Inhaloterapia: recomendaciones para Argentina 2021 / Inhalotherapy: recommendations for Argentina 2021

Resumen En las últimas décadas ha habido un importante desarrollo de dispositivos inhalados (DI) que permiten aumentar la eficacia de las drogas y disminuir los eventos adversos. Su correcto uso es de fundamental importancia para el control de las enfermedades respiratorias obstructivas. En la Argentina no existen recomendaciones locales sobre el uso de los DI. Se revisó la base biofísica, indicación, ventajas y limitaciones, técnica de correcto uso, errores frecuentes, mantenimiento y limpieza de cada DI. El uso de nebulizaciones ha quedado restringido a la administración de drogas que no están disponibles en otros DI (ejemplo: tratamiento de fibrosis quística), o ante la falla de los otros DI. No deben ser usados durante la pandemia de SARS-CoV2. Los inhaladores de dosis medida (aerosol) deben ser indicados siempre con aerocámaras (AC), las que reducen la incidencia de eventos adversos y aumentan el depósito de la droga en el pulmón. Son los dispositivos de elección junto a los inhaladores de polvo seco. Los aerosoles se deben usar en pacientes que no generan flujos inspiratorios altos. Los inhaladores de polvo seco deben recomendarse en aquellos que pueden realizar flujos inspiratorios enérgicos. Se revisaron los diferentes DI en fibrosis quística y en pacientes con asistencia respiratoria mecánica. La elección del DI dependerá de varios factores: situación clínica, edad, experiencia previa, preferencia del paciente, disponibilidad de la droga y entrenamiento alcanzado con el correcto uso.

Abstract Last decades, a broad spectrum of inhaled devices (ID) had been developed to enhance efficacy and reduce adverse events. The correct use of IDs is a critical issue for controlling obstructive respiratory diseases. There is no recommendation on inhalation therapy in Argentina. This document aims to issue local recommendations about the prescription of IDs. Each device was reviewed regarding biophysical laws, indication, strength, limitations, correct technique of use, frequent mistakes, and device cleaning and maintenance. Nebulization should be restricted to drugs that are not available in other IDs (for example, for treatment of cystic fibrosis) or where other devices fail. Nebulization is not recommended during the SARS-CoV2 pandemic. A metered-dose inhaler must always be used with an aerochamber. Aerochambers reduce the incidence of adverse events and improve lung deposition. Metered-dose inhalers must be prescribed to patients who cannot generate a high inspiratory flow and dry powders to those who can generate an energetic inspiratory flow. We reviewed the use of different IDs in patients with cystic fibrosis and under mechanical ventilation. The individual choice of an ID will be based on several variables like clinical status, age, previous experience, patient preference, drug availability, and correct use of the device.

[Inhalotherapy: Recommendations for Argentina 2021]. / Inhaloterapia: Recomendaciones para Argentina 2021.

Last decades, a broad spectrum of inhaled devices (ID) had been developed to enhance efficacy and reduce adverse events. The correct use of IDs is a critical issue for controlling obstructive respiratory diseases. There is no recommendation on inhalation therapy in Argentina. This document aims to issue local recommendations about the prescription of IDs. Each device was reviewed regarding biophysical laws, indication, strength, limitations, correct technique of use, frequent mistakes, and device cleaning and maintenance. Nebulization should be restricted to drugs that are not available in other IDs (for example, for treatment of cystic fibrosis) or where other devices fail. Nebulization is not recommended during the SARS-CoV2 pandemic. A metered-dose inhaler must always be used with an aerochamber. Aerochambers reduce the incidence of adverse events and improve lung deposition. Metered-dose inhalers must be prescribed to patients who cannot generate a high inspiratory flow and dry powders to those who can generate an energetic inspiratory flow. We reviewed the use of different IDs in patients with cystic fibrosis and under mechanical ventilation. The individual choice of an ID will be based on several variables like clinical status, age, previous experience, patient preference, drug availability, and correct use of the device.

En las últimas décadas ha habido un importante desarrollo de dispositivos inhalados (DI) que permiten aumentar la eficacia de las drogas y disminuir los eventos adversos. Su correcto uso es de fundamental importancia para el control de las enfermedades respiratorias obstructivas. En la Argentina no existen recomendaciones locales sobre el uso de los DI. Se revisó la base biofísica, indicación, ventajas y limitaciones, técnica de correcto uso, errores frecuentes, mantenimiento y limpieza de cada DI. El uso de nebulizaciones ha quedado restringido a la administración de drogas que no están disponibles en otros DI (ejemplo: tratamiento de fibrosis quística), o ante la falla de los otros DI. No deben ser usados durante la pandemia de SARS-CoV2. Los inhaladores de dosis medida (aerosol) deben ser indicados siempre con aerocámaras (AC), las que reducen la incidencia de eventos adversos y aumentan el depósito de la droga en el pulmón. Son los dispositivos de elección junto a los inhaladores de polvo seco. Los aerosoles se deben usar en pacientes que no generan flujos inspiratorios altos. Los inhaladores de polvo seco deben recomendarse en aquellos que pueden realizar flujos inspiratorios enérgicos. Se revisaron los diferentes DI en fibrosis quística y en pacientes con asistencia respiratoria mecánica. La elección del DI dependerá de varios factores: situación clínica, edad, experiencia previa, preferencia del paciente, disponibilidad de la droga y entrenamiento alcanzado con el correcto uso.

Efficacy and Safety of Text Messages Targeting Adherence to Cardiovascular Medications in Secondary Prevention: TXT2HEART Colombia Randomized Controlled Trial.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide, with a prevalence of approximately 100 million patients. There is evidence that antiplatelet agents and antihypertensive medications could reduce the risk of new vascular events in this population; however, treatment adherence is very low. An SMS text messaging intervention was recently developed based on behavior change techniques to increase adherence to pharmacological treatment among patients with a history of ASCVD. OBJECTIVE: This study aims to evaluate the efficacy and safety of an SMS text messaging intervention to improve adherence to cardiovascular medications in patients with ASCVD. METHODS: A randomized controlled clinical trial for patients with a prior diagnosis of cardiovascular events, such as acute myocardial infarction, unstable angina, cerebrovascular disease, or peripheral artery disease, in one center in Colombia was conducted. Patients randomized to the intervention arm were assigned to receive SMS text messages daily for the first 4 weeks, 5 SMS text messages on week 5, 3 SMS text messages each in weeks 6 and 7, and 1 SMS text message weekly from week 8 until week 52. In contrast, patients in the control arm received a monthly SMS text message reminding them of the next study appointment and the importance of the study, requesting information about changes in their phone number, and thanking them for participating in the study. The primary endpoint was the change in low-density lipoprotein cholesterol (LDL-C) levels, whereas the secondary endpoints were the changes in thromboxane B2 levels, heart rate, systolic and diastolic blood pressure, medication adherence, cardiac and noncardiac mortality, and hospitalization. Linear regression analyses and bivariate tests were performed. RESULTS: Of the 930 randomized patients, 805 (86.5%) completed follow-up and were analyzed for the primary endpoint. There was no evidence that the intervention changed the primary outcome (LDL-C levels; P=.41) or any of the secondary outcomes evaluated (all P>.05). There was also no evidence that the intervention was associated with adverse events. CONCLUSIONS: In this study, there was no evidence that a behavior modification intervention delivered by SMS text messaging improved LDL-C levels, blood pressure levels, or adherence at 12 months. More research is needed to evaluate whether different SMS text messaging strategies, including personalized messages and different timings, are effective; future studies should include mixed methods to better understand why, for whom, and in which context (eg, health system or social environment) SMS text messaging interventions work (or not) to improve adherence in patients with ASCVD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03098186; https://clinicaltrials.gov/ct2/show/NCT03098186. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2018-028017.

Granulomatosis eosinofílica con poliangeítis tratada con mepolizumab en dosis de 100 mg/mes / Eosinophilic Granulomatosis With Polyangiitis Treated With Mepolizumab at a Dose of 100 mg/month

No disponible

Circulating Fatty Acids and Risk of Coronary Heart Disease and Stroke: Individual Participant Data Meta-Analysis in Up to 16 126 Participants.

Background We aimed at investigating the association of circulating fatty acids with coronary heart disease (CHD) and stroke risk. Methods and Results We conducted an individual-participant data meta-analysis of 5 UK-based cohorts and 1 matched case-control study. Fatty acids (ie, omega-3 docosahexaenoic acid, omega-6 linoleic acid, monounsaturated and saturated fatty acids) were measured at baseline using an automated high-throughput serum nuclear magnetic resonance metabolomics platform. Data from 3022 incident CHD cases (13 104 controls) and 1606 incident stroke cases (13 369 controls) were included. Logistic regression was used to model the relation between fatty acids and odds of CHD and stroke, adjusting for demographic and lifestyle variables only (ie, minimally adjusted model) or with further adjustment for other fatty acids (ie, fully adjusted model). Although circulating docosahexaenoic acid, but not linoleic acid, was related to lower CHD risk in the fully adjusted model (odds ratio, 0.85; 95% CI, 0.76-0.95 per standard unit of docosahexaenoic acid), there was evidence of high between-study heterogeneity and effect modification by study design. Stroke risk was consistently lower with increasing circulating linoleic acid (odds ratio for fully adjusted model, 0.82; 95% CI, 0.75-0.90). Circulating monounsaturated fatty acids were associated with higher CHD risk across all models and with stroke risk in the fully adjusted model (odds ratio, 1.22; 95% CI, 1.03-1.44). Saturated fatty acids were not related to increased CHD risk in the fully adjusted model (odds ratio, 0.94; 95% CI, 0.82-1.09), or stroke risk. Conclusions We found consistent evidence that linoleic acid was associated with decreased risk of stroke and that monounsaturated fatty acids were associated with increased risk of CHD. The different pattern between CHD and stroke in terms of fatty acids risk profile suggests future studies should be cautious about using composite events. Different study designs are needed to assess which, if any, of the associations observed is causal.

Improving the odds of drug development success through human genomics: modelling study.

Lack of efficacy in the intended disease indication is the major cause of clinical phase drug development failure. Explanations could include the poor external validity of pre-clinical (cell, tissue, and animal) models of human disease and the high false discovery rate (FDR) in preclinical science. FDR is related to the proportion of true relationships available for discovery (γ), and the type 1 (false-positive) and type 2 (false negative) error rates of the experiments designed to uncover them. We estimated the FDR in preclinical science, its effect on drug development success rates, and improvements expected from use of human genomics rather than preclinical studies as the primary source of evidence for drug target identification. Calculations were based on a sample space defined by all human diseases - the 'disease-ome' - represented as columns; and all protein coding genes - 'the protein-coding genome'- represented as rows, producing a matrix of unique gene- (or protein-) disease pairings. We parameterised the space based on 10,000 diseases, 20,000 protein-coding genes, 100 causal genes per disease and 4000 genes encoding druggable targets, examining the effect of varying the parameters and a range of underlying assumptions, on the inferences drawn. We estimated γ, defined mathematical relationships between preclinical FDR and drug development success rates, and estimated improvements in success rates based on human genomics (rather than orthodox preclinical studies). Around one in every 200 protein-disease pairings was estimated to be causal (γ = 0.005) giving an FDR in preclinical research of 92.6%, which likely makes a major contribution to the reported drug development failure rate of 96%. Observed success rate was only slightly greater than expected for a random pick from the sample space. Values for γ back-calculated from reported preclinical and clinical drug development success rates were also close to the a priori estimates. Substituting genome wide (or druggable genome wide) association studies for preclinical studies as the major information source for drug target identification was estimated to reverse the probability of late stage failure because of the more stringent type 1 error rate employed and the ability to interrogate every potential druggable target in the same experiment. Genetic studies conducted at much larger scale, with greater resolution of disease end-points, e.g. by connecting genomics and electronic health record data within healthcare systems has the potential to produce radical improvement in drug development success rate.

Investigating associations between the built environment and physical activity among older people in 20 UK towns.

BACKGROUND: Policy initiatives such as WHO Age Friendly Cities recognise the importance of the urban environment for improving health of older people, who have both low physical activity (PA) levels and greater dependence on local neighbourhoods. Previous research in this age group is limited and rarely uses objective measures of either PA or the environment. METHODS: We investigated the association between objectively measured PA (Actigraph GT3x accelerometers) and multiple dimensions of the built environment, using a cross-sectional multilevel linear regression analysis. Exposures were captured by a novel foot-based audit tool that recorded fine-detail neighbourhood features relevant to PA in older adults, and routine data. RESULTS: 795 men and 638 women aged 69-92 years from two national cohorts, covering 20 British towns, were included in the analysis. Median time in moderate to vigorous PA (MVPA) was 27.9 (lower quartile: 13.8, upper quartile: 50.4) minutes per day. There was little evidence of associations between any of the physical environmental domains (eg, road and path quality defined by latent class analysis; number of bus stops; area aesthetics; density of shops and services; amount of green space) and MVPA. However, analysis of area-level income deprivation suggests that the social environment may be associated with PA in this age group. CONCLUSIONS: Although small effect sizes cannot be discounted, this study suggests that older individuals are less affected by their local physical environment and more by social environmental factors, reflecting both the functional heterogeneity of this age group and the varying nature of their activity spaces.

Metabolic Profiling of Adiponectin Levels in Adults: Mendelian Randomization Analysis.

BACKGROUND: Adiponectin, a circulating adipocyte-derived protein, has insulin-sensitizing, anti-inflammatory, antiatherogenic, and cardiomyocyte-protective properties in animal models. However, the systemic effects of adiponectin in humans are unknown. Our aims were to define the metabolic profile associated with higher blood adiponectin concentration and investigate whether variation in adiponectin concentration affects the systemic metabolic profile. METHODS AND RESULTS: We applied multivariable regression in ≤5909 adults and Mendelian randomization (using cis-acting genetic variants in the vicinity of the adiponectin gene as instrumental variables) for analyzing the causal effect of adiponectin in the metabolic profile of ≤37 545 adults. Participants were largely European from 6 longitudinal studies and 1 genome-wide association consortium. In the multivariable regression analyses, higher circulating adiponectin was associated with higher high-density lipoprotein lipids and lower very-low-density lipoprotein lipids, glucose levels, branched-chain amino acids, and inflammatory markers. However, these findings were not supported by Mendelian randomization analyses for most metabolites. Findings were consistent between sexes and after excluding high-risk groups (defined by age and occurrence of previous cardiovascular event) and 1 study with admixed population. CONCLUSIONS: Our findings indicate that blood adiponectin concentration is more likely to be an epiphenomenon in the context of metabolic disease than a key determinant.

Are cardiovascular risk factors also associated with the incidence of atrial fibrillation? A systematic review and field synopsis of 23 factors in 32 population-based cohorts of 20 million participants.

Established primary prevention strategies of cardiovascular diseases are based on understanding of risk factors, but whether the same risk factors are associated with atrial fibrillation (AF) remains unclear. We conducted a systematic review and field synopsis of the associations of 23 cardiovascular risk factors and incident AF, which included 84 reports based on 28 consented and four electronic health record cohorts of 20,420,175 participants and 576,602 AF events. We identified 3-19 reports per risk factor and heterogeneity in AF definition, quality of reporting, and adjustment. We extracted relative risks (RR) and 95 % confidence intervals [CI] and visualised the number of reports with inverse (RR [CI]<1.00), or direct (RR [CI]>1.00) associations. For hypertension (13/17 reports) and obesity (19/19 reports), there were direct associations with incident AF, as there are for coronary heart disease (CHD). There were inverse associations for non-White ethnicity (5/5 reports, with RR from 0.35 to 0.84 [0.82-0.85]), total cholesterol (4/13 reports from 0.76 [0.59-0.98] to 0.94 [0.90-0.97]; 8/13 reports with non-significant inverse associations), and diastolic blood pressure (2/11 reports from 0.87 [0.78-0.96] to 0.92 [0.85-0.99]; 5/11 reports with non-significant inverse associations), and direct associations for taller height (7/10 reports from 1.03 [1.02-1.05] to 1.92 [1.38-2.67]), which are in the opposite direction of known associations with CHD. A systematic evaluation of the available evidence suggests similarities as well as important differences in the risk factors for incidence of AF as compared with other cardiovascular diseases, which has implications for the primary prevention strategies for atrial fibrillation.

Net clinical benefit of warfarin in individuals with atrial fibrillation across stroke risk and across primary and secondary care.

OBJECTIVE: To investigate net clinical benefit (NCB) of warfarin in individuals with atrial fibrillation (AF) across stroke risk and across primary and secondary care. METHODS: We conducted a linked electronic health record cohort study of 70 206 individuals with initial record of diagnosis of AF in primary (n=29 568) or secondary care (n=40 638) in England (1998-2010). We defined stroke risk according to the CHA2DS2-VASc score, and followed individuals over a median 2.2 years for 7005 ischaemic strokes (IS) and for 906 haemorrhagic strokes (HS). We calculated incidence rates (IRs) and 95% CIs per 100 person-years (PYs) (IR (95% CI)/100 PY) of IS and HS, with and without use of warfarin, and the NCB (ie, number of IS avoided) per 100 PYs of warfarin use (NCB (95% CI)/100 PY). RESULTS: Compared with individuals with initial record of diagnosis in secondary care, those in primary care had lower scores of IS risk (CHA2DS2-VASc≤2: 30.8% vs 20.6%), and lower overall incidence of IS (IR (95% CI)/100 PY: 2.3 (2.2 to 2.4) vs 4.3 (4.2 to 4.4), p value=0.00); however among individuals with CHA2DS2-VASc=0, 1 or 2 there were no differences in IS rate between those with initial record of diagnosis in primary care or secondary care (IR (95% CI)/100 PY: 0.2 (0.1 to 0.3) vs 0.3 (0.2 to 0.5), p value=0.16), (IR (95% CI)/100 PY: 0.6 (0.4 to 0.7) vs 0.7 (0.6 to 0.9), p value=0.08) and (IR (95% CI)/100 PY: 1.1 (1.00 to 1.3) vs 1.4 (1.2 to 1.6), p value=0.05), respectively. For CHA2DS2-VASc=0, 1 and 2, IRs of IS with versus without warfarin were (IR (95% CI)/100 PY: 0.4 (0.2 to 0.8) vs 0.2 (0.1 to 0.3), p value=0.16), (IR (95% CI)/100 PY: 0.4 (0.3 to 0.7) vs 0.7 (0.6 to 0.8), p value=0.03) and (IR (95% CI)/100 PY: 0.8 (0.7 to 1.0) vs 1.4 (1.3 to 1.6), p value=0.00), respectively. We found a significant positive NCB of warfarin from CHA2DS2-VASc≥2 in men (NCB (95% CI)/100 PY: 0.5 (0.1 to 0.9)) and from CHA2DS2-VASc≥3 in women (NCB (95% CI)/100 PY: 1.5 (1.1 to 1.9)). CONCLUSIONS: CHA2DS2-VASc accurately stratifies IS risk in individuals with AF across both primary and secondary care. However, the incidence rate of ischaemic stroke at CHA2DS2-VASc=1 are lower than previously reported, which may change the decision to start anticoagulation with warfarin in these individuals.

Optimising measurement of health-related characteristics of the built environment: Comparing data collected by foot-based street audits, virtual street audits and routine secondary data sources.

The role of the neighbourhood environment in influencing health behaviours continues to be an important topic in public health research and policy. Foot-based street audits, virtual street audits and secondary data sources are widespread data collection methods used to objectively measure the built environment in environment-health association studies. We compared these three methods using data collected in a nationally representative epidemiological study in 17 British towns to inform future development of research tools. There was good agreement between foot-based and virtual audit tools. Foot based audits were superior for fine detail features. Secondary data sources measured very different aspects of the local environment that could be used to derive a range of environmental measures if validated properly. Future built environment research should design studies a priori using multiple approaches and varied data sources in order to best capture features that operate on different health behaviours at varying spatial scales.

Efficacy and safety of ablation for people with non-paroxysmal atrial fibrillation.

BACKGROUND: The optimal rhythm management strategy for people with non-paroxysmal (persistent or long-standing persistent) atrial fibrilation is currently not well defined. Antiarrhythmic drugs have been the mainstay of therapy. But recently, in people who have not responded to antiarrhythmic drugs, the use of ablation (catheter and surgical) has emerged as an alternative to maintain sinus rhythm to avoid long-term atrial fibrillation complications. However, evidence from randomised trials about the efficacy and safety of ablation in non-paroxysmal atrial fibrillation is limited. OBJECTIVES: To determine the efficacy and safety of ablation (catheter and surgical) in people with non-paroxysmal (persistent or long-standing persistent) atrial fibrillation compared to antiarrhythmic drugs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, conference abstracts, clinical trial registries, and Health Technology Assessment Database. We searched these databases from their inception to 1 April 2016. We used no language restrictions. SELECTION CRITERIA: We included randomised trials evaluating the effect of radiofrequency catheter ablation (RFCA) or surgical ablation compared with antiarrhythmic drugs in adults with non-paroxysmal atrial fibrillation, regardless of any concomitant underlying heart disease, with at least 12 months of follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We evaluated risk of bias using the Cochrane 'Risk of bias' tool. We calculated risk ratios (RRs) for dichotomous data with 95% confidence intervals (CIs) a using fixed-effect model when heterogeneity was low (I² <= 40%) and a random-effects model when heterogeneity was moderate or substantial (I² > 40%). Using the GRADE approach, we evaluated the quality of the evidence and used the GRADE profiler (GRADEpro) to import data from Review Manager 5 to create 'Summary of findings' tables. MAIN RESULTS: We included three randomised trials with 261 participants (mean age: 60 years) comparing RFCA (159 participants) to antiarrhythmic drugs (102) for non-paroxysmal atrial fibrillation. We generally assessed the included studies as having low or unclear risk of bias across multiple domains, with reported outcomes generally lacking precision due to low event rates. Evidence showed that RFCA was superior to antiarrhythmic drugs in achieving freedom from atrial arrhythmias (RR 1.84, 95% CI 1.17 to 2.88; 3 studies, 261 participants; low-quality evidence), reducing the need for cardioversion (RR 0.62, 95% CI 0.47 to 0.82; 3 studies, 261 participants; moderate-quality evidence), and reducing cardiac-related hospitalisation (RR 0.27, 95% CI 0.10 to 0.72; 2 studies, 216 participants; low-quality evidence) at 12 months follow-up. There was substantial uncertainty surrounding the effect of RFCA regarding significant bradycardia (or need for a pacemaker) (RR 0.20, 95% CI 0.02 to 1.63; 3 studies, 261 participants; low-quality evidence), periprocedural complications, and other safety outcomes (RR 0.94, 95% CI 0.16 to 5.68; 3 studies, 261 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: In people with non-paroxysmal atrial fibrillation, evidence suggests a superiority of RFCA to antiarrhythmic drugs in achieving freedom from atrial arrhythmias, reducing the need for cardioversion, and reducing cardiac-related hospitalisations. There was uncertainty surrounding the effect of RFCA with significant bradycardia (or need for a pacemaker), periprocedural complications, and other safety outcomes. Evidence should be interpreted with caution, as event rates were low and quality of evidence ranged from moderate to very low.

Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis.

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention. FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7.

Marginal role for 53 common genetic variants in cardiovascular disease prediction.

OBJECTIVE: We investigated discrimination and calibration of cardiovascular disease (CVD) risk scores when genotypic was added to phenotypic information. The potential of genetic information for those at intermediate risk by a phenotype-based risk score was assessed. METHODS: Data were from seven prospective studies including 11 851 individuals initially free of CVD or diabetes, with 1444 incident CVD events over 10 years' follow-up. We calculated a score from 53 CVD-related single nucleotide polymorphisms and an established CVD risk equation 'QRISK-2' comprising phenotypic measures. The area under the receiver operating characteristic curve (AUROC), detection rate for given false-positive rate (FPR) and net reclassification improvement (NRI) index were estimated for gene scores alone and in addition to the QRISK-2 CVD risk score. We also evaluated use of genetic information only for those at intermediate risk according to QRISK-2. RESULTS: The AUROC was 0.635 for QRISK-2 alone and 0.623 with addition of the gene score. The detection rate for 5% FPR improved from 11.9% to 12.0% when the gene score was added. For a 10-year CVD risk cut-off point of 10%, the NRI was 0.25% when the gene score was added to QRISK-2. Applying the genetic risk score only to those with QRISK-2 risk of 10%-<20% and prescribing statins where risk exceeded 20% suggested that genetic information could prevent one additional event for every 462 people screened. CONCLUSION: The gene score produced minimal incremental population-wide utility over phenotypic risk prediction of CVD. Tailored prediction using genetic information for those at intermediate risk may have clinical utility.

Metabolic Characterization of a Rare Genetic Variation Within APOC3 and Its Lipoprotein Lipase-Independent Effects.

BACKGROUND: Plasma triglyceride levels have been implicated in atherosclerosis and coronary heart disease. Apolipoprotein C-III (APOC3) plays a key role in the hydrolysis of triglyceride-rich lipoproteins to remnant particles by lipoprotein lipase (LPL) and their uptake by the liver. A rare variant in APOC3(rs138326449) has been associated with triglyceride, very low-density lipoprotein, and high-density lipoprotein levels, as well as risk of coronary heart disease. We aimed to characterize the impact of this locus across a broad set of mainly lipids-focused metabolic measures. METHODS AND RESULTS: A high-throughput serum nuclear magnetic resonance metabolomics platform was used to quantify 225 metabolic measures in 13 285 participants from 2 European population cohorts. We analyzed the effect of the APOC3 variant on the metabolic measures and used the common LPL(rs12678919) polymorphism to test for LPL-independent effects. Eighty-one metabolic measures showed evidence of association with APOC3(rs138326449). In addition to previously reported triglyceride and high-density lipoprotein associations, the variant was also associated with very low-density lipoprotein and high-density lipoprotein composition measures, other cholesterol measures, and fatty acids. Comparison of the APOC3 and LPL associations revealed that APOC3 association results for medium and very large very low-density lipoprotein composition are unlikely to be solely predictable by the action of APOC3 through LPL. CONCLUSIONS: We characterized the effects of the rare APOC3(rs138326449) loss of function mutation in lipoprotein metabolism, as well as the effects of LPL(rs12678919). Our results improve our understanding of the role of APOC3 in triglyceride metabolism, its LPL independent action, and the complex and correlated nature of human metabolites.

Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase.

BACKGROUND: Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. OBJECTIVES: This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. METHODS: Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. RESULTS: Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R(2) = 0.94, slope 1.00 ± 0.03). CONCLUSIONS: Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms.

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.

BACKGROUND: Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants. OBJECTIVE: To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation. METHODS: 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10(-5)) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays. RESULTS: Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10(-6), preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10(-6)). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10(-6)). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10(-7)). CONCLUSIONS: This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.

A qualitative geographical information systems approach to explore how older people over 70 years interact with and define their neighbourhood environment.

A growing body of literature explores the relationship between the built environment and health, and the methodological challenges of understanding these complex interactions across the lifecourse. The impact of the neighbourhood environment on health and behaviour amongst older adults has received less attention, despite this age group being potentially more vulnerable to barriers in their surrounding social and physical environment. A qualitative geographical information systems (QGIS) approach was taken to facilitate the understanding of how older people over 70 in 5 UK towns interact with their local neighbourhood. The concept of neighbourhood changed seasonally and over the lifecourse, and was associated with social factors such as friends, family, or community activities, rather than places. Spaces stretched further than the local, which is problematic for older people who rely on variable public transport provision. QGIS techniques prompted rich discussions on interactions with and the meanings of 'place' in older people.

Caso: Lesión pulmonar cavitada en paciente con diagnóstico de HIV / Case: Cavitated lung injury in Patient with a diagnosis of HIV

Paciente de sexo masculino de 62 años de edad. Motivo de consulta: disnea progresiva de 5 días de evolución; clase funcional I a III sin otros síntomas. Presenta antecedentes personales patológicos de HIV de 8 años de evolución sin tratamiento antirretroviral por tener carga viral baja y recuento normal de CD4; insuficiencia renal crónica secundaria a nefritis túbulo intersticial asociada al consumo de AINES por lumbalgia. El paciente es tabaquista activo con un índice de 15 paquetes/año

Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts.

BACKGROUND: High-throughput profiling of circulating metabolites may improve cardiovascular risk prediction over established risk factors. METHODS AND RESULTS: We applied quantitative nuclear magnetic resonance metabolomics to identify the biomarkers for incident cardiovascular disease during long-term follow-up. Biomarker discovery was conducted in the National Finnish FINRISK study (n=7256; 800 events). Replication and incremental risk prediction was assessed in the Southall and Brent Revisited (SABRE) study (n=2622; 573 events) and British Women's Health and Heart Study (n=3563; 368 events). In targeted analyses of 68 lipids and metabolites, 33 measures were associated with incident cardiovascular events at P<0.0007 after adjusting for age, sex, blood pressure, smoking, diabetes mellitus, and medication. When further adjusting for routine lipids, 4 metabolites were associated with future cardiovascular events in meta-analyses: higher serum phenylalanine (hazard ratio per standard deviation, 1.18; 95% confidence interval, 1.12-1.24; P=4×10(-10)) and monounsaturated fatty acid levels (1.17; 1.11-1.24; P=1×10(-8)) were associated with increased cardiovascular risk, while higher omega-6 fatty acids (0.89; 0.84-0.94; P=6×10(-5)) and docosahexaenoic acid levels (0.90; 0.86-0.95; P=5×10(-5)) were associated with lower risk. A risk score incorporating these 4 biomarkers was derived in FINRISK. Risk prediction estimates were more accurate in the 2 validation cohorts (relative integrated discrimination improvement, 8.8% and 4.3%), albeit discrimination was not enhanced. Risk classification was particularly improved for persons in the 5% to 10% risk range (net reclassification, 27.1% and 15.5%). Biomarker associations were further corroborated with mass spectrometry in FINRISK (n=671) and the Framingham Offspring Study (n=2289). CONCLUSIONS: Metabolite profiling in large prospective cohorts identified phenylalanine, monounsaturated fatty acids, and polyunsaturated fatty acids as biomarkers for cardiovascular risk. This study substantiates the value of high-throughput metabolomics for biomarker discovery and improved risk assessment.