Study protocol: a pragmatic, cluster-randomized controlled trial to evaluate the effect of implementation of the Truenat platform/MTB assays at primary health care clinics in Mozambique and Tanzania (TB-CAPT CORE).

BACKGROUND: In 2020, the WHO-approved Molbio Truenat platform and MTB assays to detect Mycobacterium tuberculosis complex (MTB) and resistance to rifampicin directly on sputum specimens. This primary health care center-based trial in Mozambique and Tanzania investigates the effect of Truenat platform/MTB assays (intervention arm) combined with rapid communication of results compared to standard of care on TB diagnosis and treatment initiation for microbiologically confirmed TB at 7 days from enrolment. METHODS: The Tuberculosis Close the Gap, Increase Access, and Provide Adequate Therapy (TB-CAPT) CORE trial employs a pragmatic cluster randomized controlled design to evaluate the impact of a streamlined strategy for delivery of Truenat platform/MTB assays testing at primary health centers. Twenty-nine centers equipped with TB microscopy units were selected to participate in the trial. Among them, fifteen health centers were randomized to the intervention arm (which involves onsite molecular testing using Truenat platform/MTB assays, process process optimization to enable same-day TB diagnosis and treatment initiation, and feedback on Molbio platform performance) or the control arm (which follows routine care, including on-site sputum smear microscopy and the referral of sputum samples to off-site Xpert testing sites). The primary outcome of the study is the absolute number and proportion of participants with TB microbiological confirmation starting TB treatment within 7 days of their first visit. Secondary outcomes include time to bacteriological confirmation, health outcomes up to 60 days from first visit, as well as user preferences, direct cost, and productivity analyses. ETHICS AND DISSEMINATION: TB-CAPT CORE trial has been approved by regulatory and ethical committees in Mozambique and Tanzania, as well as by each partner organization. Consent is informed and voluntary, and confidentiality of participants is maintained throughout. Study findings will be presented at scientific conferences and published in peer-reviewed international journals. TRIAL REGISTRATION: US National Institutes of Health's ClinicalTrials.gov, NCT04568954. Registered 23 September 2020.

The impact of obstructive sleep apnea on exercise capacity in a cardiac rehabilitation program.

PURPOSE: Cardiac rehabilitation (CR) improves clinical outcomes in patients with cardiovascular disease (CDV). Patients with CVD often have multiple comorbidities, including obstructive sleep apnea (OSA), potentially affecting their ability to participate and achieve functional improvement during CR. We aimed to test the hypothesis that OSA reduces peak exercise capacity (EC) in patients undergoing CR and to explore if OSA treatment modifies this relationship. METHODS: Data from a retrospective cohort of CR patients was analyzed. OSA was defined as a respiratory event index > 5/h or physician diagnosis. Patients with OSA were considered "treated" if using continuous positive airway pressure regularly during the CR period. Change in METs was the primary study outcome. RESULTS: Among 312 CR patients, median age of 67 years, 103 (33%) had known OSA (30 treated, 73 untreated). Patients with OSA vs. those with no OSA were more likely to be obese and male; otherwise, groups were similar. Compared with the no OSA group, patients with OSA had lower pre-CR METs (3.3 [2.9-4.5] vs. 3.9 [3.1-5], P = .01) and lower post-CR METs (5.3 [4-7] vs. 6 [4.6-7.6], P = .04), but achieved a similar increase in METs post-CR (1.8 [0.6-2.6] vs. 2.0 [0.9-3], P = .22). Furthermore, compared to no OSA, pre-CR and post-CR METs tended to be similar in patients with treated OSA, but lower in untreated patients, with similar increases in METs across all groups, even when adjusting for covariates via multivariable regression. CONCLUSION: OSA is prevalent in patients with CVD undergoing CR. CR substantially improves exercise capacity independent of OSA status, but screening for-and treatment of-OSA may improve the absolute exercise capacity achieved through CR.

Effect of Body Position and Size of Pleural Effusion on Oxygenation Status in Spontaneously Breathing Patients with Unilateral Pleural Effusion.

Abvims and Dr Rml Hospital, Delhi In unilateral pleural effusion it is necessary to find the best position for unilateral pleural effusion so that recovery can be hastened. There is scarcity of literature on the effect of body positional variations on oxygenation, and current guidelines do not address the necessity. The objective of this study is to assess the effect of body position and size of pleural effusion on oxygenation status in spontaneously breathing patients with unilateral pleural effusion. MATERIAL: This was a hospital based observational cross-sectional study having a sample size of 90 patients of unilateral pleural effusion and on the basis of severity, they were divided into 2 classes- small and large. Ipsilateral and Contralateral oxygenation were analysed separately in small and large effusions using Mann-Whitney and Wilcoxon signed rank test and final analysis was made using SPSS software. OBSERVATION: It was observed that oxygenation was better when patient lies on contralateral side in small effusion (PaO2 82.4±8.83 vs 85.01±8.24 p value <0.0001) while in cases of large effusion, oxygenation was better on ipsilateral side of effusion (82.35±10.4 vs 78.06±9.92, p value<0.0001). No significant difference was noted in case of PaCO2 levels in small and large effusion in ipsilateral and contralateral position. It was also noted that there was a significant difference in oxygen saturation. CONCLUSION: There is significant effect of body position and size of pleural effusion on oxygenation status in spontaneously breathing patient with unilateral pleural effusion.

Soil organic carbon is not just for soil scientists: measurement recommendations for diverse practitioners.

Soil organic carbon (SOC) regulates terrestrial ecosystem functioning, provides diverse energy sources for soil microorganisms, governs soil structure, and regulates the availability of organically bound nutrients. Investigators in increasingly diverse disciplines recognize how quantifying SOC attributes can provide insight about ecological states and processes. Today, multiple research networks collect and provide SOC data, and robust, new technologies are available for managing, sharing, and analyzing large data sets. We advocate that the scientific community capitalize on these developments to augment SOC data sets via standardized protocols. We describe why such efforts are important and the breadth of disciplines for which it will be helpful, and outline a tiered approach for standardized sampling of SOC and ancillary variables that ranges from simple to more complex. We target scientists ranging from those with little to no background in soil science to those with more soil-related expertise, and offer examples of the ways in which the resulting data can be organized, shared, and discoverable.

Impact of COVID-19 pandemic restrictions on pregnancy duration and outcome in Melbourne, Australia.

OBJECTIVE: To investigate the effect of restriction measures implemented to mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission during the coronavirus disease 2019 (COVID-19) pandemic on pregnancy duration and outcome. METHODS: A before-and-after study was conducted with cohort sampling in three maternity hospitals in Melbourne, Australia, including women who were pregnant when restriction measures were in place during the COVID-19 pandemic (estimated conception date between 1 November 2019 and 29 February 2020) and women who were pregnant before the restrictions (estimated conception date between 1 November 2018 and 28 February 2019). The primary outcome was delivery before 34 weeks' gestation or stillbirth. The main secondary outcome was a composite of adverse perinatal outcomes. Pregnancy outcomes were compared between women exposed to restriction measures and unexposed controls using the χ-square test and modified Poisson regression models, and duration of pregnancy was compared between the groups using survival analysis. RESULTS: In total, 3150 women who were exposed to restriction measures during pregnancy and 3175 unexposed controls were included. Preterm birth before 34 weeks or stillbirth occurred in 95 (3.0%) exposed pregnancies and in 130 (4.1%) controls (risk ratio (RR), 0.74 (95% CI, 0.57-0.96); P = 0.021). Preterm birth before 34 weeks occurred in 2.4% of women in the exposed group and in 3.4% of women in the control group (RR, 0.71 (95% CI, 0.53-0.95); P = 0.022), without evidence of an increase in the rate of stillbirth in the exposed group (0.7% vs 0.9%; RR, 0.83 (95% CI, 0.48-1.44); P = 0.515). Competing-risks regression analysis showed that the effect of the restriction measures on spontaneous preterm birth was stronger and started earlier (subdistribution hazard ratio (HR), 0.81 (95% CI, 0.64-1.03); P = 0.087) than the effect on medically indicated preterm birth (subdistribution HR, 0.89 (95% CI, 0.70-1.12); P = 0.305). The effect was stronger in women with a previous preterm birth (RR, 0.42 (95% CI, 0.21-0.82); P = 0.008) than in parous women without a previous preterm birth (RR, 0.93 (95% CI, 0.63-1.38); P = 0.714) (P for interaction = 0.044). Composite adverse perinatal outcome was less frequent in the exposed group than in controls (all women: 2.1% vs 2.9%; RR, 0.73 (95% CI, 0.54-0.99); P = 0.042); women with a previous preterm birth: 4.5% vs 8.4%; RR, 0.54 (95% CI, 0.25-1.18); P = 0.116). CONCLUSIONS: Restriction measures implemented to mitigate SARS-CoV-2 transmission during the COVID-19 pandemic were associated with a reduced rate of preterm birth before 34 weeks. This reduction was mainly due to a lower rate of spontaneous prematurity. The effect was more substantial in women with a previous preterm birth and was not associated with an increased stillbirth rate. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Unilateral axillary adenopathy following COVID-19 vaccination: a multimodality pictorial illustration and review of current guidelines.

We present a multimodality pictorial review of axillary lymphadenopathy in patients recently vaccinated against COVID-19. As the mass vaccination programme continues to be rolled out worldwide in an effort to combat the pandemic, it is important that radiologists consider recent COVID-19 vaccination in the differential diagnosis of unilateral axillary lymphadenopathy and are aware of typical appearances across all imaging methods. We review current guidelines on the management of unilateral axillary lymphadenopathy in the context of recent COVID-19 vaccination.

Accuracy of WatchPAT for the Diagnosis of Obstructive Sleep Apnea in Patients with Chronic Obstructive Pulmonary Disease.

The co-existence of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), termed the overlap syndrome (OVS), is associated with adverse outcomes that may be reversed with treatment. However, diagnosis is limited by the apparent need for in-laboratory polysomnography (PSG). WatchPAT is a portable diagnostic device that is validated for the diagnosis of OSA that might represent an attractive tool for the diagnosis of OVS.Subjects with established COPD were recruited from a general population. Subjects underwent PSG and simultaneous recording with WatchPAT. Pulmonary function testing and questionnaires were also performed.A total of 36 subjects were recruited and valid data was obtained on 33 (age 63 ± 7, BMI 28 ± 7, 61% male, FEV1 56 ± 20% predicted). There was no significant difference in the apnea-hypopnea index (AHI) between PSG and WatchPAT (19 ± 20 versus 20 ± 15 events/h; mean difference 2(-2, 5) events/h; p = 0.381). The AHI was not significantly different in rapid eye movement (REM) and non-rapid eye movement (NREM) determined by PSG versus REM and NREM determined by WatchPAT. WatchPAT slightly overestimated total and REM sleep time, and sleep efficiency. The sensitivity of WatchPAT at an AHI cut-off of ≥5, ≥15, and ≥30 events/h for corresponding PSG AHI cut-offs was 95.8, 92.3, and 88.9, respectively; specificity was 55, 65.0, and 95.8, respectively.WatchPAT is able to determine OSA reliably in patients with COPD. The availability of this additional diagnostic modality may lead to improved detection of OVS, which may in turn lead to improved outcomes for a group of COPD patients at high risk of poor outcomes.

Greater extracellular free-water in first-episode psychosis predicts better neurocognitive functioning.

Free Water Imaging is a novel diffusion magnetic resonance (MR) imaging method that is able to separate changes affecting the extracellular space from those that reflect changes in neuronal cells and processes. A previous Free Water Imaging study in schizophrenia identified significantly greater extracellular water volume in the early stages of the disorder; however, its clinical and functional sequelae have not yet been investigated. Here, we applied Free Water Imaging to a larger cohort of 63 first-episode patients with psychosis and 70 healthy matched controls to better understand the functional significance of greater extracellular water. We used diffusion MR imaging data and the Tract-Based Spatial Statistics analytic pipeline to first analyze fractional anisotropy (FA), the most commonly employed metric for assessing white matter. This comparison was then followed by Free Water Imaging analysis, where two parameters, the fractional volume of extracellular free-water (FW) and cellular tissue FA (FA-t), were estimated and compared across the entire white matter skeleton between groups, and correlated with cognitive measures at baseline and following 12 weeks of antipsychotic treatment. Our results indicated lower FA across the whole brain in patients compared with healthy controls that overlap with significant increases in FW, with only limited decreases in FA-t. In addition, higher FW correlated with better neurocognitive functioning following 12 weeks of antipsychotic treatment. We believe this is the first study to suggest that an extracellular water increase during the first-episode of psychosis, which may be indicative of an acute neuroinflammatory process, and/or cerebral edema may predict better functional outcome.

Aging phenotype(s) in kidneys of diabetic mice are p66ShcA dependent.

The p66ShcA protein controls cellular responses to oxidative stress, senescence, and apoptosis. Here, we test the hypothesis that aging phenotype(s) commonly associated with the broad category of chronic kidney disease are accelerated in diabetic kidneys and linked to the p66ShcA locus. At the organ level, tissue stem cells antagonize senescent phenotypes by replacing old dysfunctional cells. Using established methods, we isolated a highly purified population of stem cell antigen-1-positive mesenchymal stem cells (Sca-1+ MSCs) from kidneys of wild-type (WT) and p66 knockout (p66 KO) mice. Cells were plated in culture medium containing normal glucose (NG) or high glucose (HG). Reactive oxygen species (ROS) metabolism was substantially increased in WT MSCs in HG medium in association with increased cell death by apoptosis and acquisition of the senescent phenotype. DNA microarray analysis detected striking differences in the expression profiles of WT and p66 KO-MSCs in HG medium. Unexpectedly, the analysis for p66 KO-MSCs revealed upregulation of Wnt genes implicated in self-renewal and differentiation. To test the in vivo consequences of constitutive p66 expression in diabetic kidneys, we crossed the Akita diabetic mouse with the p66KO mouse. Homozygous mutation at the p66 locus delays or prevents aging phenotype(s) in the kidney that may be precursors to diabetic nephropathy.

In vitro antimicrobial susceptibility testing methods: agar dilution to 3D tissue-engineered models.

In the field of orthopaedic surgery, bacterial invasion of implants and the resulting periprosthetic infections are a common and unresolved problem. Antimicrobial susceptibility testing methods help to define the optimal treatment and identify antimicrobial resistance. This review discusses proven gold-standard techniques and recently developed models for antimicrobial susceptibility testing, while also providing a future outlook. Conventional, gold-standard methods, such as broth microdilution, are still widely applied in clinical settings. Although recently developed methods based on microfluidics and microdroplets have shown advantages over conventional methods in terms of testing speed, safety and the potential to provide a deeper insight into resistance mechanisms, extensive validation is required to translate this research to clinical practice. Recent optical and mechanical methods are complex and expensive and, therefore, not immediately clinically applicable. Novel osteoblast infection and tissue models best resemble infections in vivo. However, the integration of biomaterials into these models remains challenging and they require a long tissue culture, making their rapid clinical implementation unlikely. A method applicable for both clinical and research environments is difficult to realise. With a continuous increase in antimicrobial resistance, there is an urgent need for methods that analyse recurrent infections to identify the optimal treatment approaches. Graphical abstract Timeline of published and partly applied antimicrobial susceptibility testing methods, listed according to their underlying mechanism, complexity and application in research or clinics.

Hippocampal subregion volume changes associated with antipsychotic treatment in first-episode psychosis.

BACKGROUND: Hippocampal dysfunction is considered central to many neurobiological models of schizophrenia, yet there are few longitudinal in vivo neuroimaging studies that have investigated the relationship between antipsychotic treatment and morphologic changes within specific hippocampal subregions among patients with psychosis. METHOD: A total of 29 patients experiencing a first episode of psychosis with little or no prior antipsychotic exposure received structural neuroimaging examinations at illness onset and then following 12 weeks of treatment with either risperidone or aripiprazole in a double-blind randomized clinical trial. In addition, 29 healthy volunteers received structural neuroimaging examinations at baseline and 12-week time points. We manually delineated six hippocampal subregions [i.e. anterior cornu ammonis (CA) 1-3, posterior CA1-3, subiculum, dentate gyrus/CA4, entorhinal cortex, and fimbria] from 3T magnetic resonance images using an established method with high inter- and intra-rater reliability. RESULTS: Following antipsychotic treatment patients demonstrated significant reductions in dentate gyrus/CA4 volume and increases in subiculum volume. Healthy volunteers demonstrated non-significant volumetric changes in these subregions across the two time points. We observed a significant quadratic (i.e. inverted U) association between changes in dentate gyrus/CA4 volume and cumulative antipsychotic dosage between the scans. CONCLUSIONS: This study provides the first evidence to our knowledge regarding longitudinal in vivo volumetric changes within specific hippocampal subregions in patients with psychosis following antipsychotic treatment. The finding of a non-linear relationship between changes in dentate gyrus/CA4 subregion volume and antipsychotic exposure may provide new avenues into understanding dosing strategies for therapeutic interventions relevant to neurobiological models of hippocampal dysfunction in psychosis.

Neurocognitive subtypes in patients with bipolar disorder and their unaffected siblings.

BACKGROUND: Our previous work revealed substantial heterogeneity in the cognitive profile of bipolar disorder (BD) due to the presence of three underlying cognitive subgroups characterized as: globally impaired, selectively impaired, or cognitively intact. In an effort to determine whether these subgroups are differentially related to genetic risk for the illness, we investigated whether cognitive deficits were more pronounced in unaffected siblings (UAS) of BD probands within identified clusters. METHODS: Cluster analysis was used to identify cognitive clusters in BD (N = 60). UAS (N = 49) were classified into groups according to their proband sibling's cluster assignment; comparisons were made across all clusters and healthy controls (HCs; N = 71). RESULTS: Three cognitive clusters in BD emerged: a globally impaired (36.7%), a selectively impaired (30%), and a cognitively intact cluster (33.3%). UAS showed a qualitatively similar pattern to their BD siblings; UAS of the globally impaired BD cluster showed verbal memory and general cognitive impairments relative to HCs. In contrast, UAS of the other two clusters did not differ from HCs. CONCLUSIONS: This study corroborates findings from prior work regarding the presence of cognitive heterogeneity in BD. UAS of subjects in the globally impaired BD cluster presented with a qualitatively similar cognitive profile to their siblings and performed worse than all other BD clusters and UAS groups. This suggests that inherited risk factors may be contributing to cognitive deficits more notably in one subgroup of patients with BD, pointing toward differential causes of cognitive deficits in discrete subgroups of patients with the disorder.

Characterizing cognitive heterogeneity on the schizophrenia-bipolar disorder spectrum.

BACKGROUND: Current group-average analysis suggests quantitative but not qualitative cognitive differences between schizophrenia (SZ) and bipolar disorder (BD). There is increasing recognition that cognitive within-group heterogeneity exists in both disorders, but it remains unclear as to whether between-group comparisons of performance in cognitive subgroups emerging from within each of these nosological categories uphold group-average findings. We addressed this by identifying cognitive subgroups in large samples of SZ and BD patients independently, and comparing their cognitive profiles. The utility of a cross-diagnostic clustering approach to understanding cognitive heterogeneity in these patients was also explored. METHOD: Hierarchical clustering analyses were conducted using cognitive data from 1541 participants (SZ n = 564, BD n = 402, healthy control n = 575). RESULTS: Three qualitatively and quantitatively similar clusters emerged within each clinical group: a severely impaired cluster, a mild-moderately impaired cluster and a relatively intact cognitive cluster. A cross-diagnostic clustering solution also resulted in three subgroups and was superior in reducing cognitive heterogeneity compared with disorder clustering independently. CONCLUSIONS: Quantitative SZ-BD cognitive differences commonly seen using group averages did not hold when cognitive heterogeneity was factored into our sample. Members of each corresponding subgroup, irrespective of diagnosis, might be manifesting the outcome of differences in shared cognitive risk factors.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

Targeting the schizophrenia genome: a fast track strategy from GWAS to clinic.

The Psychiatric Genomics Consortium-Schizophrenia Workgroup (PGC-SCZ) has recently published a genomewide association study (GWAS) identifying >100 genetic loci, encompassing a total of 341 protein-coding genes, attaining genomewide significance for susceptibility to schizophrenia. Given the extremely long time (12-15 years) and expense (>$1 billion) associated with the development of novel drug targets, repurposing of drugs with known and validated targets may be the most expeditious path toward deriving clinical utility from these GWAS findings. In the present study, we examined all genes within loci implicated by the PGC-SCZ GWAS against databases of targets of both approved and registered pharmaceutical compounds. We identified 20 potential schizophrenia susceptibility genes that encode proteins that are the targets of approved drugs. Of these, we prioritized genes/targets that are of clear neuropsychiatric interest and that are also sole members of the linkage disequilibrium block surrounding a PGC-SCZ GWAS hit. In addition to DRD2, 5 genes meet these criteria: CACNA1C, CACNB2, CACNA1I, GRIN2A and HCN1. An additional 20 genes coding for proteins that are the targets of drugs in registered clinical trials, but without approved indications, were also identified. Although considerable work is still required to fully explicate the biological implications of the PGC-SCZ GWAS results, pathways related to these known, druggable targets may represent a promising starting point.

Use of Bristol Stool Form Scale to predict the adequacy of bowel preparation - a prospective study.

AIM: Inadequate bowel preparation continues to be a substantial problem for colonoscopy. The seven-point Bristol Stool Form Scale (BSFS) has been associated with delayed colonic transit in adults. We evaluated the utility of the BSFS to identify patients more likely to present with an inadequate preparation. METHOD: Two large community-based academic medical centres in New Jersey, USA, studied a prospective cohort of 411 consecutive patients undergoing outpatient colonoscopy who were prescribed similar bowel preparations. The BSFS and several other study variables were collected by gastroenterology fellows during an outpatient visit prior to scheduling colonoscopy. All colonoscopy examinations were performed in the morning by a gastroenterologist who graded the adequacy of bowel preparation. Inadequate preparation was defined as one resulting in a repeat colonoscopy at a shorter time interval than would generally be recommended based solely on risk factors or pathological findings. The ability of study variables to discriminate those who did or did not have an adequate preparation was summarized by the c-statistic. The relationship between variables that provided some discrimination and the probability of an adequate preparation was modelled using logistic regression. RESULTS: The mean age of the study sample was 56 ± 8 (SD) years and 63% were women. Bowel preparation was adequate in 337 (82%) of the patients. The BSFS ratings ranged from 1 to 7. The score was <3 in 144 (35%) indicating lower gastrointestinal motility. There was a statistically significant association between the score and the probability of an adequate bowel preparation (odds ratio 1.4; 95% confidence interval 1.2-1.7; P < 0.001) and the c-statistic was 0.64 (0.58-0.70). CONCLUSION: Use of the BSFS may help identify patients for whom standard bowel preparation most probably will not be adequate.

The SORL1 gene and convergent neural risk for Alzheimer's disease across the human lifespan.

Prior to intervention trials in individuals genetically at-risk for late-onset Alzheimer's disease, critical first steps are identifying where (neuroanatomic effects), when (timepoint in the lifespan) and how (gene expression and neuropathology) Alzheimer's risk genes impact the brain. We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multiple Alzheimer's phenotypes before the clinical onset of symptoms. Four independent samples were analyzed to determine effects of SORL1 genetic risk variants across the lifespan at multiple phenotypic levels: (1) microstructural integrity of white matter using diffusion tensor imaging in two healthy control samples (n=118, age 18-86; n=68, age 8-40); (2) gene expression using the Braincloud postmortem healthy control sample (n=269, age 0-92) and (3) Alzheimer's neuropathology (amyloid plaques and tau tangles) using a postmortem sample of healthy, mild cognitive impairment (MCI) and Alzheimer's individuals (n=710, age 66-108). SORL1 risk variants predicted lower white matter fractional anisotropy in an age-independent manner in fronto-temporal white matter tracts in both samples at 5% family-wise error-corrected thresholds. SORL1 risk variants also predicted decreased SORL1 mRNA expression, most prominently during childhood and adolescence, and significantly predicted increases in amyloid pathology in postmortem brain. Importantly, the effects of SORL1 variation on both white matter microstructure and gene expression were observed during neurodevelopmental phases of the human lifespan. Further, the neuropathological mechanism of risk appears to primarily involve amyloidogenic pathways. Interventions targeted toward the SORL1 amyloid risk pathway may be of greatest value during early phases of the lifespan.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Empirical evidence for discrete neurocognitive subgroups in bipolar disorder: clinical implications.

BACKGROUND: Recent data suggest trait-like neurocognitive impairments in bipolar disorder (BPD), with deficits about 1 s.d. below average, less severe than deficits noted in schizophrenia. The frequency of significant impairment in BPD is approximately 60%, with 40% of patients characterized as cognitively spared. This contrasts with a more homogeneous presentation in schizophrenia. It is not understood why some BPD patients develop deficits while others do not. METHOD: A total of 136 patients with BPD completed the MATRICS Consensus Cognitive Battery and data were entered into hierarchical cluster analyses to: (1) determine the optimal number of clusters (subgroups) that fit the sample; and (2) assign subjects to a specific cluster based on individual profiles. We then compared subgroups on several clinical factors and real-world community functioning. RESULTS: Three distinct neurocognitive subgroups were found: (1) an intact group with performance comparable with healthy controls on all domains but with superior social cognition; (2) a selective impairment group with moderate deficits on processing speed, attention, verbal learning and social cognition and normal functioning in other domains; and (3) a global impairment group with severe deficits across all cognitive domains comparable with deficits in schizophrenia. CONCLUSIONS: These results suggest the presence of multiple cognitive subgroups in BPD with unique profiles and begin to address the relationships between these subgroups, several clinical factors and functional outcome. Next steps will include using these data to help guide future efforts to target these disabling symptoms with treatment.