Burn injury, gender and cancer risk: population-based cohort study using data from Scotland and Western Australia

Objective: To investigate the risk of cancer and potential gender effects in persons hospitalised with burn injury. Design: Population-based retrospective cohort study using record-linkage systems in Scotland and Western Australia. Participants: Records of 37 890 and 23 450 persons admitted with a burn injury in Scotland and Western Australia, respectively, from 1983 to 2008. Deidentified extraction of all linked hospital morbidity records, mortality and cancer records were provided by the Information Service Division Scotland and the Western Australian Data Linkage Service. Main outcome measures: Total and gender-specific number of observed and expected cases of total (‘all sites’) and site-specific cancers and standardised incidence ratios (SIRs).Results: From 1983 to 2008, for female burn survivors, there was a greater number of observed versus expected notifications of total cancer with 1011 (SIR, 95% CI 1.3, 1.2to 1.4) and 244 (SIR, 95% CI 1.12, 1.05 to 1.30), respectively, for Scotland and Western Australia. No statistically significant difference in total cancer risk was found for males. Significant excesses in observed cancers among burn survivors (combined gender) in Scotland and Western Australian were found for buccal cavity, liver, larynx and respiratory tract and for cancers of the female genital tract. Conclusions: Results from the Scotland data confirmed the increased risk of total (‘all sites’) cancer previously observed among female burn survivors in Western Australia. The gender dimorphism observed in this study may be related to the role of gender in the immune response to burn injury. More research is required to understand the underlying mechanism(s) that may link burn injury with an increased risk of some cancers

Burn injury leads to increased long-term susceptibility to respiratory infection in both mouse models and population studies

Background: Burn injury initiates an acute inflammatory response that subsequently drives wound repair. However, acute disruption to the immune response is also common, leading to susceptibility to sepsis and increased morbidity and mortality. Despite increased understanding of the impact of burn injury on the immune system in the acute phase, little is known about longterm consequences of burn injury on immune function. This study was established to determine whether burn injury has long-term clinical impacts on patients' immune responses. Methods: Using a population-based retrospective longitudinal study and linked hospital morbidity and death data from Western Australia, comparative rates of hospitalisation for respiratory infections in burn patients and a non-injured comparator cohort were assessed. In addition, a mouse model of non-severe burn injury was also used in which viral respiratory infection was induced at 4 weeks post-injury using a mouse modified version of the Influenza A virus (H3NN; A/mem/71-a). Results and conclusions: The burn injured cohort contained 14893 adult patients from 1980-2012 after removal of those patients with evidence of smoke inhalation or injury to the respiratory tract. During the study follow-up study a total of 2,884 and 2,625 respiratory infection hospital admissions for the burn and uninjured cohorts, respectively, were identified. After adjusting for covariates, the burn cohort experienced significantly elevated admission rates for influenza and viral pneumonia (IRR, 95%CI: 1.73, 1.27-2.36), bacterial pneumonia (IRR, 95%CI: 2.05, 1.85-2.27) and for other types of upper and lower respiratory infections (IRR, 95% CI: 2.38, 2.09-2.71). In the mouse study an increased viral titre was observed after burn injury, accompanied by a reduced CD8 response and increased NK and NKT cells in the draining lymph nodes. This data suggests burn patients are at long-term increased risk of infection due to sustained modulation of the immune response

Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences

We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian (\u27marsupial\u27) species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation. ©2007 Nature Publishing Group

DNA methylation and body mass index from birth to adolescence : meta-analyses of epigenome-wide association studies

Background DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P <1.06 x 10(-7), with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth P-enrichment = 1; childhood P-enrichment = 2.00 x 10(-4); adolescence P-enrichment = 2.10 x 10(-7)). Conclusions There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.Peer reviewe

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Evaluation of a revised instrument to assess the needs of men diagnosed with prostate cancer

Background: This study was conducted to assess the face, content and construct validity and the internal validity of the revised version of an instrument to measure the perceived needs of men diagnosed with prostate cancer [Prostate Cancer Needs Questionnaire version 2 (PCNQv2)]. The PCNQ was constructed in two parts with Part 1 measuring needs at diagnosis and initial treatment and Part 2 measuring current needs. Methods: A random sample of 650 men diagnosed with prostate cancer attending a Urologist of the Hunter Urology Group in Newcastle, New South Wales, Australia, were invited to participate in the study and sent by post the self-administered PCNQ. Information was provided on 145 men who were considered ineligible to participate. Completed questionnaires were received from 300 men. Results: The principal components method of factor analysis with varimax orthogonal rotation identified eight factors with eigenvalues greater than 1, which together accounted for 68% of the variance in Part 1 of the PCNQ. Likewise, six factors were identified in Part 2 which accounted for 68% of the variance. Internal reliability coefficients (Cronbach's alpha) were adequate for identified factors with values ranging from 0.71 to 0.90 for Part 1, and from 0.80 to 0.92 for Part 2. Conclusions: These results support the validity and reliability of the PCNQv2 to assess the perceived needs experienced by men diagnosed with prostate cancer

Long-term mortality among older adults with burn injury: a population-based study in Australia

AbstractObjective To assess if burn injury in older adults is associated with changes in long-term all-cause mortality and to estimate the increased risk of death attributable to burn injury.Methods We conducted a population-based matched longitudinal study - based on administrative data from Western Australia's hospital morbidity data system and death register. A cohort of 6014 individuals who were aged at least 45 years when hospitalized for a first burn injury in 1980-2012 was identified. A non-injury comparison cohort, randomly selected from Western Australia's electoral roll (n= 25 759), was matched to the patients. We used Kaplan-Meier plots and Cox proportional hazards regression to analyse the data and generated mortality rate ratios and attributable risk percentages.Findings For those hospitalized with burns, 180 (3%) died in hospital and 2498 (42%) died after discharge. Individuals with burn injury had a 1.4-fold greater mortality rate than those with no injury (95% confidence interval, CI: 1.3-1.5). In this cohort, the long-term mortality attributable to burn injury was 29%. Mortality risk was increased by both severe and minor burns, with adjusted mortality rate ratios of 1.3 (95% CI: 1.1-1.9) and 2.1 (95% CI: 1.9-2.3), respectively.Conclusion Burn injury is associated with increased long-term mortality. In our study population, sole reliance on data on in-hospital deaths would lead to an underestimate of the true mortality burden associated with burn injury

Retrospective cohort study of health service use for cardiovascular disease among adults with and without a record of injury hospital admission

Objective To quantify postinjury cardiovascular-related health service use experienced by mid to older aged adults hospitalised for injury, compared with uninjured adults. Additionally, to explore the effect of beta-blocker medications on postinjury cardiovascular hospitalisations among injury patients, given the potential cardioprotective effects of beta blockers.Design A retrospective cohort study using linked administrative and survey data.Participants Records of 35 026 injured and 60 823 uninjured matched adults aged over 45 from New South Wales, Australia, who completed the 45 and up survey.Primary and secondary outcome measures Admission rates and cumulative lengths of stay for cardiovascular hospitalisations, and prescription rates for cardiovascular medications. Negative binomial and Cox proportional hazards regression modelling were used to generate incident rate ratios (IRRs) and HR.Results Compared with the uninjured, those with injury had a 19% higher adjusted rate of postinjury cardiovascular admissions (IRR 1.19, 95% CI 1.14 to 1.25), spent 40% longer in hospital for ardiovascular disease (IRR 1.40, 95% CI 1.26 to 1.57) and had slightly higher cardiovascular prescription rates (IRR 1.04, 95% CI 1.02 to 1.06), during study follow-up. Those in the injury cohort that used beta blockers both prior to and after injury (continuous) appeared to have reduced need for post-injury cardiovascular hospitalisation (IRR 1.09, 95% CI 1.17 to 1.42) compared with those commencing on beta blockers after injury (after 30 days: IRR 1.69, 95% CI 1.37 to 2.08).Conclusions Apparent increased postinjury hospitalisation rates and prolonged length of stay related to cardiovascular disease suggest that injury patients may require clinical support for an extended period after injury. Additionally, injury patients who were on continuous beta blocker treatment appeared to have lower need for post-injury cardiovascular hospitalisations. However, the data do not allow us to draw clear conclusions and further clinical research is required