Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

PET imaging of the autonomic myocardial function: methods and interpretation.

Cardiac positron emission tomography (PET) is mainly applied in myocardial perfusion and viability detection. Noninvasive imaging of myocardial innervation using PET is a valuable additional methodology in cardiac imaging. Novel methods and different PET ligands have been developed to measure presynaptic and postsynaptic function of the cardiac neuronal system. Obtained PET data can be analysed quantitatively or interpreted qualitatively. Thus far, PET is not a widely used clinical application in autonomic heart imaging; however, due to its technical advantages, the excellent properties of the imaging agents, and the availability of tools for quantification, it deserves a better position in the clinic. From a historical point of view, the focus of PET software packages for image analysis was mainly oncology and neurology driven. Actually, commercially available software for cardiac PET image analysis is still only available for the quantification of myocardial blood flow. Thus far, no commercial software package is available for the interpretation and quantification of PET innervation scans. However, image data quantification and analysis of kinetic data can be performed using adjusted generic tools. This paper gives an overview of different neuronal PET ligands, interpretation and quantification of acquired PET data

Demographic and behavioral characteristics of non-sex worker females attending sexually transmitted disease clinics in Japan: a nationwide case-control study

<p>Abstract</p> <p>Background</p> <p>Although number of sexually transmitted infections (STIs) reported in STI surveillance increased rapidly for women in Japan during the 1990s, the sexual behavior of women potentially at risk of STI infection remains unknown.</p> <p>Methods</p> <p>In order to determine the demographic and behavioral characteristics of non-sex worker (SW) females attending STI clinics, female attendees (n = 145), excluding SW, from nine clinics across Japan and female controls from the general population (n = 956), both aged 18-50 years, were compared using two data sets of nationwide sexual behavior surveys conducted in 1999.</p> <p>Results</p> <p>Although the occupation-type and education level were unrelated to STI clinic attendance in multivariate analysis, non-SW females attending STI clinics were younger (adjusted odds ratios [AOR] = 0.94, 95%CI: 0.89, 0.99), and more likely to be unmarried (AOR = 4.11, 95% CI: 1.73, 9.77) than the controls from the general population. In the previous year, STI clinic attendees were more likely to have had multiple partnerships (AOR = 3.09, 95% CI: 1.42, 6.71) and unprotected vaginal sex with regular partners (AOR = 3.59, 95% CI: 1.49, 8.64), and tended to have had their first sexual intercourse at a younger age (AOR = 1.77, 95%CI: 0.89, 3.54) and more unprotected vaginal and/or oral sex with casual partners (AOR = 2.08, 95%CI: 0.75, 5.71). Identical sexual behavior patterns were observed between the female attendees with a current diagnosis of STI (n = 72) and those before diagnosis (n = 73) and between those with a past history of STI (n = 66) and those without (n = 79).</p> <p>Conclusion</p> <p>These results indicate that not only multiple partnerships or unprotected sex with casual partners, but also unprotected vaginal sex within a regular partnership is prevalent among non-SW female STI clinic attendees. The identical sexual behavior patterns observed between female attendees with a current STI diagnosis and those without, and between those attendees with a past history of STI diagnosis and those without, indicate that the result are unlikely confounded with the cases of non-STI infection. This sexual behavior pattern may be predictive of STI infection among young Japanese women and could have contributed to the STI epidemic in women in Japan during the 1990s.</p

Complications related to deep venous thrombosis prophylaxis in trauma: a systematic review of the literature

Deep venous thrombosis prophylaxis is essential to the appropriate management of multisystem trauma patients. Without thromboprophylaxis, the rate of venous thrombosis and subsequent pulmonary embolism is substantial. Three prophylactic modalities are common: pharmacologic anticoagulation, mechanical compression devices, and inferior vena cava filtration. A systematic review was completed using PRISMA guidelines to evaluate the potential complications of DVT prophylactic options. Level one evidence currently supports the use of low molecular weight heparins for thromboprophylaxis in the trauma patient. Unfortunately, multiple techniques are not infrequently required for complex multisystem trauma patients. Each modality has potential complications. The risks of heparin include bleeding and heparin induced thrombocytopenia. Mechanical compression devices can result in local soft tissue injury, bleeding and patient non-compliance. Inferior vena cava filters migrate, cause inferior vena cava occlusion, and penetrate the vessel wall. While the use of these techniques can be life saving, they must be appropriately utilized

A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer

The purpose of this trial was to investigate the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in stage II colon cancer. Patients with stage II colon cancer were randomised to either adjuvant chemotherapy with 5-FU/LV (100 mg m−2 LV+450 mg m−2 5-FU weekly, weeks 1–6, in 8 weeks cycles × 7) or surveillance only. Five hundred patients were evaluable for analyses. After a median follow-up of 95.6 months, 55 of 252 patients (21.8%) have died in the 5-FU/LV arm and 58 of 248 patients (23.4%) in the surveillance arm. There was no statistically significant difference in overall survival (OS) between the two treatment arms (hazard ratios, HR 0.88, 95% CI 0.61–1.27, P=0.49). The relative risk for tumour relapse was higher for patients on the surveillance arm than for those on the 5-FU/LV arm; however, this difference was not statistically significant (HR 0.69, 95% CI 0.45–1.06, P=0.09). Consequently, disease-free survival (DFS) was not significantly different between the two trial arms. In conclusion, results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, in this study with limited power to detect small differences between the study arms, adjuvant chemotherapy failed to significantly improve DFS and OS

Neighborhood socioeconomic status, Medicaid coverage and medical management of myocardial infarction: Atherosclerosis risk in communities (ARIC) community surveillance

<p>Abstract</p> <p>Background</p> <p>Pharmacologic treatments are efficacious in reducing post-myocardial infarction (MI) morbidity and mortality. The potential influence of socioeconomic factors on the receipt of pharmacologic therapy has not been systematically examined, even though healthcare utilization likely influences morbidity and mortality post-MI. This study aims to investigate the association between socioeconomic factors and receipt of evidence-based treatments post-MI in a community surveillance setting.</p> <p>Methods</p> <p>We evaluated the association of census tract-level neighborhood household income (nINC) and Medicaid coverage with pharmacologic treatments (aspirin, beta [β]-blockers and angiotensin converting enzyme [ACE] inhibitors; optimal therapy, defined as receipt of two or more treatments) received during hospitalization or at discharge among 9,608 MI events in the ARIC community surveillance study (1993-2002). Prevalence ratios (PR, 95% CI), adjusted for the clustering of hospitalized MI events within census tracts and within patients, were estimated using Poisson regression.</p> <p>Results</p> <p>Seventy-eight percent of patients received optimal therapy. Low nINC was associated with a lower likelihood of receiving β-blockers (0.93, 0.87-0.98) and a higher likelihood of receiving ACE inhibitors (1.13, 1.04-1.22), compared to high nINC. Patients with Medicaid coverage were less likely to receive aspirin (0.92, 0.87-0.98), compared to patients without Medicaid coverage. These findings were independent of other key covariates.</p> <p>Conclusions</p> <p>nINC and Medicaid coverage may be two of several socioeconomic factors influencing the complexities of medical care practice patterns.</p

High-sensitivity cardiac troponin and the diagnosis of myocardial infarction in patients with renal impairment.

The benefit and utility of high-sensitivity cardiac troponin (hs-cTn) in the diagnosis of myocardial infarction in patients with kidney impairment is unclear. Here, we describe implementation of hs-cTnI testing on the diagnosis, management, and outcomes of myocardial infarction in patients with and without kidney impairment. Consecutive patients with suspected acute coronary syndrome enrolled in a stepped-wedge, cluster-randomized controlled trial were included in this pre-specified secondary analysis. Kidney impairment was defined as an eGFR under 60mL/min/1.73m2. The index diagnosis and primary outcome of type 1 and type 4b myocardial infarction or cardiovascular death at one year were compared in patients with and without kidney impairment following implementation of hs-cTnI assay with 99th centile sex-specific diagnostic thresholds. Serum creatinine concentrations were available in 46,927 patients (mean age 61 years; 47% women), of whom 9,080 (19%) had kidney impairment. hs-cTnIs were over 99th centile in 46% and 16% of patients with and without kidney impairment. Implementation increased the diagnosis of type 1 infarction from 12.4% to 17.8%, and from 7.5% to 9.4% in patients with and without kidney impairment (both significant). Patients with kidney impairment and type 1 myocardial infarction were less likely to undergo coronary revascularization (26% versus 53%) or receive dual anti-platelets (40% versus 68%) than those without kidney impairment, and this did not change post-implementation. In patients with hs-cTnI above the 99th centile, the primary outcome occurred twice as often in those with kidney impairment compared to those without (24% versus 12%, hazard ratio 1.53, 95% confidence interval 1.31 to 1.78). Thus, hs-cTnI testing increased the identification of myocardial injury and infarction but failed to address disparities in management and outcomes between those with and without kidney impairment

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Angiotensin II for the Treatment of Vasodilatory Shock

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