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New treatment opportunities are emerging in the field of lipid-lowering therapy through gene-silencing approaches. Both antisense oligonucleotide inhibition and small interfering RNA technology aim to degrade gene mRNA transcripts to reduce protein production and plasma lipoprotein levels. Elevated levels of LDL, remnant lipoproteins, and lipoprotein(a) all cause cardiovascular disease, whereas elevated levels of triglyceride-rich lipoproteins in some patients can cause acute pancreatitis. The levels of each of these lipoproteins can be reduced using gene-silencing therapies by targeting proteins that have an important role in lipoprotein production or removal (for example, the protein products of ANGPTL3, APOB, APOC3, LPA, and PCSK9). Using this technology, plasma levels of these lipoproteins can be reduced by 50-90% with 2-12 injections per year; such dramatic reductions are likely to reduce the incidence of cardiovascular disease or acute pancreatitis in at-risk patients. The reported adverse effects of these new therapies include injection-site reactions, flu-like symptoms, and low blood platelet counts. However, newer-generation drugs are more efficiently delivered to liver cells, requiring lower drug doses, which leads to fewer adverse effects. Although these findings are promising, robust evidence of cardiovascular disease reduction and long-term safety is needed before these gene-silencing technologies can have widespread implementation. Before the availability of such evidence, these drugs might have roles in patients with unmet medical needs through orphan indications. [ABSTRACT FROM AUTHOR]

Objective: We tested the hypothesis that use of and adherence to maintenance medication is low among individuals in the general population who have chronic obstructive pulmonary disease (COPD) , even in cases of severe and very severe COPD.Design and Participants: We identified 5,812 individuals with COPD from the Copenhagen General Population Study, and classified them according to the Global Initiative for Obstructive Lung Disease (GOLD) airflow limitation grades 1-4. Dispensing of fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists, long-acting anti-cholinergics, or long-acting beta2-agonists was identified in a nationwide registry. Use of medication was defined as medication dispensed during a one-year period , and adherence was calculated from dosages available in one year.Key Results: Use of fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists varied from 2 % to 61 % (p < 0.001, test for trend), long-acting anti-cholinergics varied from 0.4 % to 36 % (p < 0.001), and long-acting beta2-agonists varied from 0.3 % to 11 % (p < 0.001. Among utilizers of these medications, adherence varied from 29 % to 56 % (p < 0.001, test for trend) across GOLD 1-4 for fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists, from 51 % to 68 % (p = 0.11) for long-acting anti-cholinergics, and from 25 to 62 % (p = 0.01) for long-acting beta2-agonists.Conclusions: Use of and adherence to maintenance medication for COPD in the general population was associated with the severity of COPD as defined by GOLD, but even in severe and very severe COPD, use and adherence was low. [ABSTRACT FROM AUTHOR]

Purpose: Occupational inhalant exposures have been linked with a higher occurrence of chronic productive cough, but recent studies question the association. Methods: We included participants from two general population studies, the Copenhagen City General Population Study and the Copenhagen City Heart Study, to assess contemporary (year 2003–2017) and historical (1976–1983) occupational inhalant hazards. Job titles one year prior to study inclusion and an airborne chemical job-exposure matrix (ACE JEM) were used to estimate occupational exposure. The association between occupational exposures and self-reported chronic productive cough was studied using generalized estimating equations stratified by smoking status and cohort. Results: The population consisted of 5210 working individuals aged 20–65 from 1976 to 1983 and 64,279 from 2003 to 2017. In smokers, exposure to high levels of mineral dust, biological dust, gases & fumes and the composite variable vapours, gases, dusts or fumes (VGDF) were associated with chronic productive cough in both cohorts with odds ratios in the range of 1.2 (95% confidence interval, 1.0;1.4) to 1.6 (1.2;2.1). High levels of biological dust were only associated with an increased risk of a chronic productive cough in the 2003–2017 cohort (OR 1.5 (1.1;2.0)). In non-smokers, high levels of VGDF (OR 1.5 (1.0;2.3)) and low levels of mineral dust (OR 1.7 (1.1;2.4)) were associated with chronic productive cough in the 1976–1983 cohort, while no associations were seen in non-smokers in the 2003–2017 cohort. Conclusion: Occupational inhalant exposure remains associated with a modestly increased risk of a chronic productive cough in smokers, despite declining exposure levels during the past four decades. [ABSTRACT FROM AUTHOR]

Altered coagulation has been reported in people living with HIV (PLWH) with ongoing viral replication and may predispose to cardiovascular diseases. However, less is known about coagulation in PLWH with undetectable viral replication. In a cross-sectional observational study, we investigated whether HIV infection with undetectable viral replication is independently associated with activated partial thromboplastin time (APTT) and coagulation factor II–VII–X concentrations out of reference. Logistic regression analyses were used to assess the association of HIV infection with APTT and coagulation factor II–VII–X, after adjusting for age, sex, smoking status, alcohol consumption, BMI, diabetes and hsCRP. 936 PLWH with undetectable viral replication from the Copenhagen Co-morbidity in HIV infection study (COCOMO-study) and 2955 uninfected controls were included. Higher prevalence of short APTT was found in PLWH compared to controls (13.5% vs. 7.6%, P < 0.001). Furthermore, higher prevalence of low coagulation factor II–VII–X was found in PLWH than in controls (9.6% vs. 7.4%, P = 0.022). HIV was independently associated with short APTT (adjusted odds ratio (aOR) 2.3 (95% CI 1.7–2.9), P < 0.001) and low coagulation factor II–VII–X (aOR 1.4 (95% CI 1.0–1.9), P = 0.046). Few participants among PLWH and controls had both short APTT and low coagulation factor II–VII–X, 2.1% vs. 0.8%, respectively. We found evidence of both procoagulant (short APTT) and anticoagulant (low coagulation factor II–VII–X) alterations in PLWH with undetectable viral replication, and our findings suggest that two different coagulation phenotypes exist in participants with treated HIV infection. [ABSTRACT FROM AUTHOR]

Background: Coronary artery calcification (CAC) is commonly assessed with Agatston score (AS). A higher sensitivity and precision for the detection of CAC has been demonstrated with calibrated mass score (cMS). We hypothesized that cMS would detect low-level CAC not detectable with AS in a large asymptomatic background population.Methods: Participants (N = 2985) from the Copenhagen General Population Study were evaluated for CAC using both conventional AS and cMS. The population was grouped according to number of traditional risk factors and heart score was used to assess the risk of event for those with no CAC, those with only cMS > 0 and those with both AS and cMS > 0.Results: In participants with an AS = 0, 11% had cMS > 0. The risk profile of this cMS-only group was between that of the CAC-negative participants and those with AS > 0 and cMS > 0. Overall, 6% of the population belonged to the cMS-only group independent of the number of risk factors.Conclusion: In individuals with AS = 0, a fraction was found to have cMS > 0. Based on traditional risk factors, this group has a higher 10-year risk than individuals with both AS = 0 and cMS = 0; cMS might offer very early cardiovascular risk assessment in asymptomatic individuals.Key Points: • In individuals with AS=0, a fraction has CAC with highly sensitive cMS. • This fraction has a higher 10-year risk of cardiovascular disease. • Regardless of risk factors, 6% has CAC detectable only with cMS. • cMS might offer very early cardiovascular risk assessment in asymptomatic individuals. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer is a common cancer worldwide with no established modifiable lifestyle factors to guide prevention. The associations between polyunsaturated fatty acids (PUFAs) and prostate cancer risk have been inconsistent. Using Mendelian randomisation, we evaluated associations between PUFAs and prostate cancer risk.Methods: We used individual-level data from a consortium of 22 721 cases and 23 034 controls of European ancestry. Externally-weighted PUFA-specific polygenic risk scores (wPRSs), with explanatory variation ranging from 0.65 to 33.07%, were constructed and used to evaluate associations with prostate cancer risk per one standard deviation (s.d.) increase in genetically-predicted plasma PUFA levels using multivariable-adjusted unconditional logistic regression.Results: No overall association was observed between the genetically-predicted PUFAs evaluated in this study and prostate cancer risk. However, risk reductions were observed for short-chain PUFAs, linoleic (ORLA=0.95, 95%CI=0.92, 0.98) and α-linolenic acids (ORALA=0.96, 95%CI=0.93, 0.98), among men <62 years; whereas increased risk was found among men ⩾62 years for LA (ORLA=1.04, 95%CI=1.01, 1.07). For long-chain PUFAs (i.e., arachidonic, eicosapentaenoic, and docosapentaenoic acids), increased risks were observed among men <62 years (ORAA=1.05, 95%CI=1.02, 1.08; OREPA=1.04, 95%CI=1.01, 1.06; ORDPA=1.05, 95%CI=1.02, 1.08).Conclusion: Results from this study suggest that circulating ω-3 and ω-6 PUFAs may have a different role in the aetiology of early- and late-onset prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.Methods: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes.Results: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant.Conclusions: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers. [ABSTRACT FROM AUTHOR]

This corrects the article DOI: 10.1038/bjc.2016.50. [ABSTRACT FROM AUTHOR]