A translational framework for public health research

<p><b>Background</b></p> <p>The paradigm of translational medicine that underpins frameworks such as the Cooksey report on the funding of health research does not adequately reflect the complex reality of the public health environment. We therefore outline a translational framework for public health research.</p> <p><b>Discussion</b></p> <p>Our framework redefines the objective of translation from that of institutionalising effective interventions to that of improving population health by influencing both individual and collective determinants of health. It incorporates epidemiological perspectives with those of the social sciences, recognising that many types of research may contribute to the shaping of policy, practice and future research. It also identifies a pivotal role for evidence synthesis and the importance of non-linear and intersectoral interfaces with the public realm.</p> <p><b>Summary</b></p> <p>We propose a research agenda to advance the field and argue that resources for 'applied' or 'translational' public health research should be deployed across the framework, not reserved for 'dissemination' or 'implementation'.</p&gt

Active vitamin D (1,25-dihydroxyvitamin D) and bone health in middle-aged and elderly men: the European male aging study (EMAS)

<p>Context: There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)2D] on bone health including turnover.</p> <p>Objective: The objective of the study was to determine the influence of 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.</p> <p>Design, Setting, and Participants: Men aged 40–79 years were recruited from population registers in 8 European centers. Subjects completed questionnaires that included questions concerning lifestyle and were invited to attend for quantitative ultrasound (QUS) of the heel, assessment of height and weight, and a fasting blood sample from which 1,25(OH)2D, 25(OH)D, and PTH were measured. 1,25(OH)2D was measured using liquid chromatography tandem mass spectrometry. Bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β-cTX) were also measured. Dual-energy x-ray absorptiometry (DXA) of the hip and lumbar spine was performed in 2 centers.</p> <p>Main Outcome Measure(s): QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.</p> <p>Results: A total of 2783 men, mean age 60.0 years (SD 11.0) were included in the analysis. After adjustment for age and center, 1,25(OH)2D was positively associated with 25(OH)D but not with PTH. 25(OH)D was negatively associated with PTH. After adjustment for age, center, height, weight, lifestyle factors, and season, 1,25(OH)2D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)2D was not correlated with P1NP. 25(OH)D was positively associated with the QUS and DXA parameters but not related to either bone turnover marker. Subjects with both high 1,25(OH)2D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.</p> <p>Conclusions: Serum 1,25(OH)2D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health.</p&gt

Improvements in forecasting intense rainfall: results from the FRANC (forecasting rainfall exploiting new data assimilation techniques and novel observations of convection) project

The FRANC project (Forecasting Rainfall exploiting new data Assimilation techniques and Novel observations of Convection) has researched improvements in numerical weather prediction of convective rainfall via the reduction of initial condition uncertainty. This article provides an overview of the project’s achievements. We highlight new radar techniques: correcting for attenuation of the radar return; correction for beams that are over 90% blocked by trees or towers close to the radar; and direct assimilation of radar reflectivity and refractivity. We discuss the treatment of uncertainty in data assimilation: new methods for estimation of observation uncertainties with novel applications to Doppler radar winds, Atmospheric Motion Vectors, and satellite radiances; a new algorithm for implementation of spatially-correlated observation error statistics in operational data assimilation; and innovative treatment of moist processes in the background error covariance model. We present results indicating a link between the spatial predictability of convection and convective regimes, with potential to allow improved forecast interpretation. The research was carried out as a partnership between University researchers and the Met Office (UK). We discuss the benefits of this approach and the impact of our research, which has helped to improve operational forecasts for convective rainfall event

Active vitamin D (1,25-dihydroxyvitamin D) and bone health in middle-aged and elderly men: the European male aging study (EMAS)

<p>Context: There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)2D] on bone health including turnover.</p> <p>Objective: The objective of the study was to determine the influence of 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.</p> <p>Design, Setting, and Participants: Men aged 40–79 years were recruited from population registers in 8 European centers. Subjects completed questionnaires that included questions concerning lifestyle and were invited to attend for quantitative ultrasound (QUS) of the heel, assessment of height and weight, and a fasting blood sample from which 1,25(OH)2D, 25(OH)D, and PTH were measured. 1,25(OH)2D was measured using liquid chromatography tandem mass spectrometry. Bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β-cTX) were also measured. Dual-energy x-ray absorptiometry (DXA) of the hip and lumbar spine was performed in 2 centers.</p> <p>Main Outcome Measure(s): QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.</p> <p>Results: A total of 2783 men, mean age 60.0 years (SD 11.0) were included in the analysis. After adjustment for age and center, 1,25(OH)2D was positively associated with 25(OH)D but not with PTH. 25(OH)D was negatively associated with PTH. After adjustment for age, center, height, weight, lifestyle factors, and season, 1,25(OH)2D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)2D was not correlated with P1NP. 25(OH)D was positively associated with the QUS and DXA parameters but not related to either bone turnover marker. Subjects with both high 1,25(OH)2D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.</p> <p>Conclusions: Serum 1,25(OH)2D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health.</p&gt

Reducing Calorie Intake May Not Help You Lose Body Weight

Background Previously a meta-analysis found that multi-vitamin/mineral supplementation reduced mild psychiatric symptoms. To establish mechanisms, and to pin-point the individuals most likely to benefit, the role of various polymorphisms were examined. Supplementation was found to influence mild-psychiatric symptoms depending on the form of particular genes: genes that are risk factors for psychiatric disease and influence mechanisms by which drugs act. Methods In a double-blind trial young healthy males rated psychiatric symptoms, before and after taking vitamin/mineral supplements for three months, and the response was related to single nucleotide polymorphisms associated with catecholamines and serotonin. Outcomes With rs1800497 (Taq1A; dopamine D2 receptor), those with the CT allele benefitted from a vitamin/mineral supplement. Similarly with rs1800955 (DRD4 – dopamine D4 receptor), the mood of those with the CC allele benefitted selectively. With rs6296 (HTR1B) only those with the GC alleles responded, and with rs6311 (HTR2A) supplementation produced a beneficial response in those with the GG allele. With rs1050565 (5HTT gene - Human Serotonin Transporter gene) supplementation increased the mental health of those with the AA allele. Interpretation In a situation where a substantial proportion of patients do not benefit from drug therapy, and there is an element of trial and error when prescribing, it was proposed that future work should consider distinguishing patients depending on various polymorphisms and micro-nutrient status. In those with particular alleles, we should consider if drug administration and vitamin / mineral status interact synergistically to influence the therapeutic outcom

A randomized, controlled trial of 3.0 mg of liraglutide in weight management

BACKGROUND Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagonlike peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously. METHODS We conducted a 56-week, double-blind trial involving 3731 patients who did not have type 2 diabetes and who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 30 or a BMI of at least 27 if they had treated or untreated dyslipidemia or hypertension. We randomly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both groups received counseling on lifestyle modification. The coprimary end points were the change in body weight and the proportions of patients losing at least 5% and more than 10% of their initial body weight. RESULTS At baseline, the mean (±SD) age of the patients was 45.1±12.0 years, the mean weight was 106.2±21.4 kg, and the mean BMI was 38.3±6.4; a total of 78.5% of the patients were women and 61.2% had prediabetes. At week 56, patients in the liraglutide group had lost a mean of 8.4±7.3 kg of body weight, and those in the placebo group had lost a mean of 2.8±6.5 kg (a difference of -5.6 kg; 95% confidence interval, -6.0 to -5.1; P<0.001, with last-observation-carried-forward imputation). A total of 63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group lost at least 5% of their body weight (P<0.001), and 33.1% and 10.6%, respectively, lost more than 10% of their body weight (P<0.001). The most frequently reported adverse events with liraglutide were mild or moderate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the liraglutide group and in 5.0% of the patients in the placebo group. CONCLUSIONS In this study, 3.0 mg of liraglutide, as an adjunct to diet and exercise, was associated with reduced body weight and improved metabolic control. (Funded by Novo Nordisk; SCALE Obesity and Prediabetes NN8022-1839 ClinicalTrials.gov number, NCT01272219.)

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Low heel ultrasound parameters predict mortality in men: Results from the European Male Ageing Study (EMAS)

© The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. Background: low bone mineral density measured by dual-energy x-ray absorptiometry is associated with increased mortality. The relationship between other skeletal phenotypes and mortality is unclear. The aim of this study was to determine the relationship between quantitative heel ultrasound parameters and mortality in a cohort of European men. Methods: men aged 40-79 years were recruited for participation in a prospective study of male ageing: the European Male Ageing Study (EMAS). At baseline, subjects attended for quantitative ultrasound (QUS) of the heel (Hologic-SAHARA) and completed questionnaires on lifestyle factors and co-morbidities. Height and weight were measured. After a median of 4.3 years, subjects were invited to attend a follow-up assessment, and reasons for non-participation, including death, were recorded. The relationship between QUS parameters (broadband ultrasound attenuation [BUA] and speed of sound [SOS] ) and mortality was assessed using Cox proportional hazards model. Results: from a total of 3,244 men (mean age 59.8, standard deviation [SD] 10.8 years), 185 (5.7%) died during the follow-up period. After adjusting for age, centre, body mass index, physical activity, current smoking, number of co-morbidities and general health, each SD decrease in BUAwas associated with a 20% higher risk of mortality (hazard ratio [HR] per SD = 1.2; 95% confidence interval [CI] = 1.0-1.4). Compared with those in higher quintiles (2nd-5th), those in the lowest quintile of BUA and SOS had a greater mortality risk (BUA: HR = 1.6; 95% CI = 1.1-2.3 and SOS: HR = 1.6; 95% CI = 1.2-2.2). Conclusion: lower heel ultrasound parameters are associated with increased mortality in European men

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

IZ KAJKAVSKE MORFOLOGIJE (o DL sg. im. ž. roda)

U radu se nastoji dati odgovor na pitanje: da li je u svim govorima kajkavskoga narječja u kojima je u DL sg. imenica ženskoga roda morfem –i riječ o generalizaciji toga morfema iz nekadašnjih ja-osnova ili se u govorima s ograničenom distribucijom kontinuante jata i šva (u dijelu govora samo jata) i njegovom zamjenom vokalom i, ili vokalom i-tipa, u nenaglašenim slogovima, može govoriti o morfemu –i < -ẹ < ě