Dissecting structure-function of 3-O-sulfated heparin and engineered heparan sulfates

Heparan sulfate (HS) polysaccharides are master regulators of diverse biological processes via sulfated motifs that can recruit specific proteins. 3-O-sulfation of HS/heparin is crucial for anticoagulant activity, but despite emerging evidence for roles in many other functions, a lack of tools for deciphering structure-function relationships has hampered advances. Here, we describe an approach integrating synthesis of 3-O-sulfated standards, comprehensive HS disaccharide profiling, and cell engineering to address this deficiency. Its application revealed previously unseen differences in 3-O-sulfated profiles of clinical heparins and 3-O-sulfotransferase (HS3ST)–specific variations in cell surface HS profiles. The latter correlated with functional differences in anticoagulant activity and binding to platelet factor 4 (PF4), which underlies heparin-induced thrombocytopenia, a known side effect of heparin. Unexpectedly, cells expressing the HS3ST4 isoenzyme generated HS with potent anticoagulant activity but weak PF4 binding. The data provide new insights into 3-O-sulfate structure-function and demonstrate proof of concept for tailored cell-based synthesis of next-generation heparins

Options for Active Case Detection of Visceral Leishmaniasis in Endemic Districts of India, Nepal and Bangladesh, Comparing Yield, Feasibility and Costs

For the elimination of any infectious disease (i.e., reduction of the burden of a serious public health problem to a minor problem which can be managed by the general health services) the right mix of public health tools has to be identified for the early detection and successful treatment of new cases as well as effective vector control (in the case of vector borne diseases) at affordable costs. The paper provides a powerful example of evidence building for cost-effective early case detection in the visceral leishmaniasis elimination initiative of Bangladesh, India and Nepal. It compares the camp approach (mobile teams testing in chronic fever camps for spleen enlargement and rapid diagnostic tests) with the index case approach (screening for new cases in the neighbourhood of reported visceral leishmaniasis patients) and the incentive based approach (where basic health workers receive an allowance for detecting a new case) using subsequent house-to-house screening for the identification of the real number of un-detected cases. By applying a mix of different study methods and an itinerate research process to identify the most effective, feasible and affordable case detection method, under different environmental conditions, recommendations could be developed which help governments in shaping their visceral leishmaniasis elimination strategy

Dissecting the genetic architecture of phenology affecting adaptation of spring bread wheat genotypes to the major wheat-producing zones in India

Spring bread wheat adaptation to diverse environments is supported by various traits such as phenology and plant architecture. A large-scale genome-wide association study (GWAS) was designed to investigate and dissect the genetic architecture of phenology affecting adaptation. It used 48 datasets from 4,680 spring wheat lines. For 8 years (2014–2021), these lines were evaluated for days to heading (DH) and maturity (DM) at three sites: Jabalpur, Ludhiana, and Samastipur (Pusa), which represent the three major Indian wheat-producing zones: the Central Zone (CZ), North-Western Plain Zone (NWPZ), and North-Eastern Plain Zone (NEPZ), respectively. Ludhiana had the highest mean DH of 103.8 days and DM of 148.6 days, whereas Jabalpur had the lowest mean DH of 77.7 days and DM of 121.6 days. We identified 119 markers significantly associated with DH and DM on chromosomes 5B (76), 2B (18), 7D (10), 4D (8), 5A (1), 6B (4), 7B (1), and 3D (1). Our results clearly indicated the importance of the photoperiod-associated gene (Ppd-B1) for adaptation to the NWPZ and the Vrn-B1 gene for adaptation to the NEPZ and CZ. A maximum variation of 21.1 and 14% was explained by markers 2B_56134146 and 5B_574145576 linked to the Ppd-B1 and Vrn-B1 genes, respectively, indicating their significant role in regulating DH and DM. The results provide important insights into the genomic regions associated with the two phenological traits that influence adaptation to the major wheat-producing zones in India

Insecticide Susceptibility of Phlebotomus argentipes in Visceral Leishmaniasis Endemic Districts in India and Nepal

Visceral leishmaniasis (VL), also know as kala azar, is one of the major public health concerns India, Nepal and Bangladesh. In the Indian subcontinent, VL is caused by Leishmania donovani which is transmitted by Phlebotomus argentipes. To date, Indoor Residual Spraying (IRS) campaigns have been unable to control the disease. Vector resistance to the insecticides used has been postulated as one of the possible reasons explaining this failure. A number of studies in the region have shown a variable degree of resistance to DDT in areas where this insecticide has been widely used for IRS (mainly India). However there is no coordinated and standardized program to monitor resistance to insecticides in the region. In this study we tested P. argentipes susceptibility to DDT and deltamethrin in VL endemic villages in India and Nepal. The results confirmed the DDT resistance in India and in a border village of Nepal. P. argentipes from both countries were in general susceptible to deltamethrin, an insecticide used in some long lasting insecticidal nets

Genome-wide association mapping indicates quantitative genetic control of spot blotch resistance in bread wheat and the favorable effects of some spot blotch loci on grain yield

Spot blotch caused by the fungus Bipolaris sorokiniana poses a serious threat to bread wheat production in warm and humid wheat-growing regions of the world. Hence, the major objective of this study was to identify consistent genotyping-by-sequencing (GBS) markers associated with spot blotch resistance using genome-wide association mapping on a large set of 6,736 advanced bread wheat breeding lines from the International Maize and Wheat Improvement Center. These lines were phenotyped as seven panels at Agua Fria, Mexico between the 2013–2014 and 2019–2020 crop cycles. We identified 214 significant spot blotch associated GBS markers in all the panels, among which only 96 were significant in more than one panel, indicating a strong environmental effect on the trait and highlights the need for multiple phenotypic evaluations to identify lines with stable spot blotch resistance. The 96 consistent GBS markers were on chromosomes 1A, 1B, 1D, 2A, 3B, 4A, 5B, 5D, 6B, 7A, 7B, and 7D, including markers possibly linked to the Lr46, Sb1, Sb2 and Sb3 genes. We also report the association of the 2NS translocation from Aegilops ventricosa with spot blotch resistance in some environments. Moreover, the spot blotch favorable alleles at the 2NS translocation and two markers on chromosome 3BS (3B_2280114 and 3B_5601689) were associated with increased grain yield evaluated at several environments in Mexico and India, implying that selection for favorable alleles at these loci could enable simultaneous improvement for high grain yield and spot blotch resistance. Furthermore, a significant relationship between the percentage of favorable alleles in the lines and their spot blotch response was observed, which taken together with the multiple minor effect loci identified to be associated with spot blotch in this study, indicate quantitative genetic control of resistance. Overall, the results presented here have extended our knowledge on the genetic basis of spot blotch resistance in bread wheat and further efforts to improve genetic resistance to the disease are needed for reducing current and future losses under climate change

Effect of Village-wide Use of Long-Lasting Insecticidal Nets on Visceral Leishmaniasis Vectors in India and Nepal: A Cluster Randomized Trial

Visceral leishmaniasis (VL) is a vector-borne disease causing at least 60,000 deaths each year amongst an estimated half million cases, and until recently there have been no significant initiatives to reduce this burden. However, in 2005, the governments of India, Bangladesh and Nepal signed a memorandum of understanding at the World Health Assembly in Geneva for the elimination of the disease by 2015. In the absence of an effective vaccine, the program will rely on the active detection and prompt treatment of cases throughout the endemic region, combined with a recurrent indoor residual spraying (IRS) of all villages at risk. Vector control programs based on IRS are notorious for failing to maintain comprehensive spray coverage over time owing to logistical problems and lack of compliance by householders. Long-lasting insecticidal nets (LNs) have been postulated as an alternative or complement to IRS. Here we describe how comprehensive coverage of LN in trial communities reduced the indoor density of sand flies by 25% compared to communities without LNs. This provides an indication that LNs could be usefully deployed as a component of the VL control program in the Indian subcontinent

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe