Corrections: Association of variants in MMEL1 and CTLA4 with rheumatoid arthritis in the Han Chinese population (Annals of the Rheumatic Diseases (2011) 70, (1793-1797))

Patrick Danoy, Meng Wei, Hadler Johanna, et al. Association of variants in MMEL1 and CTLA4 with rheumatoid arthritis in the Han Chinese population. Ann Rheum Dis 2011;70:1793–97. The following authors were listed as contributing equally to the study...

Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis

Objective: To determine the influence of HLA-B27 homozygosity and HLA-DRB1 alleles in the susceptibility to, and severity of, ankylosing spondylitis in a Finnish population. Methods: 673 individuals from 261 families with ankylosing spondylitis were genotyped for HLA-DRB1 alleles and HLA-B27 heterozygosity/ homozygosity. The frequencies of HLA-B27 homozygotes in probands from these families were compared with the expected number of HLA-B27 homozygotes in controls under Hardy-Weinberg equilibrium (HWE). The effect of HLA-DRB1 alleles was assessed using a logistic regression procedure conditioned on HLA-B27 and case-control analysis. Results: HLA-B27 was detected in 93% of cases of ankylosing spondylitis. An overrepresentation of HLA-B27 homozygotes was noted in ankylosing spondylitis (11%) compared with the expected number of HLA-B27 homozygotes under HWE (4%) (odds ratio (OR) = 3.3 (95% confidence interval, 1.6 to 6.8), p = 0.002). HLA-B27 homozygosity was marginally associated with reduced BASDAI (HLA-B27 homozygotes, 4.5 (1.6); HLA-B27 heterozygotes, 5.4 (1.8) (mean (SD)), p = 0.05). Acute anterior uveitis (AAU) was present in significantly more HLA-B27 positive cases (50%) than HLA-B27 negative cases (16%) (OR = 5.4 (1.7 to 17), p<0.004). HLA-B27 positive cases had a lower average age of symptom onset (26.7 (8.0) years) compared with HLA-B27 negative cases (35.7 (11.2) years) (p<0.0001). Conclusions: HLA-627 homozygosity is associated with a moderately increased risk of ankylosing spondylitis compared with HLA-β27 heterozygosity. HLA-B27 positive cases had an earlier age of onset of ankylosing spondylitis than HLA-B27 negative cases and were more likely to develop AAU. HLA-DRB1 alleles may influence the age of symptom onset of ankylosing spondylitis.

Prospective external validation of an accelerated (2-h) acute coronary syndrome rule-out process using a contemporary troponin assay

Background: Recently there have been efforts to derive safe, efficient processes to rule out acute coronary syndrome (ACS) in emergency department (ED) chest pain patients. We aimed to prospectively validate an ACS assessment pathway (the 2-Hour Accelerated Diagnostic Protocol to Assess Patients with Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker (ADAPT) pathway) under pragmatic ED working conditions. Methods: This prospective cohort study included patients with atraumatic chest pain in whom ACS was suspected but who did not have clear evidence of ischaemia on ECG. Thrombolysis in myocardial infarction (TIMI) score and troponin (TnI Ultra) were measured at ED presentation, 2 h later and according to current national recommendations. The primary outcome of interest was the occurrence of major adverse cardiac events (MACE) including prevalent myocardial infarction (MI) at 30 days in the group who had a TIMI score of 0 and had presentation and 2-h TnI assays <99th percentile. Results: Eight hundred and forty patients were studied of whom 177 (21%) had a TIMI score of 0. There were no MI, MACE or revascularization in the per protocol and intention-to-treat 2-h troponin groups (0%, 95% confidence interval (CI) 0% to 4.5% and 0%, 95% CI 0% to 3.8%, respectively). The negative predictive value (NPV) was 100% (95% CI 95.5% to 100%) and 100% (95% CI 96.2% to 100%), respectively. Conclusions: A 2-h accelerated rule-out process for ED chest pain patients using electrocardiography, a TIMI score of 0 and a contemporary sensitive troponin assay accurately identifies a group at very low risk of 30-day MI or MACE.

A preliminary investigation into adrenal responsiveness and outcomes in patients with cardiogenic shock after acute myocardial infarction

PURPOSE: This study investigated the significance of baseline cortisol levels and adrenal response to corticotropin in shocked patients after acute myocardial infarction (AMI). METHODS: A short corticotropin stimulation test was performed in 35 patients with cardiogenic shock after AMI by intravenously injecting of 250 μg of tetracosactrin (Synacthen). Blood samples were obtained at baseline (T0) before and at 30 (T30) and 60 (T60) minutes after the test to determine plasma total cortisol (TC) and free cortisol concentrations. The main outcome measure was in-hospital mortality and its association with T0 TC and maximum response to corticotropin (maximum difference [Δ max] in cortisol levels between T0 and the highest value between T30 and T60). RESULTS: The in-hospital mortality was 37%, and the median time to death was 4 days (interquartile range, 3-9 days). There was some evidence of an increased mortality in patients with T0 TC concentrations greater than 34 μg/dL (P=.07). Maximum difference by itself was not an independent predictor of death. Patients with a T0 TC 34 μg/dL or less and Δ max greater than 9 μg/dL appeared to have the most favorable survival (91%) when compared with the other 2 groups: T0 34 μg/dL or less and Δ max 9 μg/dL or less or T0 34 μg/dL or higher and Δ max greater than 9 μg/dL (75%; P=.8) and T0 greater than 34 μg/dL and Δ max 9 μg/dL or less (60%; P=.02). Corticosteroid therapy was associated with an increased mortality (P=.03). There was a strong correlation between plasma TC and free cortisol (r=0.85). CONCLUSIONS: A high baseline plasma TC was associated with a trend toward increased mortality in patients with cardiogenic shock post-AMI. Patients with lower baseline TC, but with an inducible adrenal response, appeared to have a survival benefit. A prognostic system based on basal TC and Δ max similar to that described in septic shock appears feasible in this cohort. Corticosteroid therapy was associated with adverse outcomes. These findings require further validation in larger studies.

Limited utility of exercise stress testing in the evaluation of suspected acute coronary syndrome in patients aged less than 40 years with intermediate risk features

Objective National guidelines for management of intermediate risk patients with suspected acute coronary syndrome, in whom AMI has been excluded, advocate provocative testing to final risk stratify these patients into low risk (negative testing) or high risk (positive testing suggestive of unstable angina). Adults less than 40 years have a low pretest probability of acute coronary syndrome. The utility of exercise stress testing in young adults with chest pain suspected of acute coronary syndrome who have National Heart Foundation intermediate risk features was evaluated Methods A retrospective analysis of exercise stress testing performed on patients less than 40 years was evaluated. Patients were enrolled on a chest pain pathway and had negative serial ECGs and cardiac biomarkers before exercise stress testing to rule-out acute coronary syndrome. Chart review was completed on patients with positive stress tests. Results The 3987 patients with suspected intermediate risk acute coronary syndrome underwent exercise stress testing. One thousand and twenty-seven (25.8%) were aged less than 40 years (age 33.3 ± 4.8 years). Four of these 1027 patients had a positive exercise stress test (0.4% incidence of positive exercise stress testing). Of those, three patients had subsequent non-invasive functional testing that yielded a negative result. One patient declined further investigations. Assuming this was a true positive exercise stress test, the incidence of true positive exercise stress testing would have been 0.097% (95% confidence interval: 0.079–0.115%) (one of 1027 patients). Conclusions Routine exercise stress testing has limited value in the risk stratification of adults less than 40 years with suspected intermediate risk of acute coronary syndrome

An investigation into the effectiveness of sensory modulation in reducing seclusion within an acute mental health unit

In this paper we report the findings from an evaluation of the introduction of sensory modulation (SM) in an acute mental health inpatient unit. It was expected that SM could be used to help settle patients experiencing high levels of disturbance and that as a result, there would be less need for use of more restrictive seclusion practices. The evaluation took place in a hospital in south-east Queensland, Australia. SM was introduced in one acute unit while the other served as a control. The evaluation comprised two studies. In the first study we aimed to determine whether SM reduced the level of disturbance among patients given the opportunity to use it. In the second study we aimed to find out whether the introduction of SM reduced the frequency and duration of seclusion. In study 1, we found that most patients reported marked reduction in disturbance after using SM and there was a very large effect size for the group as a whole. In study 2, we found that frequency of seclusion dropped dramatically in the unit that introduced SM but rose slightly in the unit that did not have access to SM. The change in seclusion rate was highly significant (χ2 = 49.1, df = 1, p < 0.001). Results are discussed, having reference to the limitations inherent in a naturalistic study.

Efficacy and feasibility of a tele-health intervention for acute coronary syndrome patients with depression: Results of the 'MoodCare' randomized controlled trial

Background Depression is common after a cardiac event, yet there remain few approaches to management that are both effective and scalable. Purpose We aimed to evaluate the 6-month efficacy and feasibility of a tele-health program (MoodCare) that integrates depression management into a cardiovascular disease risk reduction program for acute coronary syndrome patients with low mood. Methods A two-arm, parallel, randomized design was used comprising 121 patients admitted to one of six hospitals for acute coronary syndrome. Results Significant treatment effects were observed for Patient Health Questionnaire 9 (PHQ9) depression (mean difference [change] = −1.8; p = 0.025; effect size: d = 0.36) for the overall sample, when compared with usual medical care. Results were more pronounced effects for those with a history of depression (mean difference [change] = −2.7; p = 0.043; effect size: d = 0.65). Conclusions MoodCare was effective for improving depression in acute coronary syndrome patients, producing effect sizes exceeding those of some face-to-face psychotherapeutic interventions and pharmacotherapy. (Trial Registration Number: ACTRN1260900038623.)

Spatiotemporal transmission dynamics of hemorrhagic fever with renal syndrome in China, 2005-2012

Background Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by many serotypes of hantaviruses. In China, HFRS has been recognized as a severe public health problem with 90% of the total reported cases in the world. This study describes the spatiotemporal dynamics of HFRS cases in China and identifies the regions, time, and populations at highest risk, which could help the planning and implementation of key preventative measures. Methods Data on all reported HFRS cases at the county level from January 2005 to December 2012 were collected from Chinese Center for Disease Control and Prevention. Geographic Information System-based spatiotemporal analyses including Local Indicators of Spatial Association and Kulldorff's space-time scan statistic were performed to detect local high-risk space-time clusters of HFRS in China. In addition, cases from high-risk and low-risk counties were compared to identify significant demographic differences. Results A total of 100,868 cases were reported during 2005–2012 in mainland China. There were significant variations in the spatiotemporal dynamics of HFRS. HFRS cases occurred most frequently in June, November, and December. There was a significant positive spatial autocorrelation of HFRS incidence during the study periods, with Moran's I values ranging from 0.46 to 0.56 (P<0.05). Several distinct HFRS cluster areas were identified, mainly concentrated in northeastern, central, and eastern of China. Compared with cases from low-risk areas, a higher proportion of cases were younger, non-farmer, and floating residents in high-risk counties. Conclusions This study identified significant space-time clusters of HFRS in China during 2005–2012 indicating that preventative strategies for HFRS should be particularly focused on the northeastern, central, and eastern of China to achieve the most cost-effective outcomes.

Proteogenomics of selective susceptibility to endotoxin using circulating acute phase biomarkers and bioassay development in sheep: a review

Scientists have injected endotoxin into animals to investigate and understand various pathologies and novel therapies for several decades. Recent observations have shown that there is selective susceptibility to Escherichia coli lipopolysaccharide (LPS) endotoxin in sheep, despite having similar breed characteristics. The reason behind this difference is unknown, and has prompted studies aiming to explain the variation by proteogenomic characterisation of circulating acute phase biomarkers. It is hypothesised that genetic trait, biochemical, immunological and inflammation marker patterns contribute in defining and predicting mammalian response to LPS. This review discusses the effects of endotoxin and host responses, genetic basis of innate defences, activation of the acute phase response (APR) following experimental LPS challenge, and the current approaches employed in detecting novel biomarkers including acute phase proteins (APP) and micro-ribonucleic acids (miRNAs) in serum or plasma. miRNAs are novel targets for elucidating molecular mechanisms of disease because of their differential expression during pathological, and in healthy states. Changes in miRNA profiles during a disease challenge may be reflected in plasma. Studies show that gel-based two-dimensional electrophoresis (2-DE) coupled with either matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) or liquid chromatography-mass spectrometry (LC-MS/MS) are currently the most used methods for proteome characterisation. Further evidence suggests that proteomic investigations are preferentially shifting from 2-DE to non-gel based LC-MS/MS coupled with data extraction by sequential window acquisition of all theoretical fragment-ion spectra (SWATH) approaches that are able to identify a wider range of proteins. Enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and most recently proteomic methods have been used to quantify low abundance proteins such as cytokines. qRT-PCR and next generation sequencing (NGS) are used for the characterisation of miRNA. Proteogenomic approaches for detecting APP and novel miRNA profiling are essential in understanding the selective resistance to endotoxin in sheep. The results of these methods could help in understanding similar pathology in humans. It might also be helpful in the development of physiological and diagnostic screening assays for determining experimental inclusion and endpoints, and in clinical trials in future

The positioning of palliative care in acute care: A multiperspective qualitative study in the context of metastatic melanoma

Objective: The positioning and meaning of palliative care within the healthcare system lacks clarity which adds a level of complexity to the process of transition to palliative care. This study explores the transition to the palliative care process in the acute care context of metastatic melanoma. Method: A theoretical framework drawing on interpretive and critical traditions informs this research. The pragmatism of symbolic interactionism and the critical theory of Habermas brought a broad orientation to the research. Integration of the theoretical framework and grounded-theory methods facilitated data generation and analysis of 29 interviews with patients, family carers, and healthcare professionals. Results: The key analytical findings depict a scope of palliative care that was uncertain for users of the system and for those working within the system. Becoming “palliative” is not a defined event; nor is there unanimity around referral to a palliative care service. As such, ambiguity and tension contribute to the difficulties involved in negotiating the transition to palliative care. Significance of Results: Our findings point to uncertainty around the scopes of practice in the transition to palliative care. The challenge in the transition process lies in achieving greater coherency of care within an increasingly specialized healthcare system. The findings may not only inform those within a metastatic melanoma context but may contribute more broadly to palliative practices within the acute care setting.

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

Background To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. Objective We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. Methods We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). Results At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10−9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10−8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10−7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10−6). Conclusion By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Background Up-to-date evidence about levels and trends in disease and injury incidence, prevalence, and years lived with disability (YLDs) is an essential input into global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013), we estimated these quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013. Methods Estimates were calculated for disease and injury incidence, prevalence, and YLDs using GBD 2010 methods with some important refi nements. Results for incidence of acute disorders and prevalence of chronic disorders are new additions to the analysis. Key improvements include expansion to the cause and sequelae list, updated systematic reviews, use of detailed injury codes, improvements to the Bayesian meta-regression method (DisMod-MR), and use of severity splits for various causes. An index of data representativeness, showing data availability, was calculated for each cause and impairment during three periods globally and at the country level for 2013. In total, 35 620 distinct sources of data were used and documented to calculated estimates for 301 diseases and injuries and 2337 sequelae. The comorbidity simulation provides estimates for the number of sequelae, concurrently, by individuals by country, year, age, and sex. Disability weights were updated with the addition of new population-based survey data from four countries. Findings Disease and injury were highly prevalent; only a small fraction of individuals had no sequelae. Comorbidity rose substantially with age and in absolute terms from 1990 to 2013. Incidence of acute sequelae were predominantly infectious diseases and short-term injuries, with over 2 billion cases of upper respiratory infections and diarrhoeal disease episodes in 2013, with the notable exception of tooth pain due to permanent caries with more than 200 million incident cases in 2013. Conversely, leading chronic sequelae were largely attributable to non-communicable diseases, with prevalence estimates for asymptomatic permanent caries and tension-type headache of 2∙4 billion and 1∙6 billion, respectively. The distribution of the number of sequelae in populations varied widely across regions, with an expected relation between age and disease prevalence. YLDs for both sexes increased from 537∙6 million in 1990 to 764∙8 million in 2013 due to population growth and ageing, whereas the age-standardised rate decreased little from 114∙87 per 1000 people to 110∙31 per 1000 people between 1990 and 2013. Leading causes of YLDs included low back pain and major depressive disorder among the top ten causes of YLDs in every country. YLD rates per person, by major cause groups, indicated the main drivers of increases were due to musculoskeletal, mental, and substance use disorders, neurological disorders, and chronic respiratory diseases; however HIV/AIDS was a notable driver of increasing YLDs in sub-Saharan Africa. Also, the proportion of disability-adjusted life years due to YLDs increased globally from 21·1% in 1990 to 31·2% in 2013. Interpretation Ageing of the world’s population is leading to a substantial increase in the numbers of individuals with sequelae of diseases and injuries. Rates of YLDs are declining much more slowly than mortality rates. The non-fatal dimensions of disease and injury will require more and more attention from health systems. The transition to nonfatal outcomes as the dominant source of burden of disease is occurring rapidly outside of sub-Saharan Africa. Our results can guide future health initiatives through examination of epidemiological trends and a better understanding of variation across countries.

Acute liver failure in children : a regional experience

Objective: To review the outcome of acute liver failure (ALF) and the effect of liver transplantation in children in Australia. Methodology: A retrospective review was conducted of all paediatric patients referred with acute liver failure between 1985 and 2000 to the Queensland Liver Transplant Service, a paediatric liver transplant centre based at the Royal Children's Hospital, Brisbane, that is one of three paediatric transplant centres in Australia. Results: Twenty-six patients were referred with ALF. Four patients did not require transplantation and recovered with medical therapy while two were excluded because of irreversible neurological changes and died. Of the 20 patients considered for transplant, three refused for social and/or religious reasons, with 17 patients listed for transplantation. One patient recovered spontaneously and one died before receiving a transplant. There were 15 transplants of which 40% (6/15) were < 2 years old. Sixty-seven per cent (10/15) survived > 1 month after transplantation. Forty per cent (6/15) survived more than 6 months after transplant. There were only four long term survivors after transplant for ALF (27%). Overall, 27% (6/22) of patients referred with ALF survived. Of the 16 patients that died, 44% (7/16) were from neurological causes. Most of these were from cerebral oedema but two patients transplanted for valproate hepatotoxicity died from neurological disease despite good graft function. Conclusions: Irreversible neurological disease remains a major cause of death in children with ALF. We recommend better patient selection and early referral and transfer to a transplant centre before onset of irreversible neurological disease to optimize outcome of children transplanted for ALF.

The nutritional management of acute diarrhea in young infants : effect of carbohydrate ingested

To compare the efficacy of a low-lactose hy-drolyzed milk formula, a lactose-free corn syrup-based milk formula, and a standard lactose-containing formula during refeeding after rehydration in infants with gastroenteritis, 135 patients older than 2 years were studied by randomized trial. Clearly demonstrated disadvantages in terms of early weight loss and longer duration of diarrhea were observed with the lactose-based formula compared with early weight gains on both the low-lactose formulae, and thus the lactose-containing formula was discontinued after 91 patients. The early weight loss with the lactose-containing formula was statistically significantly related to the degree of relative (rehydrated) underweight. The two low-lactose formulae were further compared in the remaining 44 patients. Early weight gain (48 h) was sig-nificantly greater with the lactose-hydrolyzed formula compared with the corn syrup-based formula, but no statistically significant differences were observed in duration of diarrhea, energy intake, treatment failures, or late weight gain. We conclude that the routine use of a low-lactose formula during refeeding after rehydration in infants with gastroenteritis may have some advantages in underweight infants and toddlers in whom it is important to prevent further weight loss. © 1994 Raven Press Ltd, New York.

Examining the profile and experiences of older sub-acute patients who present to public hospital emergency departments in South East Queensland: A mixed methods approach

There is a scarcity of research that informs Interface Health Service (IHS) development. This research applied a mixed methods approach to profile older emergency department patients and patterns of health service use and to explore their ED experiences in public hospital EDs in South-East Queensland. IHS was under-utilised by older people with complex co-morbidities. Lack of communication and need identification were factors that undermined the effectiveness of IHS in reaching this cohort which highlighted a need for change.