Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations.

BACKGROUND: Detection of the BRAF V600E mutation in pediatric low-grade glioma has been associated with a lower response to standard chemotherapy. In previous trials, dabrafenib (both as monotherapy and in combination with trametinib) has shown efficacy in recurrent pediatric low-grade glioma with BRAF V600 mutations, findings that warrant further evaluation of this combination as first-line therapy. METHODS: In this phase 2 trial, patients with pediatric low-grade glioma with BRAF V600 mutations who were scheduled to receive first-line therapy were randomly assigned in a 2:1 ratio to receive dabrafenib plus trametinib or standard chemotherapy (carboplatin plus vincristine). The primary outcome was the independently assessed overall response (complete or partial response) according to the Response Assessment in Neuro-Oncology criteria. Also assessed were the clinical benefit (complete or partial response or stable disease for ≥24 weeks) and progression-free survival. RESULTS: A total of 110 patients underwent randomization (73 to receive dabrafenib plus trametinib and 37 to receive standard chemotherapy). At a median follow-up of 18.9 months, an overall response occurred in 47% of the patients treated with dabrafenib plus trametinib and in 11% of those treated with chemotherapy (risk ratio, 4.31; 95% confidence interval [CI], 1.7 to 11.2; P<0.001). Clinical benefit was observed in 86% of the patients receiving dabrafenib plus trametinib and in 46% receiving chemotherapy (risk ratio, 1.88; 95% CI, 1.3 to 2.7). The median progression-free survival was significantly longer with dabrafenib plus trametinib than with chemotherapy (20.1 months vs. 7.4 months; hazard ratio, 0.31; 95% CI, 0.17 to 0.55; P<0.001). Grade 3 or higher adverse events occurred in 47% of the patients receiving dabrafenib plus trametinib and in 94% of those receiving chemotherapy. CONCLUSIONS: Among pediatric patients with low-grade glioma with BRAF V600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer progression-free survival, and a better safety profile than standard chemotherapy as first-line therapy. (Funded by Novartis; ClinicalTrials.gov number, NCT02684058.).

Heterogeneous splicing patterns resulting from KIF5A variants associated with amyotrophic lateral sclerosis.

Single-nucleotide variants (SNVs) in the gene encoding Kinesin Family Member 5A (KIF5A), a neuronal motor protein involved in anterograde transport along microtubules, have been associated with amyotrophic lateral sclerosis (ALS). ALS is a rapidly progressive and fatal neurodegenerative disease that primarily affects the motor neurons. Numerous ALS-associated KIF5A SNVs are clustered near the splice-site junctions of the penultimate exon 27 and are predicted to alter the carboxy-terminal (C-term) cargo-binding domain of KIF5A. Mis-splicing of exon 27, resulting in exon exclusion, is proposed to be the mechanism by which these SNVs cause ALS. Whether all SNVs proximal to exon 27 result in exon exclusion is unclear. To address this question, we designed an in vitro minigene splicing assay in human embryonic kidney 293 cells, which revealed heterogeneous site-specific effects on splicing: only 5' splice-site (5'ss) SNVs resulted in exon skipping. We also quantified splicing in select clustered, regularly interspaced, short palindromic repeats-edited human stem cells, differentiated to motor neurons, and in neuronal tissues from a 5'ss SNV knock-in mouse, which showed the same result. Moreover, the survival of representative 3' splice site, 5'ss, and truncated C-term variant KIF5A (v-KIF5A) motor neurons was severely reduced compared with wild-type motor neurons, and overt morphological changes were apparent. While the total KIF5A mRNA levels were comparable across the cell lines, the total KIF5A protein levels were decreased for v-KIF5A lines, suggesting an impairment of protein synthesis or stability. Thus, despite the heterogeneous effect on ribonucleic acid splicing, KIF5A SNVs similarly reduce the availability of the KIF5A protein, leading to axonal transport defects and motor neuron pathology.

Future perspective of targeted treatments in pediatric low-grade glioma (pLGG): the evolution of standard-of-care and challenges of a new era.

While surgery, when possible, remains the mainstay of pediatric low-grade glioma (pLGG) management, adjuvant therapy has significantly evolved over time. Radiation therapy was commonly used in the late 1990s for tumors that could not be resected or recurred. This resulted in significant late morbidity in this population and mortality related to secondary malignancies and chronic health conditions. Chemotherapy became the mainstay of adjuvant therapy but children still experienced late morbidity secondary to exposure to multiple lines of treatment over time. Targeted therapies emerged after the identification of frequent genetic alterations in the mitogen activated protein kinase (MAPK) pathway including KIAA1549-BRAF fusions and BRAF-V600 mutations and the near universal upregulation of the MAPK pathway in these tumors. Both BRAF and MEK inhibitors have shown efficacy in the treatment of pLGG and have led to prolonged stability in some cases. Multiple phase III clinical trials are now comparing targeted therapy to standard-of-care chemotherapy regimens setting the stage for targeted therapy to replace chemotherapy as the first-line treatment in some cases. Targeted therapy, however, is not without its challenges. There are clear examples of resistance and mechanisms of resistance have not been fully elucidated. There is also no clear duration for these therapies and rebound growth is a well-known phenomenon especially in BRAF-V600 mutant tumors. Targeted therapies are also fairly recent developments and long-term toxicities and functional outcomes are still being monitored. Very young and adolescent/young adult LGGs also carry molecular features that may not be addressed by inhibition of the MAPK pathway. Adjuvant therapy for pLGG has evolved from radiation for all unresectable or residual tumors to molecularly driven targeted therapies with improved quality of life, late effects, and less off-target toxicities. While there is still much to learn in regard to newer targeted therapies for pLGG, the era of targeted therapies for pediatric LGG is upon us.

Market Failure, State Failure: The Political Economy of Supply Chain Strengthening to Ensure Equitable Access to Vaccines and Medicines in Low- and Middle-Income Countries.

CONTEXT: Much of the existing work on the political economy of vaccine access has focused on how intellectual property rights agreements contribute to inequitable COVID-19 vaccine access between high-income and low- and middle-income countries (LMICs). The two solutions that emerged to scale up access in LMICs involved either voluntary arrangements under COVAX or a waiver of the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPs) to allow immediate access to intellectual property. However, an additional constraint on access is weak and ineffective supply chains within LMICs that have eroded over several decades of health-sector reform. METHODS: This article reviews the literature on the political economy of supply chain strengthening in LMICs and identifies key challenges to equitable access to emergent vaccines and other medicines emanating from market and state failures in internal supply chains. FINDINGS: Over the past century, supply chain policies in LMICs have alternated among an emphasis on addressing market failures contributing to unaffordability of vaccines/medicines, an emphasis on state failures contributing to unavailability of vaccines/medicines, and a more recent move toward public-private hybrid arrangements to strengthen supply chains. CONCLUSIONS: In addition to reshoring production capacity through a TRIPs waiver, the international community must address chronic weakness in internal supply chains in LMICs to ensure access to novel vaccines/medicines.

Is Redistribution Good for Our Health? Examining the Macro-Correlation between Welfare Generosity and Health across EU Nations over the Last 40 Years.

CONTEXT: Social determinants of health are finally getting much needed policy attention. Yet, their political origins remain underexplored. In this paper, we advance a theory of political determinants as accruing along three pathways of welfare state effects (redistribution, poverty reduction and status preservation) and test these assumptions by examining impacts of policy generosity on life expectancy (LE) over the last 40 years. METHODS: We merge new and existing welfare policy generosity data from the Comparative Welfare Entitlement Project (CWEP) with data on LE spanning 1980-2018 across 21 OECD countries. We then examine relationships between five welfare policy generosity measures and LE using cross-sectional differencing and auto-regressive lag models. FINDINGS: We find consistent and positive effects for total generosity (an existing measure of social insurance generosity) on LE at birth across different model specifications in the magnitude of a 0.10-0.15-year increase in LE at birth (p < 0.05) and a measure of status preservation (0.11, p < 0.05). We find less consistent support for our redistribution and poverty reduction measures. CONCLUSIONS: We conclude that in addition to generalized effects of policy generosity on health, status-preserving social insurance may be an important, and relatively overlooked, mechanism in increasing life expectancies over time in advanced democracies.

CuATSM effectively ameliorates ALS patient astrocyte-mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis.

Patient diversity and unknown disease cause are major challenges for drug development and clinical trial design for amyotrophic lateral sclerosis (ALS). Transgenic animal models do not adequately reflect the heterogeneity of ALS. Direct reprogramming of patient fibroblasts to neuronal progenitor cells and subsequent differentiation into patient astrocytes allows rapid generation of disease relevant cell types. Thus, this methodology can facilitate compound testing in a diverse genetic background resulting in a more representative population for therapeutic evaluation. Here, we used established co-culture assays with motor neurons and reprogrammed patient skin-derived astrocytes (iAs) to evaluate the effects of (SP-4-2)-[[2,2'-(1,2-dimethyl-1,2-ethanediylidene)bis[N-methylhydrazinecarbothioamidato-κN2 ,κS]](2-)]-copper (CuATSM), currently in clinical trial for ALS in Australia. Pretreatment of iAs with CuATSM had a differential effect on neuronal survival following co-culture with healthy motor neurons. Using this assay, we identified responding and non-responding cell lines for both sporadic and familial ALS (mutant SOD1 and C9ORF72). Importantly, elevated mitochondrial respiration was the common denominator in all CuATSM-responders, a metabolic phenotype not observed in non-responders. Pre-treatment of iAs with CuATSM restored mitochondrial activity to levels comparable to healthy controls. Hence, this metabolic parameter might allow selection of patient subpopulations best suited for CuATSM treatment. Moreover, CuATSM might have additional therapeutic value for mitochondrial disorders. Enhanced understanding of patient-specific cellular and molecular profiles could help improve clinical trial design in the future.

Impaired motor unit recovery and maintenance in a knock-in mouse model of ALS-associated Kif5a variant.

Kinesin family member 5A (KIF5A) is an essential, neuron-specific microtubule-associated motor protein responsible for the anterograde axonal transport of various cellular cargos. Loss of function variants in the N-terminal, microtubule-binding domain are associated with hereditary spastic paraplegia and hereditary motor neuropathy. These variants result in a loss of the ability of the mutant protein to process along microtubules. Contrastingly, gain of function splice-site variants in the C-terminal, cargo-binding domain of KIF5A are associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disease involving death of upper and lower motor neurons, ultimately leading to degradation of the motor unit (MU; an alpha motor neuron and all the myofibers it innervates) and death. These ALS-associated variants result in loss of autoinhibition, increased procession of the mutant protein along microtubules, and altered cargo binding. To study the molecular and cellular consequences of ALS-associated variants in vivo, we introduced the murine homolog of an ALS-associated KIF5A variant into C57BL/6 mice using CRISPR-Cas9 gene editing which produced mutant Kif5a mRNA and protein in neuronal tissues of heterozygous (Kif5a+/c.3005+1G>A; HET) and homozygous (Kif5ac.3005+1G>A/c.3005+1G>A; HOM) mice. HET and HOM mice appeared normal in behavioral and electrophysiological (compound muscle action potential [CMAP] and MU number estimation [MUNE]) outcome measures at one year of age. When subjected to sciatic nerve injury, HET and HOM mice have delayed and incomplete recovery of the MUNE compared to wildtype (WT) mice suggesting an impairment in MU repair. Moreover, aged mutant Kif5a mice (aged two years) had reduced MUNE independent of injury, and exacerbation of the delayed and incomplete recovery after injury compared to aged WT mice. These data suggest that ALS-associated variants may result in an impairment of the MU to respond to biological challenges such as injury and aging, leading to a failure of MU repair and maintenance. In this report, we present the behavioral, electrophysiological and pathological characterization of mice harboring an ALS-associated Kif5a variant to understand the functional consequences of KIF5A C-terminal variants in vivo.

Communities at Risk for Mpox and Stigmatizing Policies: A Randomized Survey, Republic of Korea, 2022.

Objectives. To estimate the impact of communicating to the public that men who have sex with men (MSM) are most at risk for mpox on potential stigmatization and risk perception. Methods. We conducted a survey experiment randomizing exposure to messages about mpox among a sample of the South Korean public (n = 1500) in July 2022. We randomized respondents to receive an informational message about mpox that was (1) a neutral informational message about mpox that did not highlight its origins or risk groups (control group), (2) a message explaining that the virus originated in Africa, or (3) a message emphasizing that MSM are most at risk. Results. We found that emphasizing that MSM are most at risk increases support for policies that would restrict lesbian, gay, bisexual, transgender/-sexual, queer or questioning-related events by about 7 percentage points compared with the control condition. However, the message describing African origins did not affect support for restricting travel from Africa. Neither changed risk perceptions or willingness to be vaccinated against mpox. Conclusions. Messages aimed at educating the public about most at-risk groups may trigger increased stigmatization of those groups in ways that could contribute to unnecessary persecution. (Am J Public Health. 2023;113(10):1120-1127. https://doi.org/10.2105/AJPH.2023.307347).

Development and Earliest Validation of a Portable Device for Quantification of Hallux Extension Strength (QuHalEx).

Hallux strength is associated with sports performance and balance across the lifespan, and independently predicts falls in older adults. In rehabilitation, Medical Research Council (MRC) Manual Muscle Testing (MMT) is the clinical standard for hallux strength assessment, but subtle weakness and longitudinal changes in strength may go undetected. To address the need for research-grade yet clinically feasible options, we designed a new load cell device and testing protocol to Quantify Hallux Extension strength (QuHalEx). We aim to describe the device, protocol and initial validation. In benchtop testing, we used eight precision weights to apply known loads from 9.81 to 78.5 N. In healthy adults, we performed three maximal isometric tests for hallux extension and flexion on the right and left sides. We calculated the Intraclass Correlation Coefficient (ICC) with 95% confidence interval and descriptively compared our isometric force-time output to published parameters. QuHalEx benchtop absolute error ranged from 0.02 to 0.41 (mean 0.14) N. Benchtop and human intrasession output was repeatable (ICC 0.90-1.00, p < 0.001). Hallux strength in our sample (n = 38, age 33.5 ± 9.6 years, 53% female, 55% white) ranged from 23.1 to 82.0 N peak extension force and 32.0 to 142.4 N peak flexion, and differences of ~10 N (15%) between toes of the same MRC grade (5) suggest that QuHalEx is able to detect subtle weakness and interlimb asymmetries that are missed by MMT. Our results support ongoing QuHalEx validation and device refinement with a longer-term goal of widespread clinical and research application.

An international study evaluating the epidemiology of intracranial germ cell tumors in the native versus immigrant Japanese populations: the need for an international registry.

BACKGROUND: Pediatric intra-cranial germ cell tumors (iGCTs) occur at an incidence of 0.6-1.2 cases/million/year in Western countries. The incidence is reported up to 5 times higher in Japan. It is unknown whether this increased incidence is due to genetic predisposition or environment. METHODS: The incidence of iGCTs in children ages 0-19 years was evaluated from December 1st, 1996-December 1st, 2016 in stable Japanese immigrant populations living abroad and compared to current native Japanese registry data. The incidence of medullobblastoma was used as a control to account for assumptions in the data. Sites were identified based on historical and population data of known large scale emigration from Japan during a period of industrialization from 1868-1912 which resulted in large, stable Japanese immigrant populations abroad. These three representative sites included Lima, Peru, San Paolo, Brazil, and Vancouver, Canada. Data was collected from registry and hospital-based resources within each region. RESULTS: A review of the Brain Tumor Registry of Japan from 1984-2004 revealed an incidence of 2.5 cases/million/year, lower than previously reported, and a lower incidence of medulloblastoma at 1.2 cases/million/year. Data from Vancouver, Canada, Lima, Peru, and San Paolo, Brazil included a total population of 731,174 Japanese persons. The ratio of all medulloblastoma to iGCT cases in Japan was identified as 1:2 while the ratio was 2:1, 6.5:1, and 5:1, respectively, in the other three locations. The data suggests increased incidence in native Japan may not translate to higher incidence in immigrant Japanese populations abroad and a clear genetic component was not found in our data set. CONCLUSIONS: A more precise and comprehensive study is needed to determine the cause of this difference in incidence. This study also emphasizes the importance of national and state registries and is a call to collaborate on state and country level epidemiology studies.

Comparison of toxicity following single versus tandem autologous transplant regimens for pediatric medulloblastoma.

BACKGROUND: Medulloblastoma outcomes have improved with craniospinal irradiation and chemotherapy, but such therapy has resulted in poor neurocognitive outcomes for young patients. Chemotherapy-only regimens with autologous transplant have been implemented with the intention of avoiding radiation. It is not yet known whether single or tandem transplantation is superior with respect to efficacy and/or safety. METHODS: We performed a retrospective review of children with medulloblastoma treated at Dana-Farber Cancer Institute from 1996 to 2016 who received either single or tandem autologous transplantation after completion of induction chemotherapy. We compared safety and outcome data between the two groups. RESULTS: Among 23 patients, 12 received tandem transplants. Median follow-up was 6.4 years (IQR = 0.8-10.5). There was no statistically significant difference in 5-year EFS or OS between the single (70.7 ± 14%, 80.2 ± 13%) and tandem transplant groups (57.1 ± 15%, 79.6 ± 13%). Seven tandem transplant patients received subsequent radiation while only four required radiation in the single transplant group (p = .41). In the single transplant regimen, patients experienced longer antibiotic duration (p = .03) and LOS (p = .01) and a trend toward increased number of transfusions (p = .06). Four cases of veno-occlusive disease were reported in the single transplant group (p = .04). CONCLUSIONS: Outcomes were similar between regimens, but the single transplant regimen had more hepatic complications. These data suggest that tandem transplant regimens may have reduced toxicity compared to the single transplant regimen with similar outcome measures.

Health Insurance Loss during COVID-19 May Increase Support for Universal Health Coverage.

CONTEXT: The United States is the only high-income country that relies on employer-sponsored health coverage to insure a majority of its population. Millions of Americans lost employer-sponsored health insurance during the COVID-19-induced economic downturn. We examine public opinion toward universal health coverage policies in this context. METHODS: Through a survey of 1,211 Americans in June 2020, we examine the influence of health insurance loss on support for Medicare for All (M4A) and the Affordable Care Act (ACA) in two ways. First, we examine associations between pandemic-related health insurance loss and M4A support. Second, we experimentally prime some respondents with a vignette of a sympathetic person who lost employer-sponsored coverage during COVID-19. FINDINGS: We find that directly experiencing recent health insurance loss is strongly associated (10 pp, p < 0.01) with greater M4A support and with more favorable views of extending the ACA (19.3 pp, p < 0.01). Experimental exposure to the vignette increases M4A support by 6 pp (p = 0.05). CONCLUSIONS: In the context of the COVID-19 pandemic, situational framings can induce modest change in support for M4A. However, real-world health insurance losses are associated with larger differences in support for M4A and with greater support for existing safety net policies such as the ACA.

Exploring the role and clinical implications of proteasome inhibition in medulloblastoma.

Ubiquitin proteasome-mediated protein degradation has been implicated in posttranslational oncogenesis in medulloblastoma. Current research is evaluating the clinical implications of proteasome inhibition as a therapeutic target. In medulloblastoma cell lines, proteasome inhibitors induce apoptosis and inhibit cell proliferation via multiple pathways involving activation of caspase pathways, NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway inhibition, reduced AKT/mTOR pathway activity, and pro-apoptotic protein expression. Second-generation proteasome inhibitors demonstrate blood-brain barrier penetration while maintaining antitumor effect. This review summarizes the ubiquitin-proteasome system in the pathogenesis of medulloblastoma and the potential clinical implications.

Effectiveness of Social Skills Interventions Incorporating Peer Interactions for Children With Attention Deficit Hyperactivity Disorder: A Systematic Review.

IMPORTANCE: Few studies examining the use of peers during interventions have been published, and no systematic review has been conducted to evaluate the available literature. OBJECTIVE: To examine the effectiveness of social skills interventions incorporating peers for children with attention deficit hyperactivity disorder (ADHD) to improve social interactions. DATA SOURCES: A search of five databases (CINAHL, PubMed, Web of Science, Google Scholar, and PsycINFO) produced 697 articles. Sixty-one were retrieved for full-text review, and 15 articles met inclusion criteria. STUDY SELECTION AND DATA COLLECTION: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used to abstract data. Inclusion criteria: Participants younger than age 18 yr with any ADHD pattern, social skills interventions with peer involvement, outcome measures within the domain of occupational therapy, written in English, and involved a peer as the sole or primary component at some point in the social skills intervention. Exclusion criteria: Studies older than 20 yr or that used participants with comorbidities or multiple conditions. FINDINGS: Interventions incorporating both peer categories were effective for increasing play skills, reducing undesirable social behaviors (e.g., inappropriate verbalizations, dominant behaviors, aggression), and improving communication (e.g., pragmatic language, collaboration, joint participation) and social participation. Improvements were maintained over time, as evidenced by follow-up studies. CONCLUSIONS AND RELEVANCE: Outcomes of these studies demonstrate moderate evidence that supports the use of social skills interventions incorporating peers for children with ADHD to improve social interactions, supporting their use by occupational therapists and the need for more studies. WHAT THIS ARTICLE ADDS: This article provides guidance to occupational therapy practitioners on social skills intervention options for children with ADHD.

Funding for Abstinence-Only Education and Adolescent Pregnancy Prevention: Does State Ideology Affect Outcomes?

OBJECTIVES: To examine the relationship between adolescent pregnancy-prevention and sexuality and abstinence-only education funding and adolescent birthrates over time. Also, to determine whether state ideology plays a moderating role on adolescent reproductive health, that is, whether the funding has its intended effect at reducing the number of adolescent births in conservative but not in liberal states. METHODS: We modeled time-series data on federal abstinence-only and adolescent pregnancy-prevention and sexuality education block grants to US states and rates of adolescent births (1998-2016) and adjusted for state-level confounders using 2-way fixed-effects models. RESULTS: Federal abstinence-only funding had no effect on adolescent birthrates overall but displayed a perverse effect, increasing adolescent birthrates in conservative states. Adolescent pregnancy-prevention and sexuality education funding eclipsed this effect, reducing adolescent birthrates in those states. CONCLUSIONS: The millions of dollars spent on abstinence-only education has had no effect on adolescent birthrates, although conservative states, which experience the greatest burden of adolescent births, are the most responsive to changes in sexuality education-funding streams.

What is driving global obesity trends? Globalization or "modernization"?

BACKGROUND: Worldwide obesity has more than doubled since 1980. Researchers have attributed rising obesity rates to factors related to globalization processes, which are believed to contribute to obesity by flooding low-income country markets with inexpensive but obesogenic foods and diffusing Western-style fast food outlets (dependency/world systems theory). However, alternative explanations include domestic factors such as increases in unhealthy food consumption in response to rising income and higher women's labor force participation as countries develop economically ("modernization" theory). To what extent are processes of globalization driving rising global overweight/obesity rates versus domestic economic and social development processes? This study evaluates the influence of economic globalization versus economic development and associated processes on global weight gain. RESULTS: Using two-way fixed-effects OLS regression with a panel dataset of mean body weight for 190-countries over a 30-year period (1980-2008), we find that domestic factors associated with "modernization" including increasing GDP per capita, urbanization and women's empowerment were associated with increases in mean BMI over time. There was also evidence of a curvilinear relationship between GDP per capita and BMI: among low income countries, economic growth predicted increases in BMI whereas among high-income countries, higher GDP predicted lower BMI. By contrast, economic globalization (dependency/world systems theory) did not significantly predict increases in mean BMI and cultural globalization had mixed effects. These results were robust to different model specifications, imputation approaches and variable transformations. DISCUSSION: Global increases in overweight/obesity appear to be driven more by domestic processes including economic development, urbanization and women's empowerment, and are less clearly negatively impacted by external globalization processes suggesting that the harms to health from global trade regimes may be overstated.

Does Decentralization Improve Health System Performance and Outcomes in Low- and Middle-Income Countries? A Systematic Review of Evidence From Quantitative Studies.

Policy Points: For more than 3 decades, international development agencies have advocated health system decentralization to improve health system performance in low- and middle-income countries. We found little rigorous evidence documenting the impact of decentralization processes on health system performance or outcomes in part due to challenges in measuring such far-reaching and multifaceted system-level changes. We propose a renewed research agenda that focuses on discrete definitions of decentralization and how institutional factors and mechanisms affect health system performance and outcomes within the general context of decentralized governance structures. CONTEXT: Despite the widespread adoption of decentralization reforms as a means to improve public service delivery in developing countries since the 1980s, empirical evidence of the role of decentralization on health system improvement is still limited and inconclusive. This study reviewed studies published from 2000 to 2016 with adequate research designs to identify evidence on whether and how decentralization processes have impacted health systems. METHODS: We conducted a systematic review of peer-reviewed journal articles from the public health and social science literature. We searched for articles within 9 databases using predefined search terms reflecting decentralization and health system constructs. Inclusion criteria were original research articles, low- and middle-income country settings, quantifiable outcome measures, and study designs that use comparisons or statistical adjustments. We excluded studies in high-income country settings and/or published in a non-English language. FINDINGS: Sixteen studies met our prespecified inclusion and exclusion criteria and were grouped based on outcomes measured: health system inputs (n = 3), performance (n = 7), and health outcomes (n = 7). Numerous studies addressing conceptual issues related to decentralization but without any attempt at empirical estimation were excluded. Overall, we found mixed results regarding the effects of decentralization on health system indicators with seemingly beneficial effects on health system performance and health outcomes. Only 10 studies were considered to have relatively low risks of bias. CONCLUSIONS: This study reveals the limited empirical knowledge of the impact of decentralization on health system performance. Mixed empirical findings on the role of decentralization on health system performance and outcomes highlight the complexity of decentralization processes and their systemwide effects. Thus, we propose a renewed research agenda that focuses on discrete definitions of decentralization and how institutional factors and mechanisms affect health system performance and outcomes within the general context of decentralized governance structures.

Menu labels, for better, and worse? Exploring socio-economic and race-ethnic differences in menu label use in a national sample.

Menu calorie labeling aims to empower customers to make healthier food choices, but researchers have questioned whether labels will empower those with greater health literacy, literacy or numeracy more, possibly reinforcing race-ethnic or socioeconomic inequalities in obesity. The goal of this study was to investigate differences in seeing and using restaurant menu calorie labels and whether differences have compounded over time. Using data from three rounds of the National Health and Nutrition Examination Survey covering the period 2007-2014, we investigate race-ethnic and socio-economic differences in menu label usage over time adjusting for sex, age and body weight. While menu label usage increased over time, not all groups increased their use equally. While we find that Blacks and Hispanics use labels more than Whites in sit-down restaurants, more educated individuals, higher income groups and Whites each increased the degree to which they saw and/or used labels in certain settings compared with other groups. This study reinforces concerns that menu-calorie labeling may exacerbate socio-economic and certain race-ethnic obesity differences. As menu labeling policy moves forward to be implemented federally, more attention may need to be diverted to educational campaigns accompanying the implementation and improving the labels so the information is easier to use.

The nicotine metabolite, cotinine, alters the assembly and trafficking of a subset of nicotinic acetylcholine receptors.

Exposure to nicotine alters the trafficking and assembly of nicotinic receptors (nAChRs), leading to their up-regulation on the plasma membrane. Although the mechanism is not fully understood, nicotine-induced up-regulation is believed to contribute to nicotine addiction. The effect of cotinine, the primary metabolite of nicotine, on nAChR trafficking and assembly has not been extensively investigated. We utilize a pH-sensitive variant of GFP, super ecliptic pHluorin, to differentiate between intracellular nAChRs and those expressed on the plasma membrane to quantify changes resulting from cotinine and nicotine exposure. Similar to nicotine, exposure to cotinine increases the number of α4ß2 receptors on the plasma membrane and causes a redistribution of intracellular receptors. In contrast to this, cotinine exposure down-regulates α6ß2ß3 receptors. We also used single molecule fluorescence studies to show that cotinine and nicotine both alter the assembly of α4ß2 receptors to favor the high sensitivity (α4)2(ß2)3 stoichiometry.

Are Parental Perceptions of Child Activity Levels and Overall Health More Important than Perceptions of Weight?

Objectives To examine relationships between parental perceptions of child weight and overall health, reported lifestyle behaviors and measured body mass index (BMI). Methods Using community-partnered methods, we surveyed families residing in a two census tract area identified for targeted interventions to decrease diabetes related disparities. The survey included demographics, child dietary and physical activity behaviors, and parental perception of child's health and weight. We measured child BMI using a standardized protocol. Results We surveyed parents of 116 children with a mean age of 7 years (range 3-15) with 51 % boys, 74 % Hispanic, and 26 % Black. Over half of the children (55 %) were overweight or obese. Half (50 %) of the parents underestimated their children's weight. Reported daily hours of walking and/or running trended higher (3.6 vs. 2.6 h, p = 0.08) for children perceived to be of normal weight. Parents who correctly estimated their child's weight status reported more hours of daily walking/running than parents who underestimated child weight status, 4.5 versus 2.4 h, p = 0.0002. Parents of healthy weight children were more likely to report that children were in excellent or very good health compared to parents of overweight/obese children, 75 versus 56 % respectively (p = 0.04). We found significant racial/ethnic differences in reported diet and physical activity behaviors and perception of overall health. Conclusions for Practice Parental perceptions of child health and physical activity level may be related to perceptions of their child's weight status. Study findings informed community-based initiatives for reducing diabetes risk among children.