A workshop to showcase the diversity of scientists to middle school students.

Identity matters in science, technology, engineering, mathematics, and medicine (STEMM) because it can affect an individual's long-term sense of belonging, which may in turn affect their persistence in STEMM. Early K-12 science classes often teach students about the foundational discoveries of the field, which have been predominately made, or at least published, by White men. This homogeneity can leave underrepresented individuals in STEMM feeling isolated, and underrepresented K-12 students may feel as though they cannot enter STEMM fields. This study aimed to examine these feelings of inclusivity in STEMM through an interactive workshop that asked middle schoolers to identify scientists from images of individuals with various racial and gender identities. We found that a plurality of students had a positive experience discussing diversity in science and recognizing underrepresented individuals as scientists.NEW & NOTEWORTHY We observed positive sentiments from middle school students following a workshop that showcased diversity in science. This workshop uniquely encourages students to recognize that physiologists and scientists today are much more diverse than textbooks typically demonstrate and can be adapted for middle schoolers, high schoolers, and college students.

A workshop on mitochondria for students to improve understanding of science and hypothesis forming.

There remains a clear deficiency in recruiting middle school students in science, technology, engineering, mathematics, and medicine fields, especially for those students entering physiology from underrepresented backgrounds. A large part of this may be arising from a disconnect between how science is typically practiced at a collegiate and K-12 level. Here, we have envisioned mitochondria and their diverse subcellular structures as an involver for middle school students. We present the framework for a workshop that familiarizes students with mitochondria, employing three-dimensional visual-spatial learning and real-time critical thinking and hypothesis forming. This workshop had the goal of familiarizing middle school students with the unique challenges the field currently faces and better understanding the actuality of being a scientist through critical analysis including hypothesis forming. Findings show that middle school students responded positively to the program and felt as though they had a better understanding of mitochondria. Future implications for hands-on programs to involve underrepresented students in science are discussed, as well as potential considerations to adapt it for high school and undergraduate students.NEW & NOTEWORTHY Here we employ a workshop that utilizes blended and tactile learning to teach middle schoolers about mitochondrial structure. By creating an approachable and fun workshop that can be utilized for middle school students, we seek to encourage them to join a career in physiology.

Biases arising from linked administrative data for epidemiological research: a conceptual framework from registration to analyses.

Linked administrative data offer a rich source of information that can be harnessed to describe patterns of disease, understand their causes and evaluate interventions. However, administrative data are primarily collected for operational reasons such as recording vital events for legal purposes, and planning, provision and monitoring of services. The processes involved in generating and linking administrative datasets may generate sources of bias that are often not adequately considered by researchers. We provide a framework describing these biases, drawing on our experiences of using the 100 Million Brazilian Cohort (100MCohort) which contains records of more than 131 million people whose families applied for social assistance between 2001 and 2018. Datasets for epidemiological research were derived by linking the 100MCohort to health-related databases such as the Mortality Information System and the Hospital Information System. Using the framework, we demonstrate how selection and misclassification biases may be introduced in three different stages: registering and recording of people's life events and use of services, linkage across administrative databases, and cleaning and coding of variables from derived datasets. Finally, we suggest eight recommendations which may reduce biases when analysing data from administrative sources.

Impact of Brazil's Bolsa Família Programme on cardiovascular and all-cause mortality: a natural experiment study using the 100 Million Brazilian Cohort.

BACKGROUND: Cardiovascular disease (CVD) has a disproportionate effect on mortality among the poorest people. We assessed the impact on CVD and all-cause mortality of the world's largest conditional cash transfer, Brazil's Bolsa Família Programme (BFP). METHODS: We linked administrative data from the 100 Million Brazilian Cohort with BFP receipt and national mortality data. We followed individuals who applied for BFP between 1 January 2011 and 31 December 2015, until 31 December 2015. We used marginal structural models to estimate the effect of BFP on all-age and premature (30-69 years) CVD and all-cause mortality. We conducted stratified analyses by levels of material deprivation and access to healthcare. We checked the robustness of our findings by restricting the analysis to municipalities with better mortality data and by using alternative statistical methods. RESULTS: We studied 17 981 582 individuals, of whom 4 855 324 were aged 30-69 years. Three-quarters (76.2%) received BFP, with a mean follow-up post-award of 2.6 years. We detected 106 807 deaths by all causes, of which 60 893 were premature; and 23 389 CVD deaths, of which 15 292 were premature. BFP was associated with reductions in premature all-cause mortality [hazard ratio (HR) = 0.96, 95% CI = 0.94-0.98], premature CVD (HR = 0.96, 95% CI = 0.92-1.00) and all-age CVD (HR = 0.96, 95% CI = 0.93-1.00) but not all-age all-cause mortality (HR = 1.00, 95% CI = 0.98-1.02). In stratified and robustness analyses, BFP was consistently associated with mortality reductions for individuals living in the two most deprived quintiles. CONCLUSIONS: BFP appears to have a small to null effect on premature CVD and all-cause mortality in the short term; the long-term impact remains unknown.

Comparing Anxiety and Depression in Information Technology Workers with Others in Employment: A UK Biobank Cohort Study.

OBJECTIVES: Despite reported psychological hazards of information technology (IT) work, studies of diagnosed mental health conditions in IT workers are lacking. We investigated self-reported mental health outcomes and incident anxiety/depression in IT workers compared to others in employment in a large population-based cohort. METHODS: We evaluated self-reported mental health outcomes in the UK Biobank cohort and incident diagnosed anxiety/depression through health record linkage. We used logistic regression and Cox models to compare the risks of prevalent and incident anxiety/depression among IT workers with all other employed participants. Furthermore, we compared outcomes within IT worker subgroups, and between these subgroups and other similar occupations within their major Standard Occupational Classification (SOC) group. RESULTS: Of 112 399 participants analyzed, 4093 (3.6%) were IT workers. At baseline, IT workers had a reduced odds (OR = 0.66, 95%CI: 0.52-0.85) of anxiety/depression symptoms and were less likely (OR = 0.87, 95%CI: 0.83-0.91) to have ever attended their GP for anxiety/depression, compared to all other employed participants, after adjustment for confounders. The IT technician subgroup were more likely (OR = 1.22, 95%CI: 1.07-1.40) to have previously seen their GP or a psychiatrist (OR = 1.31, 95%CI: 1.06-1.62) for anxiety/depression than their SOC counterparts. IT workers had lower incident anxiety/depression (HR = 0.84, 95%CI 0.77-0.93) compared to all other employed participants, after adjustment for confounders. CONCLUSIONS: Our findings from this, the first longitudinal study of IT worker mental health, set the benchmark in our understanding of the mental health of this growing workforce and identification of high-risk groups. This will have important implications for targeting mental health workplace interventions.

Effects of depression on employment and social outcomes: a Mendelian randomisation study.

BACKGROUND: Depression is associated with socioeconomic disadvantage. However, whether and how depression exerts a causal effect on employment remains unclear. We used Mendelian randomisation (MR) to investigate whether depression affects employment and related outcomes in the UK Biobank dataset. METHODS: We selected 227 242 working-age participants (40-64 in men, 40-59 years for women) of white British ethnicity/ancestry with suitable genetic data in the UK Biobank study. We used 30 independent genetic variants associated with depression as instruments. We conducted observational and two-sample MR analyses. Outcomes were employment status (employed vs not, and employed vs sickness/disability, unemployment, retirement or caring for home/family); weekly hours worked (among employed); Townsend Deprivation Index; highest educational attainment; and household income. RESULTS: People who had experienced depression had higher odds of non-employment, sickness/disability, unemployment, caring for home/family and early retirement. Depression was associated with reduced weekly hours worked, lower household income and lower educational attainment, and increased deprivation. MR analyses suggested depression liability caused increased non-employment (OR 1.16, 95% CI 1.06 to 1.26) and sickness/disability (OR 1.56, 95% CI 1.34 to 1.82), but was not causal for caring for home/family, early retirement or unemployment. There was little evidence from MR that depression affected weekly hours worked, educational attainment, household income or deprivation. CONCLUSIONS: Depression liability appears to cause increased non-employment, particularly by increasing disability. There was little evidence of depression affecting early retirement, hours worked or household income, but power was low. Effective treatment of depression might have important economic benefits to individuals and society.

Clinical burden, risk factor impact and outcomes following myocardial infarction and stroke: A 25-year individual patient level linkage study.

BACKGROUND: Understanding trends in the incidence and outcomes of myocardial infarction and stroke, and how these are influenced by changes in cardiovascular risk factors can inform health policy and healthcare provision. METHODS: We identified all patients 30 years or older with myocardial infarction or stroke in Scotland. Risk factor levels were determined from national health surveys. Incidence, potential impact fractions and burden attributable to risk factor changes were calculated. Risk of subsequent fatal and non-fatal events (myocardial infarction, stroke, bleeding and heart failure hospitalization) were calculated with multi-state models. FINDINGS: From 1990 to 2014, there were 372,873 (71±13 years) myocardial infarctions and 290,927 (74±13 years) ischemic or hemorrhagic strokes. Age-standardized incidence per 100,000 fell from 1,069 (95% confidence interval, 1,024-1,116) to 276 (263-290) for myocardial infarction and from 608 (581-636) to 188 (178-197) for ischemic stroke. Systolic blood pressure, smoking and cholesterol decreased, but body-mass index increased, and diabetes prevalence doubled. Changes in risk factors accounted for a 74% (57-91%) reduction in myocardial infarction and 68% (55-83%) reduction in ischemic stroke. Following myocardial infarction, the risk of death decreased (30% to 20%), but non-fatal events increased (20% to 24%) whereas the risk of both death (47% to 34%) and non-fatal events (22% to 17%) decreased following stroke. INTERPRETATION: Over the last 25 years, substantial reductions in myocardial infarction and ischemic stroke incidence are attributable to major shifts in risk factor levels. Deaths following the index event decreased for both myocardial infarction and stroke, but rates remained substantially higher for stroke. FUNDING: British heart foundation.

Effects of increased body mass index on employment status: a Mendelian randomisation study.

BACKGROUND: The obesity epidemic may have substantial implications for the global workforce, including causal effects on employment, but clear evidence is lacking. Obesity may prevent people from being in paid work through poor health or through social discrimination. We studied genetic variants robustly associated with body mass index (BMI) to investigate its causal effects on employment. DATASET/METHODS: White UK ethnicity participants of working age (men 40-64 years, women 40-59 years), with suitable genetic data were selected in the UK Biobank study (N = 230,791). Employment status was categorised in two ways: first, contrasting being in paid employment with any other status; and second, contrasting being in paid employment with sickness/disability, unemployment, early retirement and caring for home/family. Socioeconomic indicators also investigated were hours worked, household income, educational attainment and Townsend deprivation index (TDI). We conducted observational and two-sample Mendelian randomisation (MR) analyses to investigate the effect of increased BMI on employment-related outcomes. RESULTS: Regressions showed BMI associated with all the employment-related outcomes investigated. MR analyses provided evidence for higher BMI causing increased risk of sickness/disability (OR 1.08, 95% CI 1.04, 1.11, per 1 Kg/m2 BMI increase) and decreased caring for home/family (OR 0.96, 95% CI 0.93, 0.99), higher TDI (Beta 0.038, 95% CI 0.018, 0.059), and lower household income (OR 0.98, 95% CI 0.96, 0.99). In contrast, MR provided evidence for no causal effect of BMI on unemployment, early retirement, non-employment, hours worked or educational attainment. There was little evidence for causal effects differing by sex or age. Robustness tests yielded consistent results. DISCUSSION: BMI appears to exert a causal effect on employment status, largely by affecting an individual's health rather than through increased unemployment arising from social discrimination. The obesity epidemic may be contributing to increased worklessness and therefore could impose a substantial societal burden.

Mental health and health behaviours before and during the initial phase of the COVID-19 lockdown: longitudinal analyses of the UK Household Longitudinal Study.

BACKGROUND: There are concerns that COVID-19 mitigation measures, including the 'lockdown', may have unintended health consequences. We examined trends in mental health and health behaviours in the UK before and during the initial phase of the COVID-19 lockdown and differences across population subgroups. METHODS: Repeated cross-sectional and longitudinal analysis of the UK Household Longitudinal Study, including representative samples of over 27,000 adults (aged 18+) interviewed in four survey waves between 2015 and 2020. A total of 9748 adults had complete data for longitudinal analyses. Outcomes included psychological distress (General Health Questionnaire-12), loneliness, current cigarette smoking, use of e-cigarettes and alcohol consumption. Cross-sectional prevalence estimates were calculated and multilevel Poisson regression assessed associations between time period and the outcomes of interest, as well as differential associations by age, gender, education level and ethnicity. RESULTS: Psychological distress increased 1 month into lockdown with the prevalence rising from 19.4% (95% CI 18.7% to 20.1%) in 2017-2019 to 30.6% (95% CI 29.1% to 32.3%) in April 2020 (RR=1.3, 95% CI 1.2 to 1.4). Groups most adversely affected included women, young adults, people from an Asian background and those who were degree educated. Loneliness remained stable overall (RR=0.9, 95% CI 0.6 to 1.5). Smoking declined (RR=0.9, 95% CI=0.8,1.0) and the proportion of people drinking four or more times per week increased (RR=1.4, 95% CI 1.3 to 1.5), as did binge drinking (RR=1.5, 95% CI 1.3 to 1.7). CONCLUSIONS: Psychological distress increased 1 month into lockdown, particularly among women and young adults. Smoking declined, but adverse alcohol use generally increased. Effective measures are required to mitigate negative impacts on health.

The causal effects of health conditions and risk factors on social and socioeconomic outcomes: Mendelian randomization in UK Biobank.

BACKGROUND: We aimed to estimate the causal effect of health conditions and risk factors on social and socioeconomic outcomes in UK Biobank. Evidence on socioeconomic impacts is important to understand because it can help governments, policy makers and decision makers allocate resources efficiently and effectively. METHODS: We used Mendelian randomization to estimate the causal effects of eight health conditions (asthma, breast cancer, coronary heart disease, depression, eczema, migraine, osteoarthritis, type 2 diabetes) and five health risk factors [alcohol intake, body mass index (BMI), cholesterol, systolic blood pressure, smoking] on 19 social and socioeconomic outcomes in 336 997 men and women of White British ancestry in UK Biobank, aged between 39 and 72 years. Outcomes included annual household income, employment, deprivation [measured by the Townsend deprivation index (TDI)], degree-level education, happiness, loneliness and 13 other social and socioeconomic outcomes. RESULTS: Results suggested that BMI, smoking and alcohol intake affect many socioeconomic outcomes. For example, smoking was estimated to reduce household income [mean difference = -£22 838, 95% confidence interval (CI): -£31 354 to -£14 321] and the chance of owning accommodation [absolute percentage change (APC) = -20.8%, 95% CI: -28.2% to -13.4%], of being satisfied with health (APC = -35.4%, 95% CI: -51.2% to -19.5%) and of obtaining a university degree (APC = -65.9%, 95% CI: -81.4% to -50.4%), while also increasing deprivation (mean difference in TDI = 1.73, 95% CI: 1.02 to 2.44, approximately 216% of a decile of TDI). There was evidence that asthma decreased household income, the chance of obtaining a university degree and the chance of cohabiting, and migraine reduced the chance of having a weekly leisure or social activity, especially in men. For other associations, estimates were null. CONCLUSIONS: Higher BMI, alcohol intake and smoking were all estimated to adversely affect multiple social and socioeconomic outcomes. Effects were not detected between health conditions and socioeconomic outcomes using Mendelian randomization, with the exceptions of depression, asthma and migraines. This may reflect true null associations, selection bias given the relative health and age of participants in UK Biobank, and/or lack of power to detect effects.

Gene Variants at Loci Related to Blood Pressure Account for Variation in Response to Antihypertensive Drugs Between Black and White Individuals.

Selection of antihypertensive treatment according to self-defined ethnicity is recommended by some guidelines but might be better guided by individual genotype rather than ethnicity or race. We compared the extent to which variation in blood pressure response across different ethnicities may be explained by genetic factors: genetically defined ancestry and gene variants at loci known to be associated with blood pressure. We analyzed data from 5 trials in which genotyping had been performed (n=4696) and in which treatment responses to ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, thiazide or thiazide-like diuretic and calcium channel blocker were available. Genetically defined ancestry for proportion of African ancestry was computed using the 1000 genomes population database as a reference. Differences in response to the thiazide diuretic hydrochlorothiazide, the ß-blockers atenolol and metoprolol, the angiotensin-converting enzyme inhibitor lisinopril, and the angiotensin receptor blocker candesartan were more closely associated to genetically defined ancestry than self-defined ethnicity in admixed subjects. A relatively small number of gene variants related to loci associated with drug-signaling pathways (KCNK3, SULT1C3, AMH, PDE3A, PLCE1, PRKAG2) with large effect size (-3.5 to +3.5 mm Hg difference in response per allele) and differing allele frequencies in black versus white individuals explained a large proportion of the difference in response to candesartan and hydrochlorothiazide between these groups. These findings suggest that a genomic precision medicine approach can be used to individualize antihypertensive treatment within and across populations without recourse to surrogates of genetic structure such as self-defined ethnicity.

Salt stress in the renal tubules is linked to TAL-specific expression of uromodulin and an upregulation of heat shock genes.

Previously, our comprehensive cardiovascular characterization study validated Uromodulin as a blood pressure gene. Uromodulin is a glycoprotein exclusively synthesized at the thick ascending limb of the loop of Henle and is encoded by the Umod gene. Umod-/- mice have significantly lower blood pressure than Umod+/+ mice, are resistant to salt-induced changes in blood pressure, and show a leftward shift in pressure-natriuresis curves reflecting changes of sodium reabsorption. Salt stress triggers transcription factors and genes that alter renal sodium reabsorption. To date there are no studies on renal transcriptome responses to salt stress. Here we aimed use RNA-Seq to delineate salt stress pathways in tubules isolated from Umod+/+ mice (a model of sodium retention) and Umod-/- mice (a model of sodium depletion) ± 300 mosmol sodium chloride ( n = 3 per group). In response to salt stress, the tubules of Umod+/+ mice displayed an upregulation of heat shock transcripts. The greatest changes occurred in the expression of: Hspa1a (Log2 fold change 4.35, P = 2.48 e-12) and Hspa1b (Log2 fold change 4.05, P = 2.48 e-12). This response was absent in tubules of Umod-/- mice. Interestingly, seven of the genes discordantly expressed in the Umod-/- tubules were electrolyte transporters. Our results are the first to show that salt stress in renal tubules alters the transcriptome, increasing the expression of heat shock genes. This direction of effect in Umod+/+ tubules suggest the difference is due to the presence of Umod facilitating greater sodium entry into the tubule cell reflecting a specific response to salt stress.

Multifactorial disease risk calculator: Risk prediction for multifactorial disease pedigrees.

Construction of multifactorial disease models from epidemiological findings and their application to disease pedigrees for risk prediction is nontrivial for all but the simplest of cases. Multifactorial Disease Risk Calculator is a web tool facilitating this. It provides a user-friendly interface, extending a reported methodology based on a liability-threshold model. Multifactorial disease models incorporating all the following features in combination are handled: quantitative risk factors (including polygenic scores), categorical risk factors (including major genetic risk loci), stratified age of onset curves, and the partition of the population variance in disease liability into genetic, shared, and unique environment effects. It allows the application of such models to disease pedigrees. Pedigree-related outputs are (i) individual disease risk for pedigree members, (ii) n year risk for unaffected pedigree members, and (iii) the disease pedigree's joint liability distribution. Risk prediction for each pedigree member is based on using the constructed disease model to appropriately weigh evidence on disease risk available from personal attributes and family history. Evidence is used to construct the disease pedigree's joint liability distribution. From this, lifetime and n year risk can be predicted. Example disease models and pedigrees are provided at the website and are used in accompanying tutorials to illustrate the features available. The website is built on an R package which provides the functionality for pedigree validation, disease model construction, and risk prediction. Website: http://grass.cgs.hku.hk:3838/mdrc/current.

Application of Haralick texture features in brain [18F]-florbetapir positron emission tomography without reference region normalization.

OBJECTIVES: Semi-quantitative image analysis methods in Alzheimer's Disease (AD) require normalization of positron emission tomography (PET) images. However, recent studies have found variabilities associated with reference region selection of amyloid PET images. Haralick features (HFs) generated from the Gray Level Co-occurrence Matrix (GLCM) quantify spatial characteristics of amyloid PET radiotracer uptake without the need for intensity normalization. The objective of this study is to calculate several HFs in different diagnostic groups and determine the group differences. METHODS: All image and metadata were acquired through the Alzheimer's Disease Neuroimaging Initiative database. Subjects were grouped in three ways: by clinical diagnosis, by APOE e4 allele, and by Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score. Several GLCM matrices were calculated for different direction and distances (1-4 mm) from multiple regions on PET images. The HFs, contrast, correlation, dissimilarity, energy, entropy, and homogeneity, were calculated from these GLCMs. Wilcoxon tests and Student t-tests were performed on Haralick features and standardized uptake value ratio (SUVR) values, respectively, to determine group differences. In addition to statistical testing, receiver operating characteristic (ROC) curves were generated to determine the discrimination performance of the selected regional HFs and the SUVR values. RESULTS: Preliminary results from statistical testing indicate that HFs were capable of distinguishing groups at baseline and follow-up (false discovery rate corrected p<0.05) in particular regions at much higher occurrences than SUVR (81 of 252). Conversely, we observed nearly no significant differences between all groups within ROIs at baseline or follow-up utilizing SUVR. From the ROC analysis, we found that the Energy and Entropy offered the best performance to distinguish Normal versus mild cognitive impairment and ADAS-Cog negative versus ADAS-Cog positive groups. CONCLUSION: These results suggest that this technique could improve subject stratification in AD drug trials and help to evaluate the disease progression and treatment effects longitudinally without the disadvantages associated with intensity normalization.

Molecular Breast Imaging using Synthetic Projections from High-Purity Germanium Detectors: A Simulation Study.

High-Purity Germanium (HPGe) gamma cameras are an emerging technology for Molecular Breast Imaging (MBI) due to their 2D lateral spatial resolution, depth-of-interaction (DOI) estimation, and superb energy resolution. In this simulation study, we investigate the potential imaging performance of an opposing view dual-head HPGe breast imaging system using a synthetic-projection technique, which utilizes DOI data with varying degrees of overlap in an iterative OSEM reconstruction algorithm to create 3D images from which new 2D projections are then created. The radiation transport simulator Monte Carlo N-Particle was employed to generate projections from 10-mm thick HPGe detectors using tungsten parallel-hole collimators with short and wide holes. Simulations modeling 140-keV emissions from various contrast-detail and breast-torso phantoms were conducted. Synthetic projections were generated along with conjugate-counting images from collected HPGe projections. Tumor contrast, SNR, and hot-spot detection measurements were used to compare images. Results show that the synthetic projections could resolve more low-contrast tumors compared to single-camera projections and conjugate-counting methods. MBI simulations also showed increased contrast and SNR in synthetic projections compared to individual projections. In conclusion, the HPGe imaging system employing a synthetic-projection technique may offer advantages over individual dual-camera projections or conjugate-counting methods in terms of contrast, SNR, and tumor detectability.

Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes.

BACKGROUND: Congenital dilatation of the bile-duct (CDD) is a rare, mostly sporadic, disorder that results in bile retention with severe associated complications. CDD affects mainly Asians. To our knowledge, no genetic study has ever been conducted. METHODS: We aim to identify genetic risk factors by a "trio-based" exome-sequencing approach, whereby 31 CDD probands and their unaffected parents were exome-sequenced. Seven-hundred controls from the local population were used to detect gene-sets significantly enriched with rare variants in CDD patients. RESULTS: Twenty-one predicted damaging de novo variants (DNVs; 4 protein truncating and 17 missense) were identified in several evolutionarily constrained genes (p < 0.01). Six genes carrying DNVs were associated with human developmental disorders involving epithelial, connective or bone morphologies (PXDN, RTEL1, ANKRD11, MAP2K1, CYLD, ACAN) and four linked with cholangio- and hepatocellular carcinomas (PIK3CA, TLN1 CYLD, MAP2K1). Importantly, CDD patients have an excess of DNVs in cancer-related genes (p < 0.025). Thirteen genes were recurrently mutated at different sites, forming compound heterozygotes or functionally related complexes within patients. CONCLUSIONS: Our data supports a strong genetic basis for CDD and show that CDD is not only genetically heterogeneous but also non-monogenic, requiring mutations in more than one genes for the disease to develop. The data is consistent with the rarity and sporadic presentation of CDD.

Sacral agenesis: a pilot whole exome sequencing and copy number study.

BACKGROUND: Caudal regression syndrome (CRS) or sacral agenesis is a rare congenital disorder characterized by a constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. CRS is a complex condition, attributed to an abnormal development of the caudal mesoderm, likely caused by the effect of interacting genetic and environmental factors. A well-known risk factor is maternal type 1 diabetes. METHOD: Whole exome sequencing and copy number variation (CNV) analyses were conducted on 4 Caucasian trios to identify de novo and inherited rare mutations. RESULTS: In this pilot study, exome sequencing and copy number variation (CNV) analyses implicate a number of candidate genes, including SPTBN5, MORN1, ZNF330, CLTCL1 and PDZD2. De novo mutations were found in SPTBN5, MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous). Importantly, predicted damaging mutations in PTEN (heterozygous), in its direct regulator GLTSCR2 (compound heterozygous) and in VANGL1 (heterozygous) were identified. These genes had previously been linked with the CRS phenotype. Two CNV deletions, one de novo (chr3q13.13) and one homozygous (chr8p23.2), were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype. CONCLUSION: Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients.

Interplay between Schizophrenia Polygenic Risk Score and Childhood Adversity in First-Presentation Psychotic Disorder: A Pilot Study.

A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to number or severity of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing genetic vulnerability. Research on gene-environment interaction in psychosis has primarily focused on candidate genes, although the genetic effects are now known to be polygenic. This pilot study investigated whether the effect of childhood adversity on psychosis is moderated by the polygenic risk score for schizophrenia (PRS). Data were utilised from the Genes and Psychosis (GAP) study set in South London, UK. The GAP sample comprises 285 first-presentation psychosis cases and 256 unaffected controls with information on childhood adversity. We studied only white subjects (80 cases and 110 controls) with PRS data, as the PRS has limited predictive ability in patients of African ancestry. The occurrence of childhood adversity was assessed with the Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and the PRS was based on genome-wide meta-analysis results for schizophrenia from the Psychiatric Genomics Consortium. Higher schizophrenia PRS and childhood adversities each predicted psychosis status. Nevertheless, no evidence was found for interaction as departure from additivity, indicating that the effect of polygenic risk scores on psychosis was not increased in the presence of a history of childhood adversity. These findings are compatible with a multifactorial threshold model in which both genetic liability and exposure to environmental risk contribute independently to the etiology of psychosis.

Longitudinal Positron Emission Tomography in Preventive Alzheimer's Disease Drug Trials, Critical Barriers from Imaging Science Perspective.

Recent Alzheimer's trials have recruited cognitively normal people at risk for Alzheimer's dementia. Due to the lack of clinical symptoms in normal population, conventional clinical outcome measures are not suitable for these early trials. While several groups are developing new composite cognitive tests that could serve as potential outcome measures by detecting subtle cognitive changes in normal people, there is a need for longitudinal brain imaging techniques that can correlate with temporal changes in these new tests and provide additional objective measures of neuropathological changes in brain. Positron emission tomography (PET) is a nuclear medicine imaging procedure based on the measurement of annihilation photons after positron emission from radiolabeled molecules that allow tracking of biological processes in body, including the brain. PET is a well-established in vivo imaging modality in Alzheimer's disease diagnosis and research due to its capability of detecting abnormalities in three major hallmarks of this disease. These include (1) amyloid beta plaques; (2) neurofibrillary tau tangles and (3) decrease in neuronal activity due to loss of nerve cell connection and death. While semiquantitative PET imaging techniques are commonly used to set discrete cut-points to stratify abnormal levels of amyloid accumulation and neurodegeneration, they are suboptimal for detecting subtle longitudinal changes. In this study, we have identified and discussed four critical barriers in conventional longitudinal PET imaging that may be particularly relevant for early Alzheimer's disease studies. These include within and across subject heterogeneity of AD-affected brain regions, PET intensity normalization, neuronal compensations in early disease stages and cerebrovascular amyloid deposition.

Two subtypes of intervertebral disc degeneration distinguished by large-scale population-based study.

BACKGROUND CONTEXT: Lumbar disc degeneration (LDD) is a major cause of low back pain, and is a common and disabling condition worldwide. It has been defined and measured by multiple spine magnetic resonance imaging (MRI) features, but the heterogeneity among them has never been fully addressed. PURPOSE: This study examined the intercorrelations, risk factor associations, and single nucleotide polymorphism (SNP) heritabilities of lumbar disc MRI features in a large-scale sample to classify the different intervertebral disc phenotypes associated with LDD. STUDY DESIGN: A cross-sectional study was conducted consisting of 2,943 volunteers of Southern Chinese origin (mean age: 41.1 years; range: 15-55 years; 59.6% women). OUTCOME MEASURES: The outcome measures were MRI phenotypic spinal patterns and their risk factor profiles in relation to developmental or degenerative origins of disc degeneration. METHODS: Sagittal T2-weighted MRI of the lumbar spine from L1 to S1 was assessed. The MRI features of lumbar intervertebral disc changes, such as disc signal intensity loss and disc bulges or extrusions, as well as additional imaging phenotypes of end plate changes, high-intensity zones, and bone marrow changes, were evaluated. Blood samples were taken for genotyping using the HumanOmni-ZhongHua-8 BeadChip. Subject demographics, environmental, and lifestyle factors were assessed by questionnaires. Multivariate statistical techniques were used for phenotype evaluation. Polychoric correlations and local regression statistical analyses were performed. The genetic components contributed by common SNPs were estimated by comparing genetic correlations and phenotypic correlations using the Genome-Wide Complex Trait Analysis (GCTA) tool. RESULTS: The study noted that lumbar disc MRI features separated into two groups with differential patterns of risk factor associations. A subset of lumbar disc abnormalities, including end plate changes but also upper lumbar disc bulging and signal intensity loss, may have a developmental origin. Subsequent degenerative changes, typically affecting the lower lumbar discs, then emerge as individuals age and are associated with body mass index. CONCLUSIONS: This is the first large-scale study to identify two distinct patterns of lumbar disc alterations, noting degenerative changes and a possible developmental component affecting the lumbar spine. This new classification provides a starting point for a more homogeneous phenotype definition, which may provide greater statistical power and precision in future genetic and epidemiologic studies. In addition, such insights may have direct clinical implications in the prevention, therapeutics, and prognostics of patients with disc degeneration.