Genome-wide analysis of blood lipid metabolites in over 5000 South Asians reveals biological insights at cardiometabolic disease loci.

Funder: PfizerFunder: NovartisFunder: National Institute for Health ResearchFunder: MerckBackgroundGenetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies.MethodsWe characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci.ResultsWe identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci.ConclusionsOur findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci

Genome-wide analysis of blood lipid metabolites in over 5000 South Asians reveals biological insights at cardiometabolic disease loci.

The authors would like to thank Michael Inouye for his helpful comments on an earlier version of the manuscript.Peer reviewe

An Unbiased Lipid Phenotyping Approach To Study the Genetic Determinants of Lipids and Their Association with Coronary Heart Disease Risk Factors.

Direct infusion high-resolution mass spectrometry (DIHRMS) is a novel, high-throughput approach to rapidly and accurately profile hundreds of lipids in human serum without prior chromatography, facilitating in-depth lipid phenotyping for large epidemiological studies to reveal the detailed associations of individual lipids with coronary heart disease (CHD) risk factors. Intact lipid profiling by DIHRMS was performed on 5662 serum samples from healthy participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS). We developed a novel semi-targeted peak-picking algorithm to detect mass-to-charge ratios in positive and negative ionization modes. We analyzed lipid partial correlations, assessed the association of lipid principal components with established CHD risk factors and genetic variants, and examined differences between lipids for a common genetic polymorphism. The DIHRMS method provided information on 360 lipids (including fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, and sterol lipids), with a median coefficient of variation of 11.6% (range: 5.4-51.9). The lipids were highly correlated and exhibited a range of associations with clinical chemistry biomarkers and lifestyle factors. This platform can provide many novel insights into the effects of physiology and lifestyle on lipid metabolism, genetic determinants of lipids, and the relationship between individual lipids and CHD risk factors

Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity

A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.D.S. is supported by grants from the National Institutes of Health, the Fogarty International, the Wellcome Trust, the British Heart Foundation, and Pfizer. P.N. is supported by the John S. LaDue Memorial Fellowship in Cardiology from Harvard Medical School. H.-H.W. is supported by a grant from the Samsung Medical Center, Korea (SMO116163). S.K. is supported by the Ofer and Shelly Nemirovsky MGH Research Scholar Award and by grants from the National Institutes of Health (R01HL107816), the Donovan Family Foundation, and Fondation Leducq. Exome sequencing was supported by a grant from the NHGRI (5U54HG003067-11) to S.G. and E.S.L. D.G.M. is supported by a grant from the National Institutes of Health (R01GM104371). J.D. holds a British Heart Foundation Chair, European Research Council Senior Investigator Award, and NIHR Senior Investigator Award. The Cardiovascular Epidemiology Unit at the University of Cambridge, which supported the field work and genotyping of PROMIS, is funded by the UK Medical Research Council, British Heart Foundation, and NIHR Cambridge Biomedical Research Centre ... Fieldwork in the PROMIS study has been supported through funds available to investigators at the Center for Non-Communicable Diseases, Pakistan and the University of Cambridge, UK

A look at the use of popular language in certain exemplary mid-20<super>th</super>-century French and Italian novels as an index of the transition from modernism to postmodernism.

The purpose of this dissertation is to look at a certain tendency in 20th century European modernism, a tendency that consists in adopting or imitating popular idioms and oral forms in order to challenge literary tradition and authority. I intend to trace the transformation of this initial interest in linguistic types or registers into a non-mimetic modality for representing the world. The preoccupation with language as an object of inquiry, rather than as simply a vehicle for transmitting ideas and for representing reality, is one of the prime characteristics of postmodernism. The four novelists I look at---Carlo Emilio Gadda, Louis-Ferdinand Celine, Raymond Queneau and Italo Calvino---are representative of this shift from modernism to postmodernism. Popular language, which is the general term I use to indicate variously, spoken language, dialects, lower-class language and swearing, was by the late 1920s an obvious tool for the modernists to adopt in their stated revolt against a stagnant literary tradition, in part because, in the shift from philology to modern linguistics, spoken language took precedence over written language as an object of study. Nevertheless, I argue that novels by the four writers in question reveal a strong interest in examining the role that writing has in constructing reality. This turn coincides, in part, with the turn in linguistics towards a notion of language as a cognitive system that informs all of human activity. Thus language and linguistic self-reference become, in the postmodern era, a focus of novelistic writing. Each of the writers I consider here is at some level concerned with the status of language or languages in writing. I discuss Celine's project with regard to style, poetics and a certain moral hierarchy of language; Queneau's efforts to distill part of the reading experience and maximize its efficacy; and Calvino's refusal of a particular historical and literary situation which led him to postpone his linguistic and formal experiments. With Gadda, language's intersection with form implicates the act of writing itself, for his interest in popular language turns out to be connected to an understanding of writing as gesturality.Ph.D.Comparative literatureLanguage, Literature and LinguisticsRomance literatureUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125162/2/3186705.pd

Injection medialization laryngoplasty improves dysphagia in patients with unilateral vocal fold immobility

To assess patient reported swallowing outcomes before and after injection medialization laryngoplasty in patients with unilateral vocal fold immobility (UVFI). Case series with chart review of patients with UVFI who underwent injection medialization laryngoplasty at a community laryngology practice by a single clinician between October 2015 and December 2017. Patient-reported validated surveys of swallowing impairment, Eating Assessment Tool (EAT-10), demographics, etiology and duration of symptoms were recorded before and after injection. A paired t test was done on EAT-10 surveys before and after IML to assess for statistical significance. Twenty-one patients with UVFI and glottic insufficiency underwent IML between October 2015 and December 2017. Nineteen of 21 patients (90%) presented with dysphagia (EAT-10 ≥ 3). 76% of patients with dysphagia reported improvement in swallowing function after IML. The EAT-10 scores of UVFI patients with dysphagia before and after IML were 17.0 ± 14.0 and 4.2 ± 9.6, respectively (p = 0.004). Nearly all patients with UVFI and glottic insufficiency report associated dysphagia. Three fourths of these patients perceive improvement in their swallowing function after injection medialization laryngoplasty. Patients with idiopathic UVFI may have a more sustained improvement and those with severe preop dysphagia may not benefit. Further research is necessary to refine patient selection and to assess duration of improved swallowing function

Effect of route of buprenorphine on recovery and postoperative analgesic requirement in paediatric patients

Background: We compared the effects of extradural with intravenous (i.v.) buprenorphine on postoperative pain and recovery characteristics.Methods: Thirty patients, aged 11-13 years, who were undergoing inguinal hernia repair with or without orchidopexy, were randomly allocated to receive either caudal 0.5% bupivacaine alone (group A) or were additionally given i.v. buprenorphine 2.5 micro g.kg-1 (group B) or caudal buprenorphine in the same dose (group C). Patients were followed for 8 h after the end of surgery.Results: All patients remained haemodynamically stable during the study period and no clinical respiratory depression was seen. Nausea, vomiting, urinary retention and pruritus were more common in the extradural buprenorphine group. Three patients in group A, five in group B and eight in group C did not require any additional analgesia during the study period. The incidence of vomiting was 20%, 50% and 80% in groups A, B and C, respectively. Four patients in group C had urinary retention compared with one each in the other two groups.CONCLUSIONS: Administration of buprenorphine resulted in a higher incidence of side-effects

Comparision of Infection Frequency in 1-Day Vs 5-Days Post Operative Antibiotic Regimen in Open Treated Facial Fractures

Objective: To compare the frequency of surgical site infection by using postoperative prophylactic antibiotics (1day vs. &gt; 5 days) in patients following open surgical reduction of facial fractures. Design: Randomized Controlled Trial Setting: Department of Dental &amp;Maxillofacial Surgery, Liaquat National Hospital, Institute of Postgraduate Medical Studies &amp; Health Sciences, Karachi. Duration: 06months from 23 December 2016 to 22 June 2017. Subject and Methods: A total of 368 cases according to inclusion and exclusion criteria were included in this study. Patients were randomly divided into two groups. Antibiotic (Inj. Augmentin 1.2g) was given to group A from admission to 24 hours postoperatively and in Group B antibiotic was continue up to 05 days postoperatively. A surgeon evaluated participants of both groups at 1, 2, 3 and 4 weeks postoperatively for infection according to criteria of surgical site infection published by CDC. All information was noted in the proforma. Results: - The average age of the patients was 31.10±7.39 years. Rate of surgical site infection was not significant between groups (4.9% vs. 7.1%; p=0.379). Conclusion: In this study 1-day course of antibiotics postoperatively in facial fractures is as effective in preventing infective complications as a 5-day regimen. The use of prolonged postoperative antibiotics in uncomplicated facial fractures had no significant benefit in reducing the incidence of infections. Key Words: Maxillofacial Surgeons, Surgical site infection, Prophylactic antibiotics</jats:p

Exploring the adaptive mechanisms and strategies of various populations of Sporobolus ioclados in response to arid conditions in Cholistan desert

Abstract This study explored the drought resistance mechanisms of different populations of Sporobolus ioclados (Poaceae), locally known as “Sawri,” “Drabhri” and “Dhrbholi” native to Africa and the Indian Subcontinent. These populations were grown in conventional nursery practices at Khawaja Fareed Government College in Rahim Yar Khan, Pakistan, and subsequently subjected to four distinct levels of drought within carefully monitored experimental settings. The experiment was conducted in a two-factorial design involving populations and drought treatments and was repeated three times. The physiological and morphological responses of S. ioclados, including plant height, number of roots, root length, flag leaf area, stomatal features, proline concentration and nitrogen content, displayed significant variability in response to the imposed drought stress. Drought resulted in increases in proline concentration and nitrogen content. The number of roots decreased, while the length and width of the stomata increased in various populations. A combination of advanced statistical techniques, such as ANOVA, PCA, HCA, and DFA, provided a comprehensive understanding of the mechanism of plant adaptation and the extent of population diversity within the species. The Yazman and Nwab Wala populations exhibited the highest rates of photosynthesis and stomatal conductance, while S. ioclados demonstrated notable drought tolerance at the T4 level of drought stress. A negative correlation was found between proline levels, nitrogen contents, and photosynthesis, suggesting that proline has a protective role in drought. The diverse adaptation strategies indicated by S. ioclados populations have revealed the potential of this species for afforestation and climate change mitigation in dry environments