AbstractObjectiveTo characterise the clinical features of children and young people admitted to hospital with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ...infection in the UK and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to coronavirus disease 2019 (covid-19) (MIS-C).DesignProspective observational cohort study with rapid data gathering and near real time analysis.Setting260 hospitals in England, Wales, and Scotland between 17 January and 3 July 2020, with a minimum follow-up time of two weeks (to 17 July 2020).Participants651 children and young people aged less than 19 years admitted to 138 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory confirmed SARS-CoV-2.Main outcome measuresAdmission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C.ResultsMedian age was 4.6 (interquartile range 0.3-13.7) years, 35% (225/651) were under 12 months old, and 56% (367/650) were male. 57% (330/576) were white, 12% (67/576) South Asian, and 10% (56/576) black. 42% (276/651) had at least one recorded comorbidity. A systemic mucocutaneous-enteric cluster of symptoms was identified, which encompassed the symptoms for the WHO MIS-C criteria. 18% (116/632) of children were admitted to critical care. On multivariable analysis, this was associated with age under 1 month (odds ratio 3.21, 95% confidence interval 1.36 to 7.66; P=0.008), age 10-14 years (3.23, 1.55 to 6.99; P=0.002), and black ethnicity (2.82, 1.41 to 5.57; P=0.003). Six (1%) of 627 patients died in hospital, all of whom had profound comorbidity. 11% (52/456) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Children meeting MIS-C criteria were older (median age 10.7 (8.3-14.1) v 1.6 (0.2-12.9) years; P<0.001) and more likely to be of non-white ethnicity (64% (29/45) v 42% (148/355); P=0.004). Children with MIS-C were five times more likely to be admitted to critical care (73% (38/52) v 15% (62/404); P<0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with fatigue (51% (24/47) v 28% (86/302); P=0.004), headache (34% (16/47) v 10% (26/263); P<0.001), myalgia (34% (15/44) v 8% (21/270); P<0.001), sore throat (30% (14/47) v (12% (34/284); P=0.003), and lymphadenopathy (20% (9/46) v 3% (10/318); P<0.001) and to have a platelet count of less than 150 × 109/L (32% (16/50) v 11% (38/348); P<0.001) than children who did not have MIS-C. No deaths occurred in the MIS-C group.ConclusionsChildren and young people have less severe acute covid-19 than adults. A systemic mucocutaneous-enteric symptom cluster was also identified in acute cases that shares features with MIS-C. This study provides additional evidence for refining the WHO MIS-C preliminary case definition. Children meeting the MIS-C criteria have different demographic and clinical features depending on whether they have acute SARS-CoV-2 infection (polymerase chain reaction positive) or are post-acute (antibody positive).Study registrationISRCTN66726260.
Gallstone disease (GD) is one of the most common presentations to surgical units worldwide and shares several risk factors with cardiovascular disease (CVD). CVD remains the most common cause of ...death worldwide and results in considerable economic burden. Recent observational studies have demonstrated an association between GD and CVD with some studies demonstrating a stronger association with cholecystectomy. We present the findings of a meta-analysis assessing the relationship between GD and CVD. A total of fourteen cohort studies with over 1.2 million participants were included. The pooled hazard ratio (HR, 95% confidence interval CI) for association with GD from a random-effects model is 1.23 (95%CI: 1.16-1.30) for fatal and non-fatal CVD events. The association was present in females and males. Three studies report the relationship between cholecystectomy and CVD with a pooled HR of 1.41 (95%CI: 1.21-1.64) which compares to a HR of 1.30 (95%CI: 1.07-1.58) when cholecystectomy is excluded although confounding may influence this result. Our meta-analysis demonstrates a significant relationship between GD and CVD events which is present in both sexes. Further research is needed to assess the influence of cholecystectomy on this association.
Duplicate publication can introduce significant bias into a meta-analysis if studies are inadvertently included more than once. Many studies are published in more than one journal to maximize ...readership and impact of the study findings. Inclusion of multiple publications of the same study within a meta-analysis affords inappropriate weight to the duplicated data if reports of the same study are not linked together. As studies which have positive findings are more likely to be published in multiple journals this leads to a potential overestimate of the benefits of an intervention. Recent advances in immunosuppression strategies following liver transplantation have led to many studies investigating immunosuppressive regimes including immunosuppression monotherapy. In this letter we focus on a recently published meta-analysis by Lan et al investigating studies assessing immunosuppression monotherapy for liver transplantation. The authors claim to have identified fourteen separate randomised studies investigating immunosuppression monotherapy. Seven of the references appear to relate to only three studies which have been subject to duplicate publication. Several similarities can be identified in each of the duplicate publications including similar authorship, identical immunosuppression regimes, identical dates of enrolment and citation of the original publication in the subsequent manuscripts. We discuss the evidence of the duplicate publication inclusion in the meta-analysis.
Duplicate publication can introduce significant bias into a meta-analysis if studies are inadvertently included more than once. Many studies are published in more than one journal to maximize ...readership and impact of the study findings. Inclusion of multiple publications of the same study within a meta-analysis affords inappropriate weight to the duplicated data if reports of the same study are not linked together. As studies which have positive findings are more likely to be published in multiple journals this leads to a potential overestimate of the benefits of an intervention. Recent advances in immunosuppression strategies following liver transplantation have led to many studies investigating immunosuppressive regimes including immunosuppression monotherapy. In this letter we focus on a recently published meta-analysis by Lan et al investigating studies assessing immunosuppression monotherapy for liver transplantation. The authors claim to have identified fourteen separate randomised studies investigating immunosuppression monotherapy. Seven of the references appear to relate to only three studies which have been subject to duplicate publication. Several similarities can be identified in each of the duplicate publications including similar authorship, identical immunosuppression regimes, identical dates of enrolment and citation of the original publication in the subsequent manuscripts. We discuss the evidence of the duplicate publication inclusion in the meta-analysis.
Background and Aims
Genome‐wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely that many genetic determinants are ...undiscovered. The aim of this study was to identify genetic variants that represent new targets for gallstone research and treatment.
Approach and Results
We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1089 cases, 5228 controls), and conducted a GWA meta‐analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene‐based then gene‐set analysis and tissue expression of identified genes in Genotype‐Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy‐five risk loci were identified (p < 5 × 10−8), of which 46 were new. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism, and gastrointestinal motility. Anoctamin 1 (ANO1) and transmembrane Protein 147 (TMEM147), both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599‐A leads to suppression of hepatic TMEM147 expression, suggesting that the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6‐fold increased odds of gallstones compared with the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes, and C‐reactive protein concentrations, and decreased lipoprotein cholesterol concentrations.
Conclusions
This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. We implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.
Genome‐wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed ...quantitative traits. We performed a case‐control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co‐existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta‐analysis using available summary association statistics. Six risk loci were identified (P < 5*10−8) (apolipoprotein E APOE, patatin‐like phospholipase domain containing 3 PNPLA3, transmembrane 6 superfamily member 2 TM6SF2, glucokinase regulator GCKR, mitochondrial amidoxime reducing component 1 MARC1, and tribbles pseudokinase 1 TRIB1). All loci retained significance in sensitivity analyses without co‐existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta‐analysis. Rs429358 (P = 2.17*10−11) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 95% confidence interval 0.78‐0.90 and homozygotes 0.64 0.50‐0.79). Conclusion: This GWAS replicates six known NAFLD‐susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
We hypothesised that the clinical characteristics of hospitalised children and young people (CYP) with SARS-CoV-2 in the UK second wave (W2) would differ from the first wave (W1) due to the alpha ...variant (B.1.1.7), school reopening and relaxation of shielding.
Prospective multicentre observational cohort study of patients <19 years hospitalised in the UK with SARS-CoV-2 between 17/01/20 and 31/01/21. Clinical characteristics were compared between W1 and W2 (W1 = 17/01/20-31/07/20,W2 = 01/08/20-31/01/21).
2044 CYP < 19 years from 187 hospitals. 427/2044 (20.6%) with asymptomatic/incidental SARS-CoV-2 were excluded from main analysis. 16.0% (248/1548) of symptomatic CYP were admitted to critical care and 0.8% (12/1504) died. 5.6% (91/1617) of symptomatic CYP had Multisystem Inflammatory Syndrome in Children (MIS-C). After excluding CYP with MIS-C, patients in W2 had lower Paediatric Early Warning Scores (PEWS, composite vital sign score), lower antibiotic use and less respiratory and cardiovascular support than W1. The proportion of CYP admitted to critical care was unchanged. 58.0% (938/1617) of symptomatic CYP had no reported comorbidity. Patients without co-morbidities were younger (42.4%, 398/938, <1 year), had lower PEWS, shorter length of stay and less respiratory support.
We found no evidence of increased disease severity in W2 vs W1. A large proportion of hospitalised CYP had no comorbidity.
No evidence of increased severity of COVID-19 admissions amongst children and young people (CYP) in the second vs first wave in the UK, despite changes in variant, relaxation of shielding and return to face-to-face schooling. CYP with no comorbidities made up a significant proportion of those admitted. However, they had shorter length of stays and lower treatment requirements than CYP with comorbidities once those with MIS-C were excluded. At least 20% of CYP admitted in this cohort had asymptomatic/incidental SARS-CoV-2 infection. This paper was presented to SAGE to inform CYP vaccination policy in the UK.
Abstract
Surgical site infections (SSI) cause substantial morbidity and pose a burden to acute healthcare services after surgery. We aimed to investigate whether a smartphone-delivered wound ...assessment tool can expedite diagnosis and treatment of SSI after emergency abdominal surgery. This single-blinded randomised control trial (NCT02704897) enroled adult emergency abdominal surgery patients in two tertiary care hospitals. Patients were randomised (1:1) to routine postoperative care or additional access to a smartphone-delivered wound assessment tool for 30-days postoperatively. Patient-reported SSI symptoms and wound photographs were requested on postoperative days 3, 7, and 15. The primary outcome was time-to-diagnosis of SSI (Centers for Disease Control definition). 492 patients were randomised (smartphone intervention: 223; routine care: 269). There was no significant difference in the 30-day SSI rate between trial arms: 21 (9.4%) in smartphone vs 20 (7.4%,
p
= 0.513) in routine care. Among the smartphone group, 32.3% (
n
= 72) did not utilise the tool. There was no significant difference in time-to-diagnosis of SSI for patients receiving the intervention (−2.5 days, 95% CI: −6.6−1.6,
p
= 0.225). However, patients in the smartphone group had 3.7-times higher odds of diagnosis within 7 postoperative days (95% CI: 1.02−13.51,
p
= 0.043). The smartphone group had significantly reduced community care attendance (OR: 0.57, 95% CI: 0.34−0.94,
p
= 0.030), similar hospital attendance (OR: 0.76, 95% CI: 0.28−1.96, p = 0.577), and significantly better experiences in accessing care (OR: 2.02, 95% CI: 1.17−3.53,
p
= 0.013). Smartphone-delivered wound follow-up is feasible following emergency abdominal surgery. This can facilitate triage to the appropriate level of assessment required, allowing earlier postoperative diagnosis of SSI.
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