Outcomes of Six Specific Types of Post-Hospital Brain Injury Rehabilitation Programs.

OBJECTIVE: Evaluate outcomes of intensive posthospital brain injury rehabilitation programs compared to supported living (SL) programs; explore variations in outcome by diagnostic category (traumatic brain injury, stroke, and other acquired brain injury [ABI]) and specific program type. SETTING: Data were obtained from Residential Neurobehavioral, Residential Neurorehabilitation, Home and Community Neurorehabilitation, Day Treatment, Outpatient Neurorehabilitation, and SL programs serving individuals with ABI. PARTICIPANTS: A total of 2120 individuals with traumatic brain injury, stroke, or other ABI participated in this study. MAIN MEASURES: The main measures are sex, age, time since injury, and Mayo-Portland Adaptability Inventory (4th edition; MPAI-4). DESIGN: Retrospective analyses of demographic variables and MPAI-4 Total, index, and subscale Rasch-derived T-scores on admission and discharge. RESULTS: Gains on MPAI-4  Total T-scores were significantly greater for the intensive rehabilitation (IR) group in comparison to stable functioning in the SL group (F = 236.69, P < .001, partial η2 = .101) while controlling for admission/time 1 scores; similar results were found for MPAI-4 indices and subscales. For the IR cohort, discharge scores differed by diagnostic category after controlling for admission scores for the Total MPAI-4 T-score (F = 22.65, P < .001, partial η2 = .025), as well as all indices and subscales. A statistically significant interaction between program type and diagnostic group on discharge MPAI-4 Total T-scores (F = 2.55, P = .018, partial η2 = .01) after controlling for admission scores indicated that differing outcomes across diagnoses also varied by program type. Varying significant main effects and interactions were apparent for MPAI-4 indices and subscales with generally small effect sizes. CONCLUSIONS: Significant gains on MPAI-4 variables across IR program types compared to no change over a comparable period of time for SL programs supports the effectiveness of posthospital brain injury rehabilitation. This finding in the presence of small effect sizes on outcome variables for program type and for significant interactions between program type and diagnostic category suggests that participants generally were appropriately matched to program type and benefited from interventions provided through specific program types.

Distinguishing Characteristics of Admissions to Various Types of Posthospital Brain Injury Rehabilitation Programs.

OBJECTIVE: Describe and compare the demographic characteristics and disability profiles of individuals admitted to 6 types of posthospital brain injury rehabilitation (PHBIR) programs. SETTING: Data from Residential Neurobehavioral, Residential Neurorehabilitation, Home and Community Neurorehabilitation, Day Treatment, Outpatient Neurorehabilitation, and Supported Living programs serving individuals with acquired brain injury (ABI). PARTICIPANTS: Two thousand twenty-eight individuals with traumatic brain injury (TBI), stroke, or other ABI. MAIN MEASURES: Sex, age, time since injury, and Mayo-Portland Adaptability Inventory, 4th edition (MPAI-4). DESIGN: Retrospective analyses of demographic variables and MPAI-4 Total, Index, and subscale Rasch-derived T-scores on admission comparing diagnostic categories and program types within diagnostic categories. RESULTS: Participants with TBI were predominantly male, and those with stroke were generally older. Admissions to more intensive and supervised programs (residential neurobehavioral and residential neurorehabilitation) generally showed greater disability than admissions to home and community programs who were more disabled than participants in day treatment and outpatient programs. Residential neurobehavioral and supported living program participants generally were male and had TBI. Home and community admissions tended to be more delayed than residential neurorehabilitation admissions. The majority of those with other ABI were admitted to outpatient rather than more intensive programs. Additional analyses demonstrated significant differences in MPAI-4 profiles among the various program types. CONCLUSIONS: Admissions with TBI, stroke, and other ABI to PHBIR differ in demographic factors and disability profiles. When examined within each diagnostic category, demographic features and disability profiles also distinguish among admissions to the various program types. Results provide insights about decision-making in referral patterns to various types of PHBIR programs, although other factors not available for analysis (eg, participant/family preference, program, and funding availability) likely also contribute to admission patterns.

GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis.

Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson's disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

Rasch Analysis of the Mayo-Portland Adaptability Inventory for Posthospital Brain Injury Rehabilitation.

OBJECTIVES: (1) Reexamine the item structure and reliability of the Mayo-Portland Adaptability Inventory (4th ed; MPAI-4) through Rasch analysis of admission and discharge scores for a large sample of adults with acquired brain injury (ABI) who participated in various types of posthospital brain injury rehabilitation (PHBIR) programs; (2) compare differential item functioning (DIF) for traumatic brain injury (TBI), stroke and other ABI; and (3) explore the viability of more specific subscales in addition to the established indices. SETTING: Data from Residential Neurobehavioral, Residential Neurorehabilitation, Home and Community, Day Treatment, and Outpatient rehabilitation programs serving individuals with ABI. PARTICIPANTS: A total of 2154 individuals with TBI, stroke, or other ABI. DESIGN: Retrospective analysis of de-identified admission and discharge data from the Foundation to Advance Brain Rehabilitation (FABR) consortium database. MAIN MEASURE: MPAI-4. RESULTS: After adjusting 4 misfitting items and eliminating 20 misfitting persons, the MPAI-4 demonstrated real person reliability/separation = 0.93/3.52 and real item reliability/separation = 1.00/24.02. Independent Rasch analyses by diagnostic category found similar reliabilities and separations. Residual item correlations and principal component analysis of residuals (PCAR) indicated areas of local dependence arranged hierarchically reflecting the full-scale item hierarchy and providing the basis for 3 new subscales of Physical Abilities, Cognitive Abilities, and Autonomy. DIF across diagnostic categories revealed differences in item elevations characteristic of typical patients in each category. Measure means and SDs were very similar across categories. CONCLUSIONS: MPAI-4 items demonstrate very good person and item reliabilities for individuals with TBI, stroke, and other ABI at a level that supports individual evaluation. Variations in item calibrations across diagnostic categories reflect the differential characteristics of typical patients within categories. The entire measure provides an overall assessment of common sequalae of ABI, and standard indices used in combination with newly derived subscales provide more specific assessments of rehabilitation needs for treatment planning.

Multi-polygenic scores in psychiatry: From disorder specific to transdiagnostic perspectives.

The dense co-occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that transcend diagnostic boundaries. In this study, we examined the genetic liability for eight major psychiatric disorder phenotypes under both a disorder-specific and a transdiagnostic framework. The study sample (n = 513) was deeply phenotyped, consisting of 452 patients from tertiary care with mood disorders, anxiety disorders (ANX), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, and/or substance use disorders (SUD) and 61 unaffected comparison individuals. We computed subject-specific polygenic risk score (PRS) profiles and assessed their associations with psychiatric diagnoses, comorbidity status, as well as cross-disorder behavioral dimensions derived from a rich battery of psychopathology assessments. High PRSs for depression were unselectively associated with the diagnosis of SUD, ADHD, ANX, and mood disorders (p < 1e-4). In the dimensional approach, four distinct functional domains were uncovered, namely the negative valence, social, cognitive, and regulatory systems, closely matching the major functional domains proposed by the Research Domain Criteria (RDoC) framework. Critically, the genetic predisposition for depression was selectively reflected in the functional aspect of negative valence systems (R2 = 0.041, p = 5e-4) but not others. This study adds evidence to the ongoing discussion about the misalignment between current psychiatric nosology and the underlying psychiatric genetic etiology and underscores the effectiveness of the dimensional approach in both the functional characterization of psychiatric patients and the delineation of the genetic liability for psychiatric disorders.

Predicting ADHD in alcohol dependence using polygenic risk scores for ADHD.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a high degree of comorbidity, including substance misuse. We aimed to assess whether ADHD polygenic risk scores (PRS) could predict ADHD diagnosis in alcohol dependence (AD). ADHD PRS were generated for 1223 AD subjects with ADHD diagnosis information and 1818 healthy controls. ADHD PRS distributions were compared to evaluate the differences between healthy controls and AD cases with and without ADHD. We found increased ADHD PRS means in the AD cohort with ADHD (mean 0.30, standard deviation (SD) 0.92; p = 3.9 × 10-6 ); and without ADHD (mean - 0.00, SD 1.00; p = 5.2 × 10-5 ) compared to the healthy control subjects (mean - 0.17, SD 0.99). The ADHD PRS means differed within the AD group with a higher ADHD PRS mean in those with ADHD, odds ratio (OR) 1.34, confidence interval (CI) 1.10 to 1.65; p = 0.002. This study showed a positive relationship between ADHD PRS and risk of ADHD in individuals with co-occurring AD indicating that ADHD PRS may have utility in identifying individuals that are at a higher or lower risk of ADHD. Further larger studies need to be conducted to confirm the reliability of the results before ADHD PRS can be considered as a robust biomarker for diagnosis.

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura.

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.

Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses.

Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality.

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

Job exposure matrices for occupational respiratory disease: a narrative review.

BACKGROUND: Job exposure matrices (JEMs) are epidemiological tools used to provide estimations of occupational exposures when it is not feasible to complete detailed individual occupational histories. AIMS: To identify and summarize the characteristics of published general population JEMs (GPJEM) of inhalable occupational exposures applied in studies of respiratory disease. METHODS: MEDLINE and EMBASE databases were searched using pre-defined search terms, with screening performed by two independent reviewers to identify studies reporting the use of a GPJEM. JEM creation papers were subsequently identified and reviewed for each individual GPJEM, noting its characteristics in terms of occupational classification system and exposure estimates. RESULTS: From 728 studies identified in initial searches, 33 GPJEMs of inhalable occupational exposures were identified. Versions of the International Standards Classification of Occupations were the most used occupational classification system. Binary, probability and intensity-based exposure estimates were most frequently reported in GPJEMs. CONCLUSIONS: Selection of a GPJEM to apply in epidemiological research should be based on the exposure(s) of interest, time period of occupations under review, geographical region for intended use, occupation classification system used and the exposure estimate outcome.

DanMAC5: a browser of aggregated sequence variants from 8,671 whole genome sequenced Danish individuals.

OBJECTIVES: Allele counts of sequence variants obtained by whole genome sequencing (WGS) often play a central role in interpreting the results of genetic and genomic research. However, such variant counts are not readily available for individuals in the Danish population. Here, we present a dataset with allele counts for sequence variants (single nucleotide variants (SNVs) and indels) identified from WGS of 8,671 (5,418 females) individuals from the Danish population. The data resource is based on WGS data from three independent research projects aimed at assessing genetic risk factors for cardiovascular, psychiatric, and headache disorders. To enable the sharing of information on sequence variation in Danish individuals, we created summarized statistics on allele counts from anonymized data and made them available through the European Genome-phenome Archive (EGA, https://identifiers.org/ega. DATASET: EGAD00001009756 ) and in a dedicated browser, DanMAC5 (available at www.danmac5.dk ). The summary level data and the DanMAC5 browser provide insight into the allelic spectrum of sequence variants segregating in the Danish population, which is important in variant interpretation. DATA DESCRIPTION: Three WGS datasets with an average coverage of 30x were processed independently using the same quality control pipeline. Subsequently, we summarized, filtered, and merged allele counts to create a high-quality summary level dataset of sequence variants.

Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

An Observational Cohort Study of the Role of Level of Effort in Post-Acute Brain Injury Rehabilitation.

OBJECTIVE: To investigate the role of participant level of effort (LoE) on outcome in post-acute brain injury rehabilitation with the hypothesis that greater effort is associated with more positive outcomes. DESIGN: Observational cohort study. SETTING: Comprehensive integrated rehabilitation program for brain injury within a skilled nursing facility. PARTICIPANTS: Consecutive admissions with acquired brain injury (N=101). INTERVENTIONS: Individualized interdisciplinary brain injury rehabilitation; therapist rating of participant LoE with Acquired Brain Injury LoE Scale (ABI-LoES) during physical therapy, occupational therapy, and speech and language pathology sessions. MAIN OUTCOME MEASURES: Mayo-Portland Adaptability Inventory, fourth edition (MPAI-4); Supervision Rating Scale (SRS). RESULTS: Linear regression showed that discharge MPAI-4 Total T scores were significantly associated with mean ABI-LoES rating, admission MPAI-4 Total T scores, age at admission, and days from injury but not with standard deviation of ABI-LoES rating, sex, injury type, length of stay, or treatment before or during the COVID-19 pandemic. Discharge SRS scores were significantly associated with mean ABI-LoES rating, admission SRS scores, and age. A 1-unit increase in mean ABI-LoES rating was associated with 5.1-unit lower discharge MPAI-4 Total T scores and 1.5 lower discharge SRS scores, after controlling for other variables. Logistic regression showed that the odds of achieving a minimal clinically important difference on the MPAI-4 were 8.34 times higher with each 1-unit increase in mean ABI-LoES rating after controlling for other variables. Admission MPAI-4 was negatively associated with mean ABI-LoES rating (ß=-0.07, t=-8.85, P<.0001). CONCLUSIONS: After controlling for nonmodifiable variables, average ABI-LoES rating is positively associated with outcome. Initial level of disability is negatively associated with mean ABI-LoES rating.

Thirty novel sequence variants impacting human intracranial volume.

Intracranial volume, measured through magnetic resonance imaging and/or estimated from head circumference, is heritable and correlates with cognitive traits and several neurological disorders. We performed a genome-wide association study meta-analysis of intracranial volume (n = 79 174) and found 64 associating sequence variants explaining 5.0% of its variance. We used coding variation, transcript and protein levels, to uncover 12 genes likely mediating the effect of these variants, including GLI3 and CDK6 that affect cranial synostosis and microcephaly, respectively. Intracranial volume correlates genetically with volumes of cortical and sub-cortical regions, cognition, learning, neonatal and neurological traits. Parkinson's disease cases have greater and attention deficit hyperactivity disorder cases smaller intracranial volume than controls. Our Mendelian randomization studies indicate that intracranial volume associated variants either increase the risk of Parkinson's disease and decrease the risk of attention deficit hyperactivity disorder and neuroticism or correlate closely with a confounder.

Occupational asthma in teachers.

BACKGROUND: Work-related asthma symptoms are common in teachers and teaching assistants, there are few studies evaluating their causes. AIMS: To identify causes of occupational asthma in teachers and teaching assistants referred to the Birmingham Occupational Lung Disease clinic 2000-20 using evaluation of serial Peak Expiratory Flow (PEF) records. METHODS: Teachers and teaching assistants with possible occupational asthma were asked to record PEF 2-hourly at home and work for 4 weeks. Their records were evaluated with the Oasys programme. Those with a positive score for any of the three scores (area between curves (ABC), timepoint and Oasys score from discriminant analysis) were included. Repeat records were made as indicated to help identify the cause and the effects of remedial actions. RESULTS: Thirty-eight teachers or teaching assistants met the inclusion criteria with all three Oasys scores positive in 24, 2/3 scores in nine and 1/3 in five. The building was the likely cause in 17 (in new builds particularly acrylates from carpet adhesives and in old buildings mould and construction dust), bystander exposure to agents in the schools in 12 (cleaning agents, acrylates from photocopiers and chloramines from indoor pools) and materials used in the classroom in 9 (most commonly MDF in design and technology classes). We illustrate how the PEF records helped identify the cause. CONCLUSIONS: Oasys analysis of PEF records is a useful method of evaluating occupational asthma in teachers and identified difficult to confirm causes where successful remediation or redeployment was achieved.

Working memory and reaction time variability mediate the relationship between polygenic risk and ADHD traits in a general population sample.

Endophenotypes are heritable and quantifiable traits indexing genetic liability for a disorder. Here, we examined three potential endophenotypes, working memory function, response inhibition, and reaction time variability, for attention-deficit hyperactivity disorder (ADHD) measured as a dimensional latent trait in a large general population sample derived from the Adolescent Brain Cognitive DevelopmentSM Study. The genetic risk for ADHD was estimated using polygenic risk scores (PRS) whereas ADHD traits were quantified as a dimensional continuum using Bartlett factor score estimates, derived from Attention Problems items from the Child Behaviour Checklist and Effortful Control items from the Early Adolescent Temperament Questionnaire-Revised. The three candidate cognitive endophenotypes were quantified using task-based performance measures. Higher ADHD PRSs were associated with higher ADHD traits, as well as poorer working memory performance and increased reaction time variability. Lower working memory performance, poorer response inhibition, and increased reaction time variability were associated with more pronounced ADHD traits. Working memory and reaction time variability partially statistically mediated the relationship between ADHD PRS and ADHD traits, explaining 14% and 16% of the association, respectively. The mediation effect was specific to the genetic risk for ADHD and did not generalise to genetic risk for four other major psychiatric disorders. Together, these findings provide robust evidence from a large general population sample that working memory and reaction time variability can be considered endophenotypes for ADHD that mediate the relationship between ADHD PRS and ADHD traits.

Occupational asthma in office workers.

BACKGROUND: Office work has a relative perception of safety for the worker. Data from surveillance schemes and population-based epidemiological studies suggest that office work carries a low risk of occupational asthma (OA). Office workers are frequently used as comparators in studies of occupational exposure and respiratory disease. AIMS: We aimed to describe and illustrate our tertiary clinical experience of diagnosing OA in office workers. METHODS: We searched the Birmingham NHS Occupational Lung Disease Service clinical database for cases of occupational respiratory disease diagnosed between 2002 and 2020, caused by office work or in office workers. For patients with OA, we gathered existing data on demographics, diagnostic tests including Occupational Asthma SYStem (OASYS) analysis of serial peak expiratory flow and specific inhalational challenge, and employment outcome. We summarised data and displayed them alongside illustrative cases. RESULTS: There were 47 cases of OA (5% of all asthma) confirmed using OASYS analysis of PEFs in the majority. Sixty percent of cases occurred in healthcare, education and government sectors. The most frequently implicated causative exposures or agents were: indoor air (9), printing, copying and laminating (7), cleaning chemicals (4), mould and damp (4), and acrylic flooring and adhesives (4). Exposures were grouped into internal office environment, office ventilation-related and adjacent environment. CONCLUSIONS: Clinicians should be vigilant for exposures associated with OA in office workers who present with work-related symptoms, where respiratory sensitizing agents may be present. A structured approach to assessment of the workplace is recommended.