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.

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.

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.

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.

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.

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.

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.

Identification of genetic overlap and novel risk loci for attention-deficit/hyperactivity disorder and bipolar disorder.

Differential diagnosis between childhood onset attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) remains a challenge, mainly due to overlapping symptoms and high rates of comorbidity. Despite this, genetic correlation reported for these disorders is low and non-significant. Here we aimed to better characterize the genetic architecture of these disorders utilizing recent large genome-wide association studies (GWAS). We analyzed independent GWAS summary statistics for ADHD (19,099 cases and 34,194 controls) and BD (20,352 cases and 31,358 controls) applying the conditional/conjunctional false discovery rate (condFDR/conjFDR) statistical framework that increases the power to detect novel phenotype-specific and shared loci by leveraging the combined power of two GWAS. We observed cross-trait polygenic enrichment for ADHD conditioned on associations with BD, and vice versa. Leveraging this enrichment, we identified 19 novel ADHD risk loci and 40 novel BD risk loci at condFDR <0.05. Further, we identified five loci jointly associated with ADHD and BD (conjFDR < 0.05). Interestingly, these five loci show concordant directions of effect for ADHD and BD. These results highlight a shared underlying genetic risk for ADHD and BD which may help to explain the high comorbidity rates and difficulties in differentiating between ADHD and BD in the clinic. Improving our understanding of the underlying genetic architecture of these disorders may aid in the development of novel stratification tools to help reduce these diagnostic difficulties.

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.

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.

Occupational causes of hypersensitivity pneumonitis: a systematic review and compendium.

BACKGROUND: Hypersensitivity pneumonitis (HP) is caused by a variety of antigens and low-molecular-weight chemicals, often through occupational exposure. Making a diagnosis of HP and identifying a cause are challenging. Cryptogenic cases are frequently reported, and missing or incomplete exposure histories can cause misclassification. AIMS: To provide an evidence-based compendium of sources of exposure and causes of HP for the clinician, through systematic review of medical literature. METHODS: Articles related to HP causative agents and occupational exposure were searched from the databases OVID Medline (1946 to October 2020) and EMBASE (1974 to October 2020). Abstracts and full texts of articles were screened by two reviewers. Data on causative antigens, occupational source of exposure and any associated eponymous name were extracted and grouped according to source of exposure. RESULTS: A total of 1790 articles were identified, from which 305 articles met the inclusion criteria. An additional 22 articles were identified from citation lists of the selected review articles. Sources of exposure identified for HP were sorted into 14 categories of work (agricultural, plant matter processing, wood, animal-related, foodstuff, food processing, metal processing, polymers, other manufacturing, chemicals, aerosolized water, service, waste and sewage and wind instruments). CONCLUSIONS: This work is a comprehensive list of occupational causative agents and exposures causing HP. Cases are grouped by source of exposure, allowing an immediately accessible compendium of causes for use during occupational exposure assessment, which could also form the basis for a clinical questionnaire.

CNVs conferring risk of autism or schizophrenia affect cognition in controls.

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.

The impact of reclassification of C3 predominant glomerulopathies on diagnostic accuracy, outcome and prognosis in patients with C3 glomerulonephritis.

BACKGROUND: C3 glomerulonephritis is a recently described entity with heterogeneous histopathological features. This study was conducted to assess the effect of reclassification of C3 glomerulopathies on renal outcomes, mortality, and response to therapy. METHODS: We undertook a retrospective analysis of 857 renal biopsies collected at The Canberra Hospital. Samples with predominant C3 staining were reviewed by a renal histopathologist. Of 31 biopsies with predominant C3 staining, 10 fulfilled histological criteria for C3 glomerulonephritis, while the remaining 21 cases were used as C3 Controls. RESULTS: Aside from a higher incidence of C3 glomerulonephritis in Torres Strait islanders (40% vs 5% C3 Controls, p = 0.04), presentation demographics were similar between the two groups. Median creatinine at diagnosis was higher in patients with C3 glomerulonephritis (253 umol/L IQR 103-333 vs 127 umol/L C3 Controls, IQR 105-182, p = 0.01). Prior to reclassification, a majority of C3 glomerulonephritis cases were diagnosed as membranoproliferative glomerulonephritis (60% vs 5% (C3 Controls) p < 0.01). Electron microscopy demonstrated all C3 glomerulonephritis patients had C3 deposition (100% vs 38% p = 0.02), these deposits were amorphous in nature (50% vs 5% respectively p = 0.007). C3 glomerulonephritis patients had shorter median follow-up (405 days IQR 203-1197 vs 1822 days respectively, IQR 1243-3948, p = 0.02). Mortality was higher in C3 glomerulonephritis patients (30% vs 14% in C3 Controls (log rank p = 0.02)). CONCLUSION: We have devised a diagnostic and treatment algorithm based on the results of literature review and our current study. Further prospective assessment is required to review diagnostic and treatment outcomes for this disease in Australian centres.

Updated review of reported cases of reactive airways dysfunction syndrome.

BACKGROUND: A previous systematic review of the diagnosis of reactive airways dysfunction syndrome (RADS), undertaken from 1985 to 2004, found a lack of standardization of case reporting, thus misattribution of symptoms can occur. AIMS: We aimed to update the systematic review, update the list of reported causes and see whether a more structured approach to reporting has been adopted. METHODS: We undertook a systematic literature review, using the databases EMBASE and Ovid MEDLINE, with search terms 'reactive airways dysfunction syndrome' or 'asthma AND acute irritant', and reported according to PRISMA guidelines. We included papers and abstracts published from January 2005 to September 2019, and articles were grouped by the presence or absence of diagnostic features: 'definite' RADS (met Brooks' criteria) or 'possible' RADS (Brooks' criteria not met or insufficient data). We collected demographic and diagnostic data for cases, where given. RESULTS: Eleven papers and six conference abstracts met the inclusion criteria, 13 of which were case series or reports, and comprised 752 cases in total; seven articles met Brooks' criteria for RADS diagnosis. A variety of agents were implicated, with chlorine or chlorine-releasing molecules most frequently reported. CONCLUSIONS: A lack of standardized reporting of RADS remains. The majority of published articles and conference abstracts either do not meet, or contain insufficient data to judge against, Brooks' criteria, particularly in relation to onset of symptoms and bronchial hyper-reactivity or variability of airflow obstruction. Some novel agents are described, in keeping with recognized structural taxonomies.

Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits.

Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.

Occupational asthma caused by peracetic acid-hydrogen peroxide mixture.

BACKGROUND: Healthcare practice in the UK has moved away from using aldehyde disinfectants for the decontamination of endoscopes, in part due to the risk of respiratory sensitization. Peracetic acid (PAA) in combination with hydrogen peroxide (HP) is a commonly used alternative. AIM: We describe a case of occupational asthma (OA) diagnosed at our specialist occupational lung disease clinic and caused by occupational exposure to PAA-HP mixture, used as a disinfectant in an endoscope washer-disinfector machine. CASE REPORT: A 48-year-old man employed as a mycologist and environmental microbiologist at a Birmingham city hospital, UK, presented following an acute exposure to PAA-HP mixture causing lacrimation, burning optic pain and headache. He had also experienced symptoms suggestive of OA for the preceding 10 months, and the diagnosis was confirmed through OASYS analysis of serial peak expiratory flow measurements. He had been exposed to PAA-HP mixture whilst working in the endoscopy department for 12 months prior to the acute episode, and a subsequent specific inhalation challenge test was positive with a late asthmatic response to PAA-HP mixture. CONCLUSION: This case provides evidence for a sensitization mechanism in OA caused by PAA-HP mixture.

Online Differential Thermal Isotope Analysis of Hydration Water in Minerals by Cavity Ringdown Laser Spectroscopy.

We have developed a new method for measuring the isotopic composition (δ18O and δD) of different types of bonded water (e.g., molecular water, hydroxyl) contained in hydrated minerals by coupling a thermal gravimeter (TG) and a cavity ringdown laser spectrometer (CRDS). The method involves precisely step-heating a mineral sample, allowing the separation of the different types of waters that are released at different temperatures. Simultaneously, the water vapor evolved from the mineral sample is analyzed for oxygen and hydrogen isotopes by CRDS. Isotopic values for the separate peaks are calculated by integrating the product of the water amounts and its isotopic values, after correcting for background. We provide examples of the application of the differential thermal isotope analysis (DTIA) method to a variety of hydrous minerals and mineraloids including gypsum, clays, and amorphous silica (opal). The isotopic compositions of the total water evolved from a set of natural gypsum samples by DTIA are compared with the results of a conventional offline water extraction method followed by CRDS analysis. The results from both methods are in excellent agreement, and precisions (1σ) for δ18O (±0.12‰) and δD (±0.8‰) of the total gypsum hydration water from the DTIA method are comparable to that obtained by the offline method. A range of analytical challenges and solutions (e.g., spectroscopic interferences produced by VOCs in natural samples, isotopic exchange with structural oxygen, etc.) are discussed. The DTIA method has wide ranging applications for addressing fundamental problems across many disciplines in earth and planetary sciences, including paleoclimatology, sedimentology, volcanology, water exchange between the solid earth and hydrosphere, and water on Mars and other planetary bodies.

Rate of de novo mutations and the importance of father's age to disease risk.

Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 × 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.