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1.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120315482, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33853351

RESUMO

OBJECTIVE: We aimed to estimate the effect of blood pressure (BP) traits and BP-lowering medications (via genetic proxies) on peripheral artery disease. Approach and Results: Genome-wide association studies summary statistics were obtained for BP, peripheral artery disease (PAD), and coronary artery disease. Causal effects of BP on PAD were estimated by 2-sample Mendelian randomization using a range of pleiotropy-robust methods. Increased systolic BP (SBP), diastolic BP, mean arterial pressure (MAP), and pulse pressure each significantly increased risk of PAD (SBP odds ratio [OR], 1.20 [1.16-1.25] per 10 mm Hg increase, P=1×10-24; diastolic BP OR, 1.27 [1.18-1.35], P=4×10-11; MAP OR, 1.26 [1.19-1.33], P=6×10-16; pulse pressure OR, 1.31 [1.24-1.39], P=9×10-23). The effects of SBP, diastolic BP, and MAP were greater for coronary artery disease than PAD (SBP ratio of Ors, 1.06 [1.0-1.12], P=0.04; MAP ratio of OR, 1.15 [1.06-1.26], P=8.6×10-4; diastolic BP ratio of OR, 1.21 [1.08-1.35], P=6.9×10-4). Considered jointly, both pulse pressure and MAP directly increased risk of PAD (pulse pressure OR, 1.26 [1.17-1.35], P=3×10-10; MAP OR, 1.14 [1.06-1.23], P=2×10-4). The effects of antihypertensive medications were estimated using genetic instruments. SBP-lowering via ß-blocker (OR, 0.74 per 10 mm Hg decrease in SBP [95% CI, 0.65-0.84]; P=5×10-6), loop diuretic (OR, 0.66 [0.48-0.91], P=0.01), and thiazide diuretic (OR, 0.57 [0.41-0.79], P=6×10-4) associated variants were protective of PAD. CONCLUSIONS: Higher BP is likely to cause PAD. BP-lowering through ß blockers, loop diuretics, and thiazide diuretics (as proxied by genetic variants) was associated with decreased risk of PAD. Future study is needed to clarify the specific mechanisms by which BP influences PAD.

3.
Nat Rev Cardiol ; 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707768

RESUMO

Drug development in cardiovascular disease is stagnating, with lack of efficacy and adverse effects being barriers to innovation. Human genetics can provide compelling evidence of causation through approaches such as Mendelian randomization, with genetic support for causation increasing the probability of a clinical trial succeeding. Mendelian randomization applied to quantitative traits can identify risk factors for disease that are both causal and amenable to therapeutic modification. However, important differences exist between genetic investigations of a biomarker (such as HDL cholesterol) and a drug target aimed at modifying the same biomarker of interest (such as cholesteryl ester transfer protein), with implications for the methodology, interpretation and application of Mendelian randomization to drug development. Differences include the comparative nature of the genetic architecture - that is, biomarkers are typically polygenic, whereas protein drug targets are influenced by either cis-acting or trans-acting genetic variants - and the potential for drug targets to show disease associations that might differ from those of the biomarker that they are intended to modify (target-mediated pleiotropy). In this Review, we compare and contrast the use of Mendelian randomization to evaluate potential drug targets versus quantitative traits. We explain how genetic epidemiological studies can be used to assess the aetiological roles of biomarkers in disease and to prioritize drug targets, including designing their evaluation in clinical trials.

4.
BMJ Open ; 11(1): e043247, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436473

RESUMO

OBJECTIVES: A growing literature highlights the intergenerational transmission of human capital from parents to children. However, far less is known about 'upward transmission' from children to parents. In this study, we use a 1996 Botswana education policy reform as a natural experiment to identify the causal effect of children's secondary schooling on their parents' health. SETTING: Botswana's decennial census (2001 and 2011). Data were obtained through the Integrated Public Use Microdata Series and are 10% random samples of the complete population in each of these census years. PARTICIPANTS: Survey respondents who were citizens born in Botswana, at least 18 years old at the time of the census and born in or after 1975 (n=89 721). PRIMARY AND SECONDARY OUTCOME MEASURES: Parental survival and disability at the time of the census, separately for mothers and fathers. RESULTS: The 1996 reform caused a large increase in grade 10 enrolment, inducing an additional 0.4 years of schooling for the first cohorts affected (95% CI 0.3 to 0.5, p<0.001). The reform, however, had no effect on parental survival and disability by the time exposed child cohorts reach age 30. Results were robust to a wide array of sensitivity analyses. CONCLUSIONS: This study found little evidence that parents' survival and disability were affected by their offspring's educational attainment in Botswana. Parents' health may not be necessarily affected by increasing their offspring's educational attainment.

5.
J Thromb Thrombolysis ; 51(4): 978-984, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33386559

RESUMO

Disordered coagulation, endothelial dysfunction, dehydration and immobility contribute to a substantially elevated risk of deep venous thrombosis, pulmonary embolism (PE) and systemic thrombosis in coronavirus disease 2019 (Covid-19). We evaluated the prevalence of pulmonary thrombosis and reported RV (right ventricular) dilatation/dysfunction associated with Covid-19 in a tertiary referral Covid-19 centre. Of 370 patients, positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 39 patients (mean age 62.3 ± 15 years, 56% male) underwent computed tomography pulmonary angiography (CTPA), due to increasing oxygen requirements or refractory hypoxia, not improving on oxygen, very elevated D-dimer or tachycardia disproportionate to clinical condition. Thrombosis in the pulmonary vasculature was found in 18 (46.2%) patients. However, pulmonary thrombosis did not predict survival (46.2% survivors vs 41.7% non-survivors, p = 0.796), but RV dilatation was less frequent among survivors (11.5% survivors vs 58.3% non-survivors, p = 0.002). Over the following month, we observed four Covid-19 patients, who were admitted with high and intermediate-high risk PE, and we treated them with UACTD (ultrasound-assisted catheter-directed thrombolysis), and four further patients, who were admitted with PE up to 4 weeks after recovery from Covid-19. Finally, we observed a case of RV dysfunction and pre-capillary pulmonary hypertension, associated with Covid-19 extensive lung disease. We demonstrated that pulmonary thrombosis is common in association with Covid-19. Also, the thrombotic risk in the pulmonary vasculature is present before and during hospital admission, and continues at least up to four weeks after discharge, and we present UACTD for high and intermediate-high risk PE management in Covid-19 patients.

6.
Hypertension ; 77(2): 376-382, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33390040

RESUMO

Observational studies have shown an association between hypertension and atrial fibrillation (AF). Aggressive blood pressure management in patients with known AF reduces overall arrhythmia burden, but it remains unclear whether hypertension is causative for AF. To address this question, this study explored the relationship between genetic predictors of blood pressure and risk of AF. We secondarily explored the relationship between genetically proxied use of antihypertensive drugs and risk of AF. Two-sample Mendelian randomization was performed using an inverse-variance weighted meta-analysis with weighted median Mendelian randomization and Egger intercept tests performed as sensitivity analyses. Summary statistics for systolic blood pressure, diastolic blood pressure, and pulse pressure were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis and AF from the 2018 Atrial Fibrillation Genetics Consortium multiethnic genome-wide association studies. Increases in genetically proxied systolic blood pressure, diastolic blood pressure, or pulse pressure by 10 mm Hg were associated with increased odds of AF (systolic blood pressure: odds ratio [OR], 1.17 [95% CI, 1.11-1.22]; P=1×10-11; diastolic blood pressure: OR, 1.25 [95% CI, 1.16-1.35]; P=3×10-8; pulse pressure: OR, 1.1 [95% CI, 1.0-1.2]; P=0.05). Decreases in systolic blood pressure by 10 mm Hg estimated by genetic proxies of antihypertensive medications showed calcium channel blockers (OR, 0.66 [95% CI, 0.57-0.76]; P=8×10-9) and ß-blockers (OR, 0.61 [95% CI, 0.46-0.81]; P=6×10-4) decreased the risk of AF. Blood pressure-increasing genetic variants were associated with increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction with calcium channel blockade or ß-blockade could reduce the risk of AF.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33283474

RESUMO

Obstructive sleep apnoea (OSA) is a serious debilitating condition with significant morbidity and mortality affecting almost one billion adults globally. The current gold standard in the non-surgical management of airway collapse is continuous positive airway pressure (CPAP). However, non-compliance leads to a high abandon rate (27-46%). While there are multiple sites of airway obstruction during sleep, the tongue base is recognized as the key player in the pathogenesis of OSA. Poor outcomes of current tongue suspension devices are due to fracture, slippage or migration of devices. Three tongue tethering device groups, namely a polydioxanone/polyurethane combination (PDO + PU) treatment group, a PDO analytical control group, and a polypropylene (PP) descriptive control group, were implanted into 22 sheep (75-85 kg) in a two-phased study. After implant times of 8, 16, and 32 weeks, sheep were serially euthanized to allow for explantation of their tongues and chins. The PDO + PU devices remodeled during the 32-week implant period into a hybrid biological tendon-like tether through the process of gradual degradation of the PDO and collagen deposition as shown by electrophoresis, histology and mechanical testing. The control PDO device degraded completely after 32 weeks and the PP devices remained intact. The hybrid biological tendon-like tether exhibited a break-strength of 60 N, thus exceeding the maximum force to overcome upper airway collapse.

8.
Int J Epidemiol ; 2020 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-33221865

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and body mass index (BMI) are associated. However, it remains unclear whether this association reflects causal relationships in either direction or confounding. Here, we implemented genetically informed methods to examine bidirectional causality and potential confounding. METHODS: Three genetically informed methods were employed: (i) cross-lagged twin-differences analyses to assess bidirectional effects of ADHD symptoms and BMI at ages 8, 12, 14 and 16 years in 2386 pairs of monozygotic twins from the Twins Early Development Study (TEDS); (ii) within- and between-family ADHD and BMI polygenic score (PS) analyses in 3320 pairs of dizygotic TEDS twins; and (iii) two-sample bidirectional Mendelian randomization (MR) using summary statistics from genome-wide association studies (GWAS) on ADHD (N = 55,374) and BMI (N = 806,834). RESULTS: Mixed results were obtained across the three methods. Twin-difference analyses provided little support for cross-lagged associations between ADHD symptoms and BMI over time. PS analyses were consistent with bidirectional relationships between ADHD and BMI, with plausible time-varying effects from childhood to adolescence. MR findings also suggested bidirectional causal effects between ADHD and BMI. Multivariable MR indicated the presence of substantial confounding in bidirectional relationships. CONCLUSIONS: The three methods converged to highlight multiple sources of confounding in the association between ADHD and BMI. PS and MR analyses suggested plausible causal relationships in both directions. Possible explanations for mixed causal findings across methods are discussed.

9.
Addiction ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33197082

RESUMO

BACKGROUND AND AIMS: Varenicline and nicotine replacement therapy (NRT) are the most commonly used medications to quit smoking. Given their widespread use, monitoring adverse risks remains important. This study aimed to estimate the neuropsychiatric and cardiovascular risks associated with varenicline and NRT as used in routine UK care. DESIGN: Case crossover study. SETTING: UK based electronic primary care records in the Clinical Practice Research Datalink from 2006 to 2015 linked to hospital and mortality datasets. PARTICIPANTS: Adult smokers (n=?) observed in periods when exposed and not exposed to either varenicline or NRT. MEASUREMENTS: Main outcomes included suicide, self-harm, myocardial infarction (MI), all-cause death and cause-specific death (MI, chronic obstructive pulmonary disease (COPD)). In primary analyses, conditional logistic regression was used to compare the chance of varenicline or NRT exposure in the risk period (90 days prior to the event) with the chance of exposure in an earlier single reference period (91-180 days prior to the event) or multiple 90-day reference periods to increase statistical power. FINDINGS: In the primary analyses, findings were inconclusive for the associations between varenicline and the main outcomes using a single reference period, whilst NRT was associated with MI (Odds ratio (OR) 1.40, 95% Confidence interval (CI) 1.18-1.67). Using multiple reference periods, varenicline was associated with an increased risk of self-harm (OR 1.32, 95% CI 1.12-1.56) and suicide (OR 3.56, 95% CI 1.32-9.60) but a reduction in all-cause death (OR 0.75, 95% CI 0.61-0.93). NRT was associated with MI (OR 1.54, 95% CI 1.36-1.74), self-harm (OR 1.30, 95% CI 1.18-1.44), and deaths from MI (OR 1.53, 95% CI 1.11-2.10), COPD (OR 1.33, 95% CI 1.14-1.56) and all causes (OR 1.28, 95% CI 1.18-1.40) when using multiple reference periods. CONCLUSIONS: There appear to be positive associations between 1) nicotine replacement therapy (NRT) and myocardial infarction, death, and risk of self-harm and 2) varenicline and increased risk of self-harm and suicide, as well as a negative association between varenicline and all-cause death. The associations may not be causal. They may reflect health changes at the time of smoking cessation (NRT is prescribed for people with cardiac problems) or be associated with quit attempts (exposure to both medicines was associated with self-harm).

10.
Artigo em Inglês | MEDLINE | ID: mdl-33175463

RESUMO

Due to the abundance of lipoproteins in blood, it is challenging to characterize the biological functions and components of blood-derived extracellular vesicles. The aim of this study was to develop a multiple-step purification protocol to separate serum exosomes from serum proteins and lipoproteins and assess their regenerative potential. Exosomes were isolated by concentrating them in human serum using ultracentrifugation (UC), followed sequentially by density gradient (DG) UC and size exclusion chromatography (SEC). Purity and characterization were assessed by western blots, Lipoprint®, enzyme-linked immunosorbent assay, electron microscopy, mass spectrometry, and nanoparticle tracking analysis. Functionality was assessed by cell proliferation analysis and with an in vivo subcutaneous angiogenesis model. SEC alone isolated nano-sized vesicles possessing vesicle markers TSG101 and CD9, but there was a substantial presence of apolipoprotein B, predominantly derived from very-low- and intermediate-density lipoprotein particles. This was reduced to an undetectable level using the combined UC DG SEC approach. Mass spectrometry identified 224 proteins in UC DG SEC isolates relative to the 135 from SEC, with considerable increases in exosome-related proteins and reductions in lipoproteins. A consistent but limited increase in human dermal fibroblast proliferation and evidence of neovascularization enhancement were observed after exposure to UC DG SEC exosomes. An UC DG SEC purification protocol considerably improved the removal of lipoproteins during isolation of serum exosomes. The purified exosomes stimulated cell proliferation and potentially increased an in vivo angiogenic response. This multistep purification allows for more accurate identification of serum exosome functional activity and composition.

11.
Nat Commun ; 11(1): 5749, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184277

RESUMO

Numerous observational studies have attempted to identify risk factors for infection with SARS-CoV-2 and COVID-19 disease outcomes. Studies have used datasets sampled from patients admitted to hospital, people tested for active infection, or people who volunteered to participate. Here, we highlight the challenge of interpreting observational evidence from such non-representative samples. Collider bias can induce associations between two or more variables which affect the likelihood of an individual being sampled, distorting associations between these variables in the sample. Analysing UK Biobank data, compared to the wider cohort the participants tested for COVID-19 were highly selected for a range of genetic, behavioural, cardiovascular, demographic, and anthropometric traits. We discuss the mechanisms inducing these problems, and approaches that could help mitigate them. While collider bias should be explored in existing studies, the optimal way to mitigate the problem is to use appropriate sampling strategies at the study design stage.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Betacoronavirus , Viés , Humanos , Estudos Observacionais como Assunto , Pandemias , Fatores de Risco , Resultado do Tratamento
12.
Adv Ther ; 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33245530

RESUMO

INTRODUCTION: Glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) approved to date are administered by injection; therefore, patient perceptions of an oral GLP-1 RA are unknown. This discrete choice experiment explored preferences for (unbranded) oral and injectable GLP-1 RA profiles among Japanese patients with type 2 diabetes (T2D). METHODS: An online survey was designed using literature review and qualitative interview findings, and administered to Japanese patients with T2D and HbA1c ≥ 7.0% receiving oral antiglycaemic medication (with no experience of injectable antiglycaemic medication). Therapy profiles were created using Japanese head-to-head trial data for orally administered semaglutide (7 mg and 14 mg), injectable dulaglutide (0.75 mg), and injectable liraglutide (0.9 mg). Profiles were not labelled. Choice tasks tested preference between hypothetical profiles, preference between profiles with actual trial data, and willingness to initiate treatment. Relative importance of attributes was determined using conditional logit regression. RESULTS: A total of 500 respondents were analysed: mean age 61.2 years; 93.8% male; mean HbA1c 7.6%; 78.2% with HbA1c ≥ 7.0 to < 8%; 89% with HbA1c above personal target. Mean BMI was 25.4 kg/m2; 49% had obesity (≥ 25 kg/m2). The treatment attribute with greatest importance was mode and frequency of administration (49.1%), followed by nausea risk (30.8%), weight change (11.3%), and HbA1c change (8.8%). Oral semaglutide 7 and 14 mg-like profiles were both preferred: the 7 mg-like profile was preferred over dulaglutide (by 91.0% of respondents) and liraglutide (by 89.4%); the 14 mg-like profile was preferred over dulaglutide (by 88.2%) and liraglutide (by 94.4%). Willingness to initiate treatment was also higher for orally administered semaglutide-like profiles: 62.4% with 7 mg and 64.0% with 14 mg, versus 13.6% and 11.0% with injectable GLP-1 RA-like profiles. Subgroup results were generally consistent with the overall sample. CONCLUSION: Japanese patients with T2D appear to prefer oral GLP-1 RA profiles over injectable GLP-1 RA profiles, and administration appears to be the most important factor in this decision. This highlights the unmet need for an effective and orally administered GLP-1 RA for the treatment of T2D in Japan.

13.
J R Stat Soc Ser A Stat Soc ; 183(2): 681-688, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32999534

RESUMO

There is an extensive literature on the causes of educational inequalities, and the life course consequences of educational attainment. Mendelian randomization, where genetic variants associated with exposures of interest are used as proxies for those exposures, often within an instrumental variables framework, has proven highly effective at elucidating the causal effects of several risk factors in the biomedical sciences. We discuss the potential for this approach to be used in the context of social and socio-economic exposures and outcomes, such as educational attainment.

14.
Front Cardiovasc Med ; 7: 159, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33033720

RESUMO

The concept of tissue engineering evolved long before the phrase was forged, driven by the thromboembolic complications associated with the early total artificial heart programs of the 1960s. Yet more than half a century of dedicated research has not fulfilled the promise of successful broad clinical implementation. A historical account outlines reasons for this scientific impasse. For one, there was a disconnect between distinct eras each characterized by different clinical needs and different advocates. Initiated by the pioneers of cardiac surgery attempting to create neointimas on total artificial hearts, tissue engineering became fashionable when vascular surgeons pursued the endothelialisation of vascular grafts in the late 1970s. A decade later, it were cardiac surgeons again who strived to improve the longevity of tissue heart valves, and lastly, cardiologists entered the fray pursuing myocardial regeneration. Each of these disciplines and eras started with immense enthusiasm but were only remotely aware of the preceding efforts. Over the decades, the growing complexity of cellular and molecular biology as well as polymer sciences have led to surgeons gradually being replaced by scientists as the champions of tissue engineering. Together with a widening chasm between clinical purpose, human pathobiology and laboratory-based solutions, clinical implementation increasingly faded away as the singular endpoint of all strategies. Moreover, a loss of insight into the healing of cardiovascular prostheses in humans resulted in the acceptance of misleading animal models compromising the translation from laboratory to clinical reality. This was most evident in vascular graft healing, where the two main impediments to the in-situ generation of functional tissue in humans remained unheeded-the trans-anastomotic outgrowth stoppage of endothelium and the build-up of an impenetrable surface thrombus. To overcome this dead-lock, research focus needs to shift from a biologically possible tissue regeneration response to one that is feasible at the intended site and in the intended host environment of patients. Equipped with an impressive toolbox of modern biomaterials and deep insight into cues for facilitated healing, reconnecting to the "user needs" of patients would bring one of the most exciting concepts of cardiovascular medicine closer to clinical reality.

16.
Invest Ophthalmol Vis Sci ; 61(11): 7, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32886096

RESUMO

Purpose: Cross-sectional and longitudinal studies have consistently reported an association between education and myopia. However, conventional observational studies are at risk of bias due to confounding by factors such as socioeconomic position and parental educational attainment. The current study aimed to estimate the causal effect of education on refractive error using regression discontinuity analysis. Methods: Regression discontinuity analysis was applied to assess the influence on refractive error of the raising of the school leaving age (ROSLA) from 15 to 16 years introduced in England and Wales in 1972. For comparison, a conventional ordinary least squares (OLS) analysis was performed. The analysis sample comprised 21,548 UK Biobank participants born in a nine-year interval centered on September 1957, the date of birth of those first affected by ROSLA. Results: In OLS analysis, the ROSLA 1972 reform was associated with a -0.29 D (95% confidence interval [CI]: -0.36 to -0.21, P < 0.001) more negative refractive error. In other words, the refractive error of the study sample became more negative by -0.29 D during the transition from a minimum school leaving age of 15 to 16 years of age. Regression discontinuity analysis estimated the causal effect of the ROSLA 1972 reform on refractive error as -0.77 D (95% CI: -1.53 to -0.02, P = 0.04). Conclusions: Additional compulsory schooling due to the ROSLA 1972 reform was associated with a more negative refractive error, providing additional support for a causal relationship between education and myopia.

17.
Anesthesiology ; 133(5): 1007-1020, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32898216

RESUMO

BACKGROUND: Most common anesthetic agents have been implicated in causing neurodegeneration in the developing animal brain, leading to warnings regarding their use in children. The hypothesis of this study was that exposure to general anesthesia and surgery before 4 yr would associate with adverse neurodevelopmental outcomes at age 7 to 16 yr. METHODS: This cohort study comprised 13,433 children enrolled in the Avon Longitudinal Study of Parents and Children, a prospective, population-based birth cohort born between 1991 and 1993 in southwest England. Children were grouped by none, single, or multiple exposures to general anesthesia and surgery by 4 yr. Motor, cognitive, linguistic, educational, social, and behavioral developmental outcomes were evaluated at 7 to 16 yr using school examination results, validated parent/teacher questionnaires, or clinic assessments. Continuous outcomes were z-scored. P-value thresholds were corrected using false discovery rate procedures. RESULTS: This study compared 46 neurodevelopmental outcomes in 13,433 children: 8.3% (1,110) exposed singly and 1.6% (212) exposed multiply to general anesthesia and surgery. Of these, the following reached predefined levels of statistical significance (corrected P < 0.00652): dynamic balance scores were 0.3 SD (95% CI, 0.1, 0.5; P < 0.001) lower in multiply exposed children; manual dexterity performance was 0.1 SD (95% CI, 0.0, 0.2; P = 0.006) lower in singly and 0.3 SD (95% CI, 0.1, 0.4; P < 0.001) lower in multiply exposed children; and social communication scores were 0.1 SD (95% CI, 0.0, 0.2; P = 0.001) and 0.4 SD (95% CI, 0.3, 0.5; P < 0.001) lower in singly and multiply exposed children, respectively. General anesthesia and surgery were not associated with impairments in the remaining neurodevelopmental measures including: general cognitive ability; attention; working memory; reading, spelling, verbal comprehension and expression; behavioral difficulties; or national English, mathematics, and science assessments (all ≤0.1 SD; corrected P ≥ 0.00652). CONCLUSIONS: Early childhood general anesthesia and surgery were not associated with a global picture of clinically and statistically significant neurodegenerative effects, providing reassurance about the neurotoxic potential of general anesthesia. Exposure to anesthesia and surgery was associated with significantly lower motor and social linguistic performance.


Assuntos
Anestesia Geral/tendências , Comportamento Infantil/efeitos dos fármacos , Comportamento Infantil/psicologia , Desenvolvimento Infantil/efeitos dos fármacos , Pais/psicologia , Adolescente , Anestesia Geral/efeitos adversos , Criança , Comportamento Infantil/fisiologia , Desenvolvimento Infantil/fisiologia , Estudos de Coortes , Inglaterra/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos
18.
Int J Epidemiol ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32808034

RESUMO

BACKGROUND: We aimed to estimate the causal effect of health conditions and risk factors on social and socioeconomic outcomes in UK Biobank. Evidence on socioeconomic impacts is important to understand because it can help governments, policy makers and decision makers allocate resources efficiently and effectively. METHODS: We used Mendelian randomization to estimate the causal effects of eight health conditions (asthma, breast cancer, coronary heart disease, depression, eczema, migraine, osteoarthritis, type 2 diabetes) and five health risk factors [alcohol intake, body mass index (BMI), cholesterol, systolic blood pressure, smoking] on 19 social and socioeconomic outcomes in 336 997 men and women of White British ancestry in UK Biobank, aged between 39 and 72 years. Outcomes included annual household income, employment, deprivation [measured by the Townsend deprivation index (TDI)], degree-level education, happiness, loneliness and 13 other social and socioeconomic outcomes. RESULTS: Results suggested that BMI, smoking and alcohol intake affect many socioeconomic outcomes. For example, smoking was estimated to reduce household income [mean difference = -£22 838, 95% confidence interval (CI): -£31 354 to -£14 321] and the chance of owning accommodation [absolute percentage change (APC) = -20.8%, 95% CI: -28.2% to -13.4%], of being satisfied with health (APC = -35.4%, 95% CI: -51.2% to -19.5%) and of obtaining a university degree (APC = -65.9%, 95% CI: -81.4% to -50.4%), while also increasing deprivation (mean difference in TDI = 1.73, 95% CI: 1.02 to 2.44, approximately 216% of a decile of TDI). There was evidence that asthma decreased household income, the chance of obtaining a university degree and the chance of cohabiting, and migraine reduced the chance of having a weekly leisure or social activity, especially in men. For other associations, estimates were null. CONCLUSIONS: Higher BMI, alcohol intake and smoking were all estimated to adversely affect multiple social and socioeconomic outcomes. Effects were not detected between health conditions and socioeconomic outcomes using Mendelian randomization, with the exceptions of depression, asthma and migraines. This may reflect true null associations, selection bias given the relative health and age of participants in UK Biobank, and/or lack of power to detect effects.

19.
Epidemiology ; 31(6): 852-859, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32841987

RESUMO

BACKGROUND: Hypertension in midlife is associated with increased risk of Alzheimer disease and vascular dementia late in life. In addition, some antihypertensive drugs have been proposed to have cognitive benefits, independent of their effect on hypertension. Consequently, there is potential to repurpose antihypertensive drugs for the prevention of dementia. This study systematically compared seven antihypertensive drug classes for this purpose, using the Clinical Practice Research Datalink. METHODS: We assessed treatments for hypertension in an instrumental variable analysis to address potential confounding and reverse causation. We used physicians' prescribing preference as an ordinal instrument, defined by the physicians' last seven prescriptions. Participants considered were new antihypertensive users between 1996 and 2016, aged 40 and over. RESULTS: We analyzed 849,378 patients, with total follow up of 5,497,266 patient-years. We estimated that ß-adrenoceptor blockers and vasodilator antihypertensives conferred small protective effects-for example, ß-adrenoceptor blockers were associated with 13 (95% confidence interval = 6, 20) fewer cases of any dementia per 1000 treated compared with other antihypertensives. CONCLUSIONS: We estimated small differences in the effects of antihypertensive drug classes on dementia outcomes. We also show that the magnitude of the differences between drug classes is smaller than that previously reported. Future research should look to implement other causal analysis methods to address biases in conventional observational research, with the ultimate aim of triangulating the evidence concerning this hypothesis.

20.
Nat Commun ; 11(1): 3519, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665587

RESUMO

Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.


Assuntos
Análise da Randomização Mendeliana/métodos , Índice de Massa Corporal , Epidemiologia , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
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