Trends in quality of care among children with sickle cell anemia.

INTRODUCTION: For decades, it has been recommended that children with sickle cell anemia (SCA) receive antibiotic prophylaxis to prevent serious infections and undergo transcranial Doppler (TCD) screening to identify those at highest risk of overt stroke. We assessed recent temporal trends in antibiotic prophylaxis prescription fills and TCD screening among children with SCA using validated quality measures. PROCEDURE: Using validated claims-based definitions, we identified children with SCA who were enrolled in Michigan or New York State (NYS) Medicaid programs (2011-2018). Among recommended age groups, two outcomes were assessed yearly: (a) filling of ≥300 days of antibiotics, and (b) receipt of greater than or equal to one TCD. The proportion of children with each outcome was calculated by state. Temporal trends in each preventive service were assessed using generalized linear models. RESULTS: A total of 1784 children were eligible for antibiotic prophylaxis (Michigan: 384; NYS: 1400), contributing 3322 person-years. Annual rates of filling ≥300 days of antibiotics ranged from 16% to 22% and were similar by state. There was no change in rates of antibiotic filling over time in Michigan (p-value: .10), but there was a decrease in NYS (p-value: .02). A total of 3439 children with SCA were eligible for TCD screening (Michigan: 710; NYS: 2729), contributing 10,012 person-years. Annual rates of TCD screening ranged from 39% to 45%, were similar by state, and did not change over time (p-values >.05). CONCLUSIONS: Most children with SCA do not receive recommended antibiotic prophylaxis and/or TCD screening. New, sustainable, and coordinated interventions across preventive services are urgently needed.

Variation in Part-Time Work among Pediatric Subspecialties.

OBJECTIVE: To assess the part-time workforce and average hours worked per week among pediatric subspecialists in the 15 medical subspecialties certified by the American Board of Pediatrics. STUDY DESIGN: We examined data from pediatric subspecialists who enrolled in Maintenance of Certification with the American Board of Pediatrics from 2009 to 2015. Data were collected via an online survey. Providers indicated whether they worked full time or part time and estimated the average number of hours worked per week in clinical, research, education, and administrative tasks, excluding time on call. We calculated and compared the range of hours worked by those in full- and part-time positions overall, by demographic characteristics, and by subspecialty. RESULTS: Overall, 9.6% of subspecialists worked part time. There was significant variation in part-time employment rates between subspecialties, ranging from 3.8% among critical care pediatricians to 22.9% among developmental-behavioral pediatricians. Women, American medical graduates, and physicians older than 70 years of age reported higher rates of part-time employment than men, international medical graduates, and younger physicians. There was marked variation in the number of hours worked across subspecialties. Most, but not all, full-time subspecialists reported working at least 40 hours per week. More than one-half of physicians working part time in hematology and oncology, pulmonology, and transplant hepatology reported working at least 40 hours per week. CONCLUSIONS: There are unique patterns of part-time employment and hours worked per week among pediatric medical subspecialists that make simple head counts inadequate to determine the effective workforce. Our findings are limited to the 15 American Board of Pediatrics-certified medical subspecialties.

In-Hospital Quality-of-Care Measures for Pediatric Sepsis Syndrome.

BACKGROUND AND OBJECTIVES: Sepsis syndrome, comprising sepsis, severe sepsis, and septic shock, is a leading cause of child mortality and morbidity, for which the delivery of time-sensitive care leads to improved survival. We aimed to describe the development and testing of quality measures for in-hospital care of pediatric sepsis syndrome. METHODS: Seven measures of quality of care for children hospitalized with sepsis syndrome were developed by using an iterative process including literature review, development of concepts and candidate measures, and selection of measures for feasibility and importance by 2 panels of experts. The measures were tested for reliability and validity among children 0 to 18 years of age hospitalized with sepsis syndrome from January 1, 2012, to June 30, 2013. RESULTS: Of 27 hospitals, 59% had no protocol for the identification and treatment of pediatric sepsis syndrome. Blood culture was performed in only 70% of patients with pediatric sepsis syndrome. Antibiotics were administered within 1 hour of diagnosis in 70% of patients with pediatric severe sepsis or septic shock, and timely fluid resuscitation was performed in 50% of patients with severe sepsis or septic shock. Documentation of heart rate during fluid resuscitation of children with severe sepsis or septic shock was observed in 18% of cases. Two measures could not be rigorously tested for validity and reliability given the rarity of septic shock and were deemed infeasible. CONCLUSIONS: This multisite study to develop and validate measures of the quality of hospital care of children with sepsis syndrome highlights the existence of important gaps in delivery of care.

Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: an ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice.

Pregabalin is a synthetic amino acid compound effective in clinical trials for the treatment of post-herpetic neuralgia, diabetic peripheral neuropathy, generalized anxiety disorder and adjunctive therapy for partial seizures of epilepsy. However, the mechanisms by which pregabalin exerts its therapeutic effects are not yet completely understood. In vitro studies have shown that pregabalin binds with high affinity to the alpha(2)-delta (alpha(2)-delta) subunits (Type 1 and 2) of voltage-gated calcium channels. To assess whether alpha(2)-delta Type 1 is the major central nervous system (CNS) binding protein for pregabalin in vivo, a mutant mouse with an arginine-to-alanine mutation at amino acid 217 of the alpha(2)-delta Type 1 protein (R217A mutation) was generated. Previous site-directed mutagenesis studies revealed that the R217A mutation dramatically reduces alpha(2)-delta 1 binding to pregabalin in vitro. In this autoradiographic analysis of R217A mice, we show that the mutation to alpha(2)-delta Type 1 substantially reduces specific pregabalin binding in CNS regions that are known to preferentially express the alpha(2)-delta Type 1 protein, notably the neocortex, hippocampus, basolateral amygdala and spinal cord. In mutant mice, pregabalin binding was robust throughout regions where the alpha(2)-delta Type 2 subunit mRNA is abundant, such as cerebellum. These findings, in conjunction with prior in vitro binding data, provide evidence that the alpha(2)-delta Type 1 subunit of voltage-gated calcium channels is the major binding protein for pregabalin in CNS. Moreover, the distinct localization of alpha(2)-delta Type 1 and mutation-resistant binding (assumed to be alpha(2)-delta Type 2) in brain areas subserving different functions suggests that identification of subunit-specific ligands could further enhance pharmacologic specificity.

The dynamics of single chains within a model polymer melt.

Discontinuous molecular dynamics simulations are performed on a system containing 32 hard chains of length 192 at a volume fraction of phi = 0.45 to explore the idea that localized entanglements have a significant effect on the dynamics of the individual chains within an entangled polymer melt. Anomalous behavior can still be observed when studying the dynamics of the individual chains, although increased time averaging causes the anomalous relaxation-memory-release behavior that was observed previously in the system to smooth out. First, the individual chain mean squared displacements and apparent diffusion coefficients are calculated, and a wide distribution of diffusive behavior is found. Although the apparent diffusion coefficient curve averaged over all chains displays the predicted long-time diffusive behavior, the curves for the individual chains differ both qualitatively and quantitatively. They display superdiffusive, diffusive, and subdiffusive behavior, with the largest percentage of chains exhibiting superdiffusive behavior and the smallest percentage exhibiting the predicted diffusive behavior. Next, the individual chain end-to-end vector autocorrelation functions and relaxation times are determined, and a wide distribution of stress relaxation behavior is found. The times when the end-to-end vector autocorrelation functions relax completely span almost an order of magnitude in reduced time. For some chains, the end-to-end vector autocorrelation function relaxes smoothly toward zero similar to the system average; however, for other chains the relaxation is slowed greatly, indicating the presence of additional entanglements. Almost half of the chains exhibit the anomalous behavior in the end-to-end vector autocorrelation function. Finally, the dynamic properties are displayed for a single chain exhibiting anomalous relaxation-memory-release behavior, supporting the idea that the relaxation-memory-release behavior is a single-chain property.

Vascular targeting agents.

The role of the vascular network of a tumor has been the focus of much recent research. Angiogenesis, or the growth of new tumor blood vessels, was initially the main target in the development of novel antitumor agents. More recently, new therapeutic strategies have been designed to destroy established tumor blood vessels. These vascular targeting agents (VTAs) exert their action by producing a rapid shutdown of tumor blood flow, resulting in ischemia and tumor cell necrosis. VTAs can be broadly divided into biologic agents and small molecules. In contrast to the biologic agents, drug-based vascular targeting molecules have developed much further, with many clinical trials ongoing. Evidence suggests that VTAs may be useful as single agents but can be more effective when used in combination with other therapeutic regimens.

Subtype selective NMDA receptor antagonists: evaluation of some novel alkynyl analogues.

A benzylpiperidine analogue with an acetylenic linker, 5-(3-[4-(4-fluorobenzyl)-piperidin-1-yl]-prop-1-ynyl)-1,3-dihydrobenzimidazol-2-one (3), was identified as a chemical lead with excellent activity at the NR1A/2B receptor (IC50=3 nM). Efforts to optimize this activity led to focused modifications around the structural motif of 3. The synthesis and SAR studies are discussed.