Associations of cardiometabolic polygenic risk scores with cardiovascular disease in African Americans.

Background: Cardiovascular disease (CVD) is a complex disease, and genetic factors contribute individually or cumulatively to CVD risk. While African American women and men are disproportionately affected by CVD, their lack of representation in genomic investigations may widen disparities in health. We investigated the associations of cardiometabolic polygenic risk scores (PRSs) with CVD risk in African Americans. Methods: We used the Jackson Heart Study, a prospective cohort study of CVD in African American adults and the predicted atherosclerotic cardiovascular disease (ASCVD) 10-year risk. We included 40-79 years old adults without a history of coronary heart disease (CHD) or stroke at baseline. We derived genome-wide PRSs for systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, LDL cholesterol, hemoglobin A1c (HbA1c), triglycerides, and C-reactive protein (CRP) separately for each of the participants, using African-origin UK Biobank participants' genome-wide association summary statistics. We estimated the associations between PRSs and 10-year predicted ASCVD risk adjusting for age, sex, study visit date, and genetic ancestry using linear and logistic regression models. Results: Participants (n=2,077) were 63% female and 66% never-smokers. They had mean (SD) 56 (10) years of age, 127.8 (16.3) mmHg SBP, 76.3 (8.7) mmHg DBP, 200.4 (40.2) mg/dL total cholesterol, 51.7 (14.7) mg/dL HDL cholesterol, 127.2 (36.7) mg/dL LDL cholesterol, 6.0 (1.3) mmol/mol HbA1c, 108.9 (81.7) mg/dL triglycerides and 0.53 (1.1) CRP. Their median (interquartile range) predicted 10-year predicted ASCVD risk was 8.0 (4.0-15.0). Participants in the >75th percentile for HbA1c PRS had 1.42 percentage-point greater predicted 10-year ASCVD risk (1.42 [95% CI: 0.58-2.26]) and higher odds of ≥10% predicted 10-year ASCVD risk (OR: 1.46 [95% CI: 1.03-2.07]) compared with those in the <25th percentile for HbA1c PRS. Participants in the >75th percentile for SBP PRS had higher odds of ≥10% predicted 10-year ASCVD risk (OR: 1.52 [95% CI: 1.07-2.15]) compared with those in the <25th percentile for SBP PRS. Conclusion: Among 40-79 years old African Americans without CHD and stroke, higher PRSs for HbA1c and SBP were associated with CVD risk. PRSs may help stratify individuals based on their clinical risk factors for CVD early prevention and clinical management.

Shape matters: Competing mechanisms of particle shape segregation.

It is well known that granular mixtures that differ in size or shape segregate when sheared. In the past, two mechanisms have been proposed to describe this effect, and it is unclear if both exist. To settle this question, we consider a bidisperse mixture of spheroids of equal volume in a rotating drum, where the two mechanisms are predicted to act in opposite directions. We present evidence that there are two distinct segregation mechanisms driven by relative overstress. Additionally, we showed that, for nonspherical particles, these two mechanisms (kinetic and gravity) can act in different directions leading to a competition between the effects of the two. As a result, the segregation intensity varies nonmonotonically as a function of aspect ratio (AR), and, at specific points, the segregation direction changes for both prolate and oblate spheroids, explaining the surprising segregation reversal previously reported. Consistent with previous results, we found that the kinetic mechanism is dominant for (almost) spherical particles. Furthermore, for moderate aspect ratios, the kinetic mechanism is responsible for the spherical particles' segregation to the periphery of the drum, and the gravity mechanism plays only a minor role. Whereas, at the extreme values of AR, the gravity mechanism notably increases and overtakes its kinetic counterpart.

Fission chamber data acquisition system for neutron flux measurements on the Mega-Amp Spherical Tokamak Upgrade.

Neutron flux measurements are important in fusion devices for both safety requirements and physics studies. A new system has been built for the Mega-Amp Spherical Tokamak Upgrade (MAST Upgrade) that provides neutron count, DC, and Campbell mode measurements for a 1 µs period at 1 MHz. The acquisition system uses a Red Pitaya board to sample current from two fission chambers mounted on the side of the MAST-U vessel. The system-on-chip design of the Zynq-7020 on the Red Pitaya also allows a web server implementation using Flask for data retrieval and diagnostic configuration over the MAST Upgrade network.

Variability in early development and growth of Great Lakes burbot: developmental patterns in cultured and wild-caught larval burbot.

Throughout the Great Lakes, burbot Lota lota are a native, high-trophic level predator that plays a substantial ecological role. L. lota spawning occurs during wintertime and early spring with length-at-hatch of 3 mm. Wild-caught larval L. lota were obtained from three different locations: Lake Superior Keweenaw Peninsula, Ontonagon, Michigan (LSKP), Lake Michigan Midlake Reef (LMMR) and the St. Clair-Detroit River System (SCDR). Adult spawning L. lota were captured from the Sturgeon River, Pelkie, Michigan (LSSR) and were artificially fertilized; eggs were retained and reared in a laboratory setting. Throughout the first 10 weeks of development, cultured larval L .lota were randomly selected and photographed to measure morphological features. These features were contrasted between cultured larvae and wild-caught larvae to understand developmental variability in L. lota. From patterns discerned in both cultured and wild-caught larval L. lota we demonstrated the importance of asynchronous hatching, source location, and variability in larval L. lota development. Comparisons of wild-caught larval L. lota showed morphological differences, as well as variability in stage and size based on sampling month. These results established that larval L. lota development in the Great Lakes is highly flexible and both species-specific and environmental processes create the observed variability. The impact of this variability on L. lota populations must be explored to further understand this native Great Lakes species.

Massive in Silico Study of Noble Gas Binding to the Structural Proteome.

Noble gases are chemically inert, and it was therefore thought they would have little effect on biology. Paradoxically, it was found that they do exhibit a wide range of biological effects, many of which are target-specific and potentially useful and some of which have been demonstrated in vivo. The underlying mechanisms by which useful pharmacology, such as tissue and neuroprotection, anti-addiction effects, and analgesia, is elicited are relatively unexplored. Experiments to probe the interactions of noble gases with specific proteins are more difficult with gases than those with other chemicals. It is clearly impractical to conduct the large number of gas-protein experiments required to gain a complete picture of noble gas biology. Given the simplicity of atoms as ligands, in silico methods provide an opportunity to gain insight into which noble gas-protein interactions are worthy of further experimental or advanced computational investigation. Our previous validation studies showed that in silico methods can accurately predict experimentally determined noble gas binding sites in X-ray structures of proteins. Here, we summarize the largest reported in silico reverse docking study involving 127 854 protein structures and the five nonradioactive noble gases. We describe how these computational screening methods are implemented, summarize the main types of interactions that occur between noble gases and target proteins, describe how the massive data set that this study generated can be analyzed (freely available at group18.csiro.au), and provide the NDMA receptor as an example of how these data can be used to understand the molecular pharmacology underlying the biology of the noble gases. We encourage chemical biologists to access the data and use them to expand the knowledge base of noble gas pharmacology, and to use this information, together with more efficient delivery systems, to develop "atomic drugs" that can fully exploit their considerable and relatively unexplored potential in medicine.

Hippocampal volume and vasculature before and after exercise in treatment-resistant schizophrenia.

BACKGROUND: Schizophrenia is associated with poor cognitive function and elevated cardiometabolic disease risk. These health concerns may exacerbate neurocognitive dysfunction associated with hippocampal abnormalities, particularly hippocampal volume reductions. Regular exercise is thought to improve symptom severity, reduce depression, and improve cognition in schizophrenia, and may trigger exercise-mediated hippocampal growth. The potential for the benefits of exercise for treatment-resistant schizophrenia patients has not been clearly assessed. This study aims to assess the effect of exercise on hippocampal plasticity and clinical outcomes in chronic schizophrenia. METHODS: Seventeen DSM-IV criteria schizophrenia or schizoaffective disorder patients completed a customized moderate intensity 12-week aerobic or weight-bearing exercise program. Adherence rates were 83% ±â€¯9.4%) with 70% of participants completing the entire exercise program. Concomitant neuroimaging, clinical and cognitive assessments were obtained at baseline and 12-weeks. RESULTS: At follow-up, symptom severity scores (t(16) = -16.8, p. ≤ 0.0001) and social functioning (t(16) = 4.4, p. = 0.0004) improved. A trend for improved depression scores (t(16) = -2.0, p. = 0.06) with no change in anxiety, or extrapyramidal symptoms were seen. Hippocampal volume increased (t(16) = -2.54, p. = 0.02), specifically in the left CA-1 field (F(16) = -2.33, p. = 0.03). Hippocampal vascular volume was unchanged. Change in hippocampal volume and vascular volume was not significantly correlated with change in symptom severity or affect scores. CONCLUSIONS: Adjunct exercise may accelerate symptom improvement in treatment-resistant psychosis patients. While the underlying mechanism remains unclear, these results indicate that chronic schizophrenia patients experience hippocampal plasticity in response to exercise. STUDY REGISTRATION: Clinical Trials.govNCT01392885.

Clinical translation of [18F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer.

BACKGROUND: Effective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy. RESULTS: Breast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first-line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes. CONCLUSION: This study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer.

Resilience theory incorporated into urban wastewater systems management. State of the art.

Government bodies, utilities, practitioners, and researchers have growing interest in the incorporation of resilience into wastewater management. Since resilience is a multidisciplinary term, it is important to review what has been achieved in the wastewater sector, and describe the future research directions for the forthcoming years. This work presents a critical review of studies that deal with resilience in the wastewater treatment sector, with a special focus on understanding how they addressed the key elements for assessing resilience, such as stressors, system properties, metrics and interventions to increase resilience. The results showed that only 17 peer-reviewed papers and 6 relevant reports, a small subset of the work in wastewater research, directly addressed resilience. The lack of consensus in the definition of resilience, and the elements of a resilience assessment, is hindering the implementation of resilience in wastewater management. To date, no framework for resilience assessment is complete, comprehensive or directly applicable to practitioners; current examples are lacking key elements (e.g. a comprehensive study of stressors, properties and metrics, examples of cases study, ability to benchmark interventions or connectivity with broader frameworks). Furthermore, resilience is seen as an additional cost or extra effort, instead of a means to overcome project uncertainty that could unlock new opportunities for investment.

Assessing motor proficiency in young adults: The Bruininks Oseretsky Test-2 Short Form and the McCarron Assessment of Neuromuscular Development.

Currently, only two motor tests have norms extending into young adulthood - the McCarron Assessment of Neuromuscular Development (MAND, McCarron 1997) and the Bruininks Oseretsky Test of Motor Proficiency-2 (BOT-2, Bruininks & Bruininks, 2005). Research into the motor difficulties in early adulthood and health outcomes has been impeded because there is no agreed gold standard motor test for this group. The purposes of this study were to compare the discrimination accuracy, classification agreement, and predictive values, and gender distribution and prevalence of each test in identifying motor impairment (MI) in relation to DSM-V diagnostic criteria for DCD. Ninety-one young, healthy adults (M=21.4years, SD=3.3) were recruited. Those classified as MI by each test scored at one standard deviation or more below the overall mean standard score. Small, statistically significant correlations were found between the MAND and BOT-2 SF tests for score rank (r=0.370, p=0.01) and standard score values (r=0.404; p=0.01). The overall decision agreement for non-MI cases was relatively high at 85% but very low for MI cases (4.4%). Unexpectedly, gender was balanced in MI cases. BOT-2 SF identified twice as many MI cases than MAND (13.2% vs 6.6%), yet overall comparative test specificity was high (89%). Predictive values for MAND, compared against BOT-2 SF as the standard, indicated broad independence between these tests and overall, the decision statistics indicated that the two tests identified different adult cohorts with MI. Objective classification of adult motor proficiency using a gold standard assessment tool including complex and ecologically valid tasks is still elusive.

The relationship between motor proficiency and mental health outcomes in young adults: A test of the Environmental Stress Hypothesis.

Growing evidence has highlighted the importance of motor proficiency in relation to psychosocial outcomes including self-perceived competence in various domains, perceived social support, and emotional areas such as anxiety and depression. The Environmental Stress Hypothesis-elaborated (Cairney, Rigoli, & Piek, 2013) is a proposed theoretical framework for understanding these relationships and recent studies have begun examining parts of this model using child and adolescent populations. However, the extent to which the relationships between these areas exist, persist or change during early adulthood is currently unclear. The current study aimed to investigate the Environmental Stress Hypothesis in a sample of 95 young adults aged 18-30years and examined the mediating role of physical self-worth and perceived social support in the relationship between motor proficiency and internalising symptoms. The McCarron Assessment of Neuromuscular Development (McCarron, 1997) was used to assess motor proficiency, the Depression Anxiety Stress Scale (Lovibond & Lovibond, 1995) provided a measure of internalising symptoms, and the Physical Self Perceptions Profile (Fox & Corbin, 1989) and the Multidimensional Scale of Perceived Social Support (Zimet, Dahlem, Zimet, & Farley, 1988) were used to investigate the possible mediating role of physical self-worth and perceived social support respectively. Potential confounding variables such as age, gender and BMI were also considered in the analysis. Structural Equation Modelling revealed that perceived social support mediated the relationship between motor proficiency and internalising symptoms, whereas, the mediating role of physical self-worth was non-significant. The current results provide support for part of the model pathways as described in the Environmental Stress Hypothesis and suggest an important relationship between motor proficiency and psychosocial outcomes in young adults. Specifically, the results support previous literature regarding the significant role of perceived social support for mental well-being and suggest that an intervention that considers social support may also indirectly influence mental health outcomes in young adults who experience movement difficulties.

Response to sunitinib (Sutent) in chemotherapy refractory clear cell ovarian cancer.

•Case describes a response to sunitinib in clear cell ovarian cancer.•Discussion of unique molecular characteristics of clear cell ovarian cancers•Practical points regarding dosing and toxicity when using sunitinib discussed.

Fundamental problems with the cooperative breeding hypothesis. A reply to Burkart & van Schaik.

The cooperative breeding hypothesis (CBH) states that cooperative breeding, a social system in which group members help to rear offspring that are not their own, has important socio-cognitive consequences. Thornton & McAuliffe (2015; henceforth T&M) critiqued this idea on both conceptual and empirical grounds, arguing that there is no reason to predict that cooperative breeding should favour the evolution of enhanced social cognition or larger brains, nor any clear evidence that it does. In response to this critique, Burkart & van Schaik (2016 henceforth B&vS) attempt to clarify the causal logic of the CBH, revisit the data and raise the possibility that the hypothesis may only apply to primates. They concede that cooperative breeding is unlikely to generate selection pressures for enhanced socio-cognitive abilities, but argue instead that the CBH operates purely through cooperative breeding reducing social or energetic constraints. Here, we argue that this revised hypothesis is also untenable because: (1) it cannot explain why resources so released would be allocated to cognitive traits per se rather than any other fitness-related traits, (2) key assumptions are inconsistent with available evidence and (3) ambiguity regarding the predictions leaves it unclear what evidence would be required to falsify it. Ultimately, the absence of any compelling evidence that cooperative breeding is associated with elevated cognitive ability or large brains (indeed data suggest the opposite is true in non-human primates) also casts doubt on the capacity of the CBH to explain variation in cognitive traits.

Visual working memory deterioration preceding relapse in psychosis.

BACKGROUND: Relapse is distressingly common after the first episode of psychosis, yet it is poorly understood and difficult to predict. Investigating changes in cognitive function preceding relapse may provide new insights into the underlying mechanism of relapse in psychosis. We hypothesized that relapse in fully remitted first-episode psychosis patients was preceded by working memory deterioration. METHOD: Visual memory and verbal working memory were monitored prospectively in a 1-year randomized controlled trial of remitted first-episode psychosis patients assigned to medication continuation (quetiapine 400 mg/day) or discontinuation (placebo). Relapse (recurrence of positive symptoms of psychosis), visual (Visual Patterns Test) and verbal (Letter-Number span test) working memory and stressful life events were assessed monthly. RESULTS: Remitted first-episode patients (n = 102) participated in the study. Relapsers (n = 53) and non-relapsers (n = 49) had similar baseline demographic and clinical profiles. Logistic regression analyses indicated relapse was associated with visual working memory deterioration 2 months before relapse [odds ratio (OR) 3.07, 95% confidence interval (CI) 1.19-7.92, P = 0.02], more stressful life events 1 month before relapse (OR 2.11, 95% CI 1.20-3.72, P = 0.01) and medication discontinuation (OR 5.52, 95% CI 2.08-14.62, P = 0.001). CONCLUSIONS: Visual working memory deterioration beginning 2 months before relapse in remitted first-episode psychosis patients (not baseline predictor) may reflect early brain dysfunction that heralds a psychotic relapse. The deterioration was found to be unrelated to a worsening of psychotic symptoms preceding relapse. Testable predictors offer insight into the brain processes underlying relapse in psychosis.

Modifying self-assembly and species separation in three-dimensional systems of shape-anisotropic particles.

The behaviors of large, dynamic assemblies of macroscopic particles are of direct relevance to geophysical and industrial processes and may also be used as easily studied analogs to micro- or nano-scale systems, or model systems for microbiological, zoological, and even anthropological phenomena. We study vibrated mixtures of elongated particles, demonstrating that the inclusion of differing particle "species" may profoundly alter a system's dynamics and physical structure in various diverse manners. The phase behavior observed suggests that our system, despite its athermal nature, obeys a minimum free energy principle analogous to that observed for thermodynamic systems. We demonstrate that systems of exclusively spherical objects, which form the basis of numerous theoretical frameworks in many scientific disciplines, represent only a narrow region of a wide, multidimensional phase space. Thus, our results raise significant questions as to whether such models can accurately describe the behaviors of systems outside this highly specialized case.

Selective processing of auditory evoked responses with iterative-randomized stimulation and averaging: A strategy for evaluating the time-invariant assumption.

The recording of auditory evoked potentials (AEPs) at fast rates allows the study of neural adaptation, improves accuracy in estimating hearing threshold and may help diagnosing certain pathologies. Stimulation sequences used to record AEPs at fast rates require to be designed with a certain jitter, i.e., not periodical. Some authors believe that stimuli from wide-jittered sequences may evoke auditory responses of different morphology, and therefore, the time-invariant assumption would not be accomplished. This paper describes a methodology that can be used to analyze the time-invariant assumption in jittered stimulation sequences. The proposed method [Split-IRSA] is based on an extended version of the iterative randomized stimulation and averaging (IRSA) technique, including selective processing of sweeps according to a predefined criterion. The fundamentals, the mathematical basis and relevant implementation guidelines of this technique are presented in this paper. The results of this study show that Split-IRSA presents an adequate performance and that both fast and slow mechanisms of adaptation influence the evoked-response morphology, thus both mechanisms should be considered when time-invariance is assumed. The significance of these findings is discussed.

Porosity in metal-organic framework glasses.

The porosity of a glass formed by melt-quenching a metal-organic framework, has been characterized by positron annihilation lifetime spectroscopy. The results reveal porosity intermediate between the related open and dense crystalline frameworks ZIF-4 and ZIF-zni. A structural model for the glass was constructed using an amorphous polymerization algorithm, providing additional insight into the gas-inaccessible nature of porosity and the possible applications of hybrid glasses.

Defects in metal-organic frameworks: a compromise between adsorption and stability?

Defect engineering has arisen as a promising approach to tune and optimise the adsorptive performance of metal-organic frameworks. However, the balance between enhanced adsorption and structural stability remains an open question. Here both CO2 adsorption capacity and mechanical stability are calculated for the zirconium-based UiO-66, which is subject to systematic variations of defect scenarios. Modulator-dependence, defect concentration and heterogeneity are explored in isolation. Mechanical stability is shown to be compromised at high pressures where uptake is enhanced with an increase in defect concentration. Nonetheless this reduction in stability is minimised for reo type defects and defects with trifluoroacetate substitution. Finally, heterogeneity and auxeticity may also play a role in overcoming the compromise between adsorption and stability.

Estimated cost per HIV infection diagnosed through routine HIV testing offered in acute general medical admission units and general practice settings in England.

OBJECTIVES: Following national guidelines to expand HIV testing in high-prevalence areas in England, a number of pilot studies were conducted in acute general medical admission units (ACUs) and general practices (GPs) to assess the feasibility and acceptability of testing in these settings. The aim of this study was to estimate the cost per HIV infection diagnosed through routine HIV testing in these settings. METHODS: Resource use data from four 2009/2010 Department of Health pilot studies (two ACUs; two GPs) were analysed. Data from the pilots were validated and supplemented with information from other sources. We constructed possible scenarios to estimate the cost per test carried out through expanded HIV testing in ACUs and GPs, and the cost per diagnosis. RESULTS: In the pilots, cost per test ranged from £8.55 to £13.50, and offer time and patient uptake were 2 minutes and 90% in ACUs, and 5 minutes and 60% in GPs, respectively. In scenario analyses we fixed offer time, diagnostic test cost and uptake rate at 2 minutes, £6 and 80% for ACUs, and 5 minutes, £9.60 and 40% for GPs, respectively. The cost per new HIV diagnosis at a positivity of 2/1000 tests conducted was £3230 in ACUs and £7930 in GPs for tests performed by a Band 3 staff member, and £5940 in ACUs and £18 800 in GPs for tests performed by either hospital consultants or GPs. CONCLUSIONS: Expanded HIV testing may be more cost-efficient in ACUs than in GPs as a consequence of a shorter offer time, higher patient uptake, higher HIV positivity and lower diagnostic test costs. As cost per new HIV diagnosis reduces at higher HIV positivity, expanded HIV testing should be promoted in high HIV prevalence areas.

Forced axial segregation in axially inhomogeneous rotating systems.

Controlling segregation is both a practical and a theoretical challenge. Using a novel drum design comprising concave and convex geometry, we explore, through the application of both discrete particle simulations and positron emission particle tracking, a means by which radial size segregation may be used to drive axial segregation, resulting in an order of magnitude increase in the rate of separation. The inhomogeneous drum geometry explored also allows the direction of axial segregation within a binary granular bed to be controlled, with a stable, two-band segregation pattern being reliably and reproducibly imposed on the bed for a variety of differing system parameters. This strong banding is observed to persist even in systems that are highly constrained in the axial direction, where such segregation would not normally occur. These findings, and the explanations provided of their underlying mechanisms, could lead to radical new designs for a broad range of particle processing applications but also may potentially prove useful for medical and microflow applications.