Mortality in Neuromuscular Early Onset Scoliosis Following Spinal Deformity Surgery.

BACKGROUND: The purpose of this study was to report mortality and associated risk factors in neuromuscular early onset scoliosis following spinal deformity surgery. METHODS: This is a multicenter retrospective cohort study of patients with cerebral palsy (CP), spinal muscular atrophy, myelodysplasia, muscular dystrophy, or myopathy undergoing index spine surgery from 1994 to 2020. Mortality risk was calculated up to 10 years postoperatively. Proportional hazard modeling was utilized to investigate associations between risk factors and mortality rate. RESULTS: A total of 808 patients [mean age 7.7 y; 439 (54.3%) female] were identified. Postoperative 30-day, 90-day, and 120-day mortality was 0%, 0.001%, and 0.01%, respectively. 1-year, 2-year, 5-year, and 10-year mortality was 0.5%, 1.1%, 5.4%, and 17.4%, respectively. Factors associated with increased mortality rate: CP diagnosis [hazard ratio (HR): 3.14, 95% confidence interval (CI): 1.71; 5.79, P<0.001]; nonambulatory status (HR: 3.01, 95% CI: 1.06; 8.5, P=0.04)]; need for respiratory assistance (HR: 2.17, 95% CI: 1.00; 4.69, P=0.05). CONCLUSIONS: In neuromuscular patients with early onset scoliosis, mortality risk at 10 years following spine surgery was 17.4%. As mortality was 1.1% at 2 years, premature death was unlikely a direct result of spine surgery. Diagnosis (CP) and markers of disease severity (nonambulatory status, respiratory assistance) were associated with increased mortality rate. LEVEL OF EVIDENCE: Prognostic level II.

Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover.

We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.

Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models.

Pathogenic variants in the human F-box and leucine-rich repeat protein 4 (FBXL4) gene result in an autosomal recessive, multisystemic, mitochondrial disorder involving variable mitochondrial depletion and respiratory chain complex deficiencies with lactic acidemia. As no FDA-approved effective therapies for this disease exist, we sought to characterize translational C. elegans and zebrafish animal models, as well as human fibroblasts, to study FBXL4-/- disease mechanisms and identify preclinical therapeutic leads. Developmental delay, impaired fecundity and neurologic and/or muscular activity, mitochondrial dysfunction, and altered lactate metabolism were identified in fbxl-1(ok3741) C. elegans. Detailed studies of a PDHc activator, dichloroacetate (DCA), in fbxl-1(ok3741) C. elegans demonstrated its beneficial effects on fecundity, neuromotor activity, and mitochondrial function. Validation studies were performed in fbxl4sa12470 zebrafish larvae and in FBXL4-/- human fibroblasts; they showed DCA efficacy in preventing brain death, impairment of neurologic and/or muscular function, mitochondrial biochemical dysfunction, and stress-induced morphologic and ultrastructural mitochondrial defects. These data demonstrate that fbxl-1(ok3741) C. elegans and fbxl4sa12470 zebrafish provide robust translational models to study mechanisms and identify preclinical therapeutic candidates for FBXL4-/- disease. Furthermore, DCA is a lead therapeutic candidate with therapeutic benefit on diverse aspects of survival, neurologic and/or muscular function, and mitochondrial physiology that warrants rigorous clinical trial study in humans with FBXL4-/- disease.

The prototypical ranitidine analog JWS-USC-75-IX improves information processing and cognitive function in animal models.

This study was designed to evaluate further a prototypical ranitidine analog, JWS-USC-75-IX, [(3-[[[2-[[(5-dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]amino]-4-nitropyridazine, JWS], for neuropharmacologic properties that would theoretically be useful for treating cognitive and noncognitive behavioral symptoms of neuropsychiatric disorders. JWS was previously found to inhibit acetylcholinesterase (AChE) activity, serve as a potent ligand at muscarinic M2 acetylcholine receptors, and elicit positive effects on spatial learning, passive avoidance, and working memory in rodents. In the current study, JWS was evaluated for binding activity at more than 60 neurotransmitter receptors, transporters, and ion channels, as well as for inhibitory activity at AChE and butyrylcholinesterase (BChE). The results indicate that JWS inhibits AChE and BChE at low (micromolar) concentrations and that it is a functional antagonist at M2 receptors (K(B) = 320 nM). JWS was subsequently evaluated orally across additional behavioral assays in rodents (dose range, 0.03-10.0 mg/kg) as well as nonhuman primates (dose range, 0.05-2.0 mg/kg). In rats, JWS improved prepulse inhibition (PPI) of the acoustic startle response in nonimpaired rats and attenuated PPI deficits in three pharmacologic impairment models. JWS also attenuated scopolamine and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)-related impairments in a spontaneous novel object recognition task and a five-choice serial reaction time task, respectively. In monkeys, JWS elicited dose-dependent improvements of a delayed match-to-sample task as well as an attention-related version of the task where randomly presented (task-relevant) distractors were presented. Thus, JWS (potentially via effects at several drug targets) improves information processing, attention, and memory in animal models and could potentially treat the cognitive and behavioral symptoms of some neuropsychiatric illnesses.

Conceptual framework of the Controlling Asthma in American Cities Project.

The Controlling Asthma in American Cities Project (CAACP) was designed to improve the control of asthma in inner-city populations of children with a disparate burden of symptoms and adverse outcomes. As with many chronic diseases, asthma is the manifestation of multiple biologic, environmental, and social determinants. In addition to appropriate medical management, individuals with asthma must have logistical, financial, and cultural access to environments that allow avoidance of asthma triggers and encourage good asthma management practices. In recognition of this complexity, the CAACP required the seven project sites to coordinate and synchronize multiple interventions (education, healthcare access, medical management, trigger reduction) at multiple levels (individual, home, school, community, and policy) through the collaboration of relevant groups, institutions, and individuals. This paper describes the "program theory" of the CAACP project-the assumptions about how the project worked, how the components were linked, and what outcomes were anticipated. It relates the subsequent papers in the supplement to the program theory and describes how the papers can inform and guide other community-based interventions, and advance the translation of scientific knowledge to effective interventions in communities of need.

Considerations and challenges for planning a public health approach to asthma.

Addressing asthma from a public health perspective is a relatively new concept for which the literature provides little guidance. A public health approach seeks to decrease the burden of asthma and improve health outcomes at the population level, such as communities, cities, or states, by reaching large numbers of individuals with effective interventions and at reasonable cost. Projects designed to achieve a measureable impact at the population level are fundamentally different from projects or interventions designed to improve outcomes among individuals. This paper uses the experience of the Controlling Asthma in American Cities Project and a review of the relevant literature to explore some of the unique questions and considerations that are implicit when planning large-scale asthma projects intended to improve population outcomes. The paper is intended to inform decision making by local and state government agencies, managed care organizations, health systems, community coalitions, and funders. Analysis of asthma and other chronic disease projects aiming to achieve population-level impact is an area for continued public health research.

A community-based strategy for improving asthma management and outcomes for preschoolers.

Although almost one in ten (8.6%) preschool children has been diagnosed with asthma, few asthma management programs are designed for parents of preschool children. The Asthma Basics for Children program addressed this need in 2003-2008 by implementing a multi-layered approach that offered educational activities to center staff, parents, and children and PACE training to physicians in 31 Northern Manhattan daycare centers. Following program participation, 85% of parents reported reducing their child's triggers, 89% said it was easier to talk to their child's physician, and 80% were confident in their ability to manage their child's asthma. Children's any daytime symptoms dropped from 78% to 42%, any nighttime symptoms from 81% to 49%, any daycare absences from 56% to 38%, any asthma-related emergency department (ED) visits from 74% to 47%, and any asthma-related hospitalizations from 24% to 11% (p < .001 for all differences). Outcomes varied by level of exposure. In the Center-Only group (no parent participation), the only reduction was from 19% to 10% (McNemar = 3.77, p = .052) in hospitalizations. Children whose parents participated in the program had significant reductions in daycare absences (62% to 38%, McNemar = 11.1, p < .001), ED visits (72% to 43%, McNemar = 19.2, p < .001), and hospitalizations (24% to 11%, McNemar = 5.54, p = .018). Children whose parents and healthcare provider participated had the greatest improvements with asthma-related daycare absences dropping from 62% to 32% (McNemar = 9.8, p = .001), ED visits from 72% to 37% (McNemar = 14.4, p < .001), and hospitalizations from 35% to 15% (McNemar = 8.33, p = .003). This study demonstrates that a multi-layered approach can improve asthma outcomes among preschoolers with a combination of parent and provider education having the greatest impact.

A model-driven approach to qualitatively assessing the added value of community coalitions.

Community-based coalitions are commonly formed to plan and to carry out public health interventions. The literature includes evaluations of coalition structure, composition, and functioning; evaluations of community-level changes achieved through coalition activities; and the association between coalition characteristics and various indicators of success. Little information is available on the comparative advantage or "added value" of conducting public health interventions through coalitions as opposed to less structured collaborative mechanisms. This paper describes a qualitative, iterative process carried out with site representatives of the Controlling Asthma in American Cities Project (CAACP) to identify outcomes directly attributable to coalitions. The process yielded 2 complementary sets of results. The first were criteria that articulated and limited the concept of "added value of coalitions". The criteria included consensus definitions, an organizing figure, a logic model, and inclusion/exclusion criteria. The second set of results identified site-specific activities that met the definitional criteria and were, by agreement, examples of CAACP coalitions' added value. Beyond the specific findings relevant to the added value of coalitions in this project, the use of a social ecological model to identify the components of added value and the placement of those components within a logic model specific to coalitions should provide useful tools for those planning and assessing coalition-based projects.

Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity.

Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phencyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.

Is It Time for a Patient-Centered Quality Measure of Asthma Control?

Quality measures play a prominent role in the US health care system. They are used to monitor and report performance across health plans, providers, and health systems and are a foundational element of value-based payment. Measuring the quality of asthma care has been challenging because of a lack of reliable data to assess clinical processes and track patient-specific outcomes. Existing asthma Healthcare Effectiveness Data and Information Set measures rely on administrative claims-derived data on dispensed medications. These are proxy measures of appropriate prescribing but are not reflective of comprehensive asthma care. The increase in the volume and specificity of longitudinal clinical data in electronic health records, movement toward electronic quality measures, and advances in electronic clinical data systems enable the development of more meaningful measures. A patient-reported measure of asthma control would incorporate key clinical indicators such as a validated age- and culturally appropriate test, and would reflect the combined outcome of medical management, self-management education, reduction of environmental exposures, and appropriate support services. Although there is a current quality measure that includes a test of asthma control (the Optimal Asthma Control Measure), work is needed to address questions about usability, patient literacy, and the influence of setting on self-reported scores. Comprehensive reliability and validity testing of both clinical data and stratification across risk groups will be needed to determine whether a measure based on standardized assessments of asthma control indeed promote improved clinical outcomes.

Economic Evidence for US Asthma Self-Management Education and Home-Based Interventions.

The health and economic burden of asthma in the United States is substantial. Asthma self-management education (AS-ME) and home-based interventions for asthma can improve asthma control and prevent asthma exacerbations, and interest in health care-public health collaboration regarding asthma is increasing. However, outpatient AS-ME and home-based asthma intervention programs are not widely available; economic sustainability is a common concern. Thus, we conducted a narrative review of existing literature regarding economic outcomes of outpatient AS-ME and home-based intervention programs for asthma in the United States. We identified 9 outpatient AS-ME programs and 17 home-based intervention programs with return on investment (ROI) data. Most programs were associated with a positive ROI; a few programs observed positive ROIs only among selected populations (eg, higher health care utilization). Interpretation of existing data is limited by heterogeneous ROI calculations. Nevertheless, the literature suggests promise for sustainable opportunities to expand access to outpatient AS-ME and home-based asthma intervention programs in the United States. More definitive knowledge about how to maximize program benefit and sustainability could be gained through more controlled studies of specific populations and increased uniformity in economic assessments.

HIV-associated nephropathy: Epidemiology, pathogenesis, and treatment.

Initially described in 1984, human immunodeficiency virus-associated nephropathy (HIVAN) has now become a common disease within the HIV-seropositive population. It is a focal segmental glomerulosclerosis causing rapid deterioration of renal function. It is the most common cause of chronic renal disease in HIV patients and occurs almost exclusively in blacks. Through murine and human studies, it is now clear that HIVAN is caused by a direct effect of infection of renal cells by HIV-1 and that the virus actively replicates within renal cells. How the virus causes disease within cells is not yet understood, but there is evidence for factors within infected cells causing both proliferation and apoptosis. Steroids, angiotensin converting enzyme (ACE) inhibitors, and highly active antiretroviral therapy (HAART) have been used for the treatment of HIVAN, with HAART, in particular, showing a dramatic improvement in both the pathologic changes and clinical course of HIVAN.

Knowledge, attitudes, and barriers to carrier screening for the Ashkenazi Jewish panel: a Florida experience : Education and Barriers assessment for Jewish Genetic Diseases.

The knowledge, attitudes, and barriers to Jewish genetic diseases (JGDs) and screening and their relative importance in reproductive decision-making were assessed in a population-based sample of Ashkenazi Jewish young adults in Florida. These adults attended educational screening fairs hosted by The Victor Center for the Prevention of Jewish Genetic Diseases at the University of Miami. Parametric and nonparametric tests were used as appropriate to analyze data from a single group pretest/posttest design. Four hundred twelve individuals (mean age = 24.9; 54.7 % female, 45.3 % male) completed the questionnaires. Participants' level of knowledge increased from pre- to post-intervention (81.4 vs. 91.0 %; p < 0.0001). Concern about the possibility of being a carrier of a JGD was significantly higher after an educational session (5-point Likert scale mean difference = 0.45; p < 0.0001), as was their level of concern regarding having an affected child (mean difference = 0.20; p < 0.0001). The number of participants who agreed or strongly agreed that the test results would not have any influence on their reproductive behavior was lower after the session (17.2 vs. 20.8 %; p < 0.0001). This study demonstrates that an educational carrier screening program increased knowledge and elucidated awareness of the attitudes and barriers toward JGDs and carrier screening.

Tetrahydronaphthyridine and dihydronaphthyridinone ethers as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure-activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.

Public health interventions for asthma: an umbrella review, 1990-2010.

CONTEXT: Asthma is a chronic respiratory disease increasingly prevalent in the U.S., particularly among children and certain minority groups. This umbrella review sought to assess and summarize existing systematic reviews of asthma-related interventions that might be carried out or supported by state or community asthma control programs, and to identify gaps in knowledge. EVIDENCE ACQUISITION: Eleven databases were searched through September 2010, using terms related to four concepts: asthma, review, intervention, and NOT medication. Reviews of the effectiveness of medications, medical procedures, complementary and alternative medicine, psychological interventions, family therapy, and nutrients or nutritional supplements were excluded. Two coders screened each record and extracted data from the included reviews. EVIDENCE SYNTHESIS: Data analysis was conducted from May to December 2010. Of 42 included reviews, 19 assessed the effectiveness of education and/or self-management, nine the reduction of indoor triggers, nine interventions to improve the provision of health care, and five examined other interventions. Several reviews found consistent evidence of effectiveness for self-management education, and one review determined that comprehensive home-based interventions including the reduction of multiple indoor asthma triggers are effective for children. Other reviews found limited or insufficient evidence because of study limitations. CONCLUSIONS: State or community asthma control programs should prioritize (1) implementing interventions for which the present review found evidence of effectiveness and (2) evaluating promising interventions that have not yet been adequately assessed.

Effectiveness of home-based, multi-trigger, multicomponent interventions with an environmental focus for reducing asthma morbidity: a community guide systematic review.

CONTEXT: Asthma exacerbations are commonly triggered by exposure to allergens and irritants within the home. The purpose of this review was to evaluate evidence that interventions that target reducing these triggers through home visits may be beneficial in improving asthma outcomes. The interventions involve home visits by trained personnel to conduct two or more components that address asthma triggers in the home. Intervention components focus on reducing exposures to a range of asthma triggers (allergens and irritants) through environmental assessment, education, and remediation. EVIDENCE ACQUISITION: Using methods previously developed for the Guide to Community Preventive Services, a systematic review was conducted to evaluate the evidence on effectiveness of home-based, multi-trigger, multicomponent interventions with an environmental focus to improve asthma-related morbidity outcomes. The literature search identified over 10,800 citations. Of these, 23 studies met intervention and quality criteria for inclusion in the final analysis. EVIDENCE SYNTHESIS: In the 20 studies targeting children and adolescents, the number of days with asthma symptoms (symptom-days) was reduced by 0.8 days per 2 weeks, which is equivalent to 21.0 symptom-days per year (range of values: reduction of 0.6 to 2.3 days per year); school days missed were reduced by 12.3 days per year (range of values: reduction of 3.4 to 31.2 days per year); and the number of asthma acute care visits were reduced by 0.57 visits per year (interquartile interval: reduction of 0.33 to 1.71 visits per year). Only three studies reported outcomes among adults with asthma, finding inconsistent results. CONCLUSIONS: Home-based, multi-trigger, multicomponent interventions with an environmental focus are effective in improving overall quality of life and productivity in children and adolescents with asthma. The effectiveness of these interventions in adults is inconclusive due to the small number of studies and inconsistent results. Additional studies are needed to (1) evaluate the effectiveness of these interventions in adults and (2) determine the individual contributions of the various intervention components.