Predicting complete heart block after alcohol septal ablation for hypertrophic cardiomyopathy using a risk stratification model and clinical tool.

BACKGROUND: Alcohol septal ablation (ASA) is a proven method of septal reduction for patients with drug refractory, symptomatic hypertrophic obstructive cardiomyopathy (HOCM). This procedure is associated with a 6.5-11% risk of complete heart block (CHB). OBJECTIVE: The aim of this study is to determine factors that predict CHB and to develop a clinical tool for risk stratification of patients. METHODS: Patients were enrolled into an ongoing ASA study. A total of 636 patient procedures were included, 527 of whom were used in the development of the prediction tool, and 109 of whom were used for independent validation. Multivariate analysis was performed with odds ratios used to develop the clinical prediction tool. This was then internally and externally validated. RESULTS: Of the 527 in the prediction cohort, 46 developed CHB. The predictors of CHB were age ≥50 years, pre-ASA left bundle branch block (LBBB), transient procedural high-grade block, post-ASA PR prolongation ≥68 ms, and new bifascicular block. An 11-point clinical prediction tool was developed to classify these factors. Internal validation using a receiver operating characteristic curve revealed an area under the curve of 0.88 for the clinical prediction tool. External validation using 109 contemporary patients revealed a 98% negative predictive value, 24% positive predictive value, 75% sensitivity, and 81% specificity in high-risk patients. CONCLUSION: Among patients undergoing ASA, the risk of CHB can be predicted with easily obtained clinical and electrocardiographic factors. This clinical prediction tool allows identification of high-risk patients who may benefit from additional monitoring and therapy.

Increased Testing and Health Care Costs for Pediatric Cannabis Exposures.

OBJECTIVES: This study aimed to evaluate the process of identifying marijuana exposure in a children's hospital emergency department and compare the cost of diagnostic testing and procedures. METHODS: A retrospective chart review was performed on patients 31 days to 20 years old with a positive marijuana toxicology screen result between November 2009 and December 2014. Primary outcomes included time to provider recognition of marijuana exposure, number of diagnostic tests and procedures performed, and length of hospital stay. Patients were analyzed based on time of exposure recognition (forthcoming compared with not forthcoming of marijuana exposure) and age (children <12 years compared with adolescents >12 years). RESULTS: There were 37 children and 38 adolescents included. Mean time to exposure recognition was 2.3 ± 4.3 hours in children compared with 0.4 ± 0.9 hours in adolescents (P = 0.02). Patients who were not forthcoming of marijuana exposure experienced more than twice as many diagnostic tests or procedures compared with children who were forthcoming of marijuana exposure (mean, 8.91 vs 4 tests, P < 0.0001) and more than a 4-fold higher cost of potentially avoidable diagnostic tests/procedures. Length of hospital stay was significantly longer in children (18.34 ± 2.39 hours) compared with adolescents (4.22 ± 0.52 hours; P ≤ 0.0001). Few parents or guardians were able to disclose characteristics of the marijuana product. CONCLUSION: Delay in recognition of marijuana exposure is associated with high resource utilization, unnecessary medical costs, and prolonged length of stay.

Anti-infective Waste in a Pediatric Institution: Pinpointing Problems in the Process.

Purpose: At Children's Hospital Colorado (CHCO), there are approximately 40 000 inpatient anti-infective orders every year resulting over 100 000 dispenses. Significant quantities of anti-infectives are wasted, incurring roughly $100 000 in waste annually. Identifying areas for improvement will result in cost savings and ameliorate the impact of drug shortages. Summary: This descriptive report discusses the reasons for anti-infective waste at a free-standing, quaternary-care, pediatric hospital. The anti-infectives with the highest cost in waste ($) included meropenem ($38 084), micafungin ($21 690), amphotericin B liposome ($15 913). An internal audit of CHCO anti-infective waste revealed that drugs are wasted for the following reasons: patient discharge, medication order discontinuation or change, and misplaced doses. Conclusion: The CHCO Antimicrobial Stewardship Program and the Pharmacy have proposed 4 process improvement measures that will target anti-infective waste to reduce pharmaceutical waste and hospital costs. These measures may be applicable to other drug classes that likely suffer from a similar proportion of waste.

Marijuana Misadventures in Children: Exploration of a Dose-Response Relationship and Summary of Clinical Effects and Outcomes.

OBJECTIVES: This study aimed to explore a dose-response relationship of delta-9-tetrahydrocannabinol (THC) in THC-naïve children after unintentional acute exposure and compare clinical outcomes with non-naïve children. METHODS: A retrospective review was performed on children aged 31 days to 20 years who presented to Children's Hospital Colorado for care related to acute THC toxicity. The children were divided into groups based on exposure: group 1 (THC naïve) and group 2 (THC non-naïve). RESULTS: A total of 38 children (age, 3.5 [3] years) met inclusion for group 1 and an equal number of children (age, 15.1 [3.9] years) met the criteria for comparison in group 2. Eight naïve patients had documentation of estimated THC dose ingested (mean [SD], 7.13 [5.8] mg/kg; range, 2.9-19.5 mg/kg). A direct relationship between estimated oral THC dose, level of medical intervention required, and hospital disposition was observed. Lethargy/somnolence was more common in the naïve group (84% vs. 26%, P < 0.0001) whereas problems in cognition, perception, and behavior were more common in the non-naïve group (4% vs 11%, P = 0.01). The duration of clinical effect and length of hospital stay were longer in the naïve group (19.3 vs 5.0 hours, P < 0.0001) and (0.73 vs 0.19 days, P < 0.0001) respectively. CONCLUSIONS: There seems to be a direct relationship between the estimated oral THC dose (mg/kg), hospital disposition, and level of medical intervention required. Symptoms and duration of effects after THC exposure varied based on the route of exposure, age of patient, and history of previous THC experience.

Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes.

The generation of reactive oxygen species (ROS) is inherent to immune responses. ROS are crucially involved in host defense against pathogens by promoting bacterial killing, but also as signaling agents coordinating the production of cytokines. Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca(2+)-permeable channel gated via binding of ADP-ribose, a metabolite formed under conditions of cellular exposure to ROS. Here, we show that TRPM2-deficient mice are extremely susceptible to infection with Listeria monocytogenes (Lm), exhibiting an inefficient innate immune response. In a comparison with IFNγR-deficient mice, TRPM2(-/-) mice shared similar features of uncontrolled bacterial replication and reduced levels of inducible (i)NOS-expressing monocytes, but had intact IFNγ responsiveness. In contrast, we found that levels of cytokines IL-12 and IFNγ were diminished in TRPM2(-/-) mice following Lm infection, which correlated with their reduced innate activation. Moreover, TRPM2(-/-) mice displayed a higher degree of susceptibility than IL-12-unresponsive mice, and supplementation with recombinant IFNγ was sufficient to reverse the unrestrained bacterial growth and ultimately the lethal phenotype of Lm-infected TRPM2(-/-) mice. The severity of listeriosis we observed in TRPM2(-/-) mice has not been reported for any other ion channel. These findings establish an unsuspected role for ADP-ribose and ROS-mediated cation flux for innate immunity, opening up unique possibilities for immunomodulatory intervention through TRPM2.

Discovery and SAR of spirochromane Akt inhibitors.

A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA.

Altered functional properties of a TRPM2 variant in Guamanian ALS and PD.

Two related neurodegenerative disorders, Western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD), originally occurred at a high incidence on Guam, in the Kii peninsula of Japan, and in southern West New Guinea more than 50 years ago. These three foci shared a unique mineral environment characterized by the presence of severely low levels of Ca(2+) and Mg(2+), coupled with high levels of bioavailable transition metals in the soil and drinking water. Epidemiological studies suggest that genetic factors also contribute to the etiology of these disorders. Here, we report that a variant of the transient receptor potential melastatin 2 (TRPM2) gene may confer susceptibility to these diseases. TRPM2 encodes a calcium-permeable cation channel highly expressed in the brain that has been implicated in mediating cell death induced by oxidants. We found a heterozygous variant of TRPM2 in a subset of Guamanian ALS (ALS-G) and PD (PD-G) cases. This variant, TRPM2(P1018L), produces a missense change in the channel protein whereby proline 1018 (Pro(1018)) is replaced by leucine (Leu(1018)). Functional studies revealed that, unlike WT TRPM2, P1018L channels inactivate. Our results suggest that the ability of TRPM2 to maintain sustained ion influx is a physiologically important function and that its disruption may, under certain conditions, contribute to disease states.

Left ventricular concentric remodeling and impaired cardiorespiratory fitness in patients with heart failure and preserved ejection fraction.

BACKGROUND: Left ventricular (LV) concentric remodeling refers to a process by which increased LV relative wall thickness alters myocardial geometry, resulting in reduced LV end-diastolic volume (LVEDV) and stroke volume (SV). While the degree of concentric remodeling is a negative prognostic factor in heart failure with preserved ejection fraction (HFpEF), it is not known how it contributes to cardiorespiratory fitness (CRF). METHODS: We performed a retrospective analysis of patients with HFpEF who underwent treadmill single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) and cardiopulmonary exercise testing (CPX). From exercise SPECT-MPI, we recorded postexercise LVEDVi, LVESVi, SVi, LVEF, the presence and extent of perfusion defects, and perfusion reversibility. Peak oxygen consumption (VO2), the oxygen uptake efficiency slope (OUES), oxygen (O2) pulse, ventilatory efficiency (VE/VCO2 slope), ventilatory anaerobic threshold, respiratory exchange ratio, exercise time, and maximum heart rate were obtained from CPX. Data are expressed as mean (±standard deviation). Univariate and multivariate linear regression was performed. RESULTS: We identified 23 subjects who had completed both an exercise SPECT-MPI and a CPX. Patients were more commonly women (83%), black (65%), middle age (50 [±7.3] years), and obese (Body Mass Index [BMI] 39.7 [±6.0] kg/m2). Greater LVEDVi and LVESVi correlated positively with peak VO2 (R=+0.648, P=0.001; R=+0.601, P=0.002), O2 pulse (R=+0.686, P<0.001; R=+0.625, P=0.001) and OUES (R=+0.882, P<0.001; R=+0.779, P<0.001). The LVEF correlated inversely with peak VO2 and OUES (R=-0.450, P=0.031; R=-0.485, P=0.035). Perfusion defect area, grade of severity, and presence of reversibility were not associated with CRF variables. CONCLUSIONS: Postexercise reduced LV volumes correlate with measures of impaired CRF in patients with HFpEF, thus supporting a pathophysiologic role of concentric remodeling in impaired CRF in HFpEF.

Multiple coronary aneurysms in a young adult with acquired immunodeficiency syndrome.

HIV infection can cause multiple deleterious effects on the cardiovascular system. Emerging evidence has supported a direct association between HIV infection and accelerated atherosclerosis. The mechanism for atherosclerosis in HIV-positive patients is multifactorial, an interplay between conventional risk factors, HIV itself and highly active antiretroviral therapy. The case described is a 29-year-old man with HIV, non-adherent to antiretroviral therapy and with few cardiovascular risk factors, who presented with chest pain and non-ST elevation myocardial infarction. Cardiac catheterization revealed multiple coronary artery aneurysms in the left main coronary artery and the right coronary artery. Aneurysmal formation may develop from vasculitis, HIV itself, accelerated atherosclerosis, congenital formation or medications (e.g. protease inhibitors). The researchers provide a review of coronary artery disease, aneurysmal formation and vasculitic processes in the context of HIV. As this clinical entity becomes more apparent, alternative therapeutic options may need to be explored.

Signature Channels of Excitability no More: L-Type Channels in Immune Cells.

Although the concept of Ca(2+) as a universal messenger is well established, it was assumed that the regulatory mechanisms of Ca(2+)-signaling were divided along the line of electric excitability. Recent advances in molecular biology and genomics have, however, provided evidence that non-excitable cells such as immunocytes also express a wide and diverse pool of ion channels that does not differ as significantly from that of excitable cells as originally assumed. Ion channels and transporters are involved in virtually all aspects of immune response regulation, from cell differentiation and development to activation, and effector functions such as migration, antibody-secretion, phagosomal maturation, or vesicular delivery of bactericidal agents. This comprises TRP channel family members, voltage- and Ca(2+)-gated K(+)- and Na(+)-channels, as well as unexpectedly, components of the CaV1-subfamily of voltage-gated L-type Ca(2+)-channels, originally thought to be signature molecules of excitability. This article provides an overview of recent observations made in the field of CaV1 L-type channel function in the immune context, as well as presents results we obtained studying these channels in B-lymphocytes.

Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.

PURPOSE: The development and use of a decision support tool to help formulate recommendations for dosing of commonly prescribed medications in critically ill obese children are described. METHODS: Medications prescribed in 2010 to critically ill infants and children (younger than 18 years) were identified from the Pediatric Health Information System. The most commonly prescribed and therapeutically monitored medications were extracted. Supportive evidence for obesity dosing was identified through a standardized computerized search involving medical subject heading terminology and age filters using PubMed and Ovid. A usefulness scoring system was developed to rate the strength and applicability of the literature to critically ill obese children. A decision supporttool was then created to aid in the formulation of a dosing weight for each medication based on the usefulness score, published pharmacokinetic properties, clinical studies available in the primary literature, and consideration of clinical consequences of underdosing or overdosing. RESULTS: A total of 113 medications were evaluated, and 122 discrete citations, supporting 66 medications, were reviewed. Seventy-two percent of citations had general obesity dosing information, and 13% had pediatric-specific information. The overall mean usefulness score was 5.1±4.7 (median, 7). The decision support tool was incorporated to make final dosing weight recommendations for obese children. Ultimately, total body weight was recommended for 52 medications, adjusted weight for 43 medications, and ideal body weight for 18 medications. CONCLUSION: The inadequacy of obesity dosing information for most medications commonly ordered for children admitted to a pediatric intensive care unit led to the development of a decision support tool to aid in formulating dosing recommendations.