Search

Pleurotus ostreatus is a global mushroom crop with nutritional and medicinal benefits. However, the genetic basis of several commercial traits remains unknown. To address this, we analyzed the quantitative trait loci (QTLs) for two representative cultivars, "Heuktari" and "Miso," with apparently distinct alleles. A genetic map with 11 linkage groups was constructed, in which 27 QTLs were assigned to 14 traits. The explained phenotypic variations in QTLs ranged from 7.8% to 22.0%. Relatively high LOD values of 6.190 and 5.485 were estimated for the pinheading period and the number of valid stipes, respectively. Some QTL-derived molecular markers showed potential enhancement rates of selection precision in inbred lines, especially for cap shape (50%) and cap thickness (30%). Candidate genes were inferred from the QTL regions and validated using qRT-PCR, particularly for the cysteine and glutathione pathway, in relation to cap yellowness. The molecular markers in this study are expected to facilitate the breeding of the Heuktari and Miso lines and provide probes to identify related genes in P. ostreatus.

This study's objective is to test one of the key theoretical orientations in the literature on intergroup relations, realistic conflict theory, from a dynamic perspective. In this study, we focus on adolescents who are, according to the 'impressionable years'-hypothesis, most likely to change in their rejection of equal opportunities. Realistic conflict theory is applied in a dynamic way by taking into account economic characteristics related to the adolescent and the household. We employ Swiss panel data covering the period 1999-2017, containing information of both adolescents and the household they live in. Results demonstrate that there is relatively little variation within adolescents in rejection of equal opportunities for foreigners. Despite of using a broad range of characteristics related to adolescents' as well as the household's economic situation, the changes that do occur within individuals could hardly be explained by those economic changes. Socialisation theories on direct parental influences appeared to better explain changes in rejection of equal opportunities.

IntroductionPeople living with HIV/AIDS (PLHIV) are at increased risk of cardiometabolic diseases attributable to the effects of the virus, antiretroviral therapy (ART) and traditional risk factors. Most studies have focused on assessing the effect of ART on cardiometabolic diseases in PLHIV with fewer studies assessing the cardiometabolic risk profile prior to exposure to ART. Therefore, this protocol is for a systematic review and meta-analysis to estimate the global prevalence of selected cardiometabolic risk factors in ART-naïve PLHIV and their association with HIV specific factors.MethodsWe shall conduct a systematic search of observational studies on the prevalence of obesity, hypertension, diabetes, and dyslipidaemia in ART-naïve PLHIV and their association with HIV specific characteristics. We will search PubMed-MEDLINE, CINAHL, SCOPUS, Academic Search Premier, Africa-Wide Information and Africa Journals Online databases to identify relevant studies published before June 2022. Two authors will independently screen, select studies, extract data, and conduct risk of bias assessments. Disagreements between the two authors will be resolved by consensus or consulting a third reviewer. Data consistently reported across studies will be pooled using random-effects meta-analysis. Heterogeneity will be evaluated using Cochrane's Q statistic and quantified using I2 statistics. The Preferred Reporting Items for Systematic reviews and Meta-Analysis protocols (PRISMA-P) 2015 guidelines are used for the reporting of this protocol.DiscussionThis review will help determine the burden of selected cardiometabolic diseases in ART-naïve HIV-infected populations and the contribution of HIV infection, independent of ART, to cardiometabolic diseases in PLHIV. It will provide new information that can help orientate future research and potentially guide healthcare policy making. This is part of a thesis that will be submitted to the Faculty of Health Sciences, University of Cape Town, for the award of a PhD in Medicine with protocol ethical clearance number (UCT HREC 350/2021).RegistrationPROSPERO: CRD42021226001. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021226001.

Diffuse midline gliomas (DMG) are the most aggressive brain tumors of childhood and young adults, with documented 2-year survival rates 10nmol/L, or tumor tissue studies demonstrate CDK inhibition, then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy and discontinued with evidence of radiologic or clinical disease progression. The poor survival associated with diffuse midline gliomas underscore the need for improved means to evaluate efficacy of drug delivery to tumor and peritumoral tissue. The findings of this novel study, will provide real-time measurements of BBB function which have the potential to influence future prognostic and diagnostic decisions in such a lethal disease with limited treatment options. Trial registration: Clinicaltrials.gov, NCT05413304. Registered June 10, 2022, Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis.

BackgroundPossible sex differences in hepatitis A virus (HAV) incidence rates in different age groups are not well documented. We aimed to obtain stable pooled estimates of such differences based on data from a number of high-income countries.MethodsWe obtained data on incident cases of HAV by sex and age group over a period of 6-25 years from nine countries: Australia, Canada, Czech Republic, Finland, Germany, Israel, Netherland, New Zealand and Spain. Male to female incidence rate ratios (IRR) were computed for each year, by country and age group. For each age group, we used meta-analytic methods to combine the IRRs. Meta-regression was conducted to estimate the effects of age, country, and time period on the IRR.ResultsA male excess in incidence rates was consistently observed in all age groups, although in the youngest and oldest age groups, where the numbers tended to be lower, the lower bounds of the 95% confidence intervals for the IRRs were less than one. In the age groups ConclusionsThe excess HAV incidence rates in young males, pooled over a number of countries, suggest that the sex differences are likely to be due at least in part to physiological and biological differences and not just behavioral factors. At older ages, differential exposure plays an important role. These findings, seen in the context of the excess incidence rates in young males for many other infectious diseases, can provide further keys to the mechanisms of the infection.

Population-level data on predictors for attitudes towards sexual behavior are missing for Germany. The current study investigated sexual attitudes in the German population with regard to sociodemographic and sociocultural factors. Data originated from the German Health and Sexuality Survey (GeSiD; N = 4,955) carried out from October 2018 to September 2019. Computer-assisted face to face interviews were conducted with a large self-administered component due to the sensitive topics of the survey. Public acceptance towards several aspects of sexual behavior (extramarital sex, abortion, same sex sexual activities, sex work, promiscuity, sex without love) was investigated. Age, gender, education, religious aspects and migration background were introduced as predictors into logistic regression analyses. Overall, respondents rather rejected promiscuity (61%) and extramarital sex (81%) and rather supported same sex sexual activities (63-70%). Male respondents more likely rejected same sex sexual activities and abortion. Higher education was associated with more acceptance towards the sexual behaviors whereas first generation migrants, Muslim faith and religious devoutness were associated with less acceptance. Results indicate that gender is relevant in terms of sexual attitudes with male respondents tending to have more traditional and heteronormative gender role values. Furthermore, education, culture and religion play an important role concerning the liberality towards sexual behaviors. Acculturation processes of second generation migrants may lead to an adaptation of values. Comprehensive and culturally sensitive sex education may focus on differences concerning sexuality-related norms and values.

Several options to treat hospitalized severe COVID-19 patients have been suggested. The study aimed to describe survival in patients treated with convalescent COVID plasma (CCP) and to identify in-hospital mortality predictors. This prospective cohort study examined data from 112 severe COVID-19 patients hospitalized in the Corona Departments in an acute care hospital who received two units of CCP (at least one of them high-titer). Demographic and medical data was retrieved from the patients’ electronic health records (EHR). Possible predictors for in-hospital mortality were analyzed in a univariate analysis and those found to be clinically significant were further analyzed in a multivariable analysis. Median age was 67 years (IQR 55–74) and 66 (58.9%) of them were males. Of them, 20 (17.9%) died in hospital. On multivariable analysis diabetes mellitus (p = 0.004, OR 91.54), mechanical ventilation (p = 0.001, OR 59.07) and lower albumin levels at treatment (p = 0.027, OR 0.74) were significantly associated with increased in-hospital mortality. In our study, in-hospital mortality in patients receiving CCP is similar to that reported for the general population, however certain variables mentioned above were associated with increased in-hospital mortality. In the literature, these variables were also associated with a worse outcome in patients with COVID-19 who did not receive CCP. As evidence points toward a benefit from CCP treatment in immunocompromised patients, we believe the above risk factors can further define COVID-19 patients at increased risk for mortality, enabling the selection of candidates for early treatment in an outpatient setting if possible.

A number of experiments were done to further our understanding of the substrate utilization in button mushroom crops (Agaricus bisporus). An analysis of the degradation of dry matter of the substrate during a crop cycle revealed that for pin formation the upper 1/3rd layer is used, for the production of flush one all layers are involved and for flush two mainly the lower 1/3 layer is used. A reduction in substrate depth leads to a decrease in yield/m2 but an apparent increase in yield per tonne of substrate with a lower mushroom quality. A short daily interruption of the connection between the casing soil with the substrate results in a delay of the first flush. Interruptions with only part of the substrate did not lead to delay in production. Daily interruption of the connection with all or only part of the substrate leads to a shift in yield from flush one to flush two but the total yield remains unchanged. The mycelial biomass in the substrate increases from filling up to pinning, has a steeper increase during flush one, and is levelling off during flush two, indicating that in the period of venting and up to/including flush one, enzymes are secreted by growing hyphae generating nutrients to feed a fixed amount of mushroom biomass for two flushes. A sidewise extension of the substrate (without casing soil, thus not producing mushrooms) showed that the substrate at a distance more than somewhere between 20-50 cm away from the casing soil does not contribute to feeding mushrooms in the first two flushes. The observations are discussed with respect to relevant previous research.

Around 6% of all childhood malignancies represent renal tumors, of which a majority includes Wilms tumor (WT). Although survival rates have improved over the last decades, specific patients are still at risk for adverse outcome. In the Netherlands, since 2015, pediatric oncology care for renal tumors has been centralized in the Princess Máxima Center for Pediatric Oncology. Here, we describe experiences of the first 5 years of centralized care and explore whether this influences the epidemiological landscape by comparing data with the Netherlands Cancer Registry (NCR). We identified all patients

BackgroundEarly in the COVID-19 pandemic, it was noted that males seemed to have higher case-fatality rates than females. We examined the magnitude and consistency of the sex differences in age-specific case-fatality rates (CFRs) in seven countries.MethodsData on the cases and deaths from COVID-19, by sex and age group, were extracted from the national official agencies from Denmark, England, Israel, Italy, Spain, Canada and Mexico. Age-specific CFRs were computed for males and females separately. The ratio of the male to female CFRs were computed and meta-analytic methods were used to obtained pooled estimates of the male to female ratio of the CFRs over the seven countries, for all age-groups. Meta-regression and sensitivity analysis were conducted to evaluate the age and country contribution to differences.ResultsThe CFRs were consistently higher in males at all ages. The pooled M:F CFR ratios were 1.71, 1.88, 2.11, 2.11, 1.84, 1.78 and 1.49, for ages 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, 80+ respectively. In meta-regression, age group and country were associated with the heterogeneity in the CFR ratios.ConclusionsThe sex differences in the age-specific CFRs are intriguing. Sex differences in the incidence and mortality have been found in many infectious diseases. For COVID-19, factors such as sex differences in the prevalence of underlying diseases may play a part in the CFR differences. However, the consistently greater case-fatality rates in males at all ages suggests that sex-related factors impact on the natural history of the disease. This could provide important clues as to the mechanisms underlying the severity of COVID-19 in some patients.

The development of new techniques for the detection of carbapenemase activity is of great importance since the increased incident of resistance against carbapenems represents a serious threat to global public health. In this context, the matrix-assisted laser desorption/ionization approach already demonstrated to be a reliable tool for rapid carbapenemase detection. As a newly developed test, there is still a lack of in-depth analysis of its robustness and possible wider application. The main goal of this study was to evaluate the potential for using the design MBT STAR-Carba assay as the pre-characterization method for Enterobacterales and P. aeruginosa strains in terms of the produced classes of carbapenemases using modified procedure parameters-various suspension densities and incubation times. Moreover, its usefulness for the in-depth analysis and characterization of metallo-β-lactamases (MBL) was tested by applying inhibition assays. In this study, the designed assay proved to be a sensitive tool for the detection of carbapenemase hydrolytic activity, which can be successfully used to partially classify the class of carbapenemase present. Additionally, the use of defined high concentration suspensions would allow to shorten the incubation time to 1 minute for certain strains. Considering that the assay was also suitable to investigate the effect of different inhibitors on the MBL activity, it demonstrates far higher discriminatory potential than only a rapid routine carbapenemase detection tool and could be used as a susceptibility assay.

BackgroundGamma-glutamyl transferase (GGT) has recently been reported as a biomarker for cardiovascular (CVD) risk in general populations. We investigated the associations of GGT with cardio-metabolic diseases and CVD risk in South Africans living with HIV.MethodsIn this cross-sectional study, HIV-infected adults were randomly recruited across 17 HIV clinics in the Western Cape Province. Homeostatic model assessment for insulin resistance (HOMA-IR), hypertension, diabetes, metabolic syndrome by Joint Interim Statement criteria (JIS-MS), a ≥5% and ≥10% predicted risk for a CVD event within 10 years by the Framingham risk score (10-years-CVD risk) were computed. Associations between GGT and cardio-metabolic trait were explored using linear and binomial logistic regressions adjusted for age, gender, lifestyle behaviours and HIV-related characteristics.ResultsAmong 709 participants (561 women, mean age 38.6 years), log-GGT was positively associated with waist circumference (β=2.75; pConclusionsIn this study, GGT levels were associated with cardio-metabolic variables independent of HIV specific attributes. If confirmed in longitudinal studies, GGT evaluation maybe included in CVD risk monitoring strategies in people living with HIV.

Protein-metabolite interactions play an important role in the cell's metabolism and many methods have been developed to screen them in vitro. However, few methods can be applied at a large scale and not alter biological state. Here we describe a proteometabolomic approach, using chromatography to generate cell fractions which are then analyzed with mass spectrometry for both protein and metabolite identification. Integrating the proteomic and metabolomic analyses makes it possible to identify protein-bound metabolites. Applying the concept to the thermophilic fungus Chaetomium thermophilum, we predict 461 likely protein-metabolite interactions, most of them novel. As a proof of principle, we experimentally validate a predicted interaction between the ribosome and isopentenyl adenine.

BackgroundIn the past decade, estimates of malaria infections have dropped from 500 million to 225 million per year; likewise, mortality rates have dropped from 3 million to 791,000 per year. However, approximately 90% of these deaths continue to occur in sub-Saharan Africa, and 85% involve children less than 5 years of age. Malaria mortality in children generally results from one or more of the following clinical syndromes: severe anemia, acidosis, and cerebral malaria. Although much is known about the clinical and pathological manifestations of CM, insights into the biology of the malaria parasite, specifically transcription during this manifestation of severe infection, are lacking.Methods and findingsWe collected peripheral blood from children meeting the clinical case definition of cerebral malaria from a cohort in Malawi, examined the patients for the presence or absence of malaria retinopathy, and performed whole genome transcriptional profiling for Plasmodium falciparum using a custom designed Affymetrix array. We identified two distinct physiological states that showed highly significant association with the level of parasitemia. We compared both groups of Malawi expression profiles with our previously acquired ex vivo expression profiles of parasites derived from infected patients with mild disease; a large collection of in vitro Plasmodium falciparum life cycle gene expression profiles; and an extensively annotated compendium of expression data from Saccharomyces cerevisiae. The high parasitemia patient group demonstrated a unique biology with elevated expression of Hrd1, a member of endoplasmic reticulum-associated protein degradation system.ConclusionsThe presence of a unique high parasitemia state may be indicative of the parasite biology of the clinically recognized hyperparasitemic severe disease syndrome.

BackgroundChronic hepatitis C (CHC) can be eliminated as a public health threat by meeting the WHO targets: 90% of patients diagnosed and 80% treated by 2030. To achieve and monitor progress towards elimination, an updated estimate of the size of the CHC population is needed, but Denmark has no complete national CHC register. By combining existing registers in 2007, we estimated the population living with CHC to be 16,888 (0.38% of the adult population).AimTo estimate the population living with diagnosed and undiagnosed CHC in Denmark on 31 December 2016. Among additional aims were to estimate the proportion of patients attending specialised clinical care.MethodsPeople with diagnosed CHC were identified from four national registers. The total diagnosed population was estimated by capture-recapture analysis. The undiagnosed population was estimated by comparing the register data with data from two cross-sectional surveys.ResultsThe population living with diagnosed CHC in Denmark was 7,581 persons (95%CI: 7,416-12,661) of which 6,116 (81%) were identified in the four registers. The estimated undiagnosed fraction was 24%, so the total CHC infected population was 9,975 corresponding to 0.21% of the adult population (95%CI: 9,758-16,659; 0.21%-0.36%). Only 48% of diagnosed patients had received specialised clinical care.ConclusionCHC prevalence in Denmark is declining and 76% of patients have been diagnosed. Linking diagnosed patients to care and increasing efforts to test people with former or current drug use will be necessary to achieve CHC elimination.

AimThe increasing burden of comorbid HIV infection and hypertension necessitates a focus on healthcare services providing care for chronic multi-morbidities. The aim of this study was to evaluate the perceptions and experiences of 1) people living with HIV infection and comorbid hypertension, and 2) their healthcare providers, related to their diagnoses and interactions with chronic healthcare services in South Africa.MethodsThis study comprised quantitative and qualitative arms with a multi-layered approach. We randomly selected 17 public healthcare facilities providing HIV care across Cape Town and surrounding rural municipalities.ResultsInterviews were conducted with clinicians (n = 11), specialised nursing professionals (n = 10), lay counsellors (n = 12), six patients focus groups (n = 35) and 20 in-depth individual patient interviews. There were mixed views on being treated at integrated vs. separate chronic care facilities regarding quality of care and privacy/anonymity. Specialised clinics offered better care for HIV infection while hypertension and other non-communicable diseases were neglected. Privacy about HIV status maybe better maintained in integrated clinics but not if status was disclosed by having the green-coloured HIV treatment card. A single appointment date was considered advantageous as it saved time and money leading to greater compliance; however, waiting times at clinics were longer with perhaps fewer patients seen.ConclusionsThe mixed reactions elicited to the integration of healthcare services for HIV, hypertension and other non-communicable diseases highlights the complexities involved in implementing such services. Greater human resources with retraining and reskilling of healthcare staff is required for the optimal management of chronic multi-morbidities.

BackgroundPertussis is frequently reported to be more common in females than in males. However, the variability of the sources of these observations makes it difficult to estimate the magnitude and consistency of the sex differences by age. To address this question, we used meta-analytic methods to analyze pertussis national incidence rates by sex and age group from nine countries between the years 1990 and 2017.MethodsFor each age group, we used meta-analytic methods to combine the female to male incidence rate ratios (RRs) by country and year. Meta-regression was performed to assess the relative contributions of age, country and time-period to the variation in the incidence RRs.ResultsThe pooled female to male incidence RRs (with 95% CI) for ages 0-1, 1-4, 5-9 and 10-14, were 1.03 (1.01-1.06), 1.16 (1.14-1.17), 1.18 (1.15-1.22), 1.15 (1.11-1.18) respectively. For the ages 15-44, 45-64 and 65+ they were 1.65 (1.58-1.72), 1.59 (1.53-1.66), 1.20 (1.16-1.24), respectively. While there were some differences between the countries, the directions were consistent. When including age, country and time in meta-regression analyses, almost all the variation could be attributed to the differences between the age groups.ConclusionsThe consistency of the excess pertussis incidence rates in females, particularly in infants and very young children, is unlikely to be due to differences in exposure. Other factors that impact on the immune system, including chromosomal differences and hormones, should be further investigated to explain these sex differences. Future studies should consider sex for better understanding the mechanisms affecting disease incidence, with possible implications for management and vaccine development.

PurposeTo evaluate the long-term effect of 20 and 23 gauge pars plana vitrectomy (PPV) on intraocular pressure (IOP).MethodsStudy type: Monocentric retrospective cohort study. 249 eyes of 249 patients undergoing PPV due to epiretinal membrane (EM), idiopathic macular hole (IMH) or vitreoretinal traction (VT) were included. The fellow eye served as control. Exclusion criteria were factors known to influence the IOP, such as cataract surgery during follow-up, extended use of steroids, cryotherapy and silicone oil endotamponade. The relative change of IOP (operated vs. fellow eye) at 6-12 months after surgery was defined as primary endpoint. Secondary endpoints were the relative change of IOP at 3-6 and 12-24 months. Possible influencing cofactors were analysed using ANCOVA.ResultsThe primary endpoint did not show a significant IOP reduction of the operated eye relative to the fellow eye (P = 0.089, n = 84). However, the IOP of the operated eye alone was significantly reduced at 6-12 and 12-24 months after surgery (-0.75 ± 2.80 and -1.22 ± 3.29 mmHg, P = 0.008 and 0.007, respectively). The IOP of the fellow eye was also significantly reduced at the 12-24 months period (-0.75 ± 2.73 mmHg, P = 0.008). In the subgroup analysis, sclerotomy size was a significant influencing cofactor, leading to lower IOP after 20G compared to 23G vitrectomy (P = 0.04).ConclusionPars plana vitrectomy did not induce a significant long-term IOP reduction relative to the contralateral eye. However, we observed a IOP lowering potential in 20G vitrectomy.

Pleurotus ostreatus, one of the most widely cultivated edible mushrooms, produces high numbers of spores causing severe respiratory health problems for people, clogging of filters and spoilage of produce. A non-sporulating commercial variety (SPOPPO) has been successfully introduced into the market in 2006. This variety was generated by introgression breeding of a natural mutation into a commercial variety. Our cytological studies revealed that meiosis in the natural and derived sporeless strains was blocked in metaphase I, apparently resulting in a loss of spore formation. The gene(s) underlying this phenotype were mapped to an 80 kb region strongly linked to sporelessness and identified by transformation of wild type genes of this region into a sporeless strain. Sporulation was restored by re-introduction of the DNA sequence encoding the P. ostreatus meiotic recombination gene MSH4 homolog (poMSH4). Subsequent molecular analysis showed that poMSH4 in the sporeless P. ostreatus was interrupted by a DNA fragment containing a region encoding a CxC5/CxC6 cysteine cluster associated with Copia-type retrotransposons. The block of meiosis in metaphase I by a poMSH4 null mutant suggests that this protein plays an essential role in both Class I and II crossovers in mushrooms, similar to animals (mice), but unlike in plants. MSH4 was previously shown to be a target for breeding of sporeless varieties in P. pulmonarius, and the null mutant of the MSH4 homolog of S. commune (scMSH4) confers an extremely low level of spore formation. We propose that MSH4 homologs are likely to be a breeding target for sporeless strains both within Pleurotus sp. and in other Agaricales.

BackgroundCrude case-fatality rates (CFRs) for COVID-19 vary widely between countries. There are serious limitations in the CFRs when making comparisons. We examined how the age distribution of the cases is responsible for the COVID-19 CFR differences between countries.MethodsCOVID-19 cases and deaths, by ten-year age-groups, were available from the reports of seven countries. The overall and age-specific CFRs were computed for each country. The age-adjusted CFRs were computed by the direct method, using the combined number of cases in all seven countries in each age group as the standard population. A meta-analytic approach was used to obtain pooled age-specific CFRs.FindingsThe crude overall CFRs varied between 0.82% and 14.2% in the seven countries and the variation in the age-specific CFRs were much smaller. There was wide variation in the age distribution of the cases between countries. The ratio of the crude CFR for the country with the highest CFR to that with the lowest (6.28) was much lower for the age-adjusted CFRs rates (2.57).ConclusionsThe age structure of the cases explains much of differences in the crude CFRs between countries and adjusting for age substantially reduces this variation. Other factors such as the definition of cases, coding of deaths and the standard of healthcare are likely to account for much of the residual variation. It is misleading to compare the crude COVID-19 CFRs between countries and should be avoided. At the very least, age-specific and age-adjusted CFRs should be used for comparisons.

Background and aimsTo evaluate the ability of pretreatment liver stiffness measurements (pLSM) to predict hepatocellular carcinoma (HCC), incident decompensation and all-cause mortality in chronic hepatitis C (CHC) patients who achieved sustained virological response (SVR) after treatment with direct-acting antivirals (DAAs).Methods773 CHC patients with SVR after DAA treatment and no prior liver complications were identified retrospectively. Optimized cut-off of 17.5 kPa for incident HCC was selected by maximum Youden's index. Patients were grouped by pLSM: ResultsMedian follow-up was 36 months and 43.5% (336) had cirrhosis (LSM>12.5 kPa). The median pLSM was 11.6 kPa (IQR 6.7-17.8, range 2.5-75) and pLSM of ConclusionPretreatment LSM predicts risk of HCC, decompensation and all-cause mortality in patients with SVR after DAA treatment. Patients with a pLSM

AimIn view of the current context of poverty and socio-economic inequalities and the high and rising burdens of HIV infection and non-communicable diseases in South Africa, this study aims to describe the distribution of adverse life events (ALEs) by age and gender, and examine the socio-demographic characteristics, psychosocial coping mechanisms, risky lifestyle behaviours and family burden of HIV-related ill-health associated with ALEs in 25-74-year-old black residents of Cape Town.Materials and methodsIn a random cross-sectional sample, 12 ALEs, tobacco and alcohol use, sense of coherence (SOC), locus of control (LOC) and impact of HIV in the family were determined by administered questionnaires. Data analyses included descriptive statistics adjusted for the realised sample. Multivariable linear regression models assessed the independent associations of increasing number of ALEs.ResultsAmong 1099 participants, mean lifetime score of ALE categories examined was 6.1 ±2.1 (range 0-12) with men reporting significantly higher number of events compared with women (p50% of life in urban areas, >7 years of education, problematic alcohol use and poorer psychosocial coping mechanisms defined by low SOC and LOC. All four variables pertaining to HIV-related burden of ill-health in the family were significantly associated with increasing ALEs.ConclusionsConsidering that lower SOC and LOC and problem drinking were significantly linked to ALEs, policymakers need to formulate strategies that improve coping mechanisms and promote problem-solving behaviours, target the high burden of alcohol misuse and address unemployment.

The potential role of whole genome duplication (WGD) in evolution is controversial. Whereas some view WGD mainly as detrimental and an evolutionary 'dead end', there is growing evidence that the long-term establishment of polyploidy might be linked to environmental change, stressful conditions, or periods of extinction. However, despite much research, the mechanistic underpinnings of why and how polyploids might be able to outcompete non-polyploids at times of environmental upheaval remain indefinable. Here, we improved our recently developed bio-inspired framework, combining an artificial genome with an agent-based system, to form a population of so-called Digital Organisms (DOs), to examine the impact of WGD on evolution under different environmental scenarios mimicking extinction events of varying strength and frequency. We found that, under stable environments, DOs with non-duplicated genomes formed the majority, if not all, of the population, whereas the numbers of DOs with duplicated genomes increased under dramatically challenging environments. After tracking the evolutionary trajectories of individual genomes in terms of sequence and encoded gene regulatory networks (GRNs), we propose that duplicated GRNs might provide polyploids with better chances to acquire the drastic changes necessary to adapt to challenging conditions, thus endowing DOs with increased adaptive potential under extinction events. In contrast, under stable environments, random mutations might easily render the GRN less well adapted to such environments, a phenomenon that is exacerbated in duplicated, more complex GRNs. We believe that our results provide some additional insights into how genome duplication and polyploidy might help organisms to compete for novel niches and survive ecological turmoil, and confirm the usefulness of our computational simulation in studying the role of WGD in evolution and adaptation, helping to overcome some of the traditional limitations of evolution experiments with model organisms.

Hepatitis C virus (HCV) infection is prevalent among people in prison and prisons could therefore represent a unique opportunity to test risk groups for HCV. The aim of this sero-epidemiological study was to determine the incidence and prevalence of HCV infection and the corresponding risk factors in Danish prisons. Participants, recruited from eight Danish prisons, were tested for HCV using dried blood spots and filled out a questionaire with demographic data and risk factors for HCV infection. In total, 76.9% (801/1041) of all eligible prisoners consented to participate. The prevalence of HCV RNA positive prisoners was 4.2% (34/801) and the in-prison incidence rate was 0.7-1.0 per 100PY overall and 18-24/100PY among PWIDs. Infected prisoners were older than the overall population with a mean age of 42 years and only 17.6% (6/34) were younger than 35 years. The prevalence of PWID was 8.5% (68/801) and only 3% (2/68) of PWID were younger than 25 years. Among the PWID, 85.3% (58/68) had ever received opioid substitution therapy (OST) and 47.1% (32/68) were currently receiving OST. Risk factors associated with HCV infection were intravenous drug use, age ≥ 40 years, and being incarcerated ≥ 10 years. In conclusion, the prevalence of PWID in Danish prisons is low, possibly reflecting a decrease in injecting among the younger generation. This together with OST coverage could explain the low prevalence of HCV infection. However among PWIDs in prison the incidence remains high, suggesting a need for improved HCV prevention in prison.

Innovative protein engineering and chemical conjugation technologies have yielded an impressive number of drug candidates in clinical development including >80 antibody drug conjugates, >60 bispecific antibodies, >35 Fc-fusion proteins and >10 immuno-cytokines. Despite these innovations, technological advances are needed to address unmet medical needs with new pharmacological mechanisms. Age-related eye diseases are among the most common causes of blindness and poor vision in the world. Many such diseases affect the back of the eye, where the inaccessibility of the site of action necessitates therapeutic delivery via intravitreal (IVT) injection. Treatments administered via this route typically have vitreal half-lives

Transcutaneous electrical nerve stimulation (TENS) allows the artificial excitation of nerve fibres by applying electric-current pulses through electrodes on the skin's surface. This work involves the development of a simulation environment that can be used for studying transcutaneous electrotactile stimulation and its dependence on electrode layout and excitation patterns. Using an eight-electrode array implementation, it is shown how nerves located at different depths and with different orientations respond to specific injected currents, allowing the replication of already reported experimental findings and the creation of new hypotheses about the tactile sensations associated with certain stimulation patterns. The simulation consists of a finite element model of a human finger used to calculate the distribution of the electric potential in the finger tissues neglecting capacitive effects, and a cable model to calculate the excitation/inhibition of action potentials in each nerve.

BACKGROUND:Non-invasive methods are the first choice for liver fibrosis evaluation in chronic liver diseases, but few studies investigate the ability of combined methods to predict outcomes. METHODS:591 chronic hepatitis C patients with baseline liver stiffness (LSM) by FibroScan and hyaluronic acid measurements were identified retrospectively. The patients were grouped by baseline LSM: < 10kPa, 10-16.9kPa, and 17-75kPa. Primary outcomes were all-cause mortality and liver-related mortality, analyzed using cox regression and competing risk regression models, respectively. RESULTS:Median follow-up was 46.1 months. Prevalence of cirrhosis at baseline was 107/591 (18.1%). Median LSM was 6.8kPa (IQR 5.3-11.6) and divided into groups, 404/591 (68.4%) had a LSM < 10kPa, 100/591 (16.9%) had a LSM between 10-16.9kPa and 87/591 (14.7%) had a LSM between 17-75kPa. There were 69 deaths, 27 from liver-related disease. 26 patients developed cirrhosis and 30 developed complications of cirrhosis. The mortality rate in the 17-75kPa group was 9.7/100 person-years, compared to 2.2/100 person-years and 1.1/100 person-years in the 10-16.9kPa and

BACKGROUND:Glycated haemoglobin (HbA1c) test has been increasingly promoted as an alternative to fasting plasma glucose (FPG) or oral glucose tolerance test (OGTT) to diagnose dysglycaemia but its performance in HIV-infected Africans has yet to be established. This study aimed to assess the diagnostic accuracy of HbA1c for dysglycaemia including FPG-defined and OGTT-defined dysglycaemia, and OGTT-defined diabetes in HIV-infected Africans, and the effect of HbA1c-predicted dysglycaemia on Joint Interim Statement (JIS)-based prevalent metabolic syndrome (MS). METHODS:A cross-sectional study included HIV-positive patients recruited across public healthcare facilities in the Western Cape. The recommended HbA1c cut-points were tested alongside the optimal cut-points obtained from receiver operating characteristic curve analyses, while the agreement between the MS criteria were assessed using kappa statistic. RESULTS:748 participants (157 men), median age 38 years, 93% on anti-retroviral drugs were included. The optimal HbA1c cut-points of 5.75% (39.3 mmol/mol) showed 54% sensitivity, 84% specificity for FPG-defined dysglycaemia, and 52% sensitivity, 85% specificity for OGTT-defined dysglycaemia. The HbA1c value of 5.85% (40.4 mmol/mol) (63% sensitivity, 99% specificity) was optimal for diabetes. The internationally advocated cut-point of 6.5% (48 mmol/mol) had 37% sensitivity and 99% specificity for diabetes, while HbA1c ≥5.7% (≥39 mmol/mol) yielded similar performance with the study-specific cut-point for any dysglycaemia. MS prevalence by the JIS criteria (28.2%) increased to 29.7% when using HbA1c ≥5.75% (≥39.3 mmol/mol) and to 32.9% with HbA1c ≥5.7% (≥39 mmol/mol); agreement between the original and modified criteria was generally good. CONCLUSIONS:This study agrees with the internationally recommended HbA1c cut-point for detecting dysglycaemia, but not for diabetes in HIV-infected Africans. In line with previous studies in general African populations, our findings suggest that similar factors interfere with HbA1c values regardless of HIV infection status. Replacing FPG-based with HbA1c-predicted dysglycaemia in the JIS criteria to diagnose MS is feasible in HIV-infected Africans.

The importance of accounting for social and behavioural processes when studying public health emergencies has been well-recognised. For infectious disease outbreaks in particular, several methods of incorporating individual behaviour have been put forward, but very few are based on established psychological frameworks. In this paper, we develop a decision framework based on the COM-B model of behaviour change to investigate the impact of individual decision-making on public health outcomes. We demonstrate the application of our decision framework in a proof-of-concept case study based on the 2009 A(H1N1) influenza pandemic in the UK. The National Pandemic Flu Service (NPFS) was set up in England during the pandemic as a means to provide antiviral (AV) treatment to clinically ill patients with influenza-like illness, via telephone calls or internet screening, thereby averting the need to see a doctor. The evaluated patients based on a clinical algorithm and authorised AV drugs for collection via community collection points. We applied our behavioural framework to evaluate the influence of human behaviour on AV collection rates, and subsequently to identify interventions that could help improve AV collection rates. Our model was validated against empirically collected pandemic data from 2009 in the UK. We also performed a sensitivity analysis to identify potentially effective interventions by varying model parameters. Using our behavioural framework in a proof-of-concept case study, we found that interventions geared towards increasing people's 'Capability' and 'Opportunity' are likely to result in increased AV collection, potentially resulting in fewer influenza-related hospitalisations and deaths. We note that important behavioural data from public health emergencies are largely scarce. Insights obtained from models such as ours can, not only be very useful in designing healthcare interventions, but also inform future data collection.

In the present study, we applied Machine Learning (ML) methods to identify psychobiological markers of cognitive processes involved in the process of emotion elicitation as postulated by the Component Process Model (CPM). In particular, we focused on the automatic detection of five appraisal checks-novelty, intrinsic pleasantness, goal conduciveness, control, and power-in electroencephalography (EEG) and facial electromyography (EMG) signals. We also evaluated the effects on classification accuracy of averaging the raw physiological signals over different numbers of trials, and whether the use of minimal sets of EEG channels localized over specific scalp regions of interest are sufficient to discriminate between appraisal checks. We demonstrated the effectiveness of our approach on two data sets obtained from previous studies. Our results show that novelty and power appraisal checks can be consistently detected in EEG signals above chance level (binary tasks). For novelty, the best classification performance in terms of accuracy was achieved using features extracted from the whole scalp, and by averaging across 20 individual trials in the same experimental condition (UAR = 83.5 ± 4.2; N = 25). For power, the best performance was obtained by using the signals from four pre-selected EEG channels averaged across all trials available for each participant (UAR = 70.6 ± 5.3; N = 24). Together, our results indicate that accurate classification can be achieved with a relatively small number of trials and channels, but that averaging across a larger number of individual trials is beneficial for the classification for both appraisal checks. We were not able to detect any evidence of the appraisal checks under study in the EMG data. The proposed methodology is a promising tool for the study of the psychophysiological mechanisms underlying emotional episodes, and their application to the development of computerized tools (e.g., Brain-Computer Interface) for the study of cognitive processes involved in emotions.

Despite the established contribution of deregulated microRNA (miRNA) function to carcinogenesis, relatively few miRNA-cancer gene interactions have been validated, making it difficult to appreciate the true complexity of miRNA-cancer gene regulatory networks.In this effort, we identify miRNA interactomes of 17 well-established cancer genes, involved in various cancer types, through a miRNome-wide 3' UTR reporter screening. Using a novel and performant strategy for high-throughput screening data analysis, we identify 390 interactions, quadrupling the size of the known miRNA interactome for the cancer genes under investigation. Clear enrichments of established and predicted interactions underscore the validity of the interactome data set. Interactomes appear to be primarily driven by canonical binding site interactions. Nonetheless, non-canonical binding sites, such as offset 6mer and seed-mismatched or G:U wobble sites, also have regulatory activity, albeit clearly less pronounced. Furthermore, we observe enhanced regulation in the presence of 3' supplementary pairing for both canonical and non-canonical binding sites.Altogether, the cancer gene-miRNA interactome data set represents a unique resource that will aid in the unraveling of regulatory miRNA networks and the dynamic regulation of key protein-coding cancer genes. In addition, it uncovers aspects of the functional miRNA binding site's architecture and the relative contributions of different binding site types.

AIMS:To describe the distribution and examine the associations of diabetes, hypertension and hypercholesterolaemia across and within population groups, gender and body mass index (BMI) categories. METHODS:This national cross-sectional study was conducted in 2013 among ≥18-year-old black African, coloured, white and Indian adults self-selected for screening. Data collection included self-reported behavioural risk factors and clinical measurements comprising blood pressure, anthropometry and point-of-care random blood glucose and cholesterol assessments. RESULTS:Among the 7711 participants, 2488 men and 5223 women, the prevalence of diabetes and hypertension increased by BMI category across population groups. Compared with white men and women, black African men (odds ratio: 2.66, 95% confidence interval: 1.70-4.16) and women (2.10, 1.49-2.96), coloured men (2.28, 1.44-3.60) and women (2.15, 1.52-3.05) and Indian men (4.38, 2.65-7.26) and women (3.64, 2.50-5.32) were significantly more likely to have diabetes. The odds for hypertension were significantly higher only in coloured men compared with white men (1.37, 1.02-1.83), while it was significantly higher in black African, coloured and Indian women compared with white women. The odds for hypercholesterolaemia were significantly lower in black African men (0.64, 0.49-0.84) and women (0.52, 0.43-0.62) compared with white men and women, and significantly higher in Indian men (1.47, 1.05-2.08) compared with white men. Black African women compared with their male counterparts were less likely to have diabetes (0.64, 0.46-0.89). Black African (0.66, 0.54-.082), coloured (0.65, 0.50-0.84) and white (0.69, 0.53-0.88) women were significantly less likely to have hypertension compared with their male counterparts. The odds for hypercholesterolaemia were higher in coloured (1.44, 1.16-1.80) and white (1.47, 1.18-1.84) women compared with their counterparts. CONCLUSIONS:The cardio-metabolic diseases of diabetes, hypertension and hypercholesterolaemia were differentially associated with population groups and gender in South Africa. The insights obtained highlight the need for multi-disciplinary targeted management approaches in high-risk populations.

It is intriguing that a rare, inherited lysosomal storage disorder Niemann-Pick type C (NPC) shares similarities with Alzheimer's disease (AD). We have previously reported an enhanced processing of β-amyloid precursor protein (APP) by β-secretase (BACE1), a key enzyme in the pathogenesis of AD, in NPC1-null cells. In this work, we characterized regional and temporal expression and processing of the recently identified BACE1 substrates seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L), and APP, in NPC1-/- (NPC1) and NPC1+/+ (wt) mouse brains. We analysed 4-weeks old brains to detect the earliest changes associated with NPC, and 10-weeks of age to identify changes at terminal disease stage. Sez6 and Sez6L were selected due to their predominant cleavage by BACE1, and their potential role in synaptic function that may contribute to presentation of seizures and/or motor impairments in NPC patients. While an enhanced BACE1-cleavage of all three substrates was detected in NPC1 vs. wt-mouse brains at 4-weeks of age, at 10-weeks increased proteolysis by BACE1 was observed for Sez6L in the cortex, hippocampus and cerebellum of NPC1-mice. Interestingly, both APP and Sez6L were found to be expressed in Purkinje neurons and their immunostaining was lost upon Purkinje cell neurodegeneration in 10-weeks old NPC1 mice. Furthermore, in NPC1- vs. wt-mouse primary cortical neurons, both Sez6 and Sez6L showed increased punctuate staining within the endolysosomal pathway as well as increased Sez6L and BACE1-positive puncta. This indicates that a trafficking defect within the endolysosomal pathway may play a key role in enhanced BACE1-proteolysis in NPC disease. Overall, our findings suggest that enhanced proteolysis by BACE1 could be a part of NPC disease pathogenesis. Understanding the basic biology of BACE1 and the functional impact of cleavage of its substrates is important to better evaluate the therapeutic potential of BACE1 against AD and, possibly, NPC disease.

In their foundational work on the social construction of gender, Kessler and McKenna (1978) investigated the relationship between gender attribution and genital attribution. We used digital reproductions of the original stimuli to replicate their findings in the current social context. To further investigate the underlying decision processes we applied eye tracking. The stimuli shown varied in the composition of gender cues: from those more commonly associated with maleness to associated with femaleness. Applying the ethnomethodological approach originally used, participants were asked to decide for each stimulus whether they saw a man or a woman and to indicate subjective confidence with the decision. In line with the original results we found that the genital attribution contributed immensely to the gender attribution. Also, male gender was ascribed more often when the penis was present than was female gender when the vulva was shown. Eye tracking revealed that overall most dwell time as a proxy for important information was dedicated to the head, chest and genital areas of all the stimuli. Total dwell time depended on whether the gender attribution was made in line with the depicted genital, if the genital was a penis. Attributing female gender when a penis was present was associated with longer total dwell time, unlike attributing male gender with a vulva shown. This is indicative of higher cognitive effort and more difficulty ignoring the penis as opposed to the vulva. We interpret this finding in context of the persistent male dominance as well as to the socio-cultural understanding of the vulva as a concealed and therefore seemingly absent organ. In summary, we were able to show that the gender attribution is still closely linked to genital attribution when having a binary forced choice task and that the penis is a special cue in this attribution process.

Transfusion guidelines advocate restrictive rather than liberal use of red blood cells (RBC) and are based mostly on randomized trials in intensive care and surgical departments. We aimed to study RBC transfusion practice in the medical patients' population.The data in this study were collected from patients over the age of 18 years admitted to an Internal Medicine department between 2009 and 2014 who received at least one unit of packed red blood cells (RBC). In addition, data on demographics, patients' diagnoses, laboratory tests and number of transfused RBC units were extracted from the electronic health records.One thousand three hundred and twenty eight patients were included, having mean age of 75 ± 14 years. The median hemoglobin (Hb) trigger for RBC transfusion was 8.0 g/dl (IQR 7.3-8.7g/dl), and most patients received either one (43.4%) or two (33.4%) RBC units. There was no significant difference in Hb trigger between males and females (Hb 8.0 g/dl and 7.9 g/dl, respectively, p = 0.098), and a weak correlation with age (r = 0.108 p = 0.001). Patients with cardiovascular and lung diseases had a statistically significant higher Hb trigger compared to patients without those diagnoses, however the median difference between them was 0.5 g/dl or less.These "real world" data we collected show a Hb trigger compliant with the upper limit of published guidelines and influenced by medical patients' common diagnoses. Prospective trials addressing patients hospitalized in internal medicine departments could further contribute to transfusion decision algorithms.

Contrary to the many whole genome duplication events recorded for angiosperms (flowering plants), whole genome duplications in gymnosperms (non-flowering seed plants) seem to be much rarer. Although ancient whole genome duplications have been reported for most gymnosperm lineages as well, some are still contested and need to be confirmed. For instance, data for ginkgo, but particularly cycads have remained inconclusive so far, likely due to the quality of the data available and flaws in the analysis. We extracted and sequenced RNA from both the cycad Encephalartos natalensis and Ginkgo biloba. This was followed by transcriptome assembly, after which these data were used to build paralog age distributions. Based on these distributions, we identified remnants of an ancient whole genome duplication in both cycads and ginkgo. The most parsimonious explanation would be that this whole genome duplication event was shared between both species and had occurred prior to their divergence, about 300 million years ago.

Muscle atrophy is a prevalent condition in illness and aging. Identifying novel pathways that control muscle mass may lead to therapeutic advancement. We previously identified Nur77 as a transcriptional regulator of glycolysis in skeletal muscle. More recently, we showed that Nur77 expression also controls myofiber size in mice. It was unknown, however, whether Nur77's regulation of muscle size begins during developmental myogenesis or only in adulthood. To determine the importance of Nur77 throughout muscle growth, we examined myofiber size at E18.5, 3 weeks postnatal age, and in young adult mice. Using the global Nur77-/- mice, we showed that Nur77 deficiency reduced myofiber size as early as E18.5. The reduction in myofiber size became more pronounced by 3 weeks of age. We observed comparable reduction in myofiber size in young myofiber-specific Nur77-knockout mice. These findings suggest that Nur77's effect on muscle growth is intrinsic to its expression in differentiating myofibers, and not dependent on its expression in myogenic stem cells. To determine the importance of Nur77 expression in muscle accretion in mature mice, we generated an inducible-, muscle-specific, Nur77-deficient mouse model. We demonstrated that tamoxifen-induced deletion of Nur77 in 3-month-old mice reduced myofiber size. This change was accompanied by increased activity of Smad2 and FoxO3, two negative regulators of muscle mass. The role of Nur77 in muscle growth was further elaborated in the cardiotoxin-induced muscle regeneration model. Compared to wildtype mice, regenerated myofibers were smaller in Nur77-/- mice. However, when normalized to saline-injected muscle, the recovery of sarcoplasmic area was comparable between Nur77-/- and wildtype mice. These findings suggest that Nur77 deficiency compromises myofiber growth, but not the regenerative capacity of myogenic progenitor cells. Collectively, the findings presented here demonstrate Nur77 as an important regulator of muscle growth both during prenatal and postnatal myogenesis.

INTRODUCTION:Studies in the general population suggest that determinants of QoL are often sex-dependent. Sex-dependent analyses of QoL in transgender populations have not been performed so far. AIM:To identify sex-specific and potentially modifiable determinants of QoL in transgender patients. METHODS:In this cross-sectional multicentre study including 82 transwomen (TW) and 72 transmen (TM) at different treatment stages, we investigated potential determinants for QoL focusing on the impact of mood (BDI, STAI-X), sleep quality (PSQI), chronic pain (GPQ), body image (FBeK) and social support (SSS). MAIN OUTCOME MEASURE:Health-related quality of life measured with the Short Form (36) Health Survey (SF-36). RESULTS:The age-adjusted SF-36 total score and its subscales did not significantly differ between TM and TW. Using a multivariate regression analysis approach, we identified common but also sex-dependent determinants for QoL (Adjusted R2 = 0.228; 0.650 respectively). Accounting for general characteristics such as age, BMI and treatment status, sleep quality according to the PSQI was an independent and strong determinant of QoL in both sexes (β = -0.451, p = 0.003 TM; β = -0.320; p = 0.0029 TW). Chronic pain was a significant independent predictor of QoL in TM (β = -0.298; p = 0.042) but not in TW. In contrast, anxiety (β = -0.451; p< 0.001) being unemployed (β = -0.206; p = 0.020) and insecurity about the own appearance (FBeK) (β = -0.261; p = 0.01) were independent predictors of QoL in TW. The rate of those reporting high sleep disturbances (PSQI ≥5) was high with 79.2% in TW and 81.2% in TM. Accordingly, age-adjusted QoL was also significantly lower in those reporting poor sleep in both sexes. CONCLUSIONS:Sleep strongly affected QoL in both genders, while other factors, like pain and body image, seem to be gender specific in transgender individuals.

The conserved protein complex known as Mediator conveys transcriptional signals by acting as an intermediary between transcription factors and RNA polymerase II. As a result, Mediator subunits play multiple roles in regulating developmental as well as abiotic and biotic stress pathways. In this report we identify the head domain subunits MEDIATOR18 and MEDIATOR20 as important susceptibility factors for Fusarium oxysporum infection in Arabidopsis thaliana. Mutants of MED18 and MED20 display down-regulation of genes associated with jasmonate signaling and biosynthesis while up-regulation of salicylic acid associated pathogenesis related genes and reactive oxygen producing and scavenging genes. We propose that MED18 and MED20 form a sub-domain within Mediator that controls the balance of salicylic acid and jasmonate associated defense pathways.

The applicability of the internationally advocated cut-off points of waist circumference (WC) derived from Caucasians to diagnose metabolic syndrome (MS) in HIV-infected Africans is unknown. This study aimed to determine the optimal WC cutoffs for MS diagnosis in HIV-infected people receiving care at public healthcare facilities in the Western Cape Province in South Africa.Data from 748 randomly selected participants (591 women), with a median age of 38 years, were analysed. The Youden's index and the top-left-point approaches were used to determine the optimal cutoffs of WC for predicting ≥2 non-adipose MS components.The two approaches generated the same WC cut-off point in women, 92 cm (sensitivity 64%, specificity 64%) but different cut-off points in men: 87 cm (sensitivity 48%, specificity 85%) based on the Younden's index and 83 cm (sensitivity 59%, specificity 74%) by the top-left-point method. The advocated thresholds of 94 cm in men had low sensitivity (30%) but high specificity (92%) whereas 80 cm in women showed low specificity (32%) but high sensitivity (85%) for diagnosing MS in this sample. Most African-specific cut-off points performed well, with 90 cm providing acceptable performance in both men (sensitivity 43%, specificity 88%) and women (sensitivity 66%, specificity 59%).This study underlines the sub-optimal performance of internationally recommended WC thresholds for MS diagnosis in HIV-infected Africans, and supports the need to revisit the guidelines on WC criterion in African population across the board. A single threshold of 90 cm for both genders would be a practical suggestion.

Mediator is a multiprotein transcriptional co-regulator complex composed of four modules; Head, Middle, Tail, and Kinase. It conveys signals from promoter-bound transcriptional regulators to RNA polymerase II and thus plays an essential role in eukaryotic gene regulation. We describe subunit localization and activities of Mediator in Arabidopsis through metabolome and transcriptome analyses from a set of Mediator mutants. Functional metabolomic analysis based on the metabolite profiles of Mediator mutants using multivariate statistical analysis and heat-map visualization shows that different subunit mutants display distinct metabolite profiles, which cluster according to the reported localization of the corresponding subunits in yeast. Based on these results, we suggest localization of previously unassigned plant Mediator subunits to specific modules. We also describe novel roles for individual subunits in development, and demonstrate changes in gene expression patterns and specific metabolite levels in med18 and med25, which can explain their phenotypes. We find that med18 displays levels of phytoalexins normally found in wild type plants only after exposure to pathogens. Our results indicate that different Mediator subunits are involved in specific signaling pathways that control developmental processes and tolerance to pathogen infections.

To examine the characteristics of community health workers (CHWs) involved in diabetes prevention programmes (DPPs) and their contributions to expected outcomes.Electronic databases including PubMed-MEDLINE, EBSCOHost, and SCOPUS/EMBASE were searched for studies published between January 2000 and March 2016. All studies that used CHWs to implement DPP in ≥18-year-old participants without diabetes but at high risk for developing the condition, irrespective of the study design, setting or outcomes measured, were included. Results were synthesized narratively.Forty papers of 30 studies were identified. Studies were mainly community-based and conducted in minority populations in USA. Sample sizes ranged from 20 participants in a single community to 2369 participants in 46 communities. Although CHWs were generally from the local community, their qualifications, work experience and training received differed across studies. Overall the training was culturally sensitive and/or appropriate, covering topics such as the importance of good nutrition and the benefits of increased physical activity, communication and leadership. CHWs delivered a variety of interventions and also screened or recruited participants. The shared culture and language between CHWs and participants likely contributed to better programme implementation and successful outcomes.The complexity of DPPs and the diverse CHW roles preclude attributing specific outcomes to CHW involvement. Nevertheless, documenting potential CHW roles and the relevant training required may optimise CHW contributions and facilitate their involvement in DPPs in the future.

The Norwegian Lundehund is a highly endangered native dog breed. Low fertility and high frequency predisposition to intestinal disorder imply inbreeding depression. We assessed the genetic diversity of the Lundehund population from pedigree data and evaluated the potential of optimal contribution selection and cross-breeding in the long-term management of the Lundehund population. The current Norwegian Lundehund population is highly inbred and has lost 38.8% of the genetic diversity in the base population. Effective population size estimates varied between 13 and 82 depending on the method used. Optimal contribution selection alone facilitates no improvement in the current situation in the Lundehund due to the extremely high relatedness of the whole population. Addition of (replacement with) 10 breeding candidates of foreign breed to 30 Lundehund breeders reduced the parental additive genetic relationship by 40-42% (48-53%). Immediate actions are needed to increase the genetic diversity in the current Lundehund population. The only option to secure the conservation of this rare breed is to introduce individuals from foreign breeds as breeding candidates.

The development of brain imaging techniques, in particular functional magnetic resonance imaging (fMRI), made it possible to non-invasively study the hemispheric lateralization of cognitive brain functions in large cohorts. Comprehensive models of hemispheric lateralization are, however, still missing and should not only account for the hemispheric specialization of individual brain functions, but also for the interactions among different lateralized cognitive processes (e.g., language and visuospatial processing). This calls for robust and reliable paradigms to study hemispheric lateralization for various cognitive functions. While numerous reliable imaging paradigms have been developed for language, which represents the most prominent left-lateralized brain function, the reliability of imaging paradigms investigating typically right-lateralized brain functions, such as visuospatial processing, has received comparatively less attention. In the present study, we aimed to establish an fMRI paradigm that robustly and reliably identifies right-hemispheric activation evoked by visuospatial processing in individual subjects. In a first study, we therefore compared three frequently used paradigms for assessing visuospatial processing and evaluated their utility to robustly detect right-lateralized brain activity on a single-subject level. In a second study, we then assessed the test-retest reliability of the so-called Landmark task-the paradigm that yielded the most robust results in study 1. At the single-voxel level, we found poor reliability of the brain activation underlying visuospatial attention. This suggests that poor signal-to-noise ratios can become a limiting factor for test-retest reliability. This represents a common detriment of fMRI paradigms investigating visuospatial attention in general and therefore highlights the need for careful considerations of both the possibilities and limitations of the respective fMRI paradigm-in particular, when being interested in effects at the single-voxel level. Notably, however, when focusing on the reliability of measures of hemispheric lateralization (which was the main goal of study 2), we show that hemispheric dominance (quantified by the lateralization index, LI, with |LI| >0.4) of the evoked activation could be robustly determined in more than 62% and, if considering only two categories (i.e., left, right), in more than 93% of our subjects. Furthermore, the reliability of the lateralization strength (LI) was "fair" to "good". In conclusion, our results suggest that the degree of right-hemispheric dominance during visuospatial processing can be reliably determined using the Landmark task, both at the group and single-subject level, while at the same time stressing the need for future refinements of experimental paradigms and more sophisticated fMRI data acquisition techniques.

We present metaSNV, a tool for single nucleotide variant (SNV) analysis in metagenomic samples, capable of comparing populations of thousands of bacterial and archaeal species. The tool uses as input nucleotide sequence alignments to reference genomes in standard SAM/BAM format, performs SNV calling for individual samples and across the whole data set, and generates various statistics for individual species including allele frequencies and nucleotide diversity per sample as well as distances and fixation indices across samples. Using published data from 676 metagenomic samples of different sites in the oral cavity, we show that the results of metaSNV are comparable to those of MIDAS, an alternative implementation for metagenomic SNV analysis, while data processing is faster and has a smaller storage footprint. Moreover, we implement a set of distance measures that allow the comparison of genomic variation across metagenomic samples and delineate sample-specific variants to enable the tracking of specific strain populations over time. The implementation of metaSNV is available at: http://metasnv.embl.de/.

Genetic rescue, outcrossing with individuals from a related population, is used to augment genetic diversity in populations threatened by severe inbreeding and extinction. The endangered Norwegian Lundehund dog underwent at least two severe bottlenecks in the 1940s and 1960s that each left only five inbred dogs, and the approximately 1500 dogs remaining world-wide today appear to descend from only two individuals. The Lundehund has a high prevalence of a gastrointestinal disease, to which all remaining dogs may be predisposed. Outcrossing is currently performed with three Nordic Spitz breeds: Norwegian Buhund, Icelandic Sheepdog, and Norrbottenspets. Examination of single nucleotide polymorphism (SNP) genotypes based on 165K loci in 48 dogs from the four breeds revealed substantially lower genetic diversity for the Lundehund (HE 0.035) than for other breeds (HE 0.209-0.284). Analyses of genetic structure with > 15K linkage disequilibrium-pruned SNPs showed four distinct genetic clusters. Pairwise FST values between Lundehund and the candidate breeds were highest for Icelandic Sheepdog, followed by Buhund and Norrbottenspets. We assessed the presence of outlier loci among candidate breeds and examined flanking genome regions (1 megabase) for genes under possible selection to identify potential adaptive differences among breeds; outliers were observed in flanking regions of genes associated with key functions including the immune system, metabolism, cognition and physical development. We suggest crossbreeding with multiple breeds as the best strategy to increase genetic diversity for the Lundehund and to reduce the incidence of health problems. For this project, the three candidate breeds were first selected based on phenotypes and then subjected to genetic investigation. Because phenotypes are often paramount for domestic breed owners, such a strategy could provide a helpful approach for genetic rescue and restoration of other domestic populations at risk, by ensuring the involvement of owners, breeders and managers at the start of the project.

Bacteria integrate CO2 reduction and acetyl coenzyme-A (CoA) synthesis in the Wood-Ljungdal pathway. The acetyl-CoA synthase (ACS) active site is a [4Fe4S]-[NiNi] complex (A-cluster). The dinickel site structure (with proximal, p, and distal, d, ions) was studied by X-ray absorption spectroscopy in ACS variants comprising all three protein domains or only the C-terminal domain with the A-cluster. Both variants showed two square-planar Ni(II) sites and an OH- bound at Ni(II)p in oxidized enzyme and a H2O at Ni(I)p in reduced enzyme; a Ni(I)p-CO species was induced by CO incubation and a Ni(II)-CH3- species with an additional water ligand by a methyl group donor. These findings render a direct effect of the N-terminal and middle domains on the A-cluster structure unlikely.

The Rvb1/Rvb2 complex is an essential component of many cellular pathways. The Rvb1/Rvb2 complex forms a dodecameric assembly where six copies of each subunit form two heterohexameric rings. However, due to conformational variability, the way the two rings pack together is still not fully understood. Here, we present the crystal structure and two cryo-electron microscopy reconstructions of the dodecameric, full-length Rvb1/Rvb2 complex, all showing that the interaction between the two heterohexameric rings is mediated through the Rvb1/Rvb2-specific domain II. Two conformations of the Rvb1/Rvb2 dodecamer are present in solution: a stretched conformation also present in the crystal, and a compact conformation. Novel asymmetric features observed in the reconstruction of the compact conformation provide additional insight into the plasticity of the Rvb1/Rvb2 complex.

Extravasation of macrophages and formation of lipid-laden foam cells are key events in the development and progression of atherosclerosis. The degradation of atherogenic lipoproteins subsequently leads to alterations in cellular lipid metabolism that influence inflammatory signaling. Especially sphingolipids and ceramides are known to be involved in these processes. We therefore analyzed monocyte derived macrophages during differentiation and after loading with enzymatically (eLDL) and oxidatively (oxLDL) modified low-density lipoproteins (LDL).Primary human monocytes were isolated from healthy, normolipidemic blood donors using leukapheresis and counterflow elutriation. On the fourth day of MCSF-induced differentiation eLDL (40 μg/ml) or oxLDL (80 μg/ml) were added for 48h. Lipid species were analyzed by quantitative tandem mass spectrometry. Taqman qPCR was performed to investigate transcriptional changes in enzymes involved in sphingolipid metabolism. Furthermore, membrane lipids were studied using flow cytometry and confocal microscopy.MCSF dependent phagocytic differentiation of blood monocytes had only minor effects on the sphingolipid composition. Levels of total sphingomyelin and total ceramide remained unchanged, while lactosylceramides, cholesterylesters and free cholesterol decreased. At the species level most ceramide species showed a reduction upon phagocytic differentiation. Loading with eLDL preferentially increased cellular cholesterol while loading with oxLDL increased cellular ceramide content. Activation of the salvage pathway with a higher mRNA expression of acid and neutral sphingomyelinase, neutral sphingomyelinase activation associated factor and glucosylceramidase as well as increased surface expression of SMPD1 were identified as potentially underlying mechanisms. Moreover, flow-cytometric analysis revealed a higher cell-surface-expression of ceramide, lactosylceramide (CDw17), globotriaosylceramide (CD77), dodecasaccharide-ceramide (CD65s) and GM1 ganglioside upon oxLDL loading. ApoE in contrast to apoA-I preferentially bound to the ceramide enriched surfaces of oxLDL loaded cells. Confocal microscopy showed a co-localization of acid sphingomyelinase with ceramide rich membrane microdomains.eLDL leads to the formation of lipid droplets and preferentially induces cholesterol/sphingomyelin rich membrane microdomains while oxLDL promotes the development of cholesterol/ceramide rich microdomains via activation of the salvage pathway.