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1.
Artigo em Inglês | MEDLINE | ID: mdl-33627384

RESUMO

BACKGROUND: Inherited susceptibility is an important contributor to colorectal cancer (CRC) risk and rare variants in key genes or pathways could account in part for the missing proportion of CRC heritability. METHODS: We conducted an exome-wide association study including 2,327 cases and 2,966 controls of European ancestry from three large epidemiologic studies. Single variant associations were tested using logistic regression models adjusting for appropriate study-specific covariates. In addition, we examined the aggregate effects of rare coding variation at the gene and pathway levels using Bayesian model uncertainty techniques. RESULTS: In an exome-wide gene-level analysis, we identified ST6GALNAC2 as the top associated gene based on the Bayesian Risk Index (BRI) method (summary Bayes Factor[BF]BRI= 2604.23). A rare coding variant in this gene, rs139401613, was the top associated variant (P=1.01x10-6) in an exome-wide single variant analysis. Pathway-level association analyses based on the integrative Bayesian Risk Index (iBRI) method found extreme evidence of association with the DNA repair pathway (BFiBRI=17852.4), specifically with the non-homologous end joining (NHEJ, BFiBRI=437.95) and nucleotide excision repair (NER, BFiBRI=36.96) subpathways. The iBRI method also identified RPA2, PRKDC, ERCC5, ERCC8 as the top associated DNA repair genes (summary BFiBRI{greater than or equal to}10), with rs28988897, rs8178232, rs141369732, rs201642761 being the most likely associated variants in these genes, respectively. CONCLUSION: We identified novel variants and genes associated with CRC risk and provided additional evidence for a role of DNA repair in CRC tumorigenesis. IMPACT: This study provides new insights into the genetic predisposition to CRC which has potential for translation into improved risk prediction.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33578786

RESUMO

Studies on the association of maternal diabetes with motor development in children provide inconsistent findings. We searched MEDLINE/PubMed, EMBASE, Emcare, PsycINFO, and Google Scholar databases for primary observational, case-control, or cohort studies that report on the motor development of children exposed to maternal diabetes during pregnancy. Quality appraisal and data extraction were performed independently and in duplicate. A meta-analysis of summary measures was performed using random-effect models. Eighteen studies were identified for inclusion, however, only 13 were included in the meta-analysis. Exposure to maternal diabetes during pregnancy was associated with a lower pooled motor development in children and a decrease in both gross and fine motor development. Among all other factors, pre-existing diabetes and other gestational comorbidities, such as hypertension and obesity, or low socioeconomic status, also affect child development. Therefore, among children of diabetic mothers, those with other gestational comorbidities or pre-existing diabetes were more likely to be at risk developmentally.

3.
Am J Epidemiol ; 190(2): 230-238, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524116

RESUMO

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.


Assuntos
Estatura , Neoplasias Colorretais/epidemiologia , Neoplasias do Endométrio/epidemiologia , Adulto , Fatores Etários , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores Sexuais
4.
Artigo em Inglês | MEDLINE | ID: mdl-33567163

RESUMO

AIM: Decreased cancer incidence and reported changes to clinical management indicate that the COVID-19 pandemic has delayed cancer diagnosis and treatment. This study aimed to develop and apply a flexible model to estimate the impact of delayed diagnosis and treatment on survival outcomes and healthcare costs based on a shift in the disease stage at treatment initiation. METHODS: A model was developed and made publicly available to estimate population-level health economic outcomes by extrapolating and weighing stage-specific outcomes by the distribution of stages at treatment initiation. It was applied to estimate the impact of 3- and 6-month delays based on Australian data for stage I breast cancer, colorectal cancer, and lung cancer patients, and for T1 melanoma. Two approaches were explored to estimate stage shifts following a delay: (a) based on the relation between time to treatment initiation and overall survival (breast, colorectal, and lung cancer), and (b) based on the tumor growth rate (melanoma). RESULTS: Using a conservative once-off 3-month delay and considering only shifts from stage I/T1 to stage II/T2, 88 excess deaths and $12 million excess healthcare costs were predicted in Australia over 5 years for all patients diagnosed in 2020. For a 6-month delay, excess mortality and healthcare costs were 349 deaths and $46 million over 5 years. CONCLUSIONS: The health and economic impacts of delays in treatment initiation cause an imminent policy concern. More accurate individual patient data on shifts in stage of disease during and after the COVID-19 pandemic are critical for further analyses.

5.
Br J Cancer ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414539

RESUMO

BACKGROUND: Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR). METHODS: We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. RESULTS: No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96-1.03, P value = 0.90) with CRC was shown. CONCLUSIONS: Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.

6.
Gut ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414168

RESUMO

OBJECTIVE: Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers. DESIGN: Whole-exome sequencing of formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers. RESULTS: The combination of mutational signatures SBS18 and SBS36 contributing >30% of a CRC's signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10-5), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99); however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls. CONCLUSION: Assessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.

7.
J Mol Diagn ; 23(3): 358-371, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33383211

RESUMO

Patients in whom mismatch repair (MMR)-deficient cancer develops in the absence of pathogenic variants of germline MMR genes or somatic hypermethylation of the MLH1 gene promoter are classified as having suspected Lynch syndrome (SLS). Germline whole-genome sequencing (WGS) and targeted and genome-wide tumor sequencing were applied to identify the underlying cause of tumor MMR deficiency in SLS. Germline WGS was performed on samples from 14 cancer-affected patients with SLS, including two sets of first-degree relatives. MMR genes were assessed for germline pathogenic variants, including complex structural rearrangements and noncoding variants. Tumor tissue was assessed for somatic MMR gene mutations using targeted, whole-exome sequencing or WGS. Germline WGS identified pathogenic MMR variants in 3 of the 14 cases (21.4%), including a 9.5-megabase inversion disrupting MSH2 in a mother and daughter. Excluding these 3 MMR carriers, tumor sequencing identified at least two somatic MMR gene mutations in 8 of 11 tumors tested (72.7%). In a second mother-daughter pair, a somatic cause of tumor MMR deficiency was supported by the presence of double somatic MSH2 mutations in their respective tumors. More than 70% of SLS cases had double somatic MMR mutations in the absence of germline pathogenic variants in the MMR or other DNA repair-related genes on WGS, and, therefore, were confidently assigned a noninherited cause of tumor MMR deficiency.

8.
Genet Med ; 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33257847

RESUMO

PURPOSE: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants. METHODS: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. RESULTS: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. CONCLUSION: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

9.
BMC Med ; 18(1): 396, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33327948

RESUMO

BACKGROUND: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS: In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. CONCLUSIONS: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

10.
Diabetes Res Clin Pract ; : 108532, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33157114

RESUMO

INTRODUCTION: Sleep quality, quantity and timing have been shown to impact glycaemic control, with a role in insulin sensitivity, glucose tolerance and HbA1C levels, in both diabetic and non-diabetic populations. The aim of this study was to identify recommendations for sleep assessment and management in international clinical practice guidelines focused on type 2 diabetes mellitus management in adults. STUDY DESIGN: Systematic Review. METHODOLOGY: Clinical practice guidelines which focused on the management of type 2 diabetes mellitus in adults were included (n = 35). Two independent reviewers utilised the Appraisal of Guidelines for Research and Evaluation tool (AGREE) II and a third reviewer resolved any disagreements. Included guidelines were assessed for recommendations about sleep in diabetes management (n = 14). Data were extracted on sleep recommendations ,themes were generated from the extracted data and narrative syntheses were created. RESULTS: From 1114 identified papers, 35 guidelines met the inclusion criteria. Fourteen of these guidelines included recommendations pertaining to sleep, which broadly fell into five categories; sleep assessment, sleep as a therapeutic target, sleep and co-morbidities of type 2 diabetes mellitus, shift work and sleep and driving. Recommendations varied across guidelines. CONCLUSION: Few guidelines provided recommendations relating to assessment and management of sleep in type 2 diabetes care. Most of the recommendations were related to obstructive sleep apnoea. However, few guidelines discussed sleep as a therapeutic intervention for diabetes mellitus or described the potential importance of sleep quality and duration in glycaemic control. Prospero registration number: CRD42020142136.

11.
Int J Cancer ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33197272

RESUMO

Mammograms contain information that predicts breast cancer risk. We developed two novel mammogram-based breast cancer risk measures based on image brightness (Cirrocumulus) and texture (Cirrus). Their risk prediction when fitted together, and with an established measure of conventional mammographic density (Cumulus), is not known. We used three studies consisting of: 168 interval cases and 498 matched controls; 422 screen-detected cases and 1197 matched controls; and 354 younger-diagnosis cases and 944 controls frequency-matched for age at mammogram. We conducted conditional and unconditional logistic regression analyses of individually- and frequency-matched studies, respectively. We estimated measure-specific risk gradients as the change in odds per standard deviation of controls after adjusting for age and body mass index (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). For interval, screen-detected and younger-diagnosis cancer risks, the best fitting models (OPERAs [95% confidence intervals]) involved: Cumulus (1.81 [1.41-2.31]) and Cirrus (1.72 [1.38-2.14]); Cirrus (1.49 [1.32-1.67]) and Cirrocumulus (1.16 [1.03 to 1.31]); and Cirrus (1.70 [1.48 to 1.94]) and Cirrocumulus (1.46 [1.27-1.68]), respectively. The AUCs were: 0.73 [0.68-0.77], 0.63 [0.60-0.66], and 0.72 [0.69-0.75], respectively. Combined, our new mammogram-based measures have twice the risk gradient for screen-detected and younger-diagnosis breast cancer (P ≤ 10-12 ), have at least the same discriminatory power as the current polygenic risk score, and are more correlated with causal factors than conventional mammographic density. Discovering more information about breast cancer risk from mammograms could help enable risk-based personalised breast screening.

12.
Avian Dis ; 64(3): 401-406, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33205177

RESUMO

The purpose of the present study was to determine whether a correlation existed between chick mortality and the presence of Clostridium perfringens alpha-toxin and NetB-toxin genes (cpa and netB) in C. perfringens recovered from litter in commercial broiler houses. Because coccidiosis predisposes chickens to necrotic enteritis, the concentration of Eimeria oocysts in these samples was measured, and the numbers were used in similar correlation analyses. Litter samples were collected at 0, 2, and 4 wk growout from six broiler farms (18 houses total) during an anticoccidial drug (ACD) control program and from nine broiler farms (23 houses total) during an Eimeria vaccine (VAC) control program. Of these, litter samples were collected from five farms during both ACD and VAC programs. The litter samples were processed for Eimeria oocyst and C. perfringens spore enumerations by standard parasitologic and microbiologic techniques. DNA was also extracted for C. perfringens DNA for PCR detection of genes coding for alpha- and NetB-toxin. A general trend during the ACD programs was a transient decrease in both Eimeria maxima and non-E. maxima (Eamipt) numbers at 2 wk growout. The pattern was slightly different during VAC with E. maxima and Eamipt levels increasing over time. Average concentrations of C. perfringens in litter were highest at 2 wk (∼105-106 spores/g) during ACD and at placement during VAC (∼105-106 spores/g). During the ACD program, a strong correlation was observed between 0 and 3-wk chick mortality and the presence at placement (0 wk) of netB (r = 0.42-0.48) or cpa (r = 0.55-0.67). A very strong correlation was observed in 0-5-wk chick mortality and the presence of netB at 4 wk growout (0.73-0.95). During a VAC program, a strong correlation was only observed between the presence of netB at placement and 0-1-wk chick mortality (r = 0.67).

13.
JNCI Cancer Spectr ; 4(5): pkaa062, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33134836

RESUMO

Background: In many countries, population colorectal cancer (CRC) screening is based on age and family history, though more precise risk prediction could better target screening. We examined the impact of a CRC risk prediction model (incorporating age, sex, lifestyle, genomic, and family history factors) to target screening under several feasible screening scenarios. Methods: We estimated the model's predicted CRC risk distribution in the Australian population. Predicted CRC risks were categorized into screening recommendations under 3 proposed scenarios to compare with current recommendations: 1) highly tailored, 2) 3 risk categories, and 3) 4 sex-specific risk categories. Under each scenario, for 35- to 74-year-olds, we calculated the number of CRC screens by immunochemical fecal occult blood testing (iFOBT) and colonoscopy and the proportion of predicted CRCs over 10 years in each screening group. Results: Currently, 1.1% of 35- to 74-year-olds are recommended screening colonoscopy and 56.2% iFOBT, and 5.7% and 83.2% of CRCs over 10 years were predicted to occur in these groups, respectively. For the scenarios, 1) colonoscopy was recommended to 8.1% and iFOBT to 37.5%, with 36.1% and 50.1% of CRCs in each group; 2) colonoscopy was recommended to 2.4% and iFOBT to 56.0%, with 13.2% and 76.9% of cancers in each group; and 3) colonoscopy was recommended to 5.0% and iFOBT to 54.2%, with 24.5% and 66.5% of cancers in each group. Conclusions: A highly tailored CRC screening scenario results in many fewer screens but more cancers in those unscreened. Category-based scenarios may provide a good balance between number of screens and cancers detected and are simpler to implement.

14.
Avian Dis ; 64(3): 254-268, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33112952

RESUMO

A programmed self-destructive Salmonella vaccine delivery system was developed to facilitate efficient colonization in host tissues that allows release of the bacterial cell contents after lysis to stimulate mucosal, systemic, and cellular immunities against a diversity of pathogens. Adoption and modification of these technological improvements could form part of an integrated strategy for cost-effective control and prevention of infectious diseases, including those caused by parasitic pathogens. Avian coccidiosis is a common poultry disease caused by Eimeria. Coccidiosis has been controlled by medicating feed with anticoccidial drugs or administering vaccines containing low doses of virulent or attenuated Eimeria oocysts. Problems of drug resistance and nonuniform administration of these Eimeria resulting in variable immunity are prompting efforts to develop recombinant Eimeria vaccines. In this study, we designed, constructed, and evaluated a self-destructing recombinant attenuated Salmonella vaccine (RASV) lysis strain synthesizing the Eimeria tenella SO7 antigen. We showed that the RASV lysis strain χ11791(pYA5293) with a ΔsifA mutation enabling escape from the Salmonella-containing vesicle (or endosome) successfully colonized chicken lymphoid tissues and induced strong mucosal and cell-mediated immunities, which are critically important for protection against Eimeria challenge. The results from animal clinical trials show that this vaccine strain significantly increased food conversion efficiency and protection against weight gain depression after challenge with 105E. tenella oocysts with concomitant decreased oocyst output. More importantly, the programmed regulated lysis feature designed into this RASV strain promotes bacterial self-clearance from the host, lessening persistence of vaccine strains in vivo and survival if excreted, which is a critically important advantage in a vaccine for livestock animals. Our approach should provide a safe, cost-effective, and efficacious vaccine to control coccidiosis upon addition of additional protective Eimeria antigens. These improved RASVs can also be modified for use to control other parasitic diseases infecting other animal species.

15.
Med Teach ; : 1-8, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33045174

RESUMO

INTRODUCTION: Lockdowns during the COVID-19 pandemic had a disruptive effect on medical education when they prevented medical students accessing real patients. To address this, we piloted 35 medical students at home consulting remotely with patients. METHOD: We evaluated the intervention using qualitative analysis of post-experience interviews with a sample of 13 students and 10 clinical supervisors. RESULTS: The experience was perceived by all those interviewed to be both acceptable and educationally valuable. Data analysis revealed different models of implementation according to type of patients involved (acute, recently treated or expert patients) and type of communication platform used (AccuRx, Microsoft Teams or telephone). Practical and educational challenges were identified in relation to the following elements of the experience: patients consulting with students remotely, students being remotely supervised and students undertaking patient contact from home. Strategies for addressing these challenges were directly suggested by interviewees and also inferred from our analysis of the data. CONCLUSIONS: Remotely supervised medical students at home undertaking remote consultations with patients can be acceptable and educationally valuable. The intervention was piloted in a UK graduate entry medical course and so it would be useful to replicate this study in other medical student populations.

16.
Poult Sci ; 99(10): 5143-5148, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988553

RESUMO

Coccidiosis is one of the most prevalent diseases seen in the poultry industry leading to excessive economic losses. The aim of this study was to investigate the effect of butyric acid glycerol esters (BE) on the ileal and cecal microbiota in birds challenged with Eimeria maxima (EM). Ross 708 male broilers were fed a diet supplemented with 0 (control) or 0.25% BE from day 1. On day 21, half of the birds were infected with 103 EM oocysts. For determing microbiota, ileal and cecal contents and epithelial scrapings were collected at 7 and 10 D postinfection (PI). Alpha diversity of bacterial communities was mostly affected (P < 0.05) by time PI and EM infection. The richness of luminal bacterial populations in the ileum and ceca was affected (P < 0.05) by addition of BE and by time PI × EM × BE interaction, respectively. In the ileal and cecal luminal and mucosal bacterial communities, permutational multivariate analysis of variance (PERMANOVA, unweighted UniFrac) showed significant (P < 0.05) differences because of time PI and interaction between time PI, EM, and BE. Significant (P < 0.05) differences in taxonomic composition at the family level were observed in microbiota of luminal and mucosal populations of the ileum and ceca owing to time PI, EM, BE, and their interactions. The bacterial community present in the cecal lumen was characterized by the lowest number of differential bacteria, whereas the cecal mucosal community was characterized by the highest number of differentially abundant bacteria. In conclusion, our results show that EM infection and time PI has the biggest impact on microbial diversity in the chicken gut. The presence of BE in the diet had a limited effect on gut microbiota.

17.
JNCI Cancer Spectr ; 4(5): pkaa042, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32923935

RESUMO

Background: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location. Methods: We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided. Results: Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; P het =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; P het =.01) tumors. Conclusions: We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.

18.
Genes (Basel) ; 11(9)2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32967167

RESUMO

Eimeria, protozoan parasites from the phylum Apicomplexa, can cause the enteric disease coccidiosis in all farmed animals. Coccidiosis is commonly considered to be most significant in poultry; due in part to the vast number of chickens produced in the World each year, their short generation time, and the narrow profit margins associated with their production. Control of Eimeria has long been dominated by routine chemoprophylaxis, but has been supplemented or replaced by live parasite vaccination in a minority of production sectors. However, public and legislative demands for reduced drug use in food production is now driving dramatic change, replacing reliance on relatively indiscriminate anticoccidial drugs with vaccines that are Eimeria species-, and in some examples, strain-specific. Unfortunately, the consequences of deleterious selection on Eimeria population structure and genome evolution incurred by exposure to anticoccidial drugs or vaccines are unclear. Genome sequence assemblies were published in 2014 for all seven Eimeria species that infect chickens, stimulating the first population genetics studies for these economically important parasites. Here, we review current knowledge of eimerian genomes and highlight challenges posed by the discovery of new, genetically cryptic Eimeria operational taxonomic units (OTUs) circulating in chicken populations. As sequencing technologies evolve understanding of eimerian genomes will improve, with notable utility for studies of Eimeria biology, diversity and opportunities for control.

19.
Clin Orthop Relat Res ; 478(8): 1709-1718, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732555

RESUMO

BACKGROUND: Burnout and depression among healthcare professionals and trainees remain alarmingly common. In 2009, 56% of orthopaedic surgery residents reported burnout. Alcohol and illicit drug use are potential exacerbating factors of burnout and depression; however, these have been scarcely studied in residency populations. QUESTIONS/PURPOSES: (1) What proportion of orthopaedic residents report symptoms of burnout and depression? (2) What factors are independently associated with an orthopaedic resident reporting emotional exhaustion, depersonalization, low personal accomplishment, and depression? (3) What proportion of orthopaedic residents report hazardous alcohol or drug use? (4) What factors are independently associated with an orthopaedic resident reporting hazardous alcohol or drug use? METHODS: We asked 164 orthopaedic surgery programs to have their residents participate in a 34-question internet-based, anonymous survey, 28% of which (46 of 164) agreed. The survey was distributed to all 1147 residents from these programs, and 58% (661 of 1147) of these completed the survey. The respondents were evenly distributed among training years. Eighty-three percent (551 of 661) were men, 15% (101 of 661) were women, and 1% (nine of 661) preferred not to provide their gender. The survey asked about demographics, educational debt, sleep and work habits, perceived peer or program support, and substance use, and validated instruments were used to assess burnout (abbreviated Maslach Burnout Inventory), depression (Patient Health Questionnaire-2), and hazardous alcohol use (Alcohol Use Disorder Identification Test-Consumption). The main outcome measures included overall burnout, emotional exhaustion, depersonalization, low personal accomplishment, depression, and hazardous alcohol and drug use. Using the variables gathered in the survey, we performed an exploratory analysis to identify significant associations for each of the outcomes, followed by a multivariable analysis. RESULTS: Burnout was reported by 52% (342 of 661) of residents. Thirteen percent of residents (83 of 656) had positive screening results for depression. Factors independently associated with high emotional exhaustion scores included early training year (odds ratio 1.15; 95% confidence interval, 1.01-1.32; p = 0.03) unmanageable work volume (OR 3.13; 95% CI, 1.45-6.67; p < 0.01), inability to attend health maintenance appointments (OR 3.23; 95% CI, 1.69-6.25; p < 0.01), lack of exercise (OR 1.69; 95% CI, 1.08-2.70; p = 0.02), and lack of program support (OR 3.33; 95% CI, 2.00-5.56; p < 0.01). Factors independently associated with depersonalization included early training year (OR 1.27; 95% CI, 1.12-1.41; p < 0.01), inability to attend health maintenance appointments (OR 2.70; 95% CI, 1.67-4.35; p < 0.01), and lack of co-resident support (OR 2.52; 95% CI, 1.52-4.18; p < 0.01). Low personal accomplishment was associated with a lack of co-resident support (OR 2.85; 95% CI, 1.54-5.28; p < 0.01) and lack of program support (OR 2.33; 95% CI, 1.32-4.00; p < 0.01). Factors associated with depression included exceeding duty hour restrictions (OR 2.50; 95% CI, 1.43-4.35; p < 0.01) and lack of program support (OR 3.85; 95% CI, 2.08-7.14; p < 0.01). Sixty-one percent of residents (403 of 656) met the criteria for hazardous alcohol use. Seven percent of residents (48 of 656) reported using recreational drugs in the previous year. Factors independently associated with hazardous alcohol use included being a man (OR 100; 95% CI, 35-289; p < 0.01), being Asian (OR 0.31; 95% CI, 0.17-0.56; p < 0.01), single or divorced marital status (OR 2.33; 95% CI, 1.47-3.68; p < 0.01), and more sleep per night (OR 1.92; 95% CI, 1.21-3.06; p < 0.01). Finally, single or divorced marital status was associated with drug use in the past year (OR 2.30; 95% CI, 1.26-4.18; p < 0.01). CONCLUSIONS: The lack of wellness among orthopaedic surgery residents is troubling, especially because most of the associated risk factors are potentially modifiable. Programs should capitalize on the modifiable elements to combat burnout and improve overall wellbeing. Programs should also educate residents on burnout, focus on work volume, protect access to health maintenance, nurture those in the early years of training, and remain acutely aware of the risk of substance abuse. Orthopaedic surgery trainees should strive to encourage peer support, cultivate personal responsibility, and advocate for themselves or peers when faced with challenges. At a minimum, programs and educational leaders should foster an environment in which admitting symptoms of burnout is not seen as a weakness or failure. LEVEL OF EVIDENCE: Level II, prognostic study.

20.
PLoS Genet ; 16(8): e1008947, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32833970

RESUMO

Genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with various phenotypes, but together they explain only a fraction of heritability, suggesting many variants have yet to be discovered. Recently it has been recognized that incorporating functional information of genetic variants can improve power for identifying novel loci. For example, S-PrediXcan and TWAS tested the association of predicted gene expression with phenotypes based on GWAS summary statistics by leveraging the information on genetic regulation of gene expression and found many novel loci. However, as genetic variants may have effects on more than one gene and through different mechanisms, these methods likely only capture part of the total effects of these variants. In this paper, we propose a summary statistics-based mixed effects score test (sMiST) that tests for the total effect of both the effect of the mediator by imputing genetically predicted gene expression, like S-PrediXcan and TWAS, and the direct effects of individual variants. It allows for multiple functional annotations and multiple genetically predicted mediators. It can also perform conditional association analysis while adjusting for other genetic variants (e.g., known loci for the phenotype). Extensive simulation and real data analyses demonstrate that sMiST yields p-values that agree well with those obtained from individual level data but with substantively improved computational speed. Importantly, a broad application of sMiST to GWAS is possible, as only summary statistics of genetic variant associations are required. We apply sMiST to a large-scale GWAS of colorectal cancer using summary statistics from ∼120, 000 study participants and gene expression data from the Genotype-Tissue Expression (GTEx) project. We identify several novel and secondary independent genetic loci.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Neoplasias Colorretais/patologia , Biologia Computacional , Regulação Neoplásica da Expressão Gênica/genética , Variação Genética/genética , Genótipo , Humanos , Modelos Estatísticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
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