Effects of backpacking holidays in Australia on alcohol, tobacco and drug use of UK residents

BACKGROUND: Whilst alcohol and drug use among young people is known to escalate during short holidays and working breaks in international nightlife resorts, little empirical data are available on the impact of longer backpacking holidays on substance use. Here we examine changes in alcohol, tobacco and drug use when UK residents go backpacking in Australia. METHODS: Matched information on alcohol and drug use in Australia and the UK was collected through a cross sectional cohort study of 1008 UK nationals aged 18–35 years, holidaying in Sydney or Cairns, Australia, during 2005. RESULTS: The use of alcohol and other drugs by UK backpackers visiting Australia was common with use of illicit drugs being substantially higher than in peers of the same age in their home country. Individuals showed a significant increase in frequency of alcohol consumption in Australia compared to their behaviour in the UK with the proportion drinking five or more times per week rising from 20.7% (UK) to 40.3% (Australia). Relatively few individuals were recruited into drug use in Australia (3.0%, cannabis; 2.7% ecstasy; 0.7%, methamphetamine). However, over half of the sample (55.0%) used at least one illicit drug when backpacking. Risk factors for illicit drug use while backpacking were being regular club goers, being male, Sydney based, travelling without a partner or spouse, having been in Australia more than four weeks, Australia being the only destination on their vacation and drinking or smoking five or more days a week. CONCLUSION: As countries actively seek to attract more international backpacker tourists, interventions must be developed that target this population's risk behaviours. Developing messages on drunkenness and other drug use specifically for backpackers could help minimise their health risks directly (e.g. adverse drug reactions) and indirectly (e.g. accidents and violence) as well as negative impacts on the host country

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

GENOME-WIDE ASSOCIATION STUDY OF MORTALITY BENEFIT FROM BETA-BLOCKERS IN PATIENTS WITH HEART FAILURE WITH REDUCED EJECTION FRACTION

Background: Beta-blockers (BB) reduce the risk of mortality in most patients with heart failure with reduced ejection fraction (HFrEF), but not all patients benefit. Genome-wide association studies (GWAS) discovered variants influencing BB benefit in patients with hypertension, but a GWAS evaluating BB benefit in HFrEF patients has not been performed. Therefore the objective of this study was to use GWAS to discover variants influencing BB mortality benefit in HFrEF patients. Methods: HFrEF patients (n = 1,060) were enrolled in a single institution registry from 2007-15 and genotyped with the Axiom® Biobank array. The Michigan Imputation Server imputed ~7 million variants with 1000 Genomes as the reference panel. Variants with minor allele frequency \u3c 1% or deviating from Hardy Weinberg equilibrium were excluded. BB exposure was quantified from pharmacy claims based on dose and adherence. The primary endpoint was time to all-cause mortality. BB exposure by variant interactions were tested using Cox regression in R, adjusted for clinical risk factors, BB propensity, and the first two principal components. Additive genetic models were used and statistical significance was defined as p \u3c 5 × 10-8. HaploReg v4.1 identified putative mechanisms of significant variants. Results: The registry is 35% female, 51% self-reported African-Americans, and n = 993 had survival data and passed genotyping quality control. At baseline, age = 68 ± 12 yrs (mean ± sd), left ventricular ejection fraction = 35 ± 11%, and 77% were treated with BB. Follow-up was 2.4 ± 1.7 yrs with 175 deaths (18%). One variant on chromosome 19 was statistically significant: rs10416900; p = 1.2 × 10-8. This variant is 7.5 kb 5\u27 of MKNK2 and not in linkage disequilibrium (LD) with other variants. It alters DNAse in 5 tissue types and 4 regulatory motifs. Two variants on chromosome 3 were nearly significant: rs6441824 & rs4682720; p \u3c 5.9 × 10-8; 59 kb 5\u27 of TOPAZ1. These variants and many others in LD alter several regulatory mechanisms, including histone marks and DNAse. Conclusion: GWAS discovered novel candidate variants for BB mortality benefit in HFrEF patients with putative regulatory mechanisms. These data require replication in other HFrEF cohorts

Leukotriene B4 activates intracellular calcium and augments human osteoclastogenesis

INTRODUCTION: Bone erosion in inflammatory arthritis depends on the recruitment and activation of bone resorbing cells, the osteoclasts. Interleukin-23 (IL-23) has been primarily implicated in mediating inflammatory bone loss via the differentiation of Th17 receptor activator of nuclear factor κB ligand (RANKL)–producing cells. In this article, we describe a new role of IL-23 in activating the synthesis and production of leukotriene B4 (LTB4) in innate immune cells. METHODS: We utilized whole blood–derived human peripheral blood mononuclear cells (PBMCs), differentiated them towards an osteoclast lineage and then performed immunofluorescence and cytochemical staining to detect the expression of LTB4-associated receptors and enzymes such as phospholipase A2, 5-lipoxygenase and leukotriene A4 hydrolase, as well as the presence of tartrate-resistant acid phosphatase (TRAP) and F-actin rings on fully mature osteoclasts. We used enzyme immunoassays to measure LTB4 levels in culture media derived from IL-23-treated human PBMCs. We used real-time calcium imaging to study the effect of leukotrienes and requirements of different calcium sources and signaling proteins in activating intracellular calcium flux using pharmacological inhibitors to phospholipase C (U73122), membrane calcium channels (2-APB) and phosphatidylinositol 3-kinase (Wortmannin) and utilized qPCR for gene expression analysis in macrophages and osteoclasts. RESULTS: Our data show that LTB4 engagement of BLT1 and BLT2 receptors on osteoclast precursors leads to activation of phospholipase C and calcium release–activated channel–mediated intracellular calcium flux, which can activate further LTB4 autocrine production. IL-23-induced synthesis and secretion of LTB4 resulted in the upregulation of osteoclast-related genes NFATC1, MMP9, ACP5, CTSK and ITGB3 and the formation of giant, multinucleated TRAP(+) cells capable of F-actin ring formation. These effects were dependent on Ca(2+) signaling and were completely inhibited by BLT1/BLT2 and/or PLC and CRAC inhibitors. CONCLUSIONS: In conclusion, IL-23 can initiate osteoclast differentiation independently from the RANK-RANKL pathway by utilizing Ca(2+) signaling and the LTB4 signaling cascade