Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets

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

Opioid cardioprotection in the perioperative period

Many factors present during the perioperative period render patients susceptible in developing myocardial ischaemia reperfusion injury. Various mode of conditioning the heart against this type of injury has been discovered in animal models and involve powerful innate pathways that enhance cellular survival. These may be harnessed by applying a trigger either immediately before (preconditioning) or after (postconditioning) the lethal ischaemic injury, by physical or pharmacological means. Morphine was the first clinically used opioid shown to be cardioprotective but the intravenous dose required limited its use clinically. Remifentanil, an ultra-short acting opioid, was later also shown to be cardioprotective. A better understanding of how these opioids can protect the heart may enable the rational design of clinical regimens that best protect patients. The purpose of this thesis is to demonstrate and elucidate how these two agents provide cardiac protection. I first demonstrated the clinical efficacy of remifentanil preconditioning in reducing the release CKMB, cardiac troponin I, heart type fatty acid binding protein and ischaemia modified albumin following cardiopulmonary bypass. As opioids cannot be omitted completely from patients undergoing cardiac surgery due to ethical considerations, I then used a well-established animal model of ischaemia reperfusion injury to complete the remainder of the studies. I demonstrated that remifentanil postconditioning was also effective in reducing myocardial infarct size, an effect mediated through the activation of kappa and delta opioid receptor subtypes, and in part triggered at the level of the myocardium. I then confirmed previous findings showing the efficacy of intrathecal morphine preconditioning using clinically relevant doses. In addition, I demonstrated that all three opioid receptor subtypes were involved. This effect was comparable to that achievable by classical ischaemic or intravenous morphine preconditioning and is mediated by central but not peripheral opioid receptor activation. Intrathecal morphine reduces the degree of myocardial apoptosis, alters the phosphorylation of Akt and the expression of endothelial nitric oxide synthatase and opens the potassium ATP channels. It also involves spinal adenosine receptors, similar to spinal morphine mediated analgesia. Intrathecal morphine preconditioning can be abolished by the interruption of autonomic nervous system function and blockade of calcitonin gene related peptide (CGRP) and bradykinin receptors. Intrathecal morphine postconditioning also has an infarct sparing effect. It also involves the activation of central opioid receptors and peripheral adenosine and CGRP receptors. Finally I demonstrated a pivotal role of central opioid receptor in remote preconditioning by showing that selective blockade of these receptors abolished the protective effects of remote but not classical ischaemic preconditioning. Cumulatively, these results demonstrated the versatility of opioid mediated cardioprotection using morphine or remifentanil and the pivotal role of central opioid receptors in cardioprotection and revealed some of the mechanisms underlying these benefits. Not only does intrathecal morphine provide analgesia, it also generates signals that are transmitted through the autonomic nervous system resulting in changes in cellular function in the heart. This point to the possibility of a relationship between an organism’s intrinsic response to pain and the triggering of an innate organ protective response to ischaemia.published_or_final_versionAnaesthesiologyMasterDoctor of Medicin

Evidence of the impact of systemic inflammation on neuroinflammation from a non-bacterial endotoxin animal model

Abstract Background Systemic inflammation induces neuroinflammation and cellular changes such as tau phosphorylation to impair cognitive function, including learning and memory. This study uses a single model, laparotomy without any pathogen, to characterize these changes and their responses to anti-inflammatory treatment in the intermediate term. Methods In a two-part experiment, wild-type C57BL/6N mice (male, 3 month old, 25 ± 2 g) were subjected to sevoflurane anesthesia alone or to a laparotomy. Cognitive performance, systemic and neuroinflammatory responses, and tau phosphorylation were evaluated on postoperative days (POD) 1, 3, and 14. The effect of perioperative ibuprofen intervention (60 mg/kg) on these changes was then assessed. Results Mice in the laparotomy group displayed memory impairment up to POD 14 with initial high levels of inflammatory cytokines in the liver, frontal cortex (IL-1β, IL-6, and TNF-α), and hippocampus (IL-1β and IL-8). On POD 14, although most circulating and resident cytokine levels returned to normal, a significant number of microglia and astrocytes remained activated in the frontal cortex and microglia in the hippocampus, as well as abnormal tau phosphorylation in these two brain regions. Perioperative ibuprofen improved cognitive performance, attenuated systemic inflammation and glial activation, and suppressed the abnormal tau phosphorylation both in the frontal cortex and hippocampus. Conclusions Our results suggest that (1) cognitive dysfunction is associated with an unbalanced pro-inflammatory and anti-inflammatory response, tauopathy, and gliosis; (2) cognitive dysfunction, gliosis, and tauopathy following laparotomy can persist well beyond the immediate postoperative period; and (3) anti-inflammatory drugs can act rapidly to attenuate inflammatory responses in the brain and negatively modulate neuropathological changes to improve cognition. These findings may have implications for the duration of therapeutic strategies aimed at curtaining cognitive dysfunction following surgery

Sevoflurane Induces Neurotoxicity in the Animal Model with Alzheimer’s Disease Neuropathology via Modulating Glutamate Transporter and Neuronal Apoptosis

Perioperative neurocognitive disorders are frequently observed in postoperative patients and previous reports have shown that pre-existing mild cognitive impairment with accumulated neuropathology may be a risk factor. Sevoflurane is a general anesthetic agent which is commonly used in clinical practice. However, the effects of sevoflurane in postoperative subjects are still controversial, as both neurotoxic or neuroprotective effects were reported. The purpose of this study is to investigate the effects of sevoflurane in 3 × Tg mice, a specific animal model with pre-existing Alzheimer’s disease neuropathology. 3 × Tg mice and wild-type mice were exposed to 2 h of sevoflurane respectively. Cognitive function, glutamate transporter expression, MAPK kinase pathways, and neuronal apoptosis were accessed on day 7 post-exposure. Our findings indicate that sevoflurane-induced cognitive deterioration in 3 × Tg mice, which was accompanied with the modulation of glutamate transporter, MAPK signaling, and neuronal apoptosis in the cortical and hippocampal regions. Meanwhile, no significant impact was observed in wild-type mice. Our results demonstrated that prolonged inhaled sevoflurane results in the exacerbation of neuronal and cognitive dysfunction which depends on the neuropathology background

ChatGPT versus human in generating medical graduate exam multiple choice questions-A multinational prospective study (Hong Kong S.A.R., Singapore, Ireland, and the United Kingdom).

IntroductionLarge language models, in particular ChatGPT, have showcased remarkable language processing capabilities. Given the substantial workload of university medical staff, this study aims to assess the quality of multiple-choice questions (MCQs) produced by ChatGPT for use in graduate medical examinations, compared to questions written by university professoriate staffs based on standard medical textbooks.Methods50 MCQs were generated by ChatGPT with reference to two standard undergraduate medical textbooks (Harrison's, and Bailey & Love's). Another 50 MCQs were drafted by two university professoriate staff using the same medical textbooks. All 100 MCQ were individually numbered, randomized and sent to five independent international assessors for MCQ quality assessment using a standardized assessment score on five assessment domains, namely, appropriateness of the question, clarity and specificity, relevance, discriminative power of alternatives, and suitability for medical graduate examination.ResultsThe total time required for ChatGPT to create the 50 questions was 20 minutes 25 seconds, while it took two human examiners a total of 211 minutes 33 seconds to draft the 50 questions. When a comparison of the mean score was made between the questions constructed by A.I. with those drafted by humans, only in the relevance domain that the A.I. was inferior to humans (A.I.: 7.56 +/- 0.94 vs human: 7.88 +/- 0.52; p = 0.04). There was no significant difference in question quality between questions drafted by A.I. versus humans, in the total assessment score as well as in other domains. Questions generated by A.I. yielded a wider range of scores, while those created by humans were consistent and within a narrower range.ConclusionChatGPT has the potential to generate comparable-quality MCQs for medical graduate examinations within a significantly shorter time

ST36 acupoint injection with anisodamine for postoperative nausea and vomiting in female patients after bariatric surgery: a prospective, randomized controlled trial.

BackgroundThe use of multimodal pharmacological prophylactic regimes has decreased postoperative nausea and vomiting (PONV) in general but it still occurs in over 60% of female patients after bariatric surgery. This study aimed to evaluate the efficacy of ST36 acupoint injection with anisodamine in prevention of PONV among female patients after bariatric surgery.MethodsNinety patients undergoing laparoscopic sleeve gastrectomy were randomly allocated to anisodamine or control group at the ratio of 2:1. Anisodamine or normal saline was injected into Zusanli (ST36) bilaterally after induction of general anesthesia. The incidence and severity of PONV were assessed during the first 3 postoperative days and at 3&nbsp;months. The quality of early recovery of anesthesia, gastrointestinal function, sleep quality, anxiety, depression, and complications were also evaluated.ResultsBaseline and perioperative characteristics were comparable between two groups. In the anisodamine group, 25 patients (42.4%) experienced vomiting within postoperative 24&nbsp;h compared with 21 (72.4%) in the control group (relative risk 0.59; 95% confidence interval 0.40-0.85). Time to first rescue antiemetic was 6.5&nbsp;h in anisodamine group, and 1.7&nbsp;h in the control group (P = 0.011). Less rescue antiemetic was required during the first 24&nbsp;h in the anisodamine group (P = 0.024). There were no differences in either postoperative nausea or other recovery characteristics.ConclusionsThe addition of ST36 acupoint injection with anisodamine significantly reduced postoperative vomiting without affecting nausea in female patients with obesity undergoing laparoscopic sleeve gastrectomy

Implementation of an interprofessional team-based learning program involving seven undergraduate health and social care programs from two universities, and students’ evaluation of their readiness for interprofessional learning

Abstract Background Interprofessional learning is gaining momentum in revolutionizing healthcare education. During the academic year 2015/16, seven undergraduate-entry health and social care programs from two universities in Hong Kong took part in an interprofessional education program. Based on considerations such as the large number of students involved and the need to incorporate adult learning principles, team-based learning was adopted as the pedagogy for the program, which was therefore called the interprofessional team-based learning program (IPTBL). The authors describe the development and implementation of the IPTBL program and evaluate the effectiveness of the program implementation. Methods Eight hundred and one students, who are predominantly Chinese, participated in the IPTBL. The quantitative design (a pretest-posttest experimental design) was utilized to examine the students’ gains on their readiness to engage in interprofessional education (IPE). Results Three instructional units (IUs) were implemented, each around a clinical area which could engage students from complementary health and social care disciplines. Each IU followed a team-based learning (TBL) process: pre-class study, individual readiness assurance test, team readiness assurance test, appeal, feedback, and application exercise. An electronic platform was developed and was progressively introduced in the three IUs. The students’ self-perceived attainment of the IPE learning outcomes was high. Across all four subscales of RIPLS, there was significant improvement in student’s readiness to engage in interprofessional learning after the IPTBL. A number of challenges were identified: significant time involvement of the teachers, difficulty in matching students from different programs, difficulty in making IPTBL count towards a summative assessment score, difficulty in developing the LAMS platform, logistics difficulty in managing paper TBL, and inappropriateness of the venue. Conclusions Despite some challenges in developing and implementing the IPTBL program, our experience showed that TBL is a viable pedagogy to be used in interprofessional education involving hundreds of students. The significant improvement in all four subscales of RIPLS showed the effects of the IPTBL program in preparing students for collaborative practice. Factors that contributed to the success of the use of TBL for IPE are discussed

Effect of Intraoperative Dexmedetomidine on Recovery of Gastrointestinal Function After Abdominal Surgery in Older Adults

ImportancePostoperative ileus is common after abdominal surgery, and small clinical studies have reported that intraoperative administration of dexmedetomidine may be associated with improvements in postoperative gastrointestinal function. However, findings have been inconsistent and study samples have been small. Further examination of the effects of intraoperative dexmedetomidine on postoperative gastrointestinal function is needed.ObjectiveTo evaluate the effects of intraoperative intravenous dexmedetomidine vs placebo on postoperative gastrointestinal function among older patients undergoing abdominal surgery.Design, setting, and participantsThis multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at the First Affiliated Hospital of Anhui Medical University in Hefei, China (lead site), and 12 other tertiary hospitals in Anhui Province, China. A total of 808 participants aged 60 years or older who were scheduled to receive abdominal surgery with an expected surgical duration of 1 to 6 hours were enrolled. The study was conducted from August 21, 2018, to December 9, 2019.InterventionsDexmedetomidine infusion (a loading dose of 0.5 μg/kg over 15 minutes followed by a maintenance dose of 0.2 μg/kg per hour) or placebo infusion (normal saline) during surgery.Main outcomes and measuresThe primary outcome was time to first flatus. Secondary outcomes were postoperative gastrointestinal function measured by the I-FEED (intake, feeling nauseated, emesis, physical examination, and duration of symptoms) scoring system, time to first feces, time to first oral feeding, incidence of delirium, pain scores, sleep quality, postoperative nausea and vomiting, hospital costs, and hospital length of stay.ResultsAmong 808 patients enrolled, 404 were randomized to receive intraoperative dexmedetomidine, and 404 were randomized to receive placebo. In total, 133 patients (60 in the dexmedetomidine group and 73 in the placebo group) were excluded because of protocol deviations, and 675 patients (344 in the dexmedetomidine group and 331 in the placebo group; mean [SD] age, 70.2 [6.1] years; 445 men [65.9%]) were included in the per-protocol analysis. The dexmedetomidine group had a significantly shorter time to first flatus (median, 65 hours [IQR, 48-78 hours] vs 78 hours [62-93 hours], respectively; P &lt; .001), time to first feces (median, 85 hours [IQR, 68-115 hours] vs 98 hours [IQR, 74-121 hours]; P = .001), and hospital length of stay (median, 13 days [IQR, 10-17 days] vs 15 days [IQR, 11-18 days]; P = .005) than the control group. Postoperative gastrointestinal function (as measured by the I-FEED score) and delirium incidence were similar in the dexmedetomidine and control groups (eg, 248 patients [72.1%] vs 254 patients [76.7%], respectively, had I-FEED scores indicating normal postoperative gastrointestinal function; 18 patients [5.2%] vs 12 patients [3.6%] had delirium on postoperative day 3).Conclusions and relevanceIn this randomized clinical trial, the administration of intraoperative dexmedetomidine reduced the time to first flatus, time to first feces, and length of stay after abdominal surgery. These results suggest that this therapy may be a viable strategy to enhance postoperative recovery of gastrointestinal function among older adults.Trial registrationChinese Clinical Trial Registry Identifier: ChiCTR1800017232