Characterization of significant molecular determinants of virulence of Enterovirus 71 sub-genotype B4 in Rhabdomyosarcoma cells

One of the leading causes of the hand, foot and mouth disease (HFMD) is Enterovirus 71(EV-A71), displaying symptoms such as fever and ulcers in children but some strains can produce cardiopulmonary oedema which leads to death. There is no FDA-approved vaccine for prevention of severe HFMD. The molecular determinants of virulence for EV-A71 are unclear. It could be a single or a combination of amino acids that determines virulence in different EV-A71 genotype/sub-genotypes. Several EV-A71 strains bearing single nucleotide (nt) mutations were constructed and the contribution of each mutation to virulence was evaluated. The nt(s) that contributed to significant reduction in virulence in vitro were selected and each mutation was introduced separately into the genome to construct the multiply mutated EV-A71 strain (MMS) which carried six substitutions of nt(s) at the 5’-NTR (U700C), VP1-145 (E to G), VP1-98E, VP1-244K and G64R in the vaccine seed strain that had a partial deletion within the 5’-NTR region (nt. 475-485) of ∆11bp. In comparison to the wild type strain, the MMS showed low virulence as it produced very low RNA copy number, plaque count, VP1 and had 105-fold higher TCID50, indicative of a promising LAV candidate that should be further evaluated in vivo

A systematic review on the effectiveness of enteral immunonutrition (EIN) on pre- and post-operative outcomes in gastric cancer patients

Gastric cancer is one of the most common upper gastrointestinal malignancies. To date, enteral immunonutrition (EIN) has gained increasing attention as it is found to effectively enhance the host’s immunity and improve the metabolic status of gastric cancer patients undergoing gastrectomy. The health-boosting effects of EIN are believed to originate from a number of nutritional elements such as omega-3 fatty acids, glutamine, arginine and nucleic acid precursors that help reduce the incidences of post-operative complications and shorten the length of hospital stay among the aforementioned patients. However, little was known about the consistency of health-boosting benefits conferred by EIN. Hence, according to PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) protocol, this systematic review was carried out using nine meticulously and specifically selected full-length articles focusing on the pre- and post-operative effects of EIN including physical, biochemical, clinical and immunological outcomes on gastric cancer patients. Among the selected articles, seven of them focused on post-operative EIN while the remaining two concentrated on pre-operative EIN. In most of the selected studies, more than one immunonutritional components (arginine, glutamine, omega-3 fatty acid, RNA) were integrated. Patients receiving EIN showed significantly improved immunity, for example, increase in CD4+ T and NK cell counts that are responsible for fighting pathogens. In addition to that, individuals receiving EIN also showed increased levels of inflammatory biomarkers in their sera such as pre-albumin and transferrin. This results in shorter period of post-operative hospital stay that in turn permits progressive healing process and increases the survival rate due to minimal frequency of post-operative infections. Conclusively, our systematic review acknowledges that regardless of the initiation timing (pre-operative or post-operative) of immunonutrition, EIN can improve the overall health status of gastric cancer patients including infection complications and the length of hospital stay through regulation of immune responses

Diabetes in pregnancy and risk of antepartum depression: a systematic review and meta-analysis of cohort studies

Previous literature has reported that patients with diabetes in pregnancy (DIP) are at risk of developing antepartum depression but the results have been inconsistent in cohort studies. We conducted a systematic review and performed a meta-analysis to quantify the association between DIP and risk of antepartum depression in cohort studies. Medline, Cinahl, and PubMed databases were searched for studies investigating DIP involving pregnant women with pre-existing diabetes and gestational diabetes mellitus and their risk of antepartum depression that were published in journals from inception to 27 December 2019. We derived the summary estimates using a random-effects model and reported the findings as pooled relative risks (RR) and confidence interval (CI). Publication bias was assessed using a funnel plot and was quantified by Egger and Begg’s tests. Ten studies, involving 71,036 pregnant women were included in this meta-analysis. The pooled RR to develop antepartum depression was (RR = 1.430, 95% CI: 1.251–1.636) among women with gestational diabetes mellitus. Combining pregnant women with pre-existing diabetes mellitus and gestational diabetes mellitus, they had a significant increased risk of developing antepartum depression (RR = 1.431, 95% CI: 1.205–1.699) compared with those without it. In comparison, we found no association between pre-existing diabetes mellitus in pregnancy (RR = 1.300, 95% CI: 0.736–2.297) and the risk of developing antepartum depression. This study has a few limitations: first, different questionnaire and cut-off points were used in evaluation of depression across the studies. Second, there was a lack of data on history of depression prior to pregnancy, which lead to confounding bias that could not be solved by this meta-analysis. Third, data were dominated by studies in Western countries; this is due to the studies from Eastern countries failing to meet our inclusion criteria for statistical analysis. Women with gestational diabetes mellitus have an increased risk of developing antepartum depression compared to those without the disease. Therefore, more attention on the mental health status should be given on pregnant women diagnosed with pre-existing diabetes mellitus and gestational diabetes mellitus

Waning of specific antibodies against Delta and Omicron variants five months after a third dose of BNT162b2 SARS-CoV-2 vaccine in elderly individuals.

The emergence of new SARS-CoV-2 variants, such as the more transmissible Delta and Omicron variants, has raised concerns on efficacy of the COVID-19 vaccines. Here, we examined the waning of antibody responses against different variants following primary and booster vaccination. We found that antibody responses against variants were low following primary vaccination. The antibody response against Omicron was almost non-existent. Efficient boosting of antibody response against all variants, including Omicron, was observed following a third dose. The antibody response against the variants tested was significantly higher at one month following booster vaccination, compared with two months following primary vaccination, for all individuals, including the low antibody responders identified at two months following primary vaccination. The antibody response, for all variants tested, was significantly higher at four months post booster than at five months post primary vaccination, and the proportion of low responders remained low (6-11%). However, there was significant waning of antibody response in more than 95% of individuals at four months, compared to one month following booster. We also observed a robust memory B cell response following booster, which remained higher at four months post booster than prior to booster. However, the memory B cell responses were on the decline for 50% of individuals at four months following booster. Similarly, while the T cell response is sustained, at cohort level, at four months post booster, a substantial proportion of individuals (18.8 - 53.8%) exhibited T cell response at four months post booster that has waned to levels below their corresponding levels before booster. The findings show an efficient induction of immune response against SARS-CoV-2 variants following booster vaccination. However, the induced immunity by the third BNT162b2 vaccine dose was transient. The findings suggest that elderly individuals may require a fourth dose to provide protection against SARS-CoV-2

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Effectiveness of a chronic obstructive pulmonary disease integrated care pathway in a regional health system : a propensity score matched cohort study

Objective: The chronic obstructive pulmonary disease (COPD) integrated care pathway (ICP) programme was designed and implemented to ensure that the care for patients with COPD is comprehensive and integrated across different care settings from primary care to acute hospital and home. We evaluated the effectiveness of the ICP programme for patients with COPD. Design, setting and participants: A retrospective propensity score matched cohort study was conducted comparing differences between programme enrolees and propensity-matched non-enrolees in a Regional Health System in Singapore. Data on patients diagnosed with COPD who enrolled in the programme (n=95) and patients who did not enrol (n=6330) were extracted from the COPD registry and hospital administrative databases. Enrolees and non-enrolees were propensity score matched. Outcome measures: The risk of COPD hospitalisations and COPD hospital bed days savings were compared between the groups using a difference-in-difference strategy and generalised estimating equation approach. Adherence with recommended care elements for the COPD-ICP group was measured quarterly at baseline and during a 2-year follow-up period. Results: Compared with non-enrolees, COPD hospitalisation risk for ICP programme enrolees was significantly lower in year 2 (incidence rate ratio (IRR): 0.73; 95% CI 0.54 to 1.00). Similarly, COPD hospital bed days was significantly lower for enrolees in year 2 (IRR: 0.78; 95% CI 0.64 to 0.95). ICP programme patients had sustained improvements in compliance with all recommended care elements for patients with COPD. The overall all-or-none care bundle compliance rate had improved from 28% to 54%. Conclusion: The study concluded that the COPD-ICP programme was associated with reductions in COPD hospitalisation risk and COPD health utilisation in a 2-year follow-up period.MOH (Min. of Health, S’pore)Published versio

Surgical site infection after gastrointestinal surgery in children : an international, multicentre, prospective cohort study

Introduction Surgical site infection (SSI) is one of the most common healthcare-associated infections (HAIs). However, there is a lack of data available about SSI in children worldwide, especially from low-income and middle-income countries. This study aimed to estimate the incidence of SSI in children and associations between SSI and morbidity across human development settings. Methods A multicentre, international, prospective, validated cohort study of children aged under 16 years undergoing clean-contaminated, contaminated or dirty gastrointestinal surgery. Any hospital in the world providing paediatric surgery was eligible to contribute data between January and July 2016. The primary outcome was the incidence of SSI by 30 days. Relationships between explanatory variables and SSI were examined using multilevel logistic regression. Countries were stratified into high development, middle development and low development groups using the United Nations Human Development Index (HDI). Results Of 1159 children across 181 hospitals in 51 countries, 523 (45 center dot 1%) children were from high HDI, 397 (34 center dot 2%) from middle HDI and 239 (20 center dot 6%) from low HDI countries. The 30-day SSI rate was 6.3% (33/523) in high HDI, 12 center dot 8% (51/397) in middle HDI and 24 center dot 7% (59/239) in low HDI countries. SSI was associated with higher incidence of 30-day mortality, intervention, organ-space infection and other HAIs, with the highest rates seen in low HDI countries. Median length of stay in patients who had an SSI was longer (7.0 days), compared with 3.0 days in patients who did not have an SSI. Use of laparoscopy was associated with significantly lower SSI rates, even after accounting for HDI. Conclusion The odds of SSI in children is nearly four times greater in low HDI compared with high HDI countries. Policies to reduce SSI should be prioritised as part of the wider global agenda.Peer reviewe

A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease