Multilocus Heterozygosity and Coronary Heart Disease: Nested Case-Control Studies in Men and Women

Generalized allelic heterozygosity has been proposed to improve reproductive fitness and has been associated with higher blood pressure, but its association with chronic disease is not well characterized.Using the Affymetrix Genome-Wide Human 6.0 array, we performed whole genome scans in parallel case-control studies of coronary heart disease (CHD) nested in the Health Professionals Follow-up Study and Nurses' Health Study. We examined ~700,000 single nucleotide polymorphisms (SNPs) in 435 men with incident CHD and 878 matched controls and 435 women with incident CHD with 931 matched controls. We examined the relationship of genome-wide heterozygosity with risk of incident of CHD and with baseline levels of cardiovascular risk factors.In both cohorts, approximately 227650 (SD 2000) SNPs were heterozygous. The number of heterozygous SNPs was not related to risk of CHD in either men or women (adjusted odds ratios per 2000 heterozygous SNPs 1.01 [95% confidence interval, 0.91-1.13] in women and 0.94 [0.84-1.06] in men). We also found no consistent associations of genome-wide heterozygosity with levels of lipids, inflammatory markers, adhesion molecules, homocysteine, adiponectin, or body-mass index.In these parallel nested case-control studies, we found no relationship of multilocus heterozygosity with risk of CHD or its major risk factors. Studies in other populations are needed to rule out associations with lower levels of heterozygosity

Dietary fiber intake and mortality among survivors of myocardial infarction: prospective cohort study

Objective: To evaluate the associations of dietary fiber after myocardial infarction (MI) and changes in dietary fiber intake from before to after MI with all cause and cardiovascular mortality. Design: Prospective cohort study. Setting: Two large prospective cohort studies of US women and men with repeated dietary measurements: the Nurses’ Health Study and the Health Professionals Follow-Up Study. Participants: 2258 women and 1840 men who were free of cardiovascular disease, stroke, or cancer at enrollment, survived a first MI during follow-up, were free of stroke at the time of initial onset of MI, and provided food frequency questionnaires pre-MI and at least one post-MI. Main outcome measures Associations of dietary fiber post-MI and changes from before to after MI with all cause and cardiovascular mortality using Cox proportional hazards models, adjusting for drug use, medical history, and lifestyle factors. Results: Higher post-MI fiber intake was significantly associated with lower all cause mortality (comparing extreme fifths, pooled hazard ratio 0.75, 95% confidence interval 0.58 to 0.97). Greater intake of cereal fiber was more strongly associated with all cause mortality (pooled hazard ratio 0.73, 0.58 to 0.91) than were other sources of dietary fiber. Increased fiber intake from before to after MI was significantly associated with lower all cause mortality (pooled hazard ratio 0.69, 0.55 to 0.87). Conclusions: In this prospective study of patients who survived MI, a greater intake of dietary fiber after MI, especially cereal fiber, was inversely associated with all cause mortality. In addition, increasing consumption of fiber from before to after MI was significantly associated with lower all cause and cardiovascular mortality

Haptoglobin Genotype Is a Consistent Marker of Coronary Heart Disease Risk Among Individuals With Elevated Glycosylated Hemoglobin

ObjectivesThis study sought to investigate into the biologically plausible interaction between the common haptoglobin (Hp) polymorphism rs#72294371 and glycosylated hemoglobin (HbA1c) on risk of coronary heart disease (CHD).BackgroundStudies of the association between the Hp polymorphism and CHD report inconsistent results. Individuals with the Hp2-2 genotype produce Hp proteins with an impaired ability to prevent oxidative injury caused by elevated HbA1c.MethodsHbA1c concentration and Hp genotype were determined for 407 CHD cases matched 1:1 to controls (from the NHS [Nurses' Health Study]) and in a replication cohort of 2,070 individuals who served as the nontreatment group in the ICARE (Prevention of Cardiovascular Complications in Diabetic Patients With Vitamin E Treatment) study, with 29 CHD events during follow-up. Multivariate models were adjusted for lifestyle and CHD risk factors as appropriate. A pooled analysis was conducted of NHS, ICARE, and the 1 previously published analysis (a cardiovascular disease case-control sample from the Strong Heart Study).ResultsIn the NHS, Hp2-2 genotype (39% frequency) was strongly related to CHD risk only among individuals with elevated HbA1c (≥6.5%), an association that was similar in the ICARE trial and the Strong Heart Study. In a pooled analysis, participants with both the Hp2-2 genotype and elevated HbA1c had a relative risk of 7.90 (95% confidence interval: 4.43 to 14.10) for CHD compared with participants with both an Hp1 allele and HbA1c <6.5% (p for interaction = 0.004), whereas the Hp2-2 genotype with HbA1c <6.5% was not associated with risk (relative risk: 1.34 [95% confidence interval: 0.73 to 2.46]).ConclusionsHp genotype was a significant predictor of CHD among individuals with elevated HbA1c

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management

C-Reactive Protein (CRP) Gene Polymorphisms, CRP Levels, and Risk of Incident Coronary Heart Disease in Two Nested Case-Control Studies

Background: C-reactive protein (CRP), an acute phase reactant and marker of inflammation, has been shown to predict risk of incident cardiovascular events. However, few studies have comprehensively examined six common single-nucleotide polymorphisms (SNPs) in the CRP gene, haplotypes, and plasma CRP levels with risk of coronary heart disease (CHD). Methods and Findings: We conducted parallel nested case-control studies within two ongoing, prospective cohort studies of U.S. women (Nurses' Health Study) and men (Health Professionals Follow-up Study). Blood samples were available in a subset of 32,826 women and 18,225 men for biomarker and DNA analyses. During 8 and 6 years of follow-up, 249 women and 266 men developed incident nonfatal myocardial infarction or fatal CHD, and controls (498 women, 531 men) were matched 2:1 on age, smoking, and date of blood draw from participants free of cardiovascular disease at the time the case was diagnosed. Among both women and men, minor alleles were significantly associated with higher CRP levels for SNPs 1919A greater than T and 4741G greater than C, but associated with lower CRP levels for SNPs 2667G greater than C and 3872C greater than T. SNP 2667G greater than C was individually associated with increased risk of CHD in both women [OR 1.57 (95% CI 1.01–2.44); p = 0.047] and men [1.93 (95% CI 1.30–2.88); p = 0.001]. Two of the five common haplotypes were associated with lower CRP levels, and Haplotype 4 which included minor alleles for 2667 and 3872 was associated with significantly lower CRP levels and an elevated risk of CHD. The remaining SNPs or haplotypes were not associated with CHD in both populations. Conclusions: Common variation in the CRP gene was significantly associated with plasma CRP levels; however, the association between common SNPs and CRP levels did not correspond to a predicted change in CHD risk. The underlying inflammatory processes which predict coronary events cannot be captured solely by variation in the CRP gene

Low Carbohydrate Diet From Plant or Animal Sources and Mortality Among Myocardial Infarction Survivors

Background: The healthiest dietary pattern for myocardial infarction (MI) survivors is not known. Specific long‐term benefits of a low‐carbohydrate diet (LCD) are unknown, whether from animal or vegetable sources. There is a need to examine the associations between post‐MI adherence to an LCD and all‐cause and cardiovascular mortality. Methods and Results: We included 2258 women from the Nurses' Health Study and 1840 men from the Health Professional Follow‐Up Study who had survived a first MI during follow‐up and provided a pre‐MI and at least 1 post‐MI food frequency questionnaire. Adherence to an LCD high in animal sources of protein and fat was associated with higher all‐cause and cardiovascular mortality (hazard ratios of 1.33 [95% CI: 1.06 to 1.65] for all‐cause mortality and 1.51 [95% CI: 1.09 to 2.07] for cardiovascular mortality comparing extreme quintiles). An increase in adherence to an animal‐based LCD prospectively assessed from the pre‐ to post‐MI period was associated with higher all‐cause mortality and cardiovascular mortality (hazard ratios of 1.30 [95% CI: 1.03 to 1.65] for all‐cause mortality and 1.53 [95% CI: 1.10 to 2.13] for cardiovascular mortality comparing extreme quintiles). An increase in adherence to a plant‐based LCD was not associated with lower all‐cause or cardiovascular mortality. Conclusions: Greater adherence to an LCD high in animal sources of fat and protein was associated with higher all‐cause and cardiovascular mortality post‐MI. We did not find a health benefit from greater adherence to an LCD overall after MI

Prognostic biomarkers in patients with human immunodeficiency virusâ positive disease with head and neck squamous cell carcinoma

BackgroundWe examined the prognostic value of a panel of biomarkers in patients with squamous cell carcinoma of the head and neck (SCCHN) who were human immunodeficiency virus (HIV) positive (HIVâ positive head and neck cancer) and HIV negative (HIVâ negative head and neck cancer).MethodsTissue microarrays (TMAs) were constructed using tumors from 41 disease siteâ matched and ageâ matched HIVâ positive head and neck cancer cases and 44 HIVâ negative head and neck cancer controls. Expression of tumor biomarkers was assessed by immunohistochemistry (IHC) and correlations examined with clinical variables.ResultsExpression levels of the studied oncogenic and inflammatory tumor biomarkers were not differentially regulated by HIV status. Among patients with HIVâ positive head and neck cancer, laryngeal disease site (P = .003) and Clavienâ Dindo classification IV (CD4) counts <200 cells/μL (P = .01) were associated with poor prognosis. Multivariate analysis showed that p16 positivity was associated with improved overall survival (OS; P < .001) whereas increased expression of transforming growth factorâ beta (TGFâ β) was associated with poor clinical outcome (P = .001).ConclusionDisease site has significant effect on the expression of biomarkers. Expression of tumor TGFâ β could be a valuable addition to the conventional risk stratification equation for improving head and neck cancer disease management strategies.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139994/1/hed24911.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139994/2/hed24911_am.pd

The Medical Segmentation Decathlon

International challenges have become the de facto standard for comparative assessment of image analysis algorithms given a specific task. Segmentation is so far the most widely investigated medical image processing task, but the various segmentation challenges have typically been organized in isolation, such that algorithm development was driven by the need to tackle a single specific clinical problem. We hypothesized that a method capable of performing well on multiple tasks will generalize well to a previously unseen task and potentially outperform a custom-designed solution. To investigate the hypothesis, we organized the Medical Segmentation Decathlon (MSD) - a biomedical image analysis challenge, in which algorithms compete in a multitude of both tasks and modalities. The underlying data set was designed to explore the axis of difficulties typically encountered when dealing with medical images, such as small data sets, unbalanced labels, multi-site data and small objects. The MSD challenge confirmed that algorithms with a consistent good performance on a set of tasks preserved their good average performance on a different set of previously unseen tasks. Moreover, by monitoring the MSD winner for two years, we found that this algorithm continued generalizing well to a wide range of other clinical problems, further confirming our hypothesis. Three main conclusions can be drawn from this study: (1) state-of-the-art image segmentation algorithms are mature, accurate, and generalize well when retrained on unseen tasks; (2) consistent algorithmic performance across multiple tasks is a strong surrogate of algorithmic generalizability; (3) the training of accurate AI segmentation models is now commoditized to non AI experts

Impacts of biomedical hashtag-based Twitter campaign: #DHPSP utilization for promotion of open innovation in digital health, patient safety, and personalized medicine

The open innovation hub Digital Health and Patient Safety Platform (DHPSP) was recently established with the purpose to invigorate collaborative scientific research and the development of new digital products and personalized solutions aiming to improve human health and patient safety. In this study, we evaluated the effectiveness of a Twitter-based campaign centered on using the hashtag #DHPSP to promote the visibility of the DHPSP initiative. Thus, tweets containing #DHPSP were monitored for five weeks for the period 20.10.2020–24.11.2020 and were analyzed with Symplur Signals (social media analytics tool). In the study period, a total of 11,005 tweets containing #DHPSP were posted by 3020 Twitter users, generating 151,984,378 impressions. Analysis of the healthcare stakeholder-identity of the Twitter users who used #DHPSP revealed that the most of participating user accounts belonged to individuals or doctors, with the top three user locations being the United States (501 users), the United Kingdom (155 users), and India (121 users). Analysis of co-occurring hashtags and the full text of the posted tweets further revealed that the major themes of attention in the #DHPSP Twitter-community were related to the coronavirus disease 2019 (COVID-19), medicine and health, digital health technologies, and science communication in general. Overall, these results indicate that the #DHPSP initiative achieved high visibility and engaged a large body of Twitter users interested in the DHPSP focus area. Moreover, the conducted campaign resulted in an increase of DHPSP member enrollments and website visitors, and new scientific collaborations were formed. Thus, Twitter campaigns centered on a dedicated hashtag prove to be a highly efficient tool for visibility-promotion, which could be successfully utilized by healthcare-related open innovation platforms or initiatives

A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Geneenvironment interactions (G x E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G x E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G x E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G x E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant GxBMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer