In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen's d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of undernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients. CONCLUSIONS: The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.

Reduced anterior cingulate cortex volume induced by chronic stress correlates with increased behavioral emotionality and decreased synaptic puncta density.

Clinical and preclinical studies report that chronic stress induces behavioral deficits as well as volumetric and synaptic alterations in corticolimbic brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), nucleus accumbens (NAc) and hippocampus (HPC). Here, we aimed to investigate the volumetric changes associated with chronic restraint stress (CRS) and link these changes to the CRS-induced behavioral and synaptic deficits. We first confirmed that CRS increases behavioral emotionality, defined as collective scoring of anxiety- and anhedonia-like behaviors. We then demonstrated that CRS induced a reduction of total brain volume which negatively correlated with behavioral emotionality. Region-specific analysis identified that only the ACC showed significant decrease in volume following CRS (p < 0.05). Reduced ACC correlated with increased behavioral emotionality (r = -0.56; p = 0.0003). Although not significantly altered by CRS, AMY and NAc (but not the HPC) volumes were negatively correlated with behavioral emotionality. Finally, using structural covariance network analysis to assess shared volumetric variances between the corticolimbic brain regions and associated structures, we found a progressive decreased ACC degree and increased AMY degree following CRS. At the cellular level, reduced ACC volume correlated with decreased PSD95 (but not VGLUT1) puncta density (r = 0.35, p < 0.05), which also correlated with increased behavioral emotionality (r = -0.44, p < 0.01), suggesting that altered synaptic strength is an underlying substrate of CRS volumetric and behavioral effects. Our results demonstrate that CRS effects on ACC volume and synaptic density are linked to behavioral emotionality and highlight key ACC structural and morphological alterations relevant to stress-related illnesses including mood and anxiety disorders.

Recommendations for Toxicological Investigation of Drug-Impaired Driving and Motor Vehicle Fatalities-2021 Update.

This report describes updates to the National Safety Council's Alcohol, Drugs and Impairment Division's recommendations for drug testing in driving under the influence of drug (DUID) cases and motor vehicle fatalities. The updates are based on a survey of drug testing practices in laboratories in the USA and Canada, a comprehensive review of the prior recommendations and data and research on drugs most frequently detected in DUID cases. A consensus meeting was held with representative forensic science practitioners and the authors of this report to update recommendations. No changes were made to the Tier I scope; however, there were changes to cutoffs of some analytes for blood, urine and oral fluid. Due to increased prevalence in DUID cases, trazodone and difluoroethane were added to the Tier II scope. For clarification, Tier I cutoffs reflect free concentrations, and hydrolysis is recommended but not required. The consensus panel concluded that urine is an inferior matrix to blood and oral fluid as it may represent historical use or exposure unrelated to observed impairment; therefore, future iterations of these recommendations will not include urine as a recommended matrix. Laboratories currently testing urine should work with traffic safety partners to encourage the use of blood and oral fluid as more appropriate specimens and adjust their capabilities to provide that testing.

Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk.

Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing 'depression-like' shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n = 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n = 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t = -3.478, p = 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b = 0.005, p = 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997-1.018]) but correlated with symptom severity in men (rho = 0.175, p = 7.957 × 10-4) in one cohort (N = 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men.

Resident Perceptions of Assessment and Feedback in Competency-Based Medical Education: A Focus Group Study of One Internal Medicine Residency Program.

PURPOSE: As key participants in the assessment dyad, residents must be engaged with the process. However, residents' experiences with competency-based medical education (CBME), and specifically with entrustable professional activity (EPA)-based assessments, have not been well studied. The authors explored junior residents' perceptions regarding the implementation of EPA assessment and feedback initiatives in an internal medicine program. METHOD: From May to November 2018, 5 focus groups were conducted with 28 first-year internal medicine residents from the University of Toronto, exploring their experiences with facilitators and barriers to EPA-based assessments in the first years of the CBME initiative. Residents were exposed to EPA-based feedback tools from early in residency. Themes were identified using constructivist grounded theory to develop a framework to understand the resident perception of EPA assessment and feedback initiatives. RESULTS: Residents' discussions reflected a growth mindset orientation, as they valued the idea of meaningful feedback through multiple low-stakes assessments. However, in practice, feedback seeking was onerous. While the quantity of feedback had increased, the quality had not; some residents felt it had worsened, by reducing it to a form-filling exercise. The assessments were felt to have increased daily workload with consequent disrupted workflow and to have blurred the lines between formative and summative assessment. CONCLUSIONS: Residents embraced the driving principles behind CBME, but their experience suggested that changes are needed for CBME in the study site program to meet its goals. Efforts may be needed to reconcile the tension between assessment and feedback and to effectively embed meaningful feedback into CBME learning environments.

White matter microstructure in women with acute and remitted anorexia nervosa: an exploratory neuroimaging study.

Anorexia nervosa (AN) is a highly heritable psychiatric disorder characterized by starvation and emaciation and associated with changes in brain structure. The precise nature of these changes remains unclear, as does their developmental time course and capacity for reversal with weight restoration. In this exploratory neuroimaging study, we sought to characterize changes in white matter microstructure in women with acute and remitted AN. Diffusion-weighted MRI data was collected from underweight women with a current diagnosis of AN (acAN: n = 23), weight-recovered women with a past diagnosis of AN (recAN: n = 23), and age-matched healthy control women (HC: n = 24). Image processing and analysis were performed with Tract-Based Spatial Statistics, part of FSL, and group differences in voxelwise, brain-wide fractional anisotropy (FA) and mean diffusivity (MD), indices of white matter microstructure, were tested with nonparametric permutation and threshold-free cluster enhancement. No significant main effect of group on FA was identified. A significant main effect of group on MD was observed in a large cluster covering 9.2% of white matter and including substantial portions of the corpus callosum, corona radiata, internal capsule, and superior longitudinal fasciculus, and post hoc analyses revealed similar effects of group on axial diffusivity (AD) and radial diffusivity (RD). Clusterwise MD was significantly higher in acAN participants (+3.8%) and recAN participants (+2.9%) than healthy controls, and the same was true for clusterwise AD and RD. Trait-based increases in diffusivity, changes in which have been associated with atypical myelination and impaired axon integrity, suggest a link between altered white matter microstructure and vulnerability to AN, and evidence of reduced oligodendrocyte density in AN provides further support for this hypothesis. Potential mechanisms of action include atypical neurodevelopment and systemic inflammation.

Functional and cognitive outcomes after COVID-19 delirium.

PURPOSE: To ascertain delirium prevalence and outcomes in COVID-19. METHODS: We conducted a point-prevalence study in a cohort of COVID-19 inpatients at University College Hospital. Delirium was defined by DSM-IV criteria. The primary outcome was all-cause mortality at 4 weeks; secondary outcomes were physical and cognitive function. RESULTS: In 71 patients (mean age 61, 75% men), 31 (42%) had delirium, of which only 12 (39%) had been recognised by the clinical team. At 4 weeks, 20 (28%) had died, 26 (36%) were interviewed by telephone and 21 (30%) remained as inpatients. Physical function was substantially worse in people after delirium - 50 out of 166 points (95% CI - 83 to - 17, p = 0.01). Mean cognitive scores at follow-up were similar and delirium was not associated with mortality in this sample. CONCLUSIONS: Our findings indicate that delirium is common, yet under-recognised. Delirium is associated with functional impairments in the medium term.

Outcomes from COVID-19 across the range of frailty: excess mortality in fitter older people.

PURPOSE: Our aim was to quantify the mortality from COVID-19 and identify any interactions with frailty and other demographic factors. METHODS: Hospitalised patients aged ≥ 70 were included, comparing COVID-19 cases with non-COVID-19 controls admitted over the same period. Frailty was prospectively measured and mortality ascertained through linkage with national and local statutory reports. RESULTS: In 217 COVID-19 cases and 160 controls, older age and South Asian ethnicity, though not socioeconomic position, were associated with higher mortality. For frailty, differences in effect size were evident between cases (HR 1.02, 95% CI 0.93-1.12) and controls (HR 1.99, 95% CI 1.46-2.72), with an interaction term (HR 0.51, 95% CI 0.37-0.71) in multivariable models. CONCLUSIONS: Our findings suggest that (1) frailty is not a good discriminator of prognosis in COVID-19 and (2) pathways to mortality may differ in fitter compared with frailer older patients.