Sequential algorithm to stratify liver fibrosis risk in overweight/obese metabolic dysfunction-associated fatty liver disease

BackgroundNon-diabetic overweight/obese metabolic dysfunction-associated fatty liver disease (MAFLD) represents the largest subgroup with heterogeneous liver fibrosis risk. Metabolic dysfunction promotes liver fibrosis. Here, we investigated whether incorporating additional metabolic risk factors into clinical evaluation improved liver fibrosis risk stratification among individuals with non-diabetic overweight/obese MAFLD.Materials and methodsComprehensive metabolic evaluation including 75-gram oral glucose tolerance test was performed in over 1000 participants from the New Hong Kong Cardiovascular Risk Factor Prevalence Study (HK-NCRISPS), a contemporary population-based study of HK Chinese. Hepatic steatosis and fibrosis were evaluated based on controlled attenuation parameter and liver stiffness (LS) measured using vibration-controlled transient elastography, respectively. Clinically significant liver fibrosis was defined as LS ≥8.0 kPa. Our findings were validated in an independent pooled cohort comprising individuals with obesity and/or polycystic ovarian syndrome.ResultsOf the 1020 recruited community-dwelling individuals, 312 (30.6%) had non-diabetic overweight/obese MAFLD. Among them, 6.4% had LS ≥8.0 kPa. In multivariable stepwise logistic regression analysis, abnormal serum aspartate aminotransferase (AST) (OR 7.95, p<0.001) and homeostasis model assessment of insulin resistance (HOMA-IR) ≥2.5 (OR 5.01, p=0.008) were independently associated with LS ≥8.0 kPa, in a model also consisting of other metabolic risk factors including central adiposity, hypertension, dyslipidaemia and prediabetes. A sequential screening algorithm using abnormal AST, followed by elevated HOMA-IR, was developed to identify individuals with LS ≥8.0 kPa, and externally validated with satisfactory sensitivity (>80%) and negative predictive value (>90%).ConclusionA sequential algorithm incorporating AST and HOMA-IR levels improves fibrosis risk stratification among non-diabetic overweight/obese MAFLD individuals

HERON: Demonstrating a Novel Biological Platform for Small Satellite Missions

Long-duration deep space missions pose a significant health risk for both humans and their resident microorganisms. The GeneSat, PharmaSat and O/OREOS missions have previously explored biological questions regarding the effects of spaceflight on S. cerevisiase, B. subtilis, and E. coli. However, there currently exists both a knowledge and an accessibility gap in small satellite biological experiments. These payloads require precise instrumentation and complex platforms that are usually reserved for large research organizations. This makes it difficult for smaller organizations to perform biological research in low Earth orbit (LEO). To address these challenges, the University of Toronto Aerospace Team (UTAT) Space Systems Division is currently developing the HERON CubeSat. HERON houses a payload platform which measures the effects of the LEO environment on the gene expression and drug resistance of Candida albicans, a yeast commonly found in the human gut microbiome. Previous research has suggested that C. albicans might display increased pathogenicity and drug resistance in response to microgravity, which has important implications for long-duration human spaceflight. The yeast cells are housed in custom acrylic microfluidics chips containing 32 wells with channels for media and drug delivery. A measurement printed circuit board (PCB) contains custom optics capable of measuring minute changes in cell fluorescence. The entire payload stack is then housed in a temperature- and humidity-controlled 2U pressure vessel. Space Systems as a whole is an undergraduate student-led and student-funded design team, dedicated to the development of small satellite missions with a focus on education and undergraduate learning. HERON is scheduled to launch Q1 2022 into a Sun-synchronous orbit via a SpaceX Falcon 9 rocket at an altitude of approximately 550 km. Our platform is open-source and can serve as a low-cost template for future biological CubeSat missions. This paper serves as a technical and scientific description of the platform, along with the lessons learned during the payload design, assembly, and validation processes

Reproducibility of volumetric intravascular ultrasound radiofrequency-based analysis of coronary plaque composition in vivo

Intravascular ultrasound radiofrequency (RF-IVUS) data permit the analysis of coronary plaque composition in vivo and is used as an endpoint of ongoing pharmacological intervention trials. We assessed the reproducibility of volumetric RF-IVUS analyses in mild-to-moderately diseased atherosclerotic human coronary arteries in vivo. A total of 9,212 IVUS analyses on cross-sectional IVUS frames was performed to evaluate the reproducibility of volumetric RF-IVUS measurements in 33 coronary segments with a length of 27 ± 7 mm. For vessel, lumen, and plaque + media volume the relative measurement differences (P = NS for all) were (A = intraobserver comparison, same pullback) −0.40 ± 1.0%; −0.48 ± 1.4%; −0.35 ± 1.6%, (B = intraobserver comparison, repeated pullback) −0.42 ± 1.2%; −0.52 ± 1.8%; −0.43 ± 4.5% (C = interobserver comparison, same pullback) 0.71 ± 1.8%; 0.71 ± 2.2%, and 0.89 ± 5.0%, respectively. For fibrous, fibro-lipidic, calcium, and necrotic-core volumes the relative measurement differences (P = NS for all) were (A) 0.45 ± 2.1%; −1.12 ± 4.9%; −0.84 ± 2.1%; −0.22 ± 1.8%, (B) 1.40 ± 4.1%; 1.26 ± 6.7%; 2.66 ± 7.4%; 0.85 ± 4.4%, and (C) −1.60 ± 4.9%; 3.85 ± 8.2%; 1.66 ± 7.5%, and −1.58 ± 4.7%, respectively. Of note, necrotic-core volume showed on average the lowest measurement variability. Thus, in mild-to-moderate atherosclerotic coronary artery disease the reproducibility of volumetric compositional RF-IVUS measurements from the same pullback is relatively high, but lower than the reproducibility of geometrical IVUS measurements. Measurements from repeated pullbacks and by different observers show acceptable reproducibilities; the volumetric measurement of the necrotic-core shows on average the highest reproducibility of the compositional RF-IVUS measurement

Synergistic TLR2/6 and TLR9 Activation Protects Mice against Lethal Influenza Pneumonia

Lower respiratory tract infections caused by influenza A continue to exact unacceptable worldwide mortality, and recent epidemics have emphasized the importance of preventative and containment strategies. We have previously reported that induction of the lungs' intrinsic defenses by aerosolized treatments can protect mice against otherwise lethal challenges with influenza A virus. More recently, we identified a combination of Toll like receptor (TLR) agonists that can be aerosolized to protect mice against bacterial pneumonia. Here, we tested whether this combination of synthetic TLR agonists could enhance the survival of mice infected with influenza A/HK/8/68 (H3N2) or A/California/04/2009 (H1N1) influenza A viruses. We report that the TLR treatment enhanced survival whether given before or after the infectious challenge, and that protection tended to correlate with reductions in viral titer 4 d after infection. Surprisingly, protection was not associated with induction of interferon gene expression. Together, these studies suggest that synergistic TLR interactions can protect against influenza virus infections by mechanisms that may provide the basis for novel therapeutics

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe