We performed a scan for genetic variants associated with multiple phenotypes by comparing large genome-wide association studies (GWAS) of 42 traits or diseases. We identified 341 loci (at a false ...discovery rate of 10%) associated with multiple traits. Several loci are associated with multiple phenotypes; for example, a nonsynonymous variant in the zinc transporter SLC39A8 influences seven of the traits, including risk of schizophrenia (rs13107325: log-transformed odds ratio (log OR) = 0.15, P = 2 × 10(-12)) and Parkinson disease (log OR = -0.15, P = 1.6 × 10(-7)), among others. Second, we used these loci to identify traits that have multiple genetic causes in common. For example, variants associated with increased risk of schizophrenia also tended to be associated with increased risk of inflammatory bowel disease. Finally, we developed a method to identify pairs of traits that show evidence of a causal relationship. For example, we show evidence that increased body mass index causally increases triglyceride levels.
Chronic infection with hepatitis C virus is a major cause of liver disease and hepatocellular carcinoma worldwide. After the discovery of hepatitis C virus 3 decades ago, the identification of the ...structure of the viral proteins, combined with high-throughput replicon models, enabled the discovery and development of direct-acting antivirals. These agents have revolutionized patient care, with cure rates of more than 90%. We review the status of direct-acting antiviral therapies for hepatitis C virus infection and discuss remaining challenges. We highlight licensed compounds, discuss the potential to shorten therapy even further, and review different options for treatment failure and resistance. We also provide an overview of clinical experience with generic agents and evidence for their efficacy. Finally, we discuss the need for new drugs and outline promising targets for future therapies.
Highlights • Migration and population mixture have been pervasive in human history. • Ancient DNA provides a new perspective on human history and adaptation.
Evidence suggests use of herbal and conventional medicines in the treatment of Sickle Cell Disease (SCD). We examined factors associated with caregivers' use of combined herbal and conventional ...medicine to treat children with SCD. A cross-sectional study was conducted at Jinja Regional Referral Hospital between January and March 2022. Caregivers of children with SCD aged 1 to 18 years attending the Sickle Cell Clinic were interviewed using structured questionnaires. We collected data on caregivers' socio-demographic characteristics, perceptions of and intentions to use either or both therapies, self-reported use of either or both therapies and community and health-related factors. A multivariable logistic regression model was computed to assess the factors independently associated with caregivers' use of combined therapy, using Stata version 15.0. 372 caregivers were interviewed. On average, respondents were aged 34.3 years (Standard Deviation SD: ±9.8 years). 37% (n = 138) of the caregivers reported the use of both herbal and conventional medicine, 58.3% (n = 217) reported use of only conventional medicine, while 4.6% (n = 17) reported use of herbal medicine only. Higher odds of using combination therapy were found in caregivers aged 60+ years (adjusted odds ratio AOR = 11.8; 95% CI: 1.2, 115.2), those with lower secondary education (AOR = 6.2; 95% CI: 1.5, 26.0), those who believed in the safety of herbal medicine (AOR = 3.3; 95% CI: 1.5, 7.6) and those who thought that use of both therapies were safe (AOR = 7.7; 95% CI: 3.5, 17.0). More than one-third of the caregivers reported use of combined herbal and conventional medicine, most of whom were older (>60%) and had lower secondary education. There is need for targeted health promotion to educate caregivers about the dangers of using both herbal and conventional medicines in treating children with SCD.
ABSTRACT We analyze 24 binary radio pulsars in the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) nine-year data set. We make 14 significant measurements of the Shapiro ...delay, including new detections in four pulsar-binary systems (PSRs J0613−0200, J2017+0603, J2302+4442, and J2317+1439), and derive estimates of the binary-component masses and orbital inclination for these MSP-binary systems. We find a wide range of binary pulsar masses, with values as low as for PSR J1918−0642 and as high as for PSR J1614−2230 (both 68.3% credibility). We make an improved measurement of the Shapiro timing delay in the PSR J1918−0642 and J2043+1711 systems, measuring the pulsar mass in the latter system to be (68.3% credibility) for the first time. We measure secular variations of one or more orbital elements in many systems, and use these measurements to further constrain our estimates of the pulsar and companion masses whenever possible. In particular, we used the observed Shapiro delay and periastron advance due to relativistic gravity in the PSR J1903+0327 system to derive a pulsar mass of (68.3% credibility). We discuss the implications that our mass measurements have on the overall neutron-star mass distribution, and on the "mass/orbital-period" correlation due to extended mass transfer.
Long-range migrations and the resulting admixtures between populations have been important forces shaping human genetic diversity. Most existing methods for detecting and reconstructing historical ...admixture events are based on allele frequency divergences or patterns of ancestry segments in chromosomes of admixed individuals. An emerging new approach harnesses the exponential decay of admixture-induced linkage disequilibrium (LD) as a function of genetic distance. Here, we comprehensively develop LD-based inference into a versatile tool for investigating admixture. We present a new weighted LD statistic that can be used to infer mixture proportions as well as dates with fewer constraints on reference populations than previous methods. We define an LD-based three-population test for admixture and identify scenarios in which it can detect admixture events that previous formal tests cannot. We further show that we can uncover phylogenetic relationships among populations by comparing weighted LD curves obtained using a suite of references. Finally, we describe several improvements to the computation and fitting of weighted LD curves that greatly increase the robustness and speed of the calculations. We implement all of these advances in a software package, ALDER, which we validate in simulations and apply to test for admixture among all populations from the Human Genome Diversity Project (HGDP), highlighting insights into the admixture history of Central African Pygmies, Sardinians, and Japanese.
Direct-acting antiviral (DAA) therapy is used in patients with HCV-related decompensated cirrhosis with the expectation of improving hepatic function. However, little is known about the long-term ...hepatic benefit of successful antiviral treatment.
Patients with advanced/decompensated cirrhosis (model for end-stage liver disease MELD ≥10), in whom NS5A-containing DAA therapy was initiated prior to September 2018, were included (from the HCV-TARGET cohort). Treatment outcomes and the impact of treatment on short-term and long-term hepatic function were examined.
A total of 642 patients were analyzed. The mean age was 60 years, 68% were male. The median baseline MELD was 12 (range 10–39) and 64% had prior decompensation. Among patients with available virologic outcomes, 90.5% achieved a sustained virologic response at 12 weeks (SVR12). Eighty (24%) patients achieved a clinically significant decrease in MELD by ≥3 points during short-term follow-up (9–26 weeks after the end of treatment). However, in long-term follow-up (median of 4 years after treatment), mean changes in MELD (−0.30 points), total bilirubin (+0.23 mg/dl) and albumin (+0.36 g/dl) were marginal. Fifty-one patients died and 22 underwent liver transplant. In long-term follow-up, a clinically meaningful decrease in MELD of ≥3 occurred in 29% and a final MELD score of <10 was achieved in 25%.
In a large real-world experience of patients with advanced/decompensated HCV-related cirrhosis treated with DAAs, there were only marginal improvements in MELD, total bilirubin, or albumin at long-term follow-up (after achieving SVR12). These patients may remain at high risk of decompensation and must continue to be closely monitored.
NCT01474811.
Hepatitis C virus infection can now be cured with medications, even in patients who have advanced scarring of the liver (cirrhosis). In this study, we evaluated whether liver function improves or deteriorates in the long-term, following successful treatment of hepatitis C in patients with cirrhosis. We found that overall liver function was relatively stable with only 29% of patients achieving a clinically meaningful improvement in liver function, and we therefore believe that these patients require ongoing monitoring.
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•SVR was achieved in 90.5% of patients with advanced/decompensated cirrhosis treated with direct-acting antivirals.•In long-term (>4 years) follow-up, overall mean changes in MELD, total bilirubin and albumin were marginal.•A clinically meaningful decrease in MELD of ≥3 occurred in 29% and a final MELD score of <10 was achieved in 25%.•Patients with advanced/decompensated liver disease should continue to be monitored following SVR.
Abstract
Contact sites of endoplasmic reticulum (ER) and mitochondria locally convey calcium signals between the IP
3
receptors (IP3R) and the mitochondrial calcium uniporter, and are central to cell ...survival. It remains unclear whether IP3Rs also have a structural role in contact formation and whether the different IP3R isoforms have redundant functions. Using an IP3R-deficient cell model rescued with each of the three IP3R isoforms and an array of super-resolution and ultrastructural approaches we demonstrate that IP3Rs are required for maintaining ER-mitochondrial contacts. This role is independent of calcium fluxes. We also show that, while each isoform can support contacts, type 2 IP3R is the most effective in delivering calcium to the mitochondria. Thus, these studies reveal a non-canonical, structural role for the IP3Rs and direct attention towards the type 2 IP3R that was previously neglected in the context of ER-mitochondrial calcium signaling.
Despite efforts to improve HIV testing and linkage to HIV care among adolescents, young people and adult men, uptake rates remain below global targets. We conducted formative research to generate ...data necessary to inform the design of a peer-led HIV self-testing (HIVST) intervention intended to improve HIV testing uptake and linkage to HIV care in Kasensero fishing community in rural Uganda.
This qualitative study was conducted in three study communities in Kasensero fishing community in Rakai district, Uganda, in May 2019. Six single-sex focus group discussions (FGDs) comprising 7-8 participants were conducted with adolescents and young people (15-24 years) and adult men (25+ years). We collected data on people's perceptions about peer-led HIVST; potential acceptability of a peer-led HIVST intervention and suggestions on how to improve linkage to HIV care after a positive HIVST result. Peer-led HIVST was defined as an approach where trained lay people distribute HIVST kits to other people in the community. FGDs were audio-recorded with permission from the participants, transcribed verbatim and analysed manually following a thematic framework approach.
Forty-seven participants (31 men and 16 women) participated in the FGDs. Across communities and age-groups, most participants mentioned that peer-led HIVST would be generally acceptable to people in the fishing community but people will need support in performing the test due to fear of performing the test wrongly or failing to cope with HIV-positive results. Most participants felt that peer-led HIVST would bring HIV testing services closer to the community "because the peer-leader could be my immediate neighbour", making it easier for people to obtain the kits at any time of their convenience. To improve linkage to HIV care, participants felt that the use of peer-leaders to deliver the initial ART dose to self-tested HIV-positive individuals would be more preferable to the use of community-based ART groups or home-based ART initiation.
Our study shows that peer-led HIVST is potentially acceptable in the fishing community. These findings suggest that this approach can improve uptake of HIV testing and linkage to HIV care services among populations that are usually missed through conventional HIV testing services.
Abstract
The phenomenon of pulsar nulling, observed as the temporary inactivity of a pulsar, remains poorly understood both observationally and theoretically. Most observational studies that quantify ...nulling employ a variant of Ritchings algorithm, which can suffer significant biases for pulsars where the emission is weak. Using a more robust mixture model method, we study pulsar nulling in a sample of 22 recently discovered pulsars, for which we publish the nulling fractions for the first time. These data clearly demonstrate biases of the former approach and show how an otherwise nonnulling pulsar can be classified as having significant nulls. We show that the population-wide studies that find a positive correlation of nulling with pulsar period/characteristic age can similarly be biased because of the bias in estimating the nulling fraction. We use our probabilistic approach to find the evidence for periodicity in the nulls in a subset of three pulsars in our sample. In addition, we also provide improved timing parameters for 17 of the 22 pulsars that had no prior follow-up.
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