Rationale: Severe a 1 -antitrypsin deficiency (typically PiZZ homozygosity) is associated with a significantly increased risk of airflow obstruction and emphysema but the risk of chronic obstructive pulmonary disease (COPD) in PiMZ heterozygotes remains uncertain.Objectives: This was a family-based study to determine the risk of COPD in PiMZ individuals. (% predicted) (63.84 [38.45-84.35] vs. 72.8 [55.5-97.7]; P = 0.0013) compared with PiMM individuals. This effect was abrogated in never-smoking and accentuated in ever-smoking PiMZ individuals. PiMZ heterozygosity was associated with an adjusted odds ratio for COPD of 5.18 (95% confidence interval, 1.27-21.15; P = 0.02) and this was higher (odds ratio, 10.65; 95% confidence interval, 2.17-52.29; P = 0.004) in eversmoking individuals.Conclusions: These results indicate that PiMZ heterozygotes have significantly more airflow obstruction and COPD than PiMM individuals and cigarette smoke exposure exerts a significant modifier effect.
Introduction: Human Immunodeficiency Virus (HIV) has an estimated prevalence of 0.9% in India (5.2 million). Anti-retroviral drugs (ARV) are the treatments of choice and non-adherence is an important factor in treatment failure and development of resistance, as well as being a powerful predictor of survival. This study assesses adherence to ARV in HIV positive patients in Bangalore, India, a country where only 10% of those who need therapy are receiving it.
The hereditary disorder α-1 antitrypsin (AAT) deficiency results from mutations in the SERPINA1 gene and presents with emphysema in young adults and liver disease in childhood. The most common form of AAT deficiency occurs because of the Z mutation, causing the protein to fold aberrantly and accumulate in the endoplasmic reticulum (ER). This leads to ER stress and contributes significantly to the liver disease associated with the condition. In addition to hepatocytes, AAT is also synthesized by monocytes, neutrophils, and epithelial cells. In this study we show for the first time that the unfolded protein response (UPR) is activated in quiescent monocytes from ZZ individuals. Activating transcription factor 4, X-box binding protein 1, and a subset of genes involved in the UPR are increased in monocytes from ZZ compared with MM individuals. This contributes to an inflammatory phenotype with ZZ monocytes exhibiting enhanced cytokine production and activation of the NF-κB pathway when compared with MM monocytes. In addition, we demonstrate intracellular accumulation of AAT within the ER of ZZ monocytes. These are the first data showing that Z AAT protein accumulation induces UPR activation in peripheral blood monocytes. These findings change the current paradigm regarding lung inflammation in AAT deficiency, which up until now was derived from the protease–anti-protease hypothesis, but which now must include the exaggerated inflammatory response generated by accumulated aberrantly folded AAT in circulating blood cells.
(1) Paclitaxel administered as a 1-hour infusion is well tolerated; (2) this schedule of administration does not result in cumulative myelosuppression; and (3) this schedule of administration results in dose-intensive paclitaxel delivery with a favorable toxicity profile.
BackgroundChronic obstructive pulmonary disease (COPD) affects > 3 million people in the UK. Acute exacerbations of COPD (AECOPD) are the second most common reason for emergency hospital admission in the UK. Pulmonary rehabilitation is usual care for stable COPD but there is little evidence for early pulmonary rehabilitation (EPR) following AECOPD, either in hospital or immediately post discharge.ObjectiveTo assess the feasibility of recruiting patients, collecting data and delivering EPR to patients with AECOPD to evaluate EPR compared with usual care.DesignParallel-group, pilot 2 × 2 factorial randomised trial with nested qualitative research and an economic analysis.SettingTwo acute hospital NHS trusts. Recruitment was carried out from September 2015 to April 2016 and follow-up was completed in July 2016.ParticipantsEligible patients were those aged ≥ 35 years who were admitted with AECOPD, who were non-acidotic and who maintained their blood oxygen saturation level (SpO2) within a prescribed range. Exclusions included the presence of comorbidities that affected the ability to undertake the interventions.Interventions(1) Hospital EPR: muscle training delivered at the patient’s hospital bed using a cycle ergometer and (2) home EPR: a pulmonary rehabilitation programme delivered in the patient’s home. Both interventions were delivered by trained physiotherapists. Participants were allocated on a 1 : 1 : 1 : 1 ratio to (1) hospital EPR (n = 14), (2) home EPR (n = 15), (3) hospital EPR and home EPR (n = 14) and (4) control (n = 15). Outcome assessors were blind to treatment allocation; it was not possible to blind patients.Main outcome measuresFeasibility of recruiting 76 participants in 7 months at two centres; intervention delivery; views on intervention/research acceptability; clinical outcomes including the 6-minute walk distance (6WMD); and costs. Semistructured interviews with participants (n = 27) and research health professionals (n = 11), optimisation assessments and an economic analysis were also undertaken.ResultsOver 7 months 449 patients were screened, of whom most were not eligible for the trial or felt too ill/declined entry. In total, 58 participants (76%) of the target 76 participants were recruited to the trial. The primary clinical outcome (6MWD) was difficult to collect (hospital EPR,n = 5; home EPR,n = 6; hospital EPR and home EPR,n = 5; control,n = 5). Hospital EPR was difficult to deliver over 5 days because of patient discharge/staff availability, with 34.1% of the scheduled sessions delivered compared with 78.3% of the home EPR sessions. Serious adverse events were experienced by 26 participants (45%), none of which was related to the interventions. Interviewed participants generally found both interventions to be acceptable. Home EPR had a higher rate of acceptability, mainly because patients felt too unwell when in hospital to undergo hospital EPR. Physiotherapists generally found the interventions to be acceptable and valued them but found delivery difficult because of staffing issues. The health economic analysis results suggest that there would be value in conducting a larger trial to assess the cost-effectiveness of the hospital EPR and hospital EPR plus home EPR trial arms and collect more information to inform the hospital cost and quality-adjusted life-year parameters, which were shown to be key drivers of the model.ConclusionsA full-scale randomised controlled trial using this protocol would not be feasible. Recruitment and delivery of the hospital EPR intervention was difficult. The data obtained can be used to design a full-scale trial of home EPR. Because of the small sample and large confidence intervals, this study should not be used to inform clinical practice.Trial registrationCurrent Controlled Trials ISRCTN18634494.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 22, No. 11. See the NIHR Journals Library website for further project information.
BackgroundAlpha-1 antitrypsin deficiency (AATD) results from mutations in the SERPINA1 gene and classically presents with early-onset emphysema and liver disease. The most common mutation presenting with clinical evidence is the Z mutation, while the S mutation is associated with a milder plasma deficiency. AATD is an under-diagnosed condition and the World Health Organisation recommends targeted detection programmes for AATD in patients with chronic obstructive pulmonary disease (COPD), non-responsive asthma, cryptogenic liver disease and first degree relatives of known AATD patients.MethodsWe present data from the first 3,000 individuals screened following ATS/ERS guidelines as part of the Irish National Targeted Detection Programme (INTDP). We also investigated a DNA collection of 1,100 individuals randomly sampled from the general population. Serum and DNA was collected from both groups and mutations in the SERPINA1 gene detected by phenotyping or genotyping.ResultsThe Irish National Targeted Detection Programme identified 42 ZZ, 44 SZ, 14 SS, 430 MZ, 263 MS, 20 IX and 2 rare mutations. Analysis of 1,100 randomly selected individuals identified 113 MS, 46 MZ, 2 SS and 2 SZ genotypes.ConclusionOur findings demonstrate that AATD in Ireland is more prevalent than previously estimated with Z and S allele frequencies among the highest in the world. Furthermore, our targeted detection programme enriched the population of those carrying the Z but not the S allele, suggesting the Z allele is more important in the pathogenesis of those conditions targeted by the detection programme.
Distinguishing between gay venues may provide important information to better understand patterns of environmental influence and HIV/STI behavioral risk among MSM. Massachusetts MSM accessing State Health Department mobile van services (n = 214) at Gay Pride events, bars/clubs, and private safer sex parties completed a one-time, cross-sectional survey via ACASI. In the past 12 months, private safer sex party attendees reported a higher mean number of anonymous partners, were more likely to report meeting sex partners via the Internet, and were more likely to report sex while drunk; in logistic regression analyses, they were less likely to report both unprotected insertive and receptive anal sex in the past year relative to men from other venues. Private safer sex parties may represent a strategy used by some MSM to reduce HIV/STI risk. Differentiating risk behavior by venue type provides valuable information with which to effectively target interventions to reach MSM at greatest risk.
HbA(1c) trimester-specific reference intervals are required to better inform the management of pregnancies complicated by diabetes.
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