Aims/hypothesis
Both obesity and genetics contribute to cardiovascular disease (CVD). We examined whether a genetic risk score (GRS) prospectively predicted cardiovascular morbidity and mortality ...among overweight/obese individuals with type 2 diabetes and whether behavioural weight loss could diminish this association.
Methods
Look AHEAD (Action for Health in Diabetes) is a randomised controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes among overweight/obese individuals with type 2 diabetes. Of the participants, 4,016 provided consent for genetic analyses and had DNA samples passing quality control procedures. These secondary data analyses focused on whether a GRS derived from 153 single nucleotide polymorphisms (SNPs) associated with coronary artery disease in the most recent genome-wide association study predicted cardiovascular morbidity and mortality over a median of 9.6 years of follow-up, and whether ILI would diminish this association.
Results
The GRS significantly predicted the primary composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for angina in the full sample (HR, 95% CI per 1 SD increase in GRS: 1.19 1.10, 1.28) and among individuals with no known history of CVD at baseline (HR 1.18 95% CI 1.07, 1.30). In no case did ILI significantly alter this association.
Conclusions/interpretation
A GRS comprised of SNPs significantly predicts cardiovascular morbidity and mortality over 9.6 years of follow-up in Look AHEAD. Lifestyle intervention did not alter the genetic association.
Clinical Trial Registration
: NCT00017953; NCT01270763
Inconsistent associations between lipids and circulating markers of fat-soluble vitamin and carotenoid status have been reported. The aim of this hypothesis-generating study was to examine the ...contribution of the LC-MS-based lipidome, characterized by lipid class, carbon count, and the number of unsaturated bonds, to the interindividual variability in circulating concentrations of retinol, carotenoids, 25-hydroxyvitamin D.sub.3, alpha-tocopherol, y-tocopherol, and phylloquinone in 35 overweight and obese, but healthy men. A sparse partial least-squares method was used to accomplish this aim. Highly abundant phospholipids and triglycerides (TGs) contributed to the interindividual variability in phylloquinone, alpha-tocopherol, and y-tocopherol. Interindividual variability in lycopene concentrations was driven by concentrations of low-abundant TG. 25-Hydroxyvitamin D.sub.3, retinol, and the other carotenoids were not influenced by lipids. Except for lycopene, evaluation of lipids beyond class does not appear to further explain the interindividual variability in circulating concentrations of fat-soluble vitamins and carotenoids. Curr Dev Nutr 2020;4:nzaa089.
Current monoclonal antibody therapies for multiple myeloma have had limited success, perhaps due to narrow target specificity. We have previously described the ability of polyclonal rabbit ...antithymocyte globulin (rATG) to induce caspase- and cathepsin-mediated apoptosis in human B and plasma cells. We now extend this observation to myeloma cells. Complement independent cell death was measured after addition of rATG (1-1000 μg/mL) to cultures of myeloma cell lines or primary CD138+ isolates from patient bone marrow aspirates. rATG induced significant levels of apoptosis in myeloma cells as assayed by caspase induction, annexin V binding, subdiploid DNA fragmentation, plasma-membrane permeability, and loss of mitochondrial-membrane potential. Addition of complement greatly augmented myeloma-cell death. Binding of rATG to individual myeloma cell-surface proteins, primarily CD38, CD52, CD126, and CD138, was demonstrated by competitive inhibition experiments with targeted monoclonal antibodies. Three pathways of cell death were identified involving caspase activation, cathepsin D, and the genistein sensitive tyrosine kinase pathway. F(ab′)2 fragments of rATG had reduced proapoptotic activity, which was restored by coincubation with Fc fragments, and anti-CD32 or anti-CD64 antibodies. We conclude that rATG is an effective agent for in vitro induction of apoptosis in multiple myeloma, and that exploratory clinical trials may be warranted.
Psychometrically sound screening tools available to aid in the identification of lifetime history of traumatic brain injury (TBI) are limited. As such, the Traumatic Brain Injury-4 (TBI-4) was ...developed and implemented in a Veterans Health Administration (VHA) mental health clinic. To provide information regarding both the predictive validity and clinical utility of the TBI-4, the relationship between screening results and future suicide attempts was evaluated.
The aim of this study was to determine whether a positive screen on the TBI-4 was associated with increased risk for suicide attempt within 1-year post screening.
The TBI-4 was administered to 1,097 Veterans at the time of mental health intake. Follow-up data regarding suicide attempts for the year post-mental health intake were obtained from suicide behavior reports (SBRs) in Veteran electronic medical records (EMRs). Fisher's exact tests were used to determine the proportion of suicide attempts by TBI-4 status.
In the year post TBI-4 screening, significantly more Veterans who screened positive had a documented suicide attempt as compared to those who screened negative (p = 0.003).
Those with a positive TBI screen at mental health intake had a higher proportion of SBRs than those who screened negative for TBI. Findings provided further psychometric support for the TBI-4. Moreover, results suggest the inclusion of this screen could prove to be helpful in identifying those who may be at risk for future suicide attempt within 1-year post screening.
PSE is foundational to the PREP-IT (A Program of Randomized trials to Evaluate Pre-operative antiseptic skin solutions In orthopedic Trauma) program’s organizational structure and drives trial ...decisions and activities. ...of the open communication between cores and committees, stakeholders with complementary expertise in trauma and dissemination joined the patient stakeholders on the PCOAC early on in the project. Theme Illustrative quote Respondent type Group meeting approach:includes how the PCOAC operated or that participation was requested of them “Meeting as a group seems natural; everyone participates” Patient stakeholder “The educational component is most important; to have medical research clearly defined” Patient stakeholder Experience participating in the PCOAC meetings:includes details around participating in the PCOAC and whether they believed they were heard as partners in research, not just as subjects “You build the relationship in the beginning so you are checking in, not checking a box; initial delivery (of the message) of why we subjects (are) equal partners in research” Patient stakeholder “I never felt like a fish out of water.” The model of a bi-monthly meeting kept PCOAC members engaged in a comfortable manner, allowing some stakeholders to transition from being seen as a chronic patient to being treated as an expert in the patient experience, and allowed some stakeholders to close the loop on healing, giving backand insulating against the “lows (e.g., anniversary of injury and surgery dates, set-backs in their own recoveries).”
Michael Whyte, MD, described the discovery in 1923 of alkaline phosphatase (ALP), the first report in 1948 of HPP, and the many important lessons from investigation of patients, including major ...insight concerning the pathogenesis of the defective hard tissue mineralization leading to tooth loss and rickets during childhood and osteomalacia during adult life as well as identification of its etiology. Michael P. Whyte, MD Chair, Scientific Advisory Board Soft Bones Foundation Boonton, NJ, USA https://www.softbones.org/ Inorganic Pyrophosphate: Nature's Water Softener R Graham G Russell The Mellanby CentreSheffield University SheffieldUK Botnar Research CentreOxford University OxfordUK The identification of inorganic pyrophosphate (PPi) as a key regulator of biological calcification can be traced back to the 1960s, starting with the work of Fleisch and colleagues. What Patients With Hypophosphatasia Revealed About the Alkaline Phosphatase They Need Michael P Whyte Center for Metabolic Bone Disease and Molecular ResearchShriners Hospital for Children St. Louis, MOUSA Division of Bone and Mineral DiseasesDepartment of Internal MedicineWashington University School of Medicine St. Louis, MOUSA Although hypophosphatasia (HPP) is rare, manifests the greatest severity range of all skeletal diseases, and was the last rickets/osteomalacia to acquire a medical treatment, most of what we know about the function of ALP has come from studies of HPP patients. Amino acid sequence analysis of proteolytic digests of ALP purified from HPP autopsy tissues indicated HPP is an inborn error of the tissue nonspecific isoenzyme of ALP (TNSALP).
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