Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk.

BACKGROUND AND AIMS: RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases. METHODS: RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of ANGPTL3 protein-truncating variants (PTVs) associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank. RESULTS: In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on low-density lipoprotein cholesterol, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels [-0.37 (interquartile range 0.41) mmol/L] had slightly lower apoB levels (-0.06 ± 0.32 g/L) and similar CAD event rates compared with non-carriers (10.2% vs. 10.9% in carriers vs. non-carriers, P = .60). CONCLUSIONS: PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk.

Proteome-Wide Mendelian Randomization Identifies Causal Links Between Blood Proteins and Acute Pancreatitis.

BACKGROUND & AIMS: Acute pancreatitis (AP) is a complex disease and the leading cause of gastrointestinal disease-related hospital admissions. Few therapeutic options exist for AP prevention. Blood proteins with causal evidence may represent promising drug targets, but few have been causally linked with AP. Our objective was to identify blood proteins linked with AP by combining genome-wide association meta-analysis and proteome-wide Mendelian randomization (MR) studies. METHODS: We performed a genome-wide association meta-analysis totalling 10,630 patients with AP and 844,679 controls and a series of inverse-variance weighted MR analyses using cis-acting variants on 4719 blood proteins from the deCODE study (N = 35,559) and 4979 blood proteins from the Fenland study (N = 10,708). RESULTS: The meta-analysis identified genome-wide significant variants (P <5 × 10-8) at 5 loci (ABCG5/8, TWIST2, SPINK1, PRSS2 and MORC4). The proteome-wide MR analyses identified 68 unique blood proteins that may causally be associated with AP, including 29 proteins validated in both data sets. Functional annotation of these proteins confirmed expression of many proteins in metabolic tissues responsible for digestion and energy metabolism, such as the esophagus, adipose tissue, and liver as well as acinar cells of the pancreas. Genetic colocalization and investigations into the druggable genome also identified potential drug targets for AP. CONCLUSIONS: This large genome-wide association study meta-analysis for AP identified new variants linked with AP as well as several blood proteins that may be causally associated with AP. This study provides new information on the genetic architecture of this disease and identified pathways related to AP, which may be further explored as possible therapeutic targets for AP.

Gnotobiotic mice housing conditions critically influence the phenotype associated with transfer of faecal microbiota in a context of obesity.

OBJECTIVE: Faecal microbiota transplantation (FMT) in germ-free (GF) mice is a common approach to study the causal role of the gut microbiota in metabolic diseases. Lack of consideration of housing conditions post-FMT may contribute to study heterogeneity. We compared the impact of two housing strategies on the metabolic outcomes of GF mice colonised by gut microbiota from mice treated with a known gut modulator (cranberry proanthocyanidins (PAC)) or vehicle. DESIGN: High-fat high-sucrose diet-fed GF mice underwent FMT-PAC colonisation in sterile individual positive flow ventilated cages under rigorous housing conditions and then maintained for 8 weeks either in the gnotobiotic-axenic sector or in the specific pathogen free (SPF) sector of the same animal facility. RESULTS: Unexpectedly, 8 weeks after colonisation, we observed opposing liver phenotypes dependent on the housing environment of mice. Mice housed in the GF sector receiving the PAC gut microbiota showed a significant decrease in liver weight and hepatic triglyceride accumulation compared with control group. Conversely, exacerbated liver steatosis was observed in the FMT-PAC mice housed in the SPF sector. These phenotypic differences were associated with housing-specific profiles of colonising bacterial in the gut and of faecal metabolites. CONCLUSION: These results suggest that the housing environment in which gnotobiotic mice are maintained post-FMT strongly influences gut microbiota composition and function and can lead to distinctive phenotypes in recipient mice. Better standardisation of FMT experiments is needed to ensure reproducible and translatable results.

Impact of the gut microbiota and associated metabolites on cardiometabolic traits, chronic diseases and human longevity: a Mendelian randomization study.

Features of the gut microbiota have been associated with several chronic diseases and longevity in preclinical models as well as in observational studies. Whether these relations underlie causal effects in humans remains to be established. We aimed to determine whether the gut microbiota influences cardiometabolic traits as well as the risk of chronic diseases and human longevity using a comprehensive 2-Sample Mendelian randomization approach. We included as exposures 10 gut-associated metabolites and pathways and 57 microbial taxa abundance. We included as outcomes nine cardiometabolic traits (fasting glucose, fasting insulin, systolic blood pressure, diastolic blood pressure, HDL cholesterol, LDL cholesterol, triglycerides, estimated glomerular filtration rate, body mass index [BMI]), eight chronic diseases previously linked with the gut microbiota in observational studies (Alzheimer's disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease), as well as parental lifespan and longevity. We found 7 associations with evidence of causality before and after sensitivity analyses, but not after multiple testing correction (1198 tests). Most effect sizes (4/7) were small. The two largest exposure-outcome effects were markedly attenuated towards the null upon inclusion of BMI or alcohol intake frequency in multivariable MR analyses. While finding robust genetic instruments for microbiota features is challenging hence potentially inflating type 2 errors, these results do not support a large causal impact of human gut microbita features on cardiometabolic traits, chronic diseases or longevity. These results also suggest that the previously documented associations between gut microbiota and human health outcomes may not always underly causal relations.

Derivation and validation of risk prediction for posttraumatic stress symptoms following trauma exposure.

BACKGROUND: Posttraumatic stress symptoms (PTSS) are common following traumatic stress exposure (TSE). Identification of individuals with PTSS risk in the early aftermath of TSE is important to enable targeted administration of preventive interventions. In this study, we used baseline survey data from two prospective cohort studies to identify the most influential predictors of substantial PTSS. METHODS: Self-identifying black and white American women and men (n = 1546) presenting to one of 16 emergency departments (EDs) within 24 h of motor vehicle collision (MVC) TSE were enrolled. Individuals with substantial PTSS (⩾33, Impact of Events Scale - Revised) 6 months after MVC were identified via follow-up questionnaire. Sociodemographic, pain, general health, event, and psychological/cognitive characteristics were collected in the ED and used in prediction modeling. Ensemble learning methods and Monte Carlo cross-validation were used for feature selection and to determine prediction accuracy. External validation was performed on a hold-out sample (30% of total sample). RESULTS: Twenty-five percent (n = 394) of individuals reported PTSS 6 months following MVC. Regularized linear regression was the top performing learning method. The top 30 factors together showed good reliability in predicting PTSS in the external sample (Area under the curve = 0.79 ± 0.002). Top predictors included acute pain severity, recovery expectations, socioeconomic status, self-reported race, and psychological symptoms. CONCLUSIONS: These analyses add to a growing literature indicating that influential predictors of PTSS can be identified and risk for future PTSS estimated from characteristics easily available/assessable at the time of ED presentation following TSE.

ALY688 elicits adiponectin-mimetic signaling and improves insulin action in skeletal muscle cells.

Adiponectin is well established to mediate many beneficial metabolic effects, and this has stimulated great interest in development and validation of adiponectin receptor agonists as pharmaceutical tools. This study investigated the effects of ALY688, a peptide-based adiponectin receptor agonist, in rat L6 skeletal muscle cells. ALY688 significantly increased phosphorylation of several adiponectin downstream effectors, including AMPK, ACC, and p38MAPK, assessed by immunoblotting and immunofluorescence microscopy. Temporal analysis using cells expressing an Akt biosensor demonstrated that ALY688 enhanced insulin sensitivity. This effect was associated with increased insulin-stimulated Akt and IRS-1 phosphorylation. The functional metabolic significance of these signaling effects was examined by measuring glucose uptake in myoblasts stably overexpressing the glucose transporter GLUT4. ALY688 treatment increased basal glucose uptake and enhanced insulin-stimulated glucose uptake. In the model of high-glucose/high-insulin (HGHI)-induced insulin-resistant cells, both temporal studies using the Akt biosensor as well as immunoblotting to assess Akt and IRS-1 phosphorylation indicated that ALY688 significantly reduced insulin resistance. Importantly, we observed that ALY688 administration to high-fat high-sucrose-fed mice also improves glucose handling, validating its efficacy in vivo. In summary, these data indicate that ALY688 activates adiponectin signaling pathways in skeletal muscle, leading to improved insulin sensitivity and beneficial metabolic effects.

Fish oil replacement prevents, while docosahexaenoic acid-derived protectin DX mitigates end-stage-renal-disease in atherosclerotic diabetic mice.

Diabetic nephropathy (DN) remains the major cause of end-stage renal disease (ESRD). We used high-fat/high-sucrose (HFHS)-fed LDLr-/- /ApoB100/100 mice with transgenic overexpression of IGFII in pancreatic ß-cells (LRKOB100/IGFII) as a model of ESRD to test whether dietary long chain omega-3 polyunsaturated fatty acids LCω3FA-rich fish oil (FO) could prevent ESRD development. We further evaluated the potential of docosahexaenoic acid (DHA)-derived pro-resolving lipid mediators, 17-hydroxy-DHA (17-HDHA) and Protectin DX (PDX), to reverse established ESRD damage. HFHS-fed vehicle-treated LRKOB100/IGFII mice developed severe kidney dysfunction leading to ESRD, as revealed by advanced glomerular fibrosis and mesangial expansion along with reduced percent survival. The kidney failure outcome was associated with cardiac dysfunction, revealed by reduced heart rate and prolonged diastolic and systolic time. Dietary FO prevented kidney damage, lean mass loss, cardiac dysfunction, and death. 17-HDHA reduced podocyte foot process effacement while PDX treatment alleviated kidney fibrosis and mesangial expansion as compared to vehicle treatment. Only PDX therapy was effective at preserving the heart function and survival rate. These results show that dietary LCω3FA intake can prevent ESRD and cardiac dysfunction in LRKOB100/IGFII diabetic mice. Our data further reveals that PDX can protect against renal failure and cardiac dysfunction, offering a potential new therapeutic strategy against ESRD.

High touch, high trust: Using community health advocates and lawyers to address ED high utilizers.

BACKGROUND: Emergency department (ED) high utilizers are a costly group of patients due to their higher utilzation of acute care costs. At a safety-net hospital, we enrolled patients in a program which partnered with lawyers and community health advocates (CHAs) to navigate patients' social, medical and legal needs. Our aim was to decrease costs and utilization and address the patient's social determinants of heath (SDOH). METHODS: We enrolled patients with 4 or more ED visits in the prior 6 months and gave them SDOH and medical questionnaires. Patients were followed for 6 months on a weekly, then bi-monthly basis. All utilization and cost data were obtained through an internal data warehouse and evaluated using a pre-post analysis and broken down into quartiles. RESULTS: ED, admission, and total costs did not differ significantly between the 12 months pre-enrollment and the 12 months post-enrollment. Outpatient costs did increase ($2182 increase, p < 0.005). ED visits declined significantly in the post-enrollment period (IRR = 0.84, p = 0.048), with the highest impact on those with <7 ED visits. Total admissions did not decline (IRR 0.84, p = 0.059). But, among those with 4 or 5 ED visits, admission costs and visits decreased. On average, six SDOH issues were identified. Of these, approximately 30.3% were mitigated with up to 17% requiring legal help. CONCLUSION: While outpatient costs did increase, total costs did not decrease in this program. This type of non-clinical intervention may be best served for patients who are less clinically complex but significant social needs.

Cholecalciferol Supplementation Does Not Prevent the Development of Metabolic Syndrome or Enhance the Beneficial Effects of Omega-3 Fatty Acids in Obese Mice.

BACKGROUND: Cholecalciferol (D3) may improve inflammation, and thus provide protection from cardiometabolic diseases (CMD), although controversy remains. Omega-3 fatty acids (ω-3FA) may also prevent the development of CMD, but the combined effects of ω-3FA and D3 are not fully understood. OBJECTIVES: We determined the chronic independent and combined effects of D3 and ω-3FA on body weight, glucose homeostasis, and markers of inflammation in obese mice. METHODS: We gave 8-week-old male C57BL/6J mice, which had been fed a high-fat, high-sucrose (HF) diet (65.5% kcal fat, 19.8% kcal carbohydrate, and 14% kcal protein) for 12 weeks, either a standard D3 dose (+SD3; 1400 IU D3/kg diet) or a high D3 dose (+HD3; 15,000 IU D3/kg diet). We fed 1 +SD3 group and 1 +HD3 group with 4.36% (w/w) fish oil (+ω-3FA; 44% eicosapentaenoic acid, 25% docosahexaenoic acid), and fed the other 2 groups with corn oil [+omega-6 fatty acids (ω-6FA)]. A fifth group was fed a low-fat (LF; 15.5% kcal) diet. LF and HF+ω-6+SD3 differences were tested by a Student's t-test and HF treatment differences were tested by a 2-way ANOVA. RESULTS: D3 supplementation in the +HD3 groups did not significantly increase plasma total 25-hydroxyvitamin D and 25-hydroxyvitamin D3 [25(OH)D3] versus the +SD3 groups, but it increased 3-epi-25-hydroxyvitamin D3 levels by 3.4 ng/mL in the HF+ω-6+HD3 group and 4.0 ng/mL in the HF+ω-3+HD3 group, representing 30% and 70%, respectively, of the total 25(OH)D3 increase. Energy expenditure increased in those mice fed diets +ω-3FA, by 3.9% in the HF+ω-3+SD3 group and 7.4% in the HF+ω-3+HD3 group, but it did not translate into lower body weight. The glucose tolerance curves of the HF+ω-3+SD3 and HF+ω-3+HD3 groups were improved by 11% and 17%, respectively, as compared to the respective +ω-6FA groups. D3 supplementation, within the ω-3FA groups, altered the gut microbiota by increasing the abundance of S24-7 and Lachnospiraceae taxa compared to the standard dose, while within the ω-6FA groups, D3 supplementation did not modulate specific taxa. CONCLUSIONS: Overall, D3 supplementation does not prevent CMD or enhance the beneficial effects of ω-3FA in vitamin D-sufficient obese mice.

Asthma and Physical Activity in Urban Children.

OBJECTIVES: Asthma and obesity disproportionately affect urban minority children. Avoidance of physical activity contributes to obesity, and urban children with asthma are at risk for lower levels of physical activity. We examined associations between lung function and moderate to vigorous physical activity (MVPA) and moderators of this association in a diverse sample of children with asthma. METHODS: Urban children (N = 142) ages 7-9 with persistent asthma and their caregivers completed a study of asthma and physical activity. Longitudinal mixed effects models examining daily-level asthma and physical activity evaluated the association between asthma and MVPA, and the moderating effect of weight, and cultural/contextual factors on this association. RESULTS: Average daily MVPA was below recommended guidelines. Differences in MVPA were found by racial/ethnic group (p = .04) and weight (p = .001). Poorer asthma status was associated with lower MVPA in Latino and Black participants (p's < .05), and in normal weight youth (p = .01). Body mass index (BMI) moderated the association between asthma and MVPA. Those with lower BMI had more optimal asthma status and higher MVPA levels, whereas associations attenuated for participants with higher BMI (p = .04). Caregivers' perceptions of neighborhood safety and fear of asthma were marginally associated with children's symptoms and MVPA: as perceptions of safety decreased and fear increased, associations between asthma and MVPA weakened (p's = .09 and .07, respectively). CONCLUSIONS: Suboptimal asthma status is associated with less MVPA in urban children. Weight status and cultural/contextual factors play a role in the association and are worthy targets for future research and intervention.

Point-of-care influenza testing does not significantly shorten time to disposition among patients with an influenza-like illness.

INTRODUCTION: Availability of anti-viral agents and need to isolate infected patients increases the need to confirm the diagnosis of influenza before determining patient disposition. OBJECTIVES: We sought to determine if time-to-disposition (TTD) was shorter among patients tested for influenza using an Emergency Department (ED) Point-of-care (POC) test compared to core laboratory (lab) test and to determine difference in antibiotic use between groups. METHODS: We prospectively enrolled a convenience sample of ED patients for whom influenza testing was ordered during influenza season 2017. Participants were randomized to POC or lab. Data collected included demographics, chief complaint, influenza test results, turnaround time (TAT), whether antibiotics were given, and TTD. Descriptive statistics were calculated and group comparisons conducted using chi squared and Wilcoxon Rank Sum tests. RESULTS: Study population included 100 in the POC group and 97 in the lab group. Demographics were similar between POC and lab participants. More flu positive results were reported in the POC group compared to the lab group (51.0% vs. 33.0% p = 0.01). The median TTD was 146.5 min (IQR 98.5) for POC group and 165.5 min (IQR 127) for lab group (p = 0.26). The median TAT was 30.5 min (IQR 7.5) for POC group and 106.0 min (IQR 55) for core lab group (p = 0.001). Antibiotics were given to 14.0% of POC participants and 14.4% of lab participants (p = 0.93). CONCLUSIONS: Although use of a POC influenza test provided more rapid TAT than use of a core lab test, there was no significant difference in TTD or antibiotic use between groups.

Impact of a one-year lifestyle modification program on cholesterol efflux capacities in men with abdominal obesity and dyslipidemia.

Cholesterol efflux capacities (CECs) are negatively associated with cardiovascular disease risk, irrespective of plasma high-density lipoprotein (HDL) cholesterol levels. Whether interventions targeting lifestyle improve HDL-CECs is unknown. Our objective was to determine whether improving dietary quality and increasing physical activity levels improves HDL-CECs in men with abdominal obesity and dyslipidemia. Our study sample included men (48 ± 8.5 yr) with an elevated waist circumference (≥90 cm) associated with dyslipidemia (triglycerides ≥1.69 and/or HDL cholesterol <1.03 mmol/l); 113 men completed a 1-yr intervention, consisting of a healthy eating and physical activity/exercise program, and 32 were included in a control group. An oral lipid tolerance test (OLTT) was performed in a subsample of 28 men who completed the intervention, and blood was collected every 2 h for 8 h. HDL-CECs were measured using [3H]cholesterol-labeled J774 macrophages and HepG2 hepatocytes. The lifestyle modification program led to an overall improvement in the cardiometabolic risk profile, increases in J774-HDL-CEC by 14.1% (+0.88 ± 1.09%, P < 0.0001), HepG2-HDL-CEC by 3.4% (+0.17 ± 0.75%, P = 0.01), and HDL cholesterol and apolipoprotein A-1 levels (13.5%, P < 0.0001 and 14.9%, P < 0.0001, respectively). J774-HDL-CECs and HepG2-HDL-CECs did not change in the control group. The best predictor for changes in HDL-CEC was apolipoprotein A-1 level. The lifestyle modification program also improved HDL-CEC response in postprandial lipemia during an OLTT. HDL-CEC did not change during the OLTT. Our results suggest that increasing physical activity levels and improving diet quality can have a positive impact on both HDL quantity and quality in men with abdominal obesity and dyslipidemia.

Non-progressing cancer patients have persistent B cell responses expressing shared antibody paratopes that target public tumor antigens.

There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time. Anti-CTLA4 and other treatments were associated with further increases in somatic hypermutation and clonal family size. Recombinant antibodies from clonal families bound non-autologous tumor tissue and cell lines, and families possessing immunoglobulin paratope sequence motifs shared across patients exhibited increased rates of binding. We identified antibodies that caused regression of, and durable immunity toward, heterologous syngeneic tumors in mice. Our findings demonstrate convergent functional anti-tumor antibody responses targeting public tumor antigens, and provide an approach to identify antibodies with diagnostic or therapeutic utility.

The Use of Field Triage in Disaster and Mass Casualty Incidents: A Survey of Current Practices by EMS Personnel.

BACKGROUND: Mass casualty incident (MCI) triage and the use of triage tags to assign treatment priorities are not fully implemented despite emergency medical services (EMS) personnel training during drills and exercises. OBJECTIVES: To compare current field triage practices during both training and actual MCIs and identify any potential barriers to use. METHODS: During training sessions from November 2015 through March 2016, an anonymous survey was distributed to personnel in 3 distinct types of paid full-time EMS systems: Boston EMS (2-tiered, municipal third-service); Portland Fire Department (fire department-based ALS); and Stokes County EMS (county-based ALS) combined with Forsyth County EMS (county-based ALS). Data included personnel demographics and previous participation experiences in both drill and actual MCIs. Personnel with any prior MCI experience were queried regarding triage tag use and type of algorithm used. Data on barriers to use of triage tags and methods of communication of patient information were also collected. Descriptive statistics were used to analyze responses. RESULTS: Overall survey participation rate was 77.9% (464/596). Among all respondents, 38.7% (179/464) reported participating in both a drill and actual MCI's. In these cases, respondents reported less likely use of triage tags during actual MCI's compared to drills, (34.1 vs. 91.8%, p < 0.01), less likely to complete full triage (16.3 vs. 68.7%, p < 0.01) and less likely to employ geographical triage (56.8 vs. 90.4% p < 0.01). Verbal report was the most common communication method to hospitals (93.1%) when triage tags were not used. Responders reported proximity to the hospital as the most common reason for not using triage tags during an actual MCI (29.5%). CONCLUSIONS: Despite being a fundamental skill in MCI response, triage and other standard practices have not always been utilized in actual events despite training. EMS educators and disaster planners should consider strategies to better incorporate MCI practices during real world events.

Is hallway care dangerous? An observational study.

OBJECTIVES: In response to crowding the use of hallway beds has become an increasingly prevalent practice in Emergency Departments (EDs). There is limited research on whether caring for patients in hallways (HP) is associated with adverse outcomes. The goal of this study was to examine the effects of HP triage on 30 day outcomes for ED return, readmission, and mortality. METHODS: We performed a retrospective cohort study at an urban, academic ED comparing HPs (defined as HP for ≥30 min) to matched controls triaged to standard ED beds from 9/30/14 to 10/1/15. We analyzed data from the hospital's clinical data warehouse. Matched controls were selected by gender, age, ethnicity, and language. We used McNemar's test to assess the association between triage location and 30 day study outcomes. We also examined adverse outcomes by triage severity using McNemar's test. RESULTS: A total of 10,608 HPs were matched to control patients. Compared to controls, HPs had 2.0 times the odds of returning to the ED in 30 days (95% CI: 1.8-2.1), 1.6 times the odds of inpatient readmission (95% CI: 1.4-1.9), and 1.7 times the odds of readmission to observation (95% CI: 1.4-2.0). The odds ratio for mortality in HPs versus controls was 0.80, (95% CI: 0.50-1.3). CONCLUSIONS: Patients initially triaged to the hallway have an increased odds of 30 day return to the ED, observation and inpatient admission. After adjusting for ESI, the increased odds for return remained similar. The small sample size precluded testing effects of HP status on mortality.

Are Geriatric Patients Placed in an Emergency Department Observation Unit on a Chest Pain Pathway More Likely Than Non-Geriatric Patients to Re-Present to the Hospital within 30 Days?

BACKGROUND: Emergency department observation units (EDOUs) are used frequently for low-risk chest pain evaluations. OBJECTIVE: The purpose of this study was to determine whether geriatric compared to non-geriatric patients evaluated in an EDOU for chest pain have differences in unscheduled 30-day re-presentation, length of stay (LOS), and use of stress testing. METHODS: We conducted an exploratory, retrospective, cohort study at a single academic, urban ED of all adult patients placed in an EDOU chest pain protocol from June 1, 2014 to May 31, 2015. Our primary outcome was any unscheduled return visits within 30 days of discharge from the EDOU. Secondary outcomes included EDOU LOS and stress testing. We used Wilcoxon non-parametric and χ2 tests to compare geriatric to non-geriatric patients. RESULTS: There were 959 unique EDOU placements of geriatric (n = 219) and non-geriatric (n = 740) patients. Geriatric compared to non-geriatric patients had: no significant difference in unscheduled 30-day return visits after discharge from the EDOU (15.5% vs. 18.5%; p = 0.31); significantly longer median EDOU LOS (22.1 vs. 20.6 h; p < 0.01) with a greater percentage staying longer than 24 h (42% vs. 29.1%; p < 0.01). Geriatric patients had significantly fewer stress tests (39.7% vs. 51.4%; p < 0.01), more of which were nuclear stress tests (78.2% vs. 39.5%; p < 0.01). CONCLUSIONS: In this exploratory retrospective study, geriatric EDOU chest pain patients did not have an increased rate of re-presentation to the hospital within 30 days compared to non-geriatric patients. Geriatric patients had a longer EDOU LOS than non-geriatric patients. Geriatric patients in the EDOU had fewer stress tests, but more of those were nuclear stress tests.

Treatment with a novel agent combining docosahexaenoate and metformin increases protectin DX and IL-6 production in skeletal muscle and reduces insulin resistance in obese diabetic db/db mice.

AIMS: To compare the therapeutic potential of TP-113, a unique molecular entity linking DHA with metformin, for alleviating insulin resistance in obese diabetic mice through the PDX/IL-6 pathway. MATERIAL AND METHODS: We utilized the generically obese diabetic db/db mouse model for all experiments. Initial studies investigated both a dose and time course response. These results were then utilized to design a long-term (5 week) treatment protocol. Mice were gavaged twice daily with 1 of 3 treatments: 200 mg/kg BW TP113, an equivalent dose of metformin alone (70 mg/kg BW) or water. Whole-body insulin sensitivity was measured using the hyperinsulinaemic-isoglycaemic clamp procedure in awake unrestrained mice. RESULTS: We first confirmed that acute TP-113 treatment raises PDX and IL-6 levels in skeletal muscle. We next tested the long-term glucoregulatory effect of oral TP-113 in obese diabetic db/db mice and compared its effect to an equivalent dose of metformin. A 5-week oral treatment with TP-113 reduced insulin resistance compared to both vehicle treatment and metformin alone, revealed by the determination of whole-body insulin sensitivity for glucose disposal using the clamp technique. This insulin-sensitizing effect was explained primarily by improvement of insulin action to suppress hepatic glucose production in TP-113-treated mice. These effects of TP-113 were greater than that of an equivalent dose of metformin, indicating that TP-113 increases metformin efficacy for reducing insulin resistance. CONCLUSION: We conclude that TP-113 improves insulin sensitivity in obese diabetic mice through activation of the PDX/IL-6 signaling axis in skeletal muscle and improved glucoregulatory action in the liver.

Is the Pelvic Examination Still Crucial in Patients Presenting to the Emergency Department With Vaginal Bleeding or Abdominal Pain When an Intrauterine Pregnancy Is Identified on Ultrasonography? A Randomized Controlled Trial.

STUDY OBJECTIVE: We determine whether omitting the pelvic examination in emergency department (ED) evaluation of vaginal bleeding or lower abdominal pain in ultrasonographically confirmed early intrauterine pregnancy is equivalent to performing the examination. METHODS: We conducted a prospective, open-label, randomized, equivalence trial in pregnant patients presenting to the ED from February 2011 to November 2015. Patients were randomized to no pelvic examination versus pelvic examination. Inclusion criteria were aged 18 years or older, English speaking, vaginal bleeding or lower abdominal pain, positive ß-human chorionic gonadotropin result, and less than 16-week intrauterine pregnancy by ultrasonography. Thirty-day record review and follow-up call assessed for composite morbidity endpoints (unscheduled return, subsequent admission, emergency procedure, transfusion, infection, and alternate source of symptoms). Wilcoxon rank sum tests were used to assess patient satisfaction and throughput times. RESULTS: Only 202 (of a planned 720) patients were enrolled, despite extension of the study enrollment period. The composite morbidity outcome was experienced at similar rates in the intervention (no pelvic examination) and control (pelvic examination) groups (19.6% versus 22.0%; difference -2.4%; 90% confidence interval [CI] -11.8% to 7.1%). Patients in the intervention group were less likely to report feeling uncomfortable or very uncomfortable during the visit (11.2% versus 23.7%; difference -12.5; 95% CI -23.0% to -2.0%). CONCLUSION: Although there was only a small difference between the percentage of patients experiencing the composite morbidity endpoint in the 2 study groups (2.4%), the resulting 90% CI was too wide to conclude equivalence. This may have been due to insufficient power. Patients assigned to the pelvic examination group reported feeling uncomfortable more frequently.

Use of Intranasal Naloxone by Basic Life Support Providers.

STUDY OBJECTIVES: Intranasal delivery of naloxone to reverse the effects of opioid overdose by Advanced Life Support (ALS) providers has been studied in several prehospital settings. In 2006, in response to the increase in opioid-related overdoses, a special waiver from the state allowed administration of intranasal naloxone by Basic Life Support (BLS) providers in our city. This study aimed to determine: 1) if patients who received a 2-mg dose of nasal naloxone administered by BLS required repeat dosing while in the emergency department (ED), and 2) the disposition of these patients. METHODS: This was a retrospective review of patients transported by an inner-city municipal ambulance service to one of three academic medical centers. We included patients aged 18 and older that were transported by ambulance between 1/1/2006 and 12/12/2012 and who received intranasal naloxone by BLS providers as per a state approved protocol. Site investigators matched EMS run data to patients from each hospital's EMR and performed a chart review to confirm that the patient was correctly identified and to record the outcomes of interest. Descriptive statistics were then generated. RESULTS: A total of 793 patients received nasal naloxone by BLS and were transported to three hospitals. ALS intervened and transported 116 (14.6%) patients, and 11 (1.4%) were intubated in the field. There were 724 (91.3%) patients successfully matched to an ED chart. Hospital A received 336 (46.4%) patients, Hospital B received 210 (29.0%) patients, and Hospital C received 178 (24.6%) patients. Mean age was 36.2 (SD 10.5) years and 522 (72.1%) were male; 702 (97.1%) were reported to have abused heroin while 21 (2.9%) used other opioids. Nasal naloxone had an effect per the prehospital record in 689 (95.2%) patients. An additional naloxone dose was given in the ED to 64 (8.8%) patients. ED dispositions were: 507 (70.0%) discharged, 105 (14.5%) admitted, and 112 (15.5%) other (e.g., left against medical advice, left without being seen, or transferred). CONCLUSIONS: Only a small percentage of patients receiving prehospital administration of nasal naloxone by BLS providers required additional doses of naloxone in the ED and the majority of patients were discharged.

Injuries and exposures among ocean safety providers: A review of workplace injuries and exposures from 2007-2012.

Research on workplace injuries and exposures in ocean safety personnel remains limited. Despite increasing beach attendance and reliance on lifeguards for protection, the most common types of injuries, equipment resulting in injuries, and environmental exposures remains unknown. This study reviewed OSHA 300 logs summarizing workers' compensation claims from 2007-2012 to identify common body parts injured, action at time of injury, equipment causing injury, and environmental exposures. A secondary phase consisted of a cross-sectional anonymous survey to determine demographics, body part injured, equipment causing injury, sun and environmental exposures, action at time of injury, and proportion of injuries reported to the department. During the 6-year period, 304 claims from the OSHA logs were reviewed, finding the lower extremity was most commonly injured with 2921 (31.9%) cumulative lost work days (104 reported injured, 34.2%) followed by the back with 1679 (18.4%) lost work days (39 reported injuries, 12.8%). Of the 304 occupational injury claims from OSHA logs, 108 incidents (35.5%) occurred during rescues, 87 (28.6%) during normal duties, and 31 (10.2%) during training. Of survey participants, 22/52 sustained an injury, with 14 filling a worker's compensation claim. The rescueboard resulted in 7/22 injuries (31.8%) while 17 (32.7%) of respondents sought care for a sun related concern with a mean of 9.3 days lost. Occupational injuries in ocean safety personnel are largely unknown. In this study, lower extremity and back injuries were the most common musculoskeletal injuries providers encountered. Rescues and moving equipment were common actions at the time of injury. With this preliminary information, jurisdictions may develop training directed at rescue techniques and safer options for moving heavy equipment.