An Initiative to Improve Postpartum Discharge Education.

OBJECTIVE: To evaluate an online POST-BIRTH Warning Signs (PBWS) project focused on improving nurses' knowledge and how they teach individuals in the postpartum period about potential complications. DESIGN: Quality improvement project with exploratory pretest/posttest. SETTING: Seventy hospitals with maternity services throughout the United States. PARTICIPANTS: A sample of 2,363 registered nurses. INTERVENTION/MEASUREMENTS: An online educational program with four surveys and a chart audit tool were used as evaluation measures. RESULTS: There was an 11% increase in nurses' knowledge after the online course intervention. A majority of nurses reported that they would improve how they educate patients and families about PBWS, that they would change their clinical practice based on what they learned, and that their facility implemented a protocol to educate patients about PBWS after the implementation of the course. The nurses' reported confidence in their teaching increased 59% after implementation of the course. CONCLUSION: The majority of maternal deaths in the United States occur during the postpartum period. Therefore, it is vital that nurses provide standardized and structured educational messaging when teaching individuals in the postpartum period about signs and symptoms of potential complications. This quality improvement project demonstrated that the PBWS online education course was associated with an increase in nurses' knowledge and confidence when teaching about potential complications that can arise during the postpartum period.

Trends in Maternal Mortality and Severe Maternal Morbidity During Delivery-Related Hospitalizations in the United States, 2008 to 2021.

Importance: Maternal mortality and severe maternal morbidity (SMM) are important focus areas in public health. Further understanding trends, health disparities, and risk factors for these adverse outcomes is vital to public health decision-making. Objective: To describe trends and risk factors for delivery-related maternal deaths and SMM in the United States. Design, Setting, and Participants: This is a retrospective cross-sectional study using data from a large, geographically diverse, all-payer hospital administrative database. Hospital discharges from January 2008 to December 2021 with any Medicare Severity Diagnosis Related Group, International Classification of Diseases, Ninth Revision, Clinical Modification, or International Classification of Diseases, Tenth Revision, Clinical Modification delivery diagnosis or procedure code were included. Data analysis took place from February 2021 to March 2023. Exposures: Year, quarter (Q), age, race and ethnicity, delivery method. Main Outcomes and Measures: Maternal mortality, SMM during delivery-related hospitalization. Results: Overall, 11 628 438 unique hospital discharges were analyzed, with a mean (SD) age of 28 (6) years. There were 437 579 (3.8%) Asian, 92 547 (0.8%) American Indian, 1 640 355 (14.1%) Black, 1 762 392 (15.2%) Hispanic, 83 189 (0.7%) Pacific Islander, and 6 194 139 (53.3%) White patients. Regression-adjusted maternal mortality per 100 000 discharges declined from 10.6 deaths in Q1 2008 to 4.6 deaths in Q4 2021. Mortality was significantly higher among patients with advanced maternal age (eg, age 35-44 years vs 25-34 years: adjusted odds ratio [aOR], 1.49; 95% CI, 1.22-1.84). Other significant risk factors for mortality included cesarean delivery, comorbid conditions, complications, and COVID-19 diagnosis (eg, cesarean delivery: aOR, 2.28; 95% CI, 1.87-2.79). The prevalence of any SMM increased from 146.8 per 10 000 discharges in Q1 of 2008 to 179.8 per 10 000 discharges in Q4 of 2021. SMM risk factors included age 24 years or younger or age 35 years or older, belonging to a racial or ethnic minority group, cesarean delivery, Medicaid insurance, and having 1 or more comorbidities (eg, age 10-19 years: aOR, 1.39; 95% CI, 1.36-1.42). Conclusions and Relevance: This cross-sectional study found that delivery-related mortality in US hospitals decreased for all racial and ethnic groups, age groups, and modes of delivery during 2008 to 2021, likely demonstrating the impact of national strategies focused on improving maternal quality of care provided during delivery-related hospitalizations. SMM prevalence increased for all patients, with higher rates for racial and ethnic minority patients of any age. Advanced maternal age, racial or ethnic minority group status, cesarean delivery, and comorbidities were associated with higher odds of mortality and SMM.

Drowning prevention: turning the tide on a leading killer.

Drowning is a leading killer, particularly of children and young adults, yet has been greatly neglected. Despite accounting for a higher number of deaths than many other substantial public health issues, drowning has not benefitted from the targeted attention it requires, which is particularly tragic because low cost and effective drowning prevention interventions exist. Therefore, the recent UN General Assembly's adoption of a resolution on global drowning prevention is a historic first, and offers an exciting opportunity by providing a comprehensive framework and a practical roadmap that a range of actors and sectors, including governments, can follow to address the challenge of drowning prevention.

Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P5) Agonist for the Potential Treatment of Neurodegenerative Disorders.

S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris, 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam , , AAIC 2014). Herein we describe the development of a series of selective S1P5 agonists that led to the identification of compound 29, which is highly selective for S1P5 and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P5 biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P1 and S1P3 function in rats. In addition, we found that 29 improves blood-brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P5 agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood-brain barrier such as Alzheimer's disease or multiple sclerosis.

Anesthesia and organic aciduria: is the use of lactated Ringer's solution absolutely contraindicated?

BACKGROUND: Organic acidurias (OAs) are rare inborn errors of metabolism that can present with various neurologic manifestations, propensity for acute metabolic decompensation with anion-gap metabolic acidosis, developmental delay, poor feeding, and failure to thrive. OBJECTIVE: In this case series, we outline the anesthetic management and perioperative outcomes of OA patients. METHODS: We reviewed demographic characteristics, comorbidities, and perioperative course of patients with four different OAs who underwent anesthetic care at our institution between January 1, 2000, and December 31, 2013. RESULTS: Eleven patients with OA underwent 19 anesthetic procedures, of which 13 were <2 h in duration and seven were outpatient procedures. One patient with methylmalonic acidemia developed metabolic acidosis during a 10-h procedure with substantial blood loss but lacked evidence that this acidosis could be attributed to his underlying metabolic disease. The patients who received hydration with lactated Ringer's solution and/or nitrous oxide anesthetic had a perioperative course free of metabolic complication. Two patients died within 30 days of surgery from causes likely to be unrelated to anesthetic exposure. CONCLUSIONS: Our patients with various forms of metabolically compensated OAs tolerated anesthetics for surgical procedures without metabolic decompensation, even when lactated Ringer's solution was used for hydration. Measures to prevent protein catabolism and intraoperative events that may precipitate metabolic acidosis, in addition to close monitoring of acid-base status during more extensive procedures, must be part of perioperative treatment of these patients.

Refractory intraoperative hypotension with elevated serum tryptase.

Severe intraoperative hypotension has been reported in patients on angiotensin-converting enzyme inhibitors and angiotensin II receptor subtype 1 antagonists. We describe a patient on lisinopril who developed refractory intraoperative hypotension associated with increased serum tryptase level suggesting mast cell activation (allergic reaction). However, allergology workup ruled out an allergic etiology as well as mastocytosis, and hypotension recalcitrant to treatment was attributed to uninterrupted lisinopril therapy. Elevated serum tryptase was attributed to our patient's chronic renal insufficiency.

Myoclonus in patient on fluoxetine after receiving fentanyl and low-dose methylene blue during sentinel lymph node biopsy.

Serotonin released in the nerve synapses is cleared through reuptake into presynaptic neurons and metabolism with monoamine oxidase (MAO). Therapy with selective serotonin reuptake inhibitors (SSRIs) or MAO inhibitors increases serotonin concentration in the synaptic cleft and may result in serotonin syndrome (SS). Our patient undergoing sentinel lymph node biopsy was on fluoxetine (SSRI) and intraoperatively developed SS after receiving fentanyl (200 µg) and methylene blue (MAO inhibitor), 7 mg subcutaneously into the scalp. Initial presentation was several episodes of generalized muscle activity, which was later diagnosed as lower extremity myoclonus consistent with SS. Upon awakening, the patient showed no evidence of encephalopathy, and the clonus was less intense. The patient was discharge home the next day. Our case suggests the possibility that even a small dose of methylene blue, when administered simultaneously with other serotoninergic medications, may be associated with serotonin toxicity.

Associations between Charlson Comorbidity Index and surgical risk severity and the surgical outcomes in advanced-age patients.

The Charlson Comorbidity Index (CCI) has not been assessed for elderly (95 years of age or older) surgical patients. We examined the association between the CCI and life-threatening complications and 30-day mortality rate. Medical records of patients 95 years old or older from 2004 through 2008 were reviewed for major postoperative morbidity or death. Logistic regression analyses of age, sex, the CCI, American College of Cardiology/American Heart Association Surgical Risk Stratification, and surgical urgency were performed to identify associations with poor surgical outcome. One hundred eighty-seven patients were identified (mean [standard deviation] age, 96.6 [1.9] years; median [interquartile range] CCI, 4 [2 to 6]). Ninety patients (48.1%) underwent moderate-risk and 20 (10.7%) underwent high-risk surgical procedures. Twenty patients (10.7%) died within 30 postoperative days and 20 others had major morbidity. Only moderate-risk (P = 0.045) and high-risk surgical procedures (P = 0.001) were associated with poor outcome. Patients of advanced age have high rates of morbidity and death after surgical procedures. These events are associated with surgical risk stratification and are independent of patient comorbidities. Risks, benefits, and alternatives must be considered carefully and discussed with patients and their families before deciding to proceed with high-risk surgery.

Public health detailing of primary care providers: New York City's experience, 2003-2010.

OBJECTIVES: We evaluated the effectiveness of the Public Health Detailing Program in helping primary care providers and their staff to improve patient care on public health challenges. METHODS: We analyzed reported changes in clinical practice or behavior by examining providers' retention and implementation of recommendations for campaigns. RESULTS: During each campaign, 170 to 443 providers and 136 to 221 sites were reached. Among assessed providers who indicated changes in their practice behavior, the following statistically significant increases occurred from baseline to follow-up. Reported screening for clinical preventive services increased, including routinely screening for intimate partner violence (14%-42%). Clinical management increased, such as prescribing longer-lasting supplies of medicine (29%-42%). Lifestyle modification and behavior change, such as recommending increased physical activity to patients with high cholesterol levels, rose from 52% to 73%. Self-management goal setting with patients increased, such as using a clinical checkbook to track hemoglobin A1c goals (28% to 43%). CONCLUSIONS: Data suggest that public health detailing can be effective for linking public health agencies and their recommendations to providers and influencing reported changes in clinical practice behavior.

Public health detailing of primary care providers: New York City's experience, 2003-2010.

BACKGROUND: Given evidence of widespread underuse of recommended clinical preventive services and chronic disease management, New York City developed the Public Health Detailing Program, a primary care provider outreach initiative to increase uptake of best practices on public health priorities. PURPOSE: The goal of the study was to evaluate the effectiveness of the Public Health Detailing Program in helping primary care providers and their staff to improve patient care on public health challenges. METHODS: An analysis was conducted of reported changes in clinical practice or behavior by examining providers' retention and implementation of recommendations for campaigns. RESULTS: During each campaign, 170 to 443 providers and 136 to 221 sites were reached. Among providers who responded to questions on changes in their practice behavior, the following significant increases occurred from baseline to follow-up. Screening for clinical preventive services increased, including routinely screening for intimate partner violence (14%-42%). Clinical management increased, such as prescribing longer-lasting supplies of medicine (29%-42%). Lifestyle modification and behavior change, such as recommending increased physical activity to patients with high cholesterol levels, rose from 52% to 73%. Self-management goal-setting with patients increased, such as using a clinical checkbook to track hemoglobin HbA1c goals (28% to 43%). CONCLUSIONS: Data suggest that public health detailing can be effective for linking public health agencies and their recommendations to providers and influencing changes in clinical practice behavior.

Computer-assisted imaging algorithms facilitate histomorphometric quantification of kidney damage in rodent renal failure models.

INTRODUCTION: Surgical 5/6 nephrectomy and adenine-induced kidney failure in rats are frequently used models of progressive renal failure. In both models, rats develop significant morphological changes in the kidneys and quantification of these changes can be used to measure the efficacy of prophylactic or therapeutic approaches. In this study, the Aperio Genie Pattern Recognition technology, along with the Positive Pixel Count, Nuclear and Rare Event algorithms were used to quantify histological changes in both rat renal failure models. METHODS: Analysis was performed on digitized slides of whole kidney sagittal sections stained with either hematoxylin and eosin or immunohistochemistry with an anti-nestin antibody to identify glomeruli, regenerating tubular epithelium, and tubulointerstitial myofibroblasts. An anti-polymorphonuclear neutrophil (PMN) antibody was also used to investigate neutrophil tissue infiltration. RESULTS: Image analysis allowed for rapid and accurate quantification of relevant histopathologic changes such as increased cellularity and expansion of glomeruli, renal tubular dilatation, and degeneration, tissue inflammation, and mineral aggregation. The algorithms provided reliable and consistent results in both control and experimental groups and presented a quantifiable degree of damage associated with each model. CONCLUSION: These algorithms represent useful tools for the uniform and reproducible characterization of common histomorphologic features of renal injury in rats.

Addressing the implementation gap in global road safety: exploring features of an effective response and introducing a 10-country program.

Yearly, more than 1.2 million people are killed by road traffic injuries (RTIs) around the globe, and another 20 to 50 million are injured. The global burden of RTIs is predicted to rise. We explored the need for concerted action for global road safety and propose characteristics of an effective response to the gap in addressing RTIs. We propose that a successful response includes domains such as strong political will, capacity building, use of evidence-based interventions, rigorous evaluation, increased global funding, multisectoral action, and sustainability. We also present a case study of the global Road Safety in 10 Countries project, which is a new, 5-year, multipartner initiative to address the burden of RTIs in 10 low- and middle-income countries.

Identification and preliminary characterization of a potent, safe, and orally efficacious inhibitor of acyl-CoA:diacylglycerol acyltransferase 1.

A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.

Tigecycline for the treatment of severe Clostridium difficile infection.

OBJECTIVE: To evaluate the evidence for the use of tigecycline in the treatment of Clostridium difficile infection (CDI). DATA SOURCES: Searches were performed (2004 to June 2011), using the EMBASE and MEDLINE databases, with the terms tigecycline, Tygacil, Clostridium difficile, C. difficile, Clostridium difficile infection, and CDI. STUDY SELECTION: Six case reports that described the use of tigecycline for treatment of CDI were included for review. No clinical trials were identified. DATA SYNTHESIS: In all case reports except 1, tigecycline (alone or in combination with other CDI therapies) was used for the treatment of CDI that was refractory to metronidazole and/or vancomycin. In 6 of the cases, treatment success was reported following initiation of tigecycline therapy; 1 patient died following a complicated hospitalization. The treatment duration with tigecycline was 2-4 weeks. In the cases with successful outcomes, symptoms began to improve within 1 week. None of these patients experienced recurrence during follow-up of various lengths. In vitro studies demonstrated a 90% minimum inhibitory concentration range for tigecycline of 0.016-0.25 mg/L for all C. difficile isolates. Tigecycline exhibited good fecal penetration because of primary biliary excretion of unchanged drug. Up to 59% of the dose is recovered in feces following administration over 4 days in healthy volunteers. CONCLUSIONS: Case reports have suggested that tigecycline may be successful for treatment of severe or severe complicated CDI, when prior therapy has failed. Data demonstrating tigecycline use as initial therapy for CDI are limited; therefore, this option should be reserved for patients in whom other therapeutic options, including metronidazole and vancomycin, have failed. A randomized controlled trial is needed to assess the safety and efficacy of tigecycline in this patient population and better define the drug's role in the treatment of CDI.

In vivo efficacy of acyl CoA: diacylglycerol acyltransferase (DGAT) 1 inhibition in rodent models of postprandial hyperlipidemia.

Postprandial serum triglyceride concentrations have recently been identified as a major, independent risk factor for future cardiovascular events. As a result, postprandial hyperlipidemia has emerged as a potential therapeutic target. The purpose of this study was two-fold. Firstly, to describe and characterize a standardized model of postprandial hyperlipidemia in multiple rodent species; and secondly, apply these rodent models to the evaluation of a novel class of pharmacologic agent; acyl CoA:diacylglycerol acyltransferase (DGAT) 1 inhibitors. Serum triglycerides were measured before and for 4h after oral administration of a standardized volume of corn oil, to fasted C57BL/6, ob/ob, apoE(-/-) and CD-1 mice; Sprague-Dawley and JCR/LA-cp rats; and normolipidemic and hyperlipidemic hamsters. Intragastric administration of corn oil increased serum triglycerides in all animals evaluated, however the magnitude and time-course of the postprandial triglyceride excursion varied. The potent and selective DGAT-1 inhibitor A-922500 (0.03, 0.3 and 3 mg/kg, p.o.), dose-dependently attenuated the maximal postprandial rise in serum triglyceride concentrations in all species tested. At the highest dose of DGAT-1 inhibitor, the postprandial triglyceride response was abolished. This study provides a comprehensive characterization of the time-course of postprandial hyperlipidemia in rodents. In addition, the ability of DGAT-1 inhibitors to attenuate postprandial hyperlipidemia in multiple rodent models, including those that feature insulin resistance, is documented. Exaggerated postprandial hyperlipidemia is inherent to insulin-resistant states in humans and contributes to the substantially elevated cardiovascular risk observed in these patients. Therefore, by attenuating postprandial hyperlipidemia, DGAT-1 inhibition may represent a novel therapeutic approach to reduce cardiovascular risk.

Diacylglycerol acyltransferase 1 inhibition lowers serum triglycerides in the Zucker fatty rat and the hyperlipidemic hamster.

Acyl CoA/diacylglycerol acyltransferase (DGAT) 1 is one of two known DGAT enzymes that catalyze the final and only committed step in triglyceride biosynthesis. The purpose of this study was to test the hypothesis that chronic inhibition of DGAT-1 with a small-molecule inhibitor will reduce serum triglyceride concentrations in both genetic and diet-induced models of hypertriglyceridemia. Zucker fatty rats and diet-induced dyslipidemic hamsters were dosed orally with A-922500 (0.03, 0.3, and 3-mg/kg), a potent and selective DGAT-1 inhibitor, for 14 days. Serum triglycerides were significantly reduced by the 3 mg/kg dose of the DGAT-1 inhibitor in both the Zucker fatty rat (39%) and hyperlipidemic hamster (53%). These serum triglyceride changes were accompanied by significant reductions in free fatty acid levels by 32% in the Zucker fatty rat and 55% in the hyperlipidemic hamster. In addition, high-density lipoprotein-cholesterol was significantly increased (25%) in the Zucker fatty rat by A-922500 administered at 3 mg/kg. This study provides the first report that inhibition of DGAT-1, the final and only committed step of triglyceride synthesis, with a selective small-molecule inhibitor, significantly reduces serum triglyceride levels in both genetic and diet-induced animal models of hypertriglyceridemia. The results of this study support further investigation of DGAT-1 inhibition as a novel therapeutic approach to the treatment of hypertriglyceridemia in humans, and they suggest that inhibition of triglyceride synthesis may have more diverse beneficial effects on serum lipid profiles beyond triglyceride lowering.

Effect of the multitargeted receptor tyrosine kinase inhibitor, ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea], on blood pressure in conscious rats and mice: reversal with antihypertensive agents and effect on tumor growth inhibition.

ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea] is a novel multitargeted inhibitor of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase family members. ABT-869 demonstrates tumor growth inhibition in multiple preclinical animal models and in early clinical trials. VEGF receptor inhibition is also associated with reversible hypertension that may limit its benefit clinically. To evaluate optimal therapeutic approaches to prevent hypertension with VEGF receptor inhibition, we characterized the dose-dependent effects of seven antihypertensive agents from three mechanistic classes [angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs)] on hypertension induced by ABT-869 in conscious telemetry rats. We report that ABT-869-induced hypertension can be prevented and reversed with subtherapeutic or therapeutic doses of antihypertensive drugs with a general rank order of ACEi > ARB > CCB. In SCID mice, the ACE inhibitor, enalapril (C(20)H(28)N(2)O(5) x C(4)H(4)O(4)) at 30 mg/kg, prevented hypertension, with no attenuation of the antitumor efficacy of ABT-869. These studies demonstrate that the adverse cardiovascular effects of the VEGF/PDGF receptor tyrosine kinase inhibitor, ABT-869, are readily controlled by conventional antihypertensive therapy without affecting antitumor efficacy.