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This report describes the in vitro inhibition of several classes of human lymphocyte-mediated lysis by antisera from mice and rats immunized with concanavalin A-stimulated human T-enriched lymphocytes. The inhibitory antibodies in these antisera recognized molecules on the surface of cytotoxic lymphocytes, and did not bind to B-cell lines. Experiments were performed to demonstrate that these antisera were not inhibiting cytolysis by trivial mechanisms such as (i) masking of target cell antigens by anti-target cell antibodies, (ii) agglutinating effector cells, thereby preventing effector-target cell contact, or (iii) toxicity to the effector cells. Dextran dispersion experiments revealed that these antisera inhibit the post-conjugate formation phase of cytolysis mediated by cytotoxic T lymphocytes. These antisera inhibited natural killer-like cytotoxicity and lectin-dependent cell-mediated cytotoxicity as well as lysis mediated by both mixed cell culture-generated cytotoxic T lymphocytes and cytotoxic T-lymphocyte cell lines. These findings suggest that these in vitro systems of cell-mediated lysis may share a common step; however the different classes of cytolysis may have been inhibited by separate antibodies in the antisera. This rapid reproducible method of generating inhibitory antisera will facilitate the study of the molecules involved in the post-conjugate formation phase of human cytotoxic T-lymphocyte-mediated lysis. © 1982.

High levels of lymphotoxin-like activity (LT) were found in supernatants from secondarily stimulated immune mouse splenocytes activated with concanavalin A (Con A) in vitro. Splenocytes obtained from C57Bl/6 mice immune to the P815 mastocytoma were restimulated in vitro with mitomycin C-treated P815 cells, and then stimulated with Con A. High levels of unstable LT activity are rapidly (2-4 hr) released by these lectin-stimulated splenocytes. The introduction of a crosslinking agent, glutaraldehyde, was found to stabilize this LT activity and allowed us to perform more defined biochemical studies and to examine the functional activities of the LT classes. The lytic activity in these supernatants resided in the high-molecular-weight classes, termed Complex (Cx > 200,000 daltons) and alpha-heavy (αH 130,000-160,000 daltons). It was found that the Cx and αH LT classes from the secondarily stimulated immune splenocytes cause lysis of allogeneic target cells, P815 and EL-4, in a 16-hr 75Semethionine release assay, and in some cases, this lysis was specific for the sensitizing target cell. © 1981.

The high-molecular-weight (MW) complex class (MW = greater than or equal to 200,000) of lymphotoxin (LT) may be involved in the process of lymphocyte-mediated cytolysis. This LT class was produced by concanavalin A-stimulated human adenoid and tonsil lymphocytes in vitro and purified approximately 1000 fold by a scheme employing lectin affinity chromatography on concanavalin A-Sepharose, negative hydrophobic affinity chromatography on phenyl-Sepharose, and molecular sieving on Ultrogel AcA 44. A cell-lytic subunit, termed C-alpha toxin, was dissociated from this partially purified complex LT (Cx) preparation. The identification of C-alpha toxin as an alpha 2 LT form was established by its comigration with the alpha 2 LT form during native polyacrylamide gel electrophoresis (PAGE), molecular sieving, and isoelectricfocusing. In addition, C-alpha toxin was neutralized by antiserum raised against purified alpha 2 LT, and the latter was neutralized by antiserum raised against C-alpha toxin. Furthermore, preliminary evidence indicates that both alpha 2 LT and C-alpha toxin are composed of peptides with apparent MW of approximately 69,000. Additional data indicate the Cx LT form is composed of alpha 2 LT and other subunits.

Objective: Because the role of submarine warfare is shifting from strategic deterrence to littoral force projection, submarine providers will be required to manage combat trauma. Currently, submarine providers have only crystalloid available for the reversal of hemorrhagic shock. A proposal program to provide blood products on submarines was evaluated.Methods: Existing military emergency blood transfusion protocols were reviewed. The restrictions of donation/transfusion onboard submarines were considered.Results: A protocol to provide screening for, implementation of, and a reporting system for contingency blood donation and transfusion onboard submarines was created. The protocol contains all the safeguards of existing U.S. Navy contingency donor programs with the exception of pretransfusion infectious disease testing and cross-matching. However, because the program does not require laboratory capability, it can be implemented by an independent duty corpsman onboard a submarine.Conclusion: This protocol provides blood for the reversal of hemorrhagic shock onboard submarines in the event of traumatic injury. [ABSTRACT FROM AUTHOR]

Objectives: We asked if carriers of the 719Arg allele of kinesin family member 6 (KIF6) have increased risk of coronary heart disease (CHD) in a cohort of initially healthy Caucasian American women.Background: The 719Arg allele of KIF6 (rs20455) has been reported to be associated with increased risk of CHD in a large population-based prospective study, ARIC (Atherosclerosis Risk in Communities), and in the placebo arms of 2 statin trials, CARE (Cholesterol and Recurrent Events) and WOSCOPS (West of Scotland Coronary Prevention Study). However, this KIF6 variant was not specifically investigated in the female subgroup in the ARIC study, and the CARE and WOSCOPS trials included only a small number of female patients.Methods: Genotypes of the rs20455 single nucleotide polymorphism (SNP) were determined among 25,283 initially healthy Caucasian women, age 45 years and older, participating in the WHS (Women's Health Study) who were prospectively followed over a 12-year period for incident cardiovascular events. The risk associated with the 719Arg allele of KIF6 was estimated using Cox proportional hazards models that adjusted for age and traditional risk factors.Results: During follow-up, 953 women suffered a first-ever CHD event (myocardial infarction, coronary revascularization, or cardiovascular death) or first-ever ischemic stroke. Compared with noncarriers, carriers of the 719Arg allele had an increased risk of CHD (hazard ratio [HR] = 1.24 [95% confidence interval (CI) 1.04 to 1.46, p = 0.013]) and myocardial infarction (HR = 1.34 [95% CI 1.02 to 1.75, p = 0.034]) but not ischemic stroke.Conclusions: Confirming and extending previous reports, carriers of the 719Arg allele of KIF6 have 34% higher risk of myocardial infarction and 24% higher risk of CHD compared with noncarriers among 25,283 women from the WHS. [ABSTRACT FROM AUTHOR]

In clinical trials, vitamin D supplementation has been reported to reduce serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) but not high-density lipoprotein cholesterol (HDL-C). In this cohort study we evaluated the association between changes in vitamin D (25-hydroxyvitamin D) and changes in lipid levels in a real-world setting. Changes in lipid levels over a 1-year period were evaluated among individuals whose vitamin D levels increased (group 1) or decreased (group 2) by ≥ 10 ng/mL in year 2018 versus 2017 (cohort 1; n = 5580), in 2019 versus 2018 (cohort 2, n = 6057), or in 2020 versus 2019 (cohort 3, n = 7249). In each cohort, levels of TC, LDL-C, and TG decreased in group 1 and increased in group 2. Between-group differences in average changes in the 3 cohorts ranged from 10.71 to 12.02 mg/dL for TC, from 7.42 to 8.95 mg/dL for LDL-C, and from 21.59 to 28.09 mg/dL for TG. These differences were significant after adjusting for age, sex, race, education, body mass index, blood pressure, smoking status, geographical location, and baseline levels of vitamin D and lipids (P < 0.001). Changes in vitamin D levels were not significantly associated with changes in HDL-C levels., (© 2021. The Author(s).)

Bespoke (custom-built) Raspberry Pi cameras are increasingly popular research tools in the fields of behavioral ecology and conservation, because of their comparative flexibility in programmable settings, ability to be paired with other sensors, and because they are typically cheaper than commercially built models.Here, we describe a novel, Raspberry Pi-based camera system that is fully portable and yet weatherproof-especially to humidity and salt spray. The camera was paired with a passive infrared sensor, to create a movement-triggered camera capable of recording videos over a 24-hr period. We describe an example deployment involving "retro-fitting" these cameras into artificial nest boxes on Praia Islet, Azores archipelago, Portugal, to monitor the behaviors and interspecific interactions of two sympatric species of storm-petrel (Monteiro's storm-petrel Hydrobates monteiroi and Madeiran storm-petrel Hydrobates castro ) during their respective breeding seasons.Of the 138 deployments, 70% of all deployments were deemed to be "Successful" (Successful was defined as continuous footage being recorded for more than one hour without an interruption), which equated to 87% of the individual 30-s videos. The bespoke cameras proved to be easily portable between 54 different nests and reasonably weatherproof (~14% of deployments classed as "Partial" or "Failure" deployments were specifically due to the weather/humidity), and we make further trouble-shooting suggestions to mitigate additional weather-related failures.Here, we have shown that this system is fully portable and capable of coping with salt spray and humidity, and consequently, the camera-build methods and scripts could be applied easily to many different species that also utilize cavities, burrows, and artificial nests, and can potentially be adapted for other wildlife monitoring situations to provide novel insights into species-specific daily cycles of behaviors and interspecies interactions., Competing Interests: We declare we have no conflict of interests., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Microhabitats with distinct biotic and abiotic properties exist within landscapes, and this microhabitat variation can have dramatic impacts on the phenology and physiology of the organisms occupying them. The Antarctic midge Belgica antarctica inhabits diverse microhabitats along the Western Antarctic Peninsula that vary in macrophyte composition, hygric qualities, nutrient input, and thermal patterns. Here, we compare seasonal physiological changes in five populations of B. antarctica living in close proximity but in different microhabitats in the vicinity of Palmer Station, Antarctica. Thermal regimes among our sample locations differed in both mean temperature and thermal stability. Between the warmest and coldest sites, seasonal mean temperatures differed by 2.6˚C and degree day accumulations above freezing differed by a factor of 1.7. Larval metabolic and growth rates varied among the sites, and adult emergence occurred at different times. Distinct microhabitats also corresponded with differences in body composition, as lipid and carbohydrate content of larvae differed across sites. Further, seasonal changes in carbohydrate and protein content were dependent on site, indicating fine-scale variation in the biochemical composition of larvae as they prepare for winter. Together, these results demonstrate that variation in microhabitat properties influences the ontogeny, phenology, physiology, and biochemical makeup of midge populations living in close proximity. These results have implications for predicting responses of Antarctic ecosystems to environmental change., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Low vitamin D levels have been reported to be associated with increased risk of SARS-CoV-2 infection. Independent, well-powered studies could further our understanding of this association., Objective: To examine whether low levels of vitamin D are associated with SARS-CoV-2 seropositivity, an indicator of previous infection., Design, Setting, and Participants: This is a cohort study of employees and spouses who elected to be tested for SARS-CoV-2 IgG as part of an annual employer-sponsored health screening program conducted in August to November 2020. This program includes commonly assessed demographic, biometric, and laboratory variables, including total vitamin D measurement. Baseline (prepandemic) levels of vitamin D and potential confounders were obtained from screening results from the previous year (September 2019 to January 2020). Data analysis was performed from December 2020 to March 2021., Exposures: Low total serum 25-hydroxyvitamin D, defined as either less than 20 ng/mL or less than 30 ng/mL., Main Outcomes and Measures: The main outcome was SARS-CoV-2 seropositivity, as determined with US Food and Drug Administration emergency use-authorized assays. The association of SARS-CoV-2 seropositivity with vitamin D levels was assessed by multivariable logistic regression analyses and propensity score analyses., Results: The 18 148 individuals included in this study had test results for SARS-CoV-2 IgG in 2020 and vitamin D levels from the prepandemic and pandemic periods. Their median (interquartile range) age was 47 (37-56) years, 12 170 (67.1%) were women, 900 (5.0%) were seropositive, 4498 (24.8%) had a vitamin D level less than 20 ng/mL, and 10 876 (59.9%) had a vitamin D level less than 30 ng/mL before the pandemic. In multivariable models adjusting for age, sex, race/ethnicity, education, body mass index, blood pressure, smoking status, and geographical location, SARS-CoV-2 seropositivity was not associated with having a vitamin D level less than 20 ng/mL before (odds ratio [OR], 1.04; 95% CI, 0.88-1.22) or during (OR, 0.93; 95% CI, 0.79-1.09) the pandemic; it was also not associated with having a vitamin D level less than 30 ng/mL before (OR, 1.09; 95% CI, 0.93-1.27) or during (OR, 1.05; 95% CI, 0.91-1.23) the pandemic. Similar results were observed in propensity score analyses. SARS-CoV-2 seropositivity was associated with obesity (OR, 1.26; 95% CI, 1.08-1.46), not having a college degree (OR, 1.40; 95% CI, 1.21-1.62), and Asian (OR, 1.46; 95% CI, 1.13-1.87), Black (OR, 2.74; 95% CI, 2.25-3.34), Hispanic (OR, 2.65; 95% CI, 2.15-3.27), American Indian or Alaska Native, and Native Hawaiian or other Pacific Islander (OR, 2.01; OR, 1.54-2.62) race/ethnicity, and was inversely associated with high blood pressure (OR, 0.82; 95% CI, 0.70-0.96), smoking (OR, 0.60; 95% CI, 0.47-0.78), and residing in the US Northeast (OR, 0.75; 95% CI, 0.62-0.92) and West (OR, 0.54; 95% CI, 0.44-0.67)., Conclusions and Relevance: In this cohort study, SARS-CoV-2 seropositivity was not associated with low levels of vitamin D independently of other risk factors.

Because chronic kidney disease (CKD) is underdiagnosed, many patients do not receive care that could slow or prevent progression. Potential CKD patients can be identified during employee wellness events and referred into care by a CKD outreach program. This study assessed the health and economic benefits associated with a CKD outreach program. A model-based cost-effectiveness analysis was conducted for a cohort of patients at risk for CKD under 2 scenarios: wellness events with a CKD outreach program and wellness events without outreach. The outreach program identified potential CKD patients based on estimated glomerular filtration rates. Health outcomes and total cost to payers were estimated with Markov models using 1-year cycles. Because outreach could be offered to either patients with diabetes or to all potential CKD patients, these groups were modeled separately. The authors assumed 40% percent of potential CKD patients accepted the invitation to participate in the CKD outreach program. Model parameters were taken from peer-reviewed literature. The study was conducted from the perspective of self-insured employers over a 5-year time horizon. The study found that the CKD outreach program resulted in a gain of 2.3 quality-adjusted life-years and saved $500,211 when 1000 potential CKD patients with diabetes were invited. When potential CKD patients were invited without regard for diabetes status, 0.8 quality-adjusted life-years were gained at a cost savings of $34,161. The authors concluded that CKD outreach programs can improve health outcomes for patients with CKD and save costs for payers.

Importance: Married couples and domestic partners have been reported to share similar environmental exposures, adopt similar behavior patterns, and have similar transferable characteristics. However, the degree to which couples share similar levels of cardiovascular risk factors and behaviors is uncertain., Objective: To assess within-couple concordance of the American Heart Association-defined Life's Simple 7 (LS7)., Design, Setting, and Participants: Cross-sectional study with a longitudinal substudy of employees and spouses (or domestic partners) who participated in an employer-sponsored health assessment program throughout the United States between October 2014 and December 2018. Data were analyzed from November 1, 2019, to August 4, 2020., Exposures: Having a spouse or domestic partner., Main Outcomes and Measures: The LS7 risk factors and behaviors (smoking status, body mass index, exercise, diet, total cholesterol, blood pressure, and fasting glucose) were assessed by questionnaires, examinations, and laboratory tests. LS7 categories were scored as 2 for ideal, 1 for intermediate, or 0 for poor and summed to generate a CV health score., Results: The study included 10 728 participants (5364 couples): 7% were African American, 11% Hispanic, 21% Asian, and 54% White (median [interquartile range] age, 50 [41-57] years for men and 47 [39-55] for women). For most couples, both members were in the ideal category or both were in a nonideal category. Concordance ranged from 53% (95% CI, 52%-54%) for cholesterol to 95% (95% CI, 94%-95%) for diet. For the CV health score, in 79% (95% CI, 78%-80%) of couples both members were in a nonideal category, which was associated mainly with unhealthy diet (94% [95% CI, 93%-94%] of couples) and inadequate exercise (53% [95% CI, 52%-55%] of couples). However, in most couples, both members were in the ideal category for smoking status (60% [95% CI, 59%-61%] of couples) and glucose (56% [95% CI, 55%-58%]). Except for total cholesterol, when 1 member of a couple was in the ideal category, the other member was likely also to be in the ideal category: the adjusted odds ratios for also being in the ideal category ranged from 1.3 (95% CI, 1.1-1.5; P ≤ .001) for blood pressure to 10.6 (95% CI, 7.4-15.3; P ≤ .001) for diet. Concordance differed by ethnicity, socioeconomic status, and geographic location. A 5-year longitudinal analysis of 2186 couples found modest changes in concordance of blood pressure (from 55% [95% CI, 53%-57%] to 59% [95% CI, 57%-61%]; P < .001 for trend) and fasting glucose (from 64% [95% CI, 62%-66%] to 59% [95% CI, 57%-61%]; P < .001 for trend) with no change in other factors., Conclusions and Relevance: In this study, high concordance of nonideal behaviors was found within couples; behavioral modification programs may benefit both the targeted and the nontargeted member of a couple.

We evaluated the cost-effectiveness of test-and-treat scenarios for vaginitis, scenarios based on clinical and microscopic examination (CME), nucleic acid amplification testing (NAAT), or nonamplified nucleic acid probe (probe) testing. The symptom resolution outcome and the payer cost of diagnosis and treatment were estimated in decision analytical models in a hypothetical patient population. Compared with probe testing, NAAT resulted in symptom resolution in more patients (615 versus 475 per 1000 tested) at a cost of $210 per incremental symptom resolution, a cost lower than the willingness to pay for symptom resolution ($871) implied by payer coverage for probe testing. Following a negative CME, the NAAT scenario resulted in symptom resolution in more patients (650 per 1000 patients tested) than did either CME (525) or the CME probe testing-based scenario (602) at incremental cost-effectiveness ratios lower than the willingness to pay implied by coverage for CME. Therefore, NAAT is likely to cost-effectively improve health outcomes for patients with vaginitis., Competing Interests: Conflict of interest The authors are employees of Quest Diagnostics., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background The American Heart Association and American College of Cardiology guidelines defined patient-management groups that would benefit from lowering of low-density lipoprotein cholesterol (LDL-C). We assessed gaps in dyslipidemia care among employees and spouses with health benefits. Methods and Results We studied 17 889 employees and spouses who were covered by an employer-sponsored health plan and participated in an annual health assessment. Using medical claims, laboratory tests, and risk assessment questionnaires, we found that 43% of participants were in one of 4 patient-management groups: secondary prevention, severe hypercholesterolemia (LDL-C ≥190 mg/dL at least once in the preceding 5 years), diabetes mellitus, or elevated 10-year risk of cardiovascular disease. To assess gaps in dyslipidemia care, we used LDL-C ≤70 mg/dL as the goal for both the secondary prevention group and those in the elevated 10-year risk group with >20% risk; LDL-C ≤100 mg/dL was used for the other groups. Among those in patient-management groups, 27.3% were in the secondary prevention group, 7.4% were in the severe hypercholesterolemia group, 29.9% were in the diabetes mellitus group, and 35.4% were in the elevated 10-year risk group. About 74% of those in patient-management groups had above-goal LDL-C levels, whereas only 31% had evidence of a lipid-lowering therapy in the past 6 months: 45% in the secondary prevention group, 31% in the severe hypercholesterolemia group, 36% in the diabetes mellitus group, and 17% in the elevated 10-year risk group. Conclusions The substantial gaps in LDL-C treatment and goal attainment among members of an employer-sponsored medical plan who were mostly aware of their LDL-C levels indicate the need for gap-closure initiatives.

Introduction: Pit viper bites are a source of significant morbidity and mortality. Pit viper bites can cause venom-induced consumptive coagulopathy (VICC), typically evaluated with laboratory-based conventional coagulation tests (CCTs). However, CCTs require a laboratory and average 1 h to conduct. Thromboelastography (TEG) provides real-time, point-of-care tests of coagulation that are fast and require no separate laboratory facilities, which could be advantageous in both hospital and austere settings. However, the relative efficacy of TEG versus CCTs was unclear, particularly at low venom concentrations. Therefore, the objectives of this study were to test human blood with various concentrations of pit viper venom using CCTs and TEG to determine dose-dependent changes, lowest observed effect concentration (LOEC), and sensitivity to detecting samples out of normal diagnostic range., Methods: Blood samples from 20 volunteers were mixed with varying concentrations of western diamond back rattlesnake (Crotalus atrox) venom based on the mouse LD50 IV (none, 0.5%, 1%, 2%, 33%, 66%, and 100% LD50 IV ). Samples were split and assessed with both CCTs including prothrombin time (PT), international normalized ratio (INR), partial thromboplastin time (PTT), fibrinogen, and D-dimer, along with TEG measures of reaction time (R), kinetic time (K), rate of clot formation (α-angle), and clot strength (MA). Data were analyzed as dose-dependent concentration-based changes in raw values and in percent of samples exceeding diagnostic thresholds using ANOVA and nonparametric statistics at the p < .05 threshold., Results: All evaluations showed significant concentration-dependent changes, and 100% of samples exceeded diagnostic thresholds at 33%LD50 IV and above, save D-dimer. At 0.5%LD50 IV , R, K, α-angle, PT, and INR were significantly different from controls, and at 1%LD50 IV , mean values exceeded diagnostic thresholds for R, K, α-angle, MA, PT, and INR, but not for PTT, D-dimer, or fibrinogen. At 2%LD50 IV, 100% of samples were out of normal range for K, α-angle, and PT . CONCLUSION: TEG is effective in coagulopathy evaluations of in vitro simulated pit viper envenomation. At low venom concentrations, TEG performed as well or better than the majority of CCTs. These findings provide empirical evidence supporting the use of TEG to rapidly and accurately evaluate VICC., (Published by Elsevier Ltd.)

IntroductionEmergency physicians are using bolus-dose vasopressors to temporize hypotensive patients until more definitive blood pressure support can be established. Despite a paucity of clinical outcome data, emergency department applications are expanding into the prehospital setting. This series presents two cases of field expedient vasopressor use by emergency medicine providers for preflight stabilization during aeromedical evacuation to a hospital ship as part of the United States Navy disaster response in Puerto Rico. A critical approach and review of the literature are discussed.Case ReportTwo critically ill patients were managed in an austere environment as a result of the devastation from Hurricane Maria (Yabucoa, Puerto Rico; 2017). They both exhibited signs of respiratory distress, hemodynamic instability, and distributive shock requiring definitive airway management and hemodynamic support prior to aeromedical evacuation.DiscussionThe novel use of field expedient vasopressors prior to induction for rapid sequence intubation was successfully and safely employed in both cases. Both patients had multiple risk factors for peri-induction cardiac arrest given their presenting hemodynamics. Despite their illness severity, both patients were induced, transported, and ultimately admitted to the intensive care unit (ICU) in stable condition following administration of the field expedient vasopressors.Conclusion:Field expedient vasopressors were safely and effectively employed in an austere field environment during a disaster response. This case series contributes to the growing body of literature of safe bolus-dose vasopressor use by emergency physicians to temporize hypotensive patients in resource-constrained situations. HardwickJM, MurnanSD, Morrison-PonceDP, DevlinJJ. Field expedient vasopressors during aeromedical evacuation: a case series from the Puerto Rico disaster response. Prehosp Disaster Med. 2018;33(6):668-672.

Context: Insulin resistance (IR) can progress to type 2 diabetes. Therefore, timely identification of IR could facilitate disease prevention efforts. However, direct measurement of IR is not feasible in a clinical setting., Objective: Develop a clinically practical probability score to assess IR in apparently healthy individuals based on levels of insulin, C-peptide, and other risk factors., Design: Cross-sectional study., Participants: Apparently healthy individuals who volunteered to participate in studies of IR., Main Outcome Measure: IR, defined as the top tertile of steady-state plasma glucose during an insulin-suppression test., Results: In a study of 535 participants, insulin, C-peptide, creatinine, body mass index (BMI), and triglycerides to high-density lipoprotein cholesterol ratio (TG/HDL-C) were independently associated with IR (all P < 0.05) in a model that included age, sex, ethnicity, BMI, blood pressure, insulin, C-peptide, fasting glucose, low-density lipoprotein cholesterol, TG/HDL-C, alanine aminotransferase, and creatinine. For an IR probability score based on a model that included insulin, C-peptide, creatinine, TG/HDL-C, and BMI, the odds ratio was 26.7 (95% CI 14.0 to 50.8) for those with scores >66% compared with those with scores <33%. When only insulin and C-peptide were included in the model, the odds ratio was 15.6 (95% CI 7.5 to 32.4) for those with scores >66% compared with those with scores <33%., Conclusions: An IR probability score based on insulin, C-peptide, creatinine, TG/HDL-C, and BMI or a score based on only insulin and C-peptide may help assess IR in apparently healthy individuals.

Aim: Nitromethane, found in fuels used for short distance racing, model cars, and model airplanes, produces a falsely elevated serum creatinine with standard creatinine analysis via the Jaffé method. Erroneous creatinine elevation often triggers extensive testing, leads to inaccurate diagnoses, and delayed or inappropriate medical interventions. Multiple reports in the literature identify "enzymatic assays" as an alternative method to detect the true value of creatinine, but this ambiguity does not help providers translate what type of enzymatic assay testing can be done in real time to determine if there is indeed false elevation., Methods: We report seven cases of ingested nitromethane where creatinine was determined via Beckman Coulter ® analyser using the Jaffé method, Vitros ® analyser, or i-Stat ® point-of-care testing. Nitromethane was detected and semi-quantified using a common clinical toxic alcohol analysis method, and quantified by headspace-gas chromatography-mass spectrometry., Results: When creatinine was determined using i-Stat ® point-of-care testing or a Vitros ® analyser, levels were within the normal range. Comparatively, all initial creatinine levels obtained via the Jaffé method were elevated. Nitromethane concentrations ranged from 42 to 310 μg/mL., Conclusions: These cases demonstrate reliable assessment of creatinine through other enzymatic methods using a Vitros ® analyser or i-STAT ® . Additionally, nitromethane is detectable and quantifiable using routine alcohols gas chromatography analysis and by headspace-gas chromatography-mass spectrometry.

Background: Atrial fibrillation (AF) is the most commonly encountered arrhythmia and is associated with an elevated risk of stroke. Improving the identification of patients with the highest risk for AF to enable appropriate surveillance and treatment, if necessary, is critical to reducing AF-associated morbidity and mortality. Multiple common single nucleotide polymorphisms (SNPs) are unequivocally associated with the lifetime risk of AF. In the current study we aimed to prospectively validate an AF genetic risk score (GRS) in previously undiagnosed patients at risk for AF., Methods and Findings: Individuals 40 years of age or older with 1 clinical risk factor for AF, presenting with symptoms of AF, or with a first diagnosis of AF, were enrolled for genetic testing and ambulatory cardiac rhythm monitoring with an adhesive patch monitor or a long-term Holter monitor (mean wear time 10 days 21 hours and 13 days 18 hours, respectively). An AF event was the first diagnosis of AF by ECG, patch monitor, or long-term Holter monitor. The AF GRS was determined for each participant based on the weighted contribution of 12 genetic risk loci. Of 904 participants, 85 manifested AF. Their mean age was 66.2 (SD 11.8) years; 38% of participants were male. Participants in the highest quintile of AF GRS were more likely (odds ratio 3.11; 95% CI 1.27-7.58; p = 0.01) to have had an AF event than participants in the lowest quintile after adjusting for age, sex, smoking status, BMI, hypertension, diabetes mellitus, heart failure, and prior myocardial infarction. Study limitations included an ethnically homogenous population, a restricted rhythm monitoring period, and the evolving discovery of SNPs associated with AF., Conclusions: Prospective assessment of a GRS for AF identified participants with elevated risk of AF beyond established clinical criteria. Accordingly, a GRS for AF could be incorporated into overall risk assessment to better identify patients at the highest risk of developing AF, although further testing in larger populations is needed to confirm these findings., Trial Registration: ClinicalTrials.gov NCT01970969.

Background: Genetic diagnosis of unexplained global developmental delay and intellectual disability (GDD/ID) often ends the diagnostic odyssey and can lead to changes in clinical management., Objective: The objective of this study was to investigate the cost effectiveness of testing scenarios involving several methods used to diagnose GDD/ID: karyotyping, chromosomal microarray analysis (CMA), and targeted next-generation sequencing (NGS)., Methods: We used decision-tree models to estimate the number of genetic diagnoses, the cost from a payers' perspective in the USA, and the incremental cost per additional genetic diagnosis. Model parameters were taken from peer-reviewed literature and governmental fee schedules., Results: CMA testing results in more genetic diagnoses at an incremental cost of US $2692 per additional diagnosis compared with karyotyping, which has an average cost per diagnosis of US $11,033. Performing both tests sequentially results in the same number of diagnoses, but the total cost is less when CMA testing is done first and karyotyping second. Furthermore, when CMA testing yields a variant of unknown significance, additional genetic diagnoses can be obtained at an incremental cost of US $4220 by CMA testing of both parents, and when parents are not available or the patient had a normal CMA result, targeted NGS of the patient can add diagnoses at a further incremental cost of US $12,295., Conclusion: These results provide a cost effectiveness rationale for the use of CMA as the first-tier test for the genetic diagnosis of unexplained GDD/ID and further indicate that testing of both parents may be cost effective when a variant of unknown significance is detected in the patient.

Objective: Hemoglobin A 1c (HbA 1c ) can be used to assess type 2 diabetes (T2D) risk. We asked whether HbA 1c was associated with T2D risk in four scenarios of clinical information availability: 1 ) HbA 1c alone, 2 ) fasting laboratory tests, 3 ) clinic data, and 4 ) fasting laboratory tests and clinic data., Research Design and Methods: We studied a prospective cohort of white ( N = 11,244) and black ( N = 2,294) middle-aged participants without diabetes in the Framingham Heart Study and Atherosclerosis Risk in Communities study. Association of HbA 1c with incident T2D (defined by medication use or fasting glucose [FG] ≥126 mg/dL) was evaluated in regression models adjusted for 1 ) age and sex (demographics); 2 ) demographics, FG, HDL, and triglycerides; 3 ) demographics, BMI, blood pressure, and T2D family history; or 4 ) all preceding covariates. We combined results from cohort and race analyses by random-effects meta-analyses. Subsidiary analyses tested the association of HbA 1c with developing T2D within 8 years or only after 8 years., Results: Over 20 years, 3,315 individuals developed T2D. With adjustment for demographics, the odds of T2D increased fourfold for each percentage-unit increase in HbA 1c . The odds ratio (OR) was 4.00 (95% CI 3.14, 5.10) for blacks and 4.73 (3.10, 7.21) for whites, resulting in a combined OR of 4.50 (3.35, 6.03). After adjustment for fasting laboratory tests and clinic data, the combined OR was 2.68 (2.15, 3.34) over 20 years, 5.79 (2.51, 13.36) within 8 years, and 2.23 (1.94, 2.57) after 8 years., Conclusions: HbA 1c predicts T2D in different common scenarios and is useful for identifying individuals with elevated T2D risk in both the short- and long-term., (© 2017 by the American Diabetes Association.)

Background and Aims: After assessing the risk for cardiovascular disease (CVD) based on traditional risk factors, decisions concerning lipid lowering therapy might remain uncertain. To investigate whether lipoprotein subfraction levels could aid these decisions, we assessed the association between lipoprotein subfractions and CVD, after adjustment for traditional risk factors including standard lipids., Methods: Using a case-cohort design, participants were randomly drawn from the Malmö Prevention Project (MPP), a population-based prospective study of 18,240 participants, and supplemented with additional incident CVD events (5764 participants, 1784 CVD events)., Results: Low density lipoprotein particle number (LDL-P) and individual subfractions ranging in size from very-small to large were associated with CVD (continuous p value (p cont ) < 0.001) while adjusting for age, sex, hypertension, smoking, and diabetes. After further adjustment for LDL-C, HDL-C, and triglycerides, very small LDL subfraction (b) (LDL-VS (b)) remained associated with CVD (HR = 1.23, 95% CI, 1.06 to 1.43 for top vs. bottom quartile, p cont  = 0.03). Among participants with low/intermediate risk [without diabetes and with LDL-C <3.36 mmol/L (<130 mg/dL)], the fully adjusted HR for LDL-small (top vs. bottom quartile) was 1.48 (95% CI 1.02 to 2.17, p cont  = 0.03). Among those with very-high risk (>20% 10-year risk of CVD), LDL-VS(a) and LDL-VS(b) were associated with CVD in fully adjusted models (HR = 1.37, 95% CI 1.12 to 1.67 and HR = 1.28, 95% CI 1.07 to 1.53, respectively, p cont ≤0.03)., Conclusions: Smaller LDL particles are associated with incident CVD independently of traditional risk factors, including standard lipids, in participants with low/intermediate and very-high risk, who might benefit from improved risk assessment., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The National Comprehensive Cancer Network recommends that women who carry gene variants that confer substantial risk for breast cancer consider risk-reduction strategies, that is, enhanced surveillance (breast magnetic resonance imaging and mammography) or prophylactic surgery. Pathogenic variants can be detected in women with a family history of breast or ovarian cancer syndromes by multigene panel testing., Objectives: To investigate whether using a seven-gene test to identify women who should consider risk-reduction strategies could cost-effectively increase life expectancy., Methods: We estimated effectiveness and lifetime costs from a payer perspective for two strategies in two hypothetical cohorts of women (40-year-old and 50-year-old cohorts) who meet the National Comprehensive Cancer Network-defined family history criteria for multigene testing. The two strategies were the usual test strategy for variants in BRCA1 and BRCA2 and the seven-gene test strategy for variants in BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, and PALB2. Women found to have a pathogenic variant were assumed to undergo either prophylactic surgery or enhanced surveillance., Results: The incremental cost-effectiveness ratio for the seven-gene test strategy compared with the BRCA1/2 test strategy was $42,067 per life-year gained or $69,920 per quality-adjusted life-year gained for the 50-year-old cohort and $23,734 per life-year gained or $48,328 per quality-adjusted life-year gained for the 40-year-old cohort. In probabilistic sensitivity analysis, the seven-gene test strategy cost less than $100,000 per life-year gained in 95.7% of the trials for the 50-year-old cohort., Conclusions: Testing seven breast cancer-associated genes, followed by risk-reduction management, could cost-effectively improve life expectancy for women at risk of hereditary breast cancer., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: The 2013 ACC/AHA guideline recommended either no statin therapy or moderate-intensity statin therapy (MST) for intermediate risk patients-those with 5-7.5% 10-year risk and without cardiovascular disease (CVD), hypercholesterolemia or diabetes. The guideline further suggested that the therapy choice be based on patient-clinician discussions of risks and benefits. Since low-density lipoprotein particle (LDL-P) levels were reported to be associated with CVD independently of traditional risk factors in intermediate and low risk patients, we investigated the cost-effectiveness of using LDL-P levels to identify intermediate risk patients likely to benefit from initiating or intensifying statin therapy., Methods: We evaluated 5 care strategies for intermediate risk patients. These included the strategies suggested by the guideline: no-statin therapy and MST. We compared each of these strategies to a related strategy that incorporated LDL-P testing. No-statin therapy was compared with the strategy of MST for those with high LDL-P levels and no statin therapy for all other patients (test-and-MST). MST was compared with the strategy of high-intensity statin therapy (HST) for those with high LDL-P levels and MST for all other patients (test-and-HST). We also evaluated the strategy of HST for all. Costs (payer perspective) and utilities were assessed over a 5-year time horizon in a Markov model of 100,000 hypothetical intermediate risk patients., Results: HST dominated all other strategies, costing less and-despite causing 739 more cases of diabetes than did MST-resulting in more quality adjusted life-years (QALYs). For patient-clinician discussions that would otherwise lead to the MST strategy, we found the test-and-HST strategy reduced costs by $4.67 MM and resulted in 134 fewer CVD events and 115 additional QALYs. For patient-clinician discussions that would otherwise lead to no statin therapy, we found that the test-and-MST strategy reduced costs by $3.25 MM, resulted in 97 fewer CVD events and 44 additional QALYs., Conclusions: The HST strategy was cost saving and improved outcomes in intermediate risk patients. For patient and clinicians concerned about the adverse events associated with HST, using LDL-P levels to target intensified statin therapy could improve outcomes and reduce costs.

Aims: Genetic risk scores (GRSs) have been associated with coronary heart disease (CHD) in large studies. We asked whether expanding an established 27-variant GRS (GRS27) to a 50-variant GRS (GRS50) improved CHD prediction and whether GRSs are independent of self-reported family history of CHD., Methods and Results: The association between GRSs and incident CHD was assessed in Cox models adjusting for established risk factors in 23 595 participants of the Malmö Diet and Cancer study--a prospective, population-based study. During a median follow-up of 14.4 years, 2213 participants experienced a first CHD event. After adjustment for established risk factors, both GRS27 and GRS50 were associated with incident CHD [hazard ratio (HR) = 1.70 for high (top quintile) vs. low (bottom quintile) of GRS27; 95% confidence interval (CI): 1.48-1.94; Ptrend = 1.6 × 10(-15) and HR = 1.92 for GRS50; 95% CI: 1.67-2.20; Ptrend = 6.2 × 10(-22)]. Adding 23 single nucleotide polymorphisms (SNPs) to GRS27 improved risk prediction (P = 3 × 10(-6)). Further adjustment for self-reported family history did not appreciably change the risk estimates of either GRS27 (HR = 1.65; 95% CI: 1.45-1.89) or GRS50 (HR = 1.87; 95% CI: 1.63-2.14). The addition of GRS50 to established risk factors, including self-reported family history, improved discrimination (P < 0.0001) and reclassification (continuous net reclassification improvement index = 0.17, P < 0.0001). In young participants (below median age), those with high GRS50 had 2.4-fold greater risk (95% CI: 1.85-3.12) than those with low GRS50., Conclusion: The addition of 23 SNPs to an existing GRS27 improved CHD risk prediction and was independent of self-reported family history. Coronary heart disease risk assessment by GRS could be particularly useful in young individuals., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Atrial fibrillation (AF) increases risk of stroke, and although this stroke risk can be ameliorated by warfarin therapy, some patients decline to adhere to warfarin therapy. A prospective clinical study could be conducted to determine whether knowledge of genetic risk for AF could increase adherence to warfarin therapy for patients who initially declined therapy. As a prelude to a potential prospective clinical study, we investigated whether the use of genetic information to increase adherence could be cost effective., Methods: Markov model assessed costs and utilities of two care strategies for AF patients who declined warfarin therapy. In the usual care strategy patients received aspirin. In the test strategy genetic risk for AF was assessed (genotype of the 4q25 locus) and some patients with a positive genetic test (≥1 risk allele) were assumed to adhere to warfarin therapy. The remaining patients received aspirin. The incremental cost-effectiveness ratio (ICER) was the ratio of the costs differential and the quality adjusted life-years (QALYs) differential for the two strategies., Results: We found that the 4q25 genetic testing strategy, compared with the usual care strategy (aspirin therapy), would be cost-effective (ICER $ 47,148) if 2.1 % or more of the test positive patients were to adhere to warfarin therapy. The test strategy would become a cost saving strategy if 5.3 % or more of the test positive patients were to adhere to warfarin therapy. If 20 % of test positive patients were to adhere to warfarin therapy in a hypothetical cohort of 1000 patients, 7 stroke events would be prevented and 3 extra-cranial major bleeding events would be caused over 5 years, resulting in a cost savings of ~ $250,000 and a net gain of 9 QALYs., Discussion: A clinical study to assess the impact of patient knowledge of genetic risk of AF on adherence to warfarin therapy would be merited because even a modest increase in patient adherence would make a genetic testing strategy cost-effective., Conclusion: Providing patients who declined warfarin therapy with information about their genetic risk of AF would be cost effective if this genetic risk information resulted in modest increases in adherence.

Background: Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy., Methods: A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48,421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis., Findings: When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55-1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT., Interpretation: A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy., Funding: National Institutes of Health., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To determine whether a next-generation sequencing (NGS) panel of 34 cancer-associated genes would cost-effectively aid in the treatment selection for patients with metastatic melanoma, compared with a single-site BRAF V600 mutation test., Methods: A decision model was developed to estimate the costs and health outcomes of the two test strategies. The cost effectiveness of these two strategies was analyzed from a payer perspective over a 2-year time horizon with model parameters taken from the literature., Results: In the base case, the gene sequencing panel strategy resulted in a cost of US$120,022 and 0.721 quality-adjusted life years (QALYs) per patient, whereas the single-site mutation test strategy resulted in a cost of US$128,965 and 0.704 QALYs. Thus, the gene sequencing panel strategy cost US$8943 less per patient and increased QALYs by 0.0174 per patient. Sensitivity analyses showed that, compared with the single-site mutation test strategy, the gene sequencing panel strategy had a 90.9% chance of having reduced costs and increased QALYs, with the cost of the gene sequencing panel test having minimal effect on the incremental cost., Conclusion: Compared with the single-site mutation test, the use of an NGS panel of 34 cancer-associated genes as an aid in selecting therapy for patients with metastatic melanoma reduced costs and increased QALYs. If the base-case results were applied to the 8900 patients diagnosed with metastatic melanoma in the USA each year, the gene sequencing panel strategy could result in an annual savings of US$79.6 million and a gain of 155 QALYs.

Objective: To describe practice patterns of medical toxicologists in the United States of America (USA), Europe, and Asia Pacific Region regarding management of drug induced QT prolongation and torsades de pointes in overdose., Methods: A survey was developed to assess current practice patterns and consistency with guidelines published by the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC). It was reviewed by our department research committee and the American College of Medical Toxicology (ACMT). The ACMT, European Association of Poisons Centres and Clinical Toxicologists, and Asia Pacific Association of Medical Toxicology electronically disseminated the survey to their physician members in the USA, Europe and Asia Pacific Region., Results: The overall response rate was 37% (229/617) (36% USA; 32% Europe; 52% Asia Pacific Region). Twelve toxicologists from Asia Pacific Region and Europe used the QT nomogram (Australia-5, New Zealand-1, United Kingdom-1) or QT alone (France-1, Russia-1, Romania-1, Germany-1, Philippines-1), in lieu of the corrected QT (QTc) to determine risks of developing torsades de pointes. Because only those who used QTc could proceed through the remainder of the survey, only 217 could do so. Approximately half of the respondents (52%) did not calculate QTc manually and based decisions on the electrocardiogram machines automated measurement. For those who corrected the QT interval themselves, the most common formula used was Bazett's (40%). There is great variation in the QTc value considered prolonged. Most responders considered QTc greater than 450 ms in men (28%) and 460 ms in women (25%) to be prolonged. Interestingly, approximately 15% of participants did not consider the QTc prolonged until it exceeded 500 ms in both men and women. Given an overdose scenario of a male patient with a QTc of 560 ms, heart rate of 90 beats/minute, 59% would not recommend administering intravenous magnesium sulfate. Forty-five percent and 36% believed magnesium could shorten QTc and prevent torsades de pointes, respectively. In addition, almost 90% believed administering 1-2 boluses of intravenous magnesium is safe, even when serum magnesium is not available. In regards to cardiac pacing of patients with QT prolongation and torsades de pointes, only 38% of the participating toxicologists' responses agreed with AHA/ACC/ESC recommendations. Furthermore, 21% would not pace a patient who developed torsades de pointes regardless of the scenario., Discussion and Conclusions: The results indicate that medical toxicologists have considerable heterogeneity in terms of management practices for overdose patients with QT prolongation and torsades de pointes. Medical toxicologists may benefit from developing evidence-based consensus guidelines for the management of this relatively common finding in overdose of QT-prolonging drugs.

Background: The prediction of recurrent venous thrombosis using individual genetic risk predictors has proven to be challenging. The aim of this study was to assess whether multiple genetic single nucleotide polymorphism (SNP) analysis would predict recurrent venous thrombosis., Methods and Results: Patients with a first venous thrombosis were followed for a recurrent venous thrombosis up to 2009 (MEGA follow-up study), which occurred in 608 out of 4100 patients (2.7%/year). Thirty-one common thrombosis-associated single nucleotide polymorphisms (SNPs) were associated with the risk of recurrence. A genetic risk score (GRS) for each individual was calculated by summing the number of risk-increasing alleles for each of the 31 SNPs and for a simplified model consisting of 5 SNPs: rs6025, rs1799963, rs8176719, rs2066865, and rs2036914. The risk of recurrence associated with the GRS was calculated continuously and after stratification in a low and high score. All individual SNPs were at most mildly associated with recurrence risk. Regarding the 31-SNP GRS, recurrence risk was highest in patients with ≥31 and lowest in patients with <21 risk alleles. The discriminative power of the 5-SNP GRS was similar to that of the 31-SNP GRS. The 6-year cumulative incidence of recurrence was high for individuals with ≥5 (20.3%; 95% confidence interval, 16.5-24.1) and low for individuals with ≤1 (9.4%; 95% confidence interval, 6.7-12.1) risk alleles. Predictive power improved after stratification into provoked and unprovoked first events and sex., Conclusions: Multiple genetic SNP analysis is useful in the prediction of recurrent thrombosis, even more so when combining this model with clinical risk factors., (© 2014 American Heart Association, Inc.)

Introduction: The seeds of Abrus precatorius contain the highly toxic plant protein abrin. There is no antidote for abrin poisoning. Management, largely supportive, may consist of administering intravenous fluids, anti-emetics, and activated charcoal depending on the time of exposure. We report the presentation of a single case of unintentional abrin poisoning confirmed by the quantitation of L-abrine biomarker., Case Report: A previously healthy 22-month-old, 11.5-kg female presented to the hospital after ingesting approximately 20 rosary peas (A. precatorius) sold as a "peace bracelet". Her primary manifestations were episodes of forceful emesis that included food particles progressing to clear gastric fluid. The patient was tachycardic (HR = 134 bpm) but had brisk capillary refill and normal blood pressure (96/60 mmHg). Laboratory testing revealed elevated blood urea nitrogen (16 mg/dL) and serum creatinine (0.4 mg/dL). In the emergency department, the patient was resuscitated with 40 mL/kg normal saline via peripheral IV and received ondansetron (0.15 mg/kg IV) to control retching. The patient was discharged well 24 h after the ingestion., Discussion: This is the first case of human abrin toxin poisoning confirmed by the quantitation of L-abrine as a biomarker. Quantifying the levels of abrin toxin in the body after exposure can help clinicians make informed decisions when managing patients with symptomatic exposures to seeds of A. precatorius.