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1.
Neurology ; 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627500

RESUMO

OBJECTIVE: We sought to identify an abbreviated test of impaired olfaction, amenable for use in busy clinical environments in prodromal (isolated REM sleep Behavior Disorder (iRBD)) and manifest Parkinson's disease (PD). METHODS: 890 PD and 313 control participants in the Discovery cohort study underwent Sniffin' stick odour identification assessment. Random forests were initially trained to distinguish individuals with poor (functional anosmia/hyposmia) and good (normosmia/super-smeller) smell ability using all 16 Sniffin' sticks. Models were retrained using the top 3 sticks ranked by order of predictor importance. One randomly selected 3-stick model was tested in a second independent PD dataset (n=452) and in two iRBD datasets (Discovery n=241; Marburg n=37) before being compared to previously described abbreviated Sniffin' stick combinations. RESULTS: In differentiating poor from good smell ability, the overall area under the curve (AUC) value associated with the top 3 sticks (Anise/Licorice/Banana) was 0.95 in the development dataset (sensitivity:90%, specificity:92%, positive predictive value:92%, negative predictive value:90%). Internal and external validation confirmed AUCs≥0.90. The combination of 3-stick model determined poor smell and an RBD screening questionnaire score of ≥5, separated iRBD from controls with a sensitivity, specificity, PPV and NPV of 65%, 100%, 100% and 30%. CONCLUSIONS: Our 3-Sniffin'-stick model holds potential utility as a brief screening test in the stratification of individuals with PD and iRBD according to olfactory dysfunction. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a 3-Sniffin'-stick model distinguishes individuals with poor and good smell ability and can be used to screen for individuals with iRBD.

2.
Hum Mol Genet ; 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33517400

RESUMO

Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33426560

RESUMO

BACKGROUND: Cohort studies are among the most robust of observational studies but have issues with external validity. This study assesses threats to external validity (generalisability) in the European QUALity (EQUAL) study, a cohort study of people over 65 years with stage 4/5 chronic kidney disease. METHODS: Patients meeting the EQUAL inclusion criteria were identified in The Health Improvement Network database and stratified into those attending renal units (secondary care cohort-SCC) and not (primary care cohort-PCC). Survival, progression to renal replacement therapy (RRT), and hospitalisation were compared. RESULTS: The analysis included 250, 633, and 2,464 patients in EQUAL, PCC, and SCC. EQUAL had a higher proportion of men in comparison to PCC and SCC (60.0% vs. 34.8% vs. 51.4%). Increasing age (≥85 years odds ratio (OR) 0.25 (95% confidence interval (CI) 0.15-0.40)) and comorbidity (Charlson Comorbidity Index ≥ 4 OR 0.69 (CI 0.52-0.91)) were associated with non-participation in EQUAL. EQUAL had a higher proportion of patients starting RRT at 1 year compared to SCC (8.1% vs. 2.1%%, p < 0.001). Patients in the PCC and SCC had increased risk of Hospitalisation (incidence rate ratio=1.76 (95% CI 1.27-2.47) & 2.13 (95% CI 1.59-2.86)) and mortality at one year (hazard ratio=3.48 (95% CI 2.1-5.7) & 1.7 (95% CI 1.1-2.7)) compared to EQUAL. CONCLUSIONS: This study provides evidence of how participants in a cohort study can differ from the broader population of patients, which is essential when considering external validity and applying to local practice.

4.
Clin J Am Soc Nephrol ; 16(2): 194-203, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33468533

RESUMO

BACKGROUND AND OBJECTIVES: Pre-emptive kidney transplantation is advocated as best practice for children with kidney failure who are transplant eligible; however, it is limited by late presentation. We aimed to determine whether socioeconomic deprivation and/or geographic location (distance to the center and rural/urban residence) are associated with late presentation, and to what degree these factors could explain differences in accessing pre-emptive transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cohort study using prospectively collected United Kingdom Renal Registry and National Health Service Blood and Transplant data from January 1, 1996 to December 31, 2016 was performed. We included children aged >3 months to ≤16 years at the start of KRT. Multivariable logistic regression models were used to determine associations between the above exposures and our outcomes: late presentation (defined as starting KRT within 90 days of first nephrology review) and pre-emptive transplantation, with a priori specified covariates. RESULTS: Analysis was performed on 2160 children (41% females), with a median age of 3.8 years (interquartile range, 0.2-9.9 years) at first nephrology review. Excluding missing data, 478 were late presenters (24%); 565 (26%) underwent pre-emptive transplantation, none of whom were late presenting. No association was seen between distance or socioeconomic deprivation with late presentation, in crude or adjusted analyses. Excluding late presenters, greater area affluence was associated with higher odds of pre-emptive transplantation, (odds ratio, 1.20 per quintile greater affluence; 95% confidence interval, 1.10 to 1.31), with children of South Asian (odds ratio, 0.52; 95% confidence interval, 0.36 to 0.76) or Black ethnicity (odds ratio, 0.31; 95% confidence interval, 0.12 to 0.80) less likely to receive one. A longer distance to the center was associated with pre-emptive transplantation on crude analyses; however, this relationship was attenuated (odds ratio, 1.02 per 10 km; 95% confidence interval, 0.99 to 1.05) in the multivariable model. CONCLUSIONS: Socioeconomic deprivation or geographic location are not associated with late presentation in children in the United Kingdom. Geographic location was not independently associated with pre-emptive transplantation; however, children from more affluent areas were more likely to receive a pre-emptive transplant.

5.
J Bone Miner Res ; 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33373491

RESUMO

Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997-2016) and SIDIAP (2007-2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m2 , aged 40 years or older were identified. New bisphosphonate users were propensity score-matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD. © 2020 American Society for Bone and Mineral Research (ASBMR).

6.
PLoS One ; 15(12): e0244709, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382793

RESUMO

BACKGROUND: When detected early, inexpensive measures can slow chronic kidney disease progression to kidney failure which, for children, confers significant morbidity and impacts growth and development. Our objective was to determine the incidence of late presentation of childhood chronic kidney disease and its associated risk factors. METHODS: We searched MEDLINE, Embase, PubMed, Web of Science, Cochrane Library and CINAHL, grey literature and registry websites for observational data describing children <21 years presenting to nephrology services, with reference to late presentation (or synonyms thereof). Independent second review of eligibility, data extraction, and risk of bias was undertaken. Meta-analysis was used to generate pooled proportions for late presentation by definition and investigate risk factors. Meta-regression was undertaken to explore heterogeneity. RESULTS: Forty-five sources containing data from 30 countries were included, comprising 19,339 children. Most studies (37, n = 15,772) described children first presenting in kidney failure as a proportion of the chronic kidney disease population (mean proportion 0.43, 95% CI 0.34-0.54). Using this definition, the median incidence was 2.1 (IQR 0.9-3.9) per million age-related population. Risk associations included non-congenital disease and older age. Studies of hospitalised patients, or from low- or middle-income countries, that had older study populations than high-income countries, had higher proportions of late presentation. CONCLUSIONS: Late presentation is a global problem among children with chronic kidney disease, with higher proportions seen in studies of hospitalised children or from low/middle-income countries. Children presenting late are older and more likely to have non-congenital kidney disease than timely presenting children. A consensus definition is important to further our understanding and local populations should identify modifiable barriers beyond age and disease to improve access to care.

7.
Int J Epidemiol ; 2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-33221853

RESUMO

BACKGROUND: Low socio-economic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear. METHODS: We examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles in ∼30 000 adults and 4000 children across 10 UK and Finnish cohort studies. RESULTS: In risk-factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA), omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including levels of their respective lipid constituents) and cholesterol measures across different density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared with non-manual workers. All three indicators of low SEP were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids. CONCLUSIONS: Our work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally unfavourable metabolic profile, consistent across ages and cohorts. The metabolites we found to be associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities.

8.
Eur J Cancer Care (Engl) ; : e13345, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33184924

RESUMO

BACKGROUND: When GPs suspect a brain tumour, a referral for specialist assessment and subsequent brain imaging is generally the first option. NICE has recommended that GPs have rapid direct access to brain imaging for adults with progressive sub-acute loss of central nervous function; however, no studies have evaluated the cost-effectiveness. METHODS: We developed a cost-effectiveness model based on data from one region of the UK with direct access computed tomography (DACT), routine data from GP records and the literature, to explore whether unrestricted DACT for patients with suspected brain tumour might be more cost-effective than criteria-based DACT or no DACT. RESULTS: Although criteria-based DACT allows some patients without brain tumour to avoid imaging, our model suggests this may increase costs of diagnosis due to non-specific risk criteria and high costs of diagnosing or 'ruling out' brain tumours by other pathways. For patients diagnosed with tumours, differences in outcomes between the three diagnostic strategies are small. CONCLUSIONS: Unrestricted DACT may reduce diagnostic costs; however, the evidence is not strong and further controlled studies are required. Criteria-based access to CT for GPs might reduce demand for DACT, but imperfect sensitivity and specificity of current risk stratification mean that it will not necessarily be cost-effective.

9.
J Arthroplasty ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33160808

RESUMO

BACKGROUND: The National Joint Registry for England, Wales, Northern Ireland and the Isle of Man (NJR) has monitored the performance of consultant surgeons performing primary total hip (THR) or knee replacements (KR) since 2007. The aims of this study were: 1) To describe the surgical practice of consultant hip and knee replacement surgeons in the National Joint Registry for England and Wales (NJR), stratified by potential outlier status for revisions. 2) To compare the practice of revision outlier and non-outlier surgeons. METHODS: We combined NJR primary THR and KR data from 2008-2017 separately with relevant anonymised NJR outlier notification records. We described the surgical practice of outliers and non-outliers by surgical workload, implant choice, and patients' clinical and demographic characteristics. We explored associations between surgeon-level factors and outlier status with conditional logistic regression models. RESULTS: We included 764,888 primary THRs by 3213 surgeons and 889,954 primary KRs by 3084 surgeons performed between 2008-2017. One hundred and eleven (3.5%) THR and 114 (3.7%) KR consultant surgeons were potential revision outliers. Surgeons who used more types of implant had increased odds of being an outlier (KR: OR/additional implant = 1.35, 95%CI 1.17-1.55; THR: OR = 1.12, 95%CI 1.06-1.18). CONCLUSIONS: The use of more types of implant is associated with increased risk of being a potential revision outlier. Further research is required to understand why surgeons use many different implants and to what extent this is responsible for the effects observed here.

10.
Int J Epidemiol ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33150399

RESUMO

BACKGROUND: It is established that Alzheimer's disease (AD) patients experience sleep disruption. However, it remains unknown whether disruption in the quantity, quality or timing of sleep is a risk factor for the onset of AD. METHODS: We used the largest published genome-wide association studies of self-reported and accelerometer-measured sleep traits (chronotype, duration, fragmentation, insomnia, daytime napping and daytime sleepiness), and AD. Mendelian randomization (MR) was used to estimate the causal effect of self-reported and accelerometer-measured sleep parameters on AD risk. RESULTS: Overall, there was little evidence to support a causal effect of sleep traits on AD risk. There was some suggestive evidence that self-reported daytime napping was associated with lower AD risk [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.50-0.99). Some other sleep traits (accelerometer-measured 'eveningness' and sleep duration, and self-reported daytime sleepiness) had ORs of a similar magnitude to daytime napping, but were less precisely estimated. CONCLUSIONS: Overall, we found very limited evidence to support a causal effect of sleep traits on AD risk. Our findings provide tentative evidence that daytime napping may reduce AD risk. Given that this is the first MR study of multiple self-report and objective sleep traits on AD risk, findings should be replicated using independent samples when such data become available.

11.
J Clin Med ; 9(11)2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-33233422

RESUMO

There is ethnic inequity in access to living-donor kidney transplants in the UK. This study asked kidney patients from Black, Asian and minority ethnic groups why members of their family were not able to be living kidney donors. Responses were compared with responses from White individuals. This questionnaire-based mixed-methods study included adults transplanted between 1/4/13-31/3/17 at 14 UK hospitals. Participants were asked to indicate why relatives could not donate, selecting all options applicable from: Age; Health; Weight; Location; Financial/Cost; Job; Blood group; No-one to care for them after donation. A box entitled 'Other-please give details' was provided for free-text entries. Multivariable logistic regression was used to analyse the association between the likelihood of selecting each reason for non-donation and the participant's self-reported ethnicity. Qualitative responses were analysed using inductive thematic analysis. In total, 1240 questionnaires were returned (40% response). There was strong evidence that Black, Asian and minority ethnic group individuals were more likely than White people to indicate that family members lived too far away to donate (adjusted odds ratio (aOR) = 3.25, 95% Confidence Interval (CI) 2.30-4.58), were prevented from donating by financial concerns (aOR = 2.95, 95% CI 2.02-4.29), were unable to take time off work (aOR = 1.88, 95% CI 1.18-3.02), were "not the right blood group" (aOR = 1.65, 95% CI 1.35-2.01), or had no-one to care for them post-donation (aOR = 3.73, 95% CI 2.60-5.35). Four qualitative themes were identified from responses from Black, Asian and minority ethnic group participants: 'Burden of disease within the family'; 'Differing religious interpretations'; 'Geographical concerns'; and 'A culture of silence'. Patients perceive barriers to living kidney donation in the UK Black, Asian and minority ethnic population. If confirmed, these could be targeted by interventions to redress the observed ethnic inequity.

12.
Front Neurol ; 11: 576121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33071952

RESUMO

The impact of sex and gender on disease incidence, progression, and provision of care has gained increasing attention in many areas of medicine. Biological factors-sex-and sociocultural and behavioral factors-gender-greatly impact on health and disease. While sex can modulate disease progression and response to therapy, gender can influence patient-provider communication, non-pharmacological disease management, and need for assistance. Sex and gender issues are especially relevant in chronic progressive diseases, such as Parkinson's disease (PD), because affected patients require multidisciplinary care for prolonged periods of time. In this perspective paper, we draw from evidence in the field of PD and various other areas of medicine to address how sex and gender could impact PD care provision. We highlight examples for which differences have been reported and formulate research topics and considerations on how to optimize the multidisciplinary care of persons with PD.

13.
Mov Disord ; 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33111402

RESUMO

BACKGROUND: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies have identified variants associated with disease risk, but not progression. The objective of the current study was to identify genetic variants associated with PD progression. METHODS: We analyzed 3 large longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntington's disease, in which we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analyzed in linear regression in genome-wide association studies. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis. RESULTS: There was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE ε4 tagging variant, rs429358, was significantly associated with composite and cognitive progression in PD. Conditional analysis revealed several independent signals in the APOE locus for cognitive progression. No single variants were associated with motor progression. However, in gene-based analysis, ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (P = 5.3 × 10-6 ). CONCLUSIONS: We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE ε4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts are needed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.

14.
Cochrane Database Syst Rev ; 9: CD013564, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32901926

RESUMO

BACKGROUND: Brain tumours are recognised as one of the most difficult cancers to diagnose because presenting symptoms, such as headache, cognitive symptoms, and seizures, may be more commonly attributable to other, more benign conditions. Interventions to reduce the time to diagnosis of brain tumours include national awareness initiatives, expedited pathways, and protocols to diagnose brain tumours, based on a person's presenting symptoms and signs; and interventions to reduce waiting times for brain imaging pathways. If such interventions reduce the time to diagnosis, it may make it less likely that people experience clinical deterioration, and different treatment options may be available. OBJECTIVES: To systematically evaluate evidence on the effectiveness of interventions that may influence: symptomatic participants to present early (shortening the patient interval), thresholds for primary care referral (shortening the primary care interval), and time to imaging diagnosis (shortening the secondary care interval and diagnostic interval). To produce a brief economic commentary, summarising the economic evaluations relevant to these interventions. SEARCH METHODS: For evidence on effectiveness, we searched CENTRAL, MEDLINE, and Embase from January 2000 to January 2020; Clinicaltrials.gov to May 2020, and conference proceedings from 2014 to 2018. For economic evidence, we searched the UK National Health Services Economic Evaluation Database from 2000 to December 2014. SELECTION CRITERIA: We planned to include studies evaluating any active intervention that may influence the diagnostic pathway, e.g. clinical guidelines, direct access imaging, public health campaigns, educational initiatives, and other interventions that might lead to early identification of primary brain tumours. We planned to include randomised and non-randomised comparative studies. Included studies would include people of any age, with a presentation that might suggest a brain tumour. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed titles identified by the search strategy, and the full texts of potentially eligible studies. We resolved discrepancies through discussion or, if required, by consulting another review author. MAIN RESULTS: We did not identify any studies for inclusion in this review. We excluded 115 studies. The main reason for exclusion of potentially eligible intervention studies was their study design, due to a lack of control groups. We found no economic evidence to inform a brief economic commentary on this topic. AUTHORS' CONCLUSIONS: In this version of the review, we did not identify any studies that met the review inclusion criteria for either effectiveness or cost-effectiveness. Therefore, there is no evidence from good quality studies on the best strategies to reduce the time to diagnosis of brain tumours, despite the prioritisation of research on early diagnosis by the James Lind Alliance in 2015. This review highlights the need for research in this area.


Assuntos
Neoplasias Encefálicas/diagnóstico , Detecção Precoce de Câncer/métodos , Humanos , Fatores de Tempo
15.
Cell ; 182(5): 1198-1213.e14, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32888493

RESUMO

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

16.
Cell ; 182(5): 1214-1231.e11, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32888494

RESUMO

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

17.
BMJ Open ; 10(9): e033045, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928843

RESUMO

OBJECTIVE: To investigate the association of volume of total hip arthroplasty (THA) between consultants and within the same consultant in the previous year and the hazard of revision using multilevel survival models. DESIGN: Prospective cohort study using data from a national joint replacement register. SETTING: Elective THA across all private and public centres in England and Wales between April 2003 and February 2017. PARTICIPANTS: Patients aged 50 years or more undergoing THA for osteoarthritis. INTERVENTION: The volume of THA conducted in the preceding 365 days to the index procedure. MAIN OUTCOME AND MEASURE: Revision surgery (excision, addition or replacement) of a primary THA. RESULTS: Of the 579 858 patients undergoing primary THA (mean baseline age 69.8 years (SD 10.2)), 61.1% were women. Multilevel survival found differing results for between and within-consultant effects. There was a strong volume-revision association between consultants, with a near-linear 43.3% (95% CI 29.1% to 57.4%) reduction of the risk of revision comparing consultants with volumes between 1 and 200 procedures annually. Changes in individual surgeons (within-consultant) case volume showed no evidence of an association with revision. CONCLUSION: Separation of between-consultant and within-consultant effects of surgical volume reveals how volume contributes to the risk of revision after THA. The lack of association within-consultants suggests that individual changes to consultant volume alone will have little effect on outcomes following THA.These novel findings provide strong evidence supporting the practice of specialisation of hip arthroplasty. It does not support the practice of low-volume consultants increasing their personal volume as it is unlikely their results would improve if this is the only change. Limiting the exposure of patients to consultants with low volumes of THA and greater utilisation of centres with higher volume surgeons with better outcomes may be beneficial to patients.

18.
PLoS Med ; 17(8): e1003234, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32764760

RESUMO

BACKGROUND: In common with many other low- and middle-income countries (LMICs), rural to urban migrants in India are at increased risk of obesity, but it is unclear whether this is due to increased energy intake, reduced energy expenditure, or both. Knowing this and the relative contribution of specific dietary and physical activity behaviours to greater adiposity among urban migrants could inform policies for control of the obesity epidemic in India and other urbanising LMICs. In the Indian Migration Study, we previously found that urban migrants had greater prevalence of obesity and diabetes compared with their nonmigrant rural-dwelling siblings. In this study, we investigated the relative contribution of energy intake and expenditure and specific diet and activity behaviours to greater adiposity among urban migrants in India. METHODS AND FINDINGS: The Indian Migration Study was conducted between 2005 and 2007. Factory workers and their spouses from four cities in north, central, and south of India, together with their rural-dwelling siblings, were surveyed. Self-reported data on diet and physical activity was collected using validated questionnaires, and adiposity was estimated from thickness of skinfolds. The association of differences in dietary intake, physical activity, and adiposity between siblings was examined using multivariable linear regression. Data on 2,464 participants (median age 43 years) comprised of 1,232 sibling pairs (urban migrant and their rural-dwelling sibling) of the same sex (31% female) were analysed. Compared with the rural siblings, urban migrants had 18% greater adiposity, 12% (360 calories/day) more energy intake, and 18% (11 kilojoules/kg/day) less energy expenditure (P < 0.001 for all). Energy intake and expenditure were independently associated with increased adiposity of urban siblings, accounting for 4% and 6.5% of adiposity difference between siblings, respectively. Difference in dietary fat/oil (10 g/day), time spent engaged in moderate or vigorous activity (69 minutes/day), and watching television (30 minutes/day) were associated with difference in adiposity between siblings, but no clear association was observed for intake of fruits and vegetables, sugary foods and sweets, cereals, animal and dairy products, and sedentary time. The limitations of this study include a cross-sectional design, systematic differences in premigration characteristics of migrants and nonmigrants, low response rate, and measurement error in estimating diet and activity from questionnaires. CONCLUSIONS: We found that increased energy intake and reduced energy expenditure contributed equally to greater adiposity among urban migrants in India. Policies aimed at controlling the rising prevalence of obesity in India and potentially other urbanising LMICs need to be multicomponent, target both energy intake and expenditure, and focus particularly on behaviours such as dietary fat/oil intake, time spent on watching television, and time spent engaged in moderate or vigorous intensity physical activity.


Assuntos
Adiposidade/fisiologia , Dieta/tendências , Ingestão de Energia/fisiologia , Exercício Físico/fisiologia , População Rural/tendências , Migrantes , População Urbana/tendências , Adulto , Índice de Massa Corporal , Estudos Transversais , Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Metabolismo Energético/fisiologia , Feminino , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Autorrelato
19.
BMJ Open ; 10(8): e033646, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32859657

RESUMO

OBJECTIVES: This study has three objectives. (1) Investigate the association between body mass index (BMI) and the efficacy of primary hip replacement using a patient-reported outcome measure (PROMs) with a measurement floor and ceiling, (2) Explore the performance of different estimation methods to estimate change in PROMs score following surgery using a simulation study and real word data where data has measurement floors and ceilings and (3) Lastly, develop guidance for practising researchers on the analysis of PROMs in the presence of floor and ceiling effects. DESIGN: Simulation study and prospective national medical device register. SETTING: National Register of Joint Replacement and Medical Devices. METHODS: Using a Monte Carlo simulation study and data from a national joint replacement register (162 513 patients with pre- and post-surgery PROMs), we investigate simple approaches for the analysis of outcomes with floor and ceiling effects that are measured at two occasions: linear and Tobit regression (baseline adjusted analysis of covariance, change-score analysis, post-score analysis) in addition to linear and multilevel Tobit models. PRIMARY OUTCOME: The primary outcome of interest is change in PROMs from pre-surgery to 6 months post-surgery. RESULTS: Analysis of data with floor and ceiling effects with models that fail to account for these features induce substantial bias. Single-level Tobit models only correct for floor or ceiling effects when the exposure of interest is not associated with the baseline score. In observational data scenarios, only multilevel Tobit models are capable of providing unbiased inferences. CONCLUSIONS: Inferences from pre- post-studies that fail to account for floor and ceiling effects may induce spurious associations with substantial risk of bias. Multilevel Tobit models indicate the efficacy of total hip replacement is independent of BMI. Restricting access to total hip replacement based on a patients BMI can not be supported by the data.

20.
PLoS Med ; 17(7): e1003183, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32692751

RESUMO

BACKGROUND: Undernutrition during intrauterine life and early childhood is hypothesised to increase the risk of cardiovascular disease (Developmental Origins of Health and Disease Hypothesis), but experimental evidence from humans is limited. This hypothesis has major implications for control of the cardiovascular disease epidemic in South Asia (home to a quarter of world's population), where a quarter of newborns have low birth weight. We investigated whether, in an area with prevalent undernutrition, supplemental nutrition offered to pregnant women and their offspring below the age of 6 years was associated with a lower risk of cardiovascular disease in the offspring when they were young adults. METHODS AND FINDINGS: The Hyderabad Nutrition Trial was a community-based nonrandomised controlled intervention trial conducted in 29 villages near Hyderabad, India (1987-1990). Protein-calorie food supplement was offered daily to pregnant and lactating women (2.09 MJ energy and 20-25 g protein) and their offspring (1.25 MJ energy and 8-10 g protein) until the age of six years in the 15 intervention villages, but not in the 14 control villages. A total of 1,826 participants (949 from the intervention villages and 877 from the control villages, representing 70% of the cohort) at a mean age of 21.6 years (62% males) were examined between 2009 and 2012. The mean body mass index (BMI) of the participants was 20 kg/m2 and the mean systolic blood pressure was 115 mm Hg. The age, sex, socioeconomic position, and urbanisation-adjusted effects of intervention (beta coefficients and 95% confidence intervals) on outcomes were as follows: carotid intima-media thickness, 0.01 mm (-0.01 to 0.03), p = 0.36; arterial stiffness (augmentation index), -1.1% (-2.5 to 0.3), p = 0.097; systolic blood pressure, 0.5 mm Hg (-0.6 to 1.6), p = 0.36; BMI, -0.13 kg/m2 (-0.75 to 0.09), p = 0.093; low-density lipoprotein (LDL) cholesterol, 0.06 mmol/L (-0.07 to 0.2), p = 0.37; and fasting insulin (log), -0.06 mU/L (-0.19 to 0.07), p = 0.43. The limitations of this study include nonrandomised allocation of intervention and lack of data on compliance, and potential for selection bias due to incomplete follow-up. CONCLUSIONS: Our results showed that in an area with prevalent undernutrition, protein-calorie food supplements offered to pregnant women and their offspring below the age of 6 years were not associated with lower levels of cardiovascular risk factors among offspring when they were young adults. Our findings, coupled with evidence from other intervention studies to date, suggest that policy makers should attach limited value to cardiovascular health benefits of maternal and child protein-calorie food supplementation programmes.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Suplementos Nutricionais , Adolescente , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Espessura Intima-Media Carotídea , Feminino , Seguimentos , Humanos , Índia , Masculino , Desnutrição/dietoterapia , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Fatores de Risco , Adulto Jovem
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