Advancing health equity through partnerships of state Medicaid agencies, Medicaid managed care organizations, and health care delivery organizations.

Background: Reducing health inequities in marginalized populations, including people with Medicaid insurance, requires care transformation to address medical and social needs that is supported and incentivized by tailored payment methods. Collaboration across health care stakeholders is essential to overcome health system fragmentation and implement sustainable reform in the United States (U.S.). This paper explores how multi-stakeholder teams operationalized the Roadmap to Advance Health Equity model during early stages of their journey to (a) build cultures of equity and (b) integrate health equity into care transformation and payment reform initiatives. Methods: Advancing Health Equity: Leading Care, Payment, and Systems Transformation is a national program in the U.S. funded by the Robert Wood Johnson Foundation that brings together multi-stakeholder teams to design and implement initiatives to advance health equity. Each team consisted of representatives from state Medicaid agencies, Medicaid managed care organizations, and health care delivery organizations in seven U.S. states. Between June and September 2021, semi-structured interviews were conducted with representatives (n = 23) from all seven teams about experiences implementing the Roadmap to Advance Health Equity model with technical assistance from Advancing Health Equity. Results: Facilitators of building cultures of equity included (1) build upon preexisting intra-organizational cultures of equity, (2) recruit and promote diverse staff and build an inclusive culture, and (3) train staff on health equity and anti-racism. Teams faced challenges building inter-organizational cultures of equity. Facilitators of identifying a health equity focus area and its root causes included (1) use data to identify a health equity focus and (2) overcome stakeholder assumptions about inequities. Facilitators of implementing care transformation and payment reform included (1) partner with Medicaid members and individual providers and (2) support and incentivize equitable care and outcomes with payment. Facilitators of sustainability planning included (1) identify evidence of improved health equity focus and (2) maintain relationships among stakeholders. Teams faced challenges determining the role of the state Medicaid agency. Conclusions: Multi-stakeholder teams shared practical strategies for implementing the Roadmap to Advance Health Equity that can inform future efforts to build intra- and inter-organizational cultures of equity and integrate health equity into care delivery and payment systems.

Effect of Handedness on Learned Controllers and Sensorimotor Noise During Trajectory-Tracking.

In human-in-the-loop control systems, operators can learn to manually control dynamic machines with either hand using a combination of reactive (feedback) and predictive (feedforward) control. This article studies the effect of handedness on learned controllers and performance during a trajectory-tracking task. In an experiment with 18 participants, subjects perform an assay of unimanual trajectory-tracking and disturbance-rejection tasks through second-order machine dynamics, first with one hand then the other. To assess how hand preference (or dominance) affects learned controllers, we extend, validate, and apply a nonparametric modeling method to estimate the concurrent feedback and feedforward controllers. We find that performance improves because feedback adapts, regardless of the hand used. We do not detect statistically significant differences in performance or learned controllers between hands. Adaptation to reject disturbances arising exogenously (i.e., applied by the experimenter) and endogenously (i.e., generated by sensorimotor noise) explains observed performance improvements.

Health care use and spending for Medicaid patients diagnosed with opioid use disorder receiving primary care in Federally Qualified Health Centers and other primary care settings.

INTRODUCTION: This nationwide study builds on prior research, which suggests that Federally Qualified Health Centers (FQHCs) and other primary care providers are associated with increased access to opioid use disorder (OUD) treatment. We compare health care utilization, spending, and quality for Medicaid patients diagnosed with OUD who receive primary care at FQHCs and Medicaid patients who receive most primary care in other settings, such as physician offices (non-FQHCs). We hypothesized that the integrated care model of FQHCs would be associated with greater access to medication for opioid use disorder (MOUD) and/or behavioral health therapy and lower rates of potentially inappropriate co-prescribing. METHODS: This cross-sectional study examined 2012 Medicaid Analytic eXtract files for patients diagnosed with OUD receiving most (>50%) primary care at FQHCs (N = 37,142) versus non-FQHCs (N = 196,712) in all 50 states and Washington DC. We used propensity score overlap weighting to adjust for measurable confounding between patients who received care at FQHCs versus non-FQHCs and increase generalizability of findings given variation in Medicaid programs and substance use policies across states. RESULTS: FQHC patients displayed higher primary care utilization and fee-for-service spending, and similar or lower utilization and fee-for-service spending for other health service categories. Contrary to our hypotheses, non-FQHC patients were more likely to receive timely (≤90 days) MOUD (buprenorphine, methadone, naltrexone, or suboxone) (Relative Risk [RR] = 1.10, 95% CI: 1.07, 1.12) and more likely be retained in medication treatment (>180 days) (RR = 1.12, 95% CI: 1.09, 1.14). However, non-FQHC patients were less likely to receive behavioral health therapy (mental health or substance use therapy) (RR = 0.90, 95% CI: 0.88, 0.92) and less likely to remain in behavioral health treatment (RR = 0.92, 95% CI: 0.89, 0.94). Non-FQHC patients were more likely to fill potentially inappropriate prescriptions of benzodiazepines and opioids after OUD diagnosis (RR = 1.35, 95% CI: 1.30, 1.40). CONCLUSIONS: Observed patterns suggest that Medicaid patients diagnosed with OUD who obtained primary care at FQHCs received more integrated care compared to non-FQHC patients. Greater care integration may be associated with increased access to behavioral health therapy and quality of care (lower potentially inappropriate co-prescribing) but not necessarily greater access to MOUD.

Understanding the Aggressive Practices of Nonprofit Hospitals in Pursuit of Patient Debt.

Nonprofit hospitals have attracted scrutiny for aggressive collection activities against patients, which persist despite the Patient Protection and Affordable Care Act's attempt to limit particularly egregious practices, called "extraordinary collection actions" (ECAs). This study examines the prevalence of ECAs and characteristics of nonprofit hospitals that reported this behavior as of 2016. Using Community Benefit Insight data, characteristics of hospitals that reported ECAs are compared with hospitals that did not report these practices. ECAs include reporting patient debt to credit agencies, filing lawsuits, placing liens on residences, and issuing civil arrest. Predictors of ECAs among nonprofit hospitals are identified using logistic regression analysis. The prevalence of ECAs is examined for the 2010-2016 time period, and nonprofit hospitals that reported ECAs are mapped to show the geographic distribution. Hospitals reporting ECAs significantly differed in total revenue, system membership, bed size, urban location, financial assistance policy use, and use of poverty guidelines for discounted care. In full logistic regression models, lower total hospital revenue was a significant predictor of ECAs. As social workers, it is vital to understand the landscape of nonprofit hospital collection actions to advocate for policy that protects patients from predatory practices while holding nonprofit hospitals accountable.

Knowledge Does Not Correspond to Adherence of Renal Diet Restrictions in Patients With Chronic Kidney Disease Stage 3-5.

OBJECTIVES: Nutrition plays a critical role in delaying the progression of chronic kidney disease (CKD); however, adherence to nutrition recommendation in patients with non-dialysis-dependent CKD (NDD-CKD) has been underexplored. The objective of this research is to determine patients with NDD-CKD adherence to nutrition recommendation, and whether knowledge of dietary recommendations impacts adherence. DESIGN AND METHODS: Patients with NDD-CKD and a glomerular filtration rate <45 mL/min were recruited from an urban, outpatient nephrology clinic. To assess adherence, patients completed an online Food Frequency Questionnaire. Knowledge of renal diet restrictions and food sources of sodium, potassium, and phosphorus was assessed by a CKD Knowledge Questionnaire. RESULTS: A total of 63 patients completed both the Food Frequency Questionnaire and CKD Knowledge Questionnaire. Patients were consuming excess protein (average intake of 1.16 g/kg; 65-81% of patients' intake above goal), sodium (average intake of 3,117 mg, 67-91% of patients' intake above goal), and phosphorus (average intake of 1,153 mg, 59-70% of patients' intake above goal). In patients without hyperkalemia, only 32-43% of patients consumed adequate potassium. People with hyperkalemia did not consume less potassium than those without hyperkalemia (2,327 vs. 2,564 mg, P = .36). Awareness of diet restriction was not associated with reduced intake of phosphorus (785 vs. 907 mg, P = .21), protein (54.4 vs. 57.0 g, P = .71), or potassium (1,793 vs. 2,076 mg, P = .27). Greater knowledge of nutrient food sources did not correlate to reduced intake of sodium (r = -0.078, P = .54) or phosphorus (r = -0.053, P = .68), or potassium in people with hyperkalemia (r = 0.025, P = .92). CONCLUSIONS: Patients with NDD-CKD consume excess sodium, phosphorus, and protein, whereas potassium intake is inadequate in people without hyperkalemia. Greater knowledge of the renal diet was not associated with increased adherence to dietary restrictions. Instruction efforts should go beyond providing nutrient-based diet information, and instead emphasize healthy food patterns and incorporate counseling to promote behavior change.

Motifome comparison between modern human, Neanderthal and Denisovan.

BACKGROUND: The availability of the genomes of two archaic humans, Neanderthal and Denisovan, and that of modern humans provides researchers an opportunity to investigate genetic differences between these three subspecies on a genome-wide scale. Here we describe an algorithm that predicts statistically significant motifs based on the difference between a given motif's actual and expected distributions. The algorithm was previously applied to plants but was modified for this work. RESULTS: The result of applying the algorithm to the human, Neanderthal, and Denisovan genomes is a catalog of potential regulatory motifs in these three human subspecies. We examined the distributions of these motifs in genetic elements including human retroviruses, human accelerated regions, and human accelerated conserved noncoding sequences regions. Differences in these distributions could be the origin of differences in phenotype between the three subspecies. Twenty significant motifs common to all three genomes were found; thirty-three were found in endogenous retroviruses in Neanderthal and Denisovan. Ten of these motifs mapped to the 22 bp core of MiR-1304. The core of this genetic element regulates the ENAM and AMTN genes, which take part in odontogenesis and whose 3' UTRs contained significant motifs. The introns of 20 genes were found to contain a large number of significant motifs, which were also overrepresented in 49 human accelerated regions. These genes include NAV2, SorCS2, TRAPPC9, GRID1, PRDM16, CAMTA1, and ASIC which are all involved in neuroregulation. Further analysis of these genes using the GO database indicates that many are associated with neurodevelopment. Also, varying numbers of significant motifs were found to occur in regions of the Neanderthal and Denisovan genomes that are missing from the human genome, suggesting further functional differences between modern and archaic humans. CONCLUSION: Although Neanderthal and Denisovan are now extinct, detailed examination of elements from their genomes can shed light on possible phenotypic and cognitive differences between these two archaic human subspecies and modern humans. Genetic similarities and differences between these three subspecies and other fossil hominids would also be of interest.

Extending health insurance coverage to the informal sector: Lessons from a private micro health insurance scheme in Lagos, Nigeria.

BACKGROUND: As a growing number of low- and middle-income countries commit to achieving universal health coverage, one key challenge is how to extend coverage to informal sector workers. Micro health insurance (MHI) provides a potential model to finance health services for this population. This study presents lessons from a pilot study of a mandatory MHI plan offered by a private insurance company and distributed through a microfinance bank to urban, informal sector workers in Lagos, Nigeria. METHODS: Study methods included a survey of microfinance clients, key informant interviews, and a review of administrative records. RESULTS: Demographic, health care seeking, and willingness-to-pay data suggested that microfinance clients, particularly women, could benefit from a comprehensive MHI plan that improved access to health care and reduced out-of-pocket spending on health services. However, administrative data revealed declining enrollment, and key informant interviews further suggested low use of the health insurance plan. Key implementation challenges, including changes to mandatory enrollment requirements, insufficient client education and marketing, misaligned incentives, and weak back-office systems, undermined enrollment and use of the plan. CONCLUSIONS: Mandatory MHI plans, intended to mitigate adverse selection and facilitate private insurers' entry into new markets, present challenges for covering informal sector workers, including when distributed through agents such as a microfinance bank. Properly aligning the incentives of the insurer and the agent are critical to effectively distribute and service insurance. Further, an urban environment presents unique challenges for distributing MHI, addressing client perceptions of health insurance, and meeting their health care needs.

Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers.

GSK2982772 is a highly selective inhibitor of receptor-interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo-controlled, double-blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1-120 mg) or placebo in a crossover design during each of 4 treatment periods. In Part B, subjects received repeat doses of GSK2982772 (20 mg once daily [QD] to up to 120 mg twice daily [BID]) or placebo for 14 days. Part C was an open-label relative bioavailability study comparing 20-mg tablets vs capsules. Safety, tolerability, pharmacokinetics (PK), RIPK1 target engagement (TE), and pharmacodynamics (PD) were assessed. The most common adverse events (AEs) were contact dermatitis and headache. Most AEs were mild in intensity, and there were no deaths or serious AEs. The PK of GSK2982772 was approximately linear over the dose range studied (up to 120 mg BID). There was no evidence of drug accumulation upon repeat dosing. Greater than 90% RIPK1 TE was achieved over a 24-hour period for the 60-mg and 120-mg BID dosing regimens. Single and repeat doses of GSK2982772 were safe and well tolerated. PK profiles showed dose linearity. The high levels of RIPK1 TE support progression into Phase II clinical trials for further clinical development.

Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites.

The BRAF inhibitor dabrafenib was recently approved for the treatment of certain BRAF V600 mutation-positive tumors, either alone or in combination therapy with the mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 inhibitor, trametinib. This article presents the dabrafenib transporter-mediated drug-drug interaction (DDI) risk assessment, which is currently an important part of drug development, regulatory submission, and drug registration. Dabrafenib and its major circulating metabolites (hydroxy-, carboxy-, and desmethyl-dabrafenib) were investigated as inhibitors of the clinically relevant transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, and OAT3. The DDI Guidance risk assessment decision criteria for inhibition of BCRP, OATP1B1 and OAT3 were slightly exceeded and therefore a minor DDI effect resulting from inhibition of these transporters remained possible. Biliary secretion is the major excretion pathway of dabrafenib-related material (71.1% of orally administered radiolabeled dose recovered in feces), whereas urinary excretion was observed as well (22.7% of the dose). In vitro uptake into human hepatocytes of the dabrafenib metabolites, but not of dabrafenib parent compound, was mediated, at least in part, by hepatic uptake transporters. The transporters responsible for uptake of the pharmacologically active hydroxy- and desmethyl dabrafenib could not be identified, whereas carboxy-dabrafenib was a substrate of several OATPs. Dabrafenib, hydroxy-, and desmethyl-dabrafenib were substrates of P-gp and BCRP, whereas carboxy-dabrafenib was not. Although a small increase in exposure to carboxy-dabrafenib upon inhibition of OATPs and an increase in exposure to desmethyl-dabrafenib upon inhibition of P-gp or BCRP cannot be excluded, the clinical significance of such increases is likely to be low.

A retrospective review of the Honduras AIN-C program guided by a community health worker performance logic model.

BACKGROUND: Factors that influence performance of community health workers (CHWs) delivering health services are not well understood. A recent logic model proposed categories of support from both health sector and communities that influence CHW performance and program outcomes. This logic model has been used to review a growth monitoring program delivered by CHWs in Honduras, known as Atención Integral a la Niñez en la Comunidad (AIN-C). METHODS: A retrospective review of AIN-C was conducted through a document desk review and supplemented with in-depth interviews. Documents were systematically coded using the categories from the logic model, and gaps were addressed through interviews. Authors reviewed coded data for each category to analyze program details and outcomes as well as identify potential issues and gaps in the logic model. RESULTS: Categories from the logic model were inconsistently represented, with more information available for health sector than community. Context and input activities were not well documented. Information on health sector systems-level activities was available for governance but limited for other categories, while not much was found for community systems-level activities. Most available information focused on program-level activities with substantial data on technical support. Output, outcome, and impact data were drawn from various resources and suggest mixed results of AIN-C on indicators of interest. CONCLUSIONS: Assessing CHW performance through a desk review left gaps that could not be addressed about the relationship of activities and performance. There were critical characteristics of program design that made it contextually appropriate; however, it was difficult to identify clear links between AIN-C and malnutrition indicators. Regarding the logic model, several categories were too broad (e.g., technical support, context) and some aspects of AIN-C did not fit neatly in logic model categories (e.g., political commitment, equity, flexibility in implementation). The CHW performance logic model has potential as a tool for program planning and evaluation but would benefit from additional supporting tools and materials to facilitate and operationalize its use.

Field tests for round-trip imaging at a 1.4 km distance with change detection and ranging using a short-wave infrared super-continuum laser.

Field tests have been conducted of a broadband illuminator for active hyperspectral imaging (HSI) using a short-wave infrared supercontinuum laser (SWIR-SCL). We demonstrated irradiance comparable to the sun for two-way measurements at a 1.4 km distance between laser and target, and performed change detection and ranging. The experimental results suggest that the range resolution of our method is ∼1.5 cm even at the 1.4 km distance. Hence, we demonstrated the possibility to perform HSI with active broadband illumination using the SWIR-SCL. To our knowledge, this experiment is the first-ever to test two-way propagation of the active HSI illumination over a long distance. The 64 W SWIR-SCL provides near sunlight-equivalent illumination over multiple square meters, and the laser could enable HSI 24 h a day, even under a cloud cover, as well as enhanced capabilities such as change detection and ranging.

Providing free pregnancy test kits to community health workers increases distribution of contraceptives: results from an impact evaluation in Madagascar.

OBJECTIVES: To improve access to contraceptives in remote and rural areas, sub-Saharan African countries are allowing community health workers (CHWs) to distribute hormonal contraceptives. Before offering hormonal contraceptives, CHWs must determine pregnancy status but often lack a reliable way to do so. No studies have evaluated the impact of providing CHWs with urine pregnancy test kits. We assessed the impact of giving CHWs free pregnancy test kits on the number of new clients purchasing hormonal contraceptives from CHWs. STUDY DESIGN: We implemented a randomized experiment in Eastern Madagascar among CHWs who sell injectable and oral hormonal contraceptives. A total of 622 CHWs were stratified by region and randomly assigned at the individual level. Treatment-group CHWs were given free pregnancy tests to distribute (n analyzed=272) and control-group CHWs did not receive the tests (n analyzed=263). We estimated an ordinary least-squares regression model, with the monthly number of new hormonal contraceptive clients per CHW as our primary outcome. RESULTS: We find that providing CHWs with free pregnancy test kits increases the number of new hormonal contraceptive clients. Treatment-group CHWs provide hormonal contraceptives to 3.1 new clients per month, compared to 2.5 in the control group. This difference of 0.7 clients per month (95% confidence interval 0.13-1.18; p=.014) represents a 26% increase. CONCLUSIONS: Giving CHWs free pregnancy tests is an effective way to increase distribution of hormonal contraceptives. As pregnancy tests become increasingly affordable for health-care systems in developing countries, community-based distribution programs should consider including the tests as a low-cost addition to CHWs' services. IMPLICATIONS: No study has evaluated the impact of giving CHWs free urine pregnancy test kits for distribution to improve provision of hormonal contraceptives. Giving CHWs free pregnancy test kits significantly increases the number of clients to whom they sell hormonal contraceptives. Community-based distribution programs should consider including these tests among CHWs' services.

Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib.

The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation-positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC(0- ∞) decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC(0- τ) and C(max) increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC(0-τ) increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC(0-τ) increased 47%, with no change in C(max), after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More-frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib.

The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk.

Dabrafenib is a potent ATP-competitive inhibitor for the V600 mutant b-rapidly accelerated fibrosarcoma (b-raf) kinase currently approved in the United States for the treatment of metastatic melanoma. Studies were conducted in human liver microsomes, recombinant human cytochrome P450 (P450) enzymes, and human hepatocytes to investigate the potential of dabrafenib and its major circulating metabolites to perpetrate pharmacokinetic drug-drug interactions (DDIs) as well as have their own pharmacokinetics affected (victim) by coadministered drugs. Dabrafenib metabolism was mediated by CYP2C8 (56% to 67%) and CYP3A4 (24%); in addition, it has demonstrated inhibition of CYP2C8, 2C9, 2C19, 3A4 (atorvastatin), and (nifedipine), with calculated IC50 values of 8.2, 7.2, 22.4, 16, and 32 µM. It also demonstrated metabolism-dependent inhibition of CYP3A4 with a maximal inactivation rate constant of 0.040 minute(-1) and a concentration required to achieve half-maximal inactivation for CYP3A4 of 38 µM. Hydroxy-dabrafenib inhibited CYP1A2, 2C9, and 3A4 (midazolam) with calculated IC50 values of 83, 29, and 44 µM, and carboxy-dabrafenib did not inhibit any of the P450 enzymes tested. Desmethyl-dabrafenib inhibited CYP2B6, 2C8, 2C9, 2C19, and 3A4 (midazolam, atorvastatin, and nifedipine) with calculated IC50 values of 78, 47, 6.3, 36, 17, 20, and 28 µM, respectively. At 30 µM dabrafenib showed increases in CYP2B6 and CYP3A4 mRNA expression indicative of induction. The potential clinical relevance of these findings was explored by using mechanistic static mathematical models to estimate the magnitude of change (area under the curve change) as a result of P450-mediated DDI interactions. This risk-assessment approach indicated that dabrafenib is unlikely to perpetrate any in vivo DDIs by inhibition mechanisms, but is a likely inducer of CYP3A4 and a victim of CYP3A4 and CYP2C8 inhibitors. Furthermore, inclusion of the in vitro drug interaction data for dabrafenib metabolites did not impact the overall clinical risk assessment.

Metabolism and disposition of oral dabrafenib in cancer patients: proposed participation of aryl nitrogen in carbon-carbon bond cleavage via decarboxylation following enzymatic oxidation.

A phase I study was conducted to assess the metabolism and excretion of [(14)C]dabrafenib (GSK2118436; N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt), a BRAF inhibitor, in four patients with BRAF V600 mutation-positive tumors after a single oral dose of 95 mg (80 µCi). Assessments included the following: 1) plasma concentrations of dabrafenib and metabolites using validated ultra-high-performance liquid chromatography--tandem mass spectrometry methods, 2) plasma and blood radioactivity, 3) urinary and fecal radioactivity, and 4) metabolite profiling. Results showed the mean total recovery of radioactivity was 93.8%, with the majority recovered in feces (71.1% of administered dose). Urinary excretion accounted for 22.7% of the dose, with no detection of parent drug in urine. Dabrafenib is metabolized primarily via oxidation of the t-butyl group to form hydroxy-dabrafenib. Hydroxy-dabrafenib undergoes further oxidation to carboxy-dabrafenib, which subsequently converts to desmethyl-dabrafenib via a pH-dependent decarboxylation. The half-lives for carboxy- and desmethyl-dabrafenib were longer than for parent and hydroxy-dabrafenib (18-20 vs. 5-6 hours). Based on area under the plasma concentration-time curve, dabrafenib, hydroxy-, carboxy-, and desmethyl-dabrafenib accounted for 11%, 8%, 54%, and 3% of the plasma radioactivity, respectively. These results demonstrate that the major route of elimination of dabrafenib is via oxidative metabolism (48% of the dose) and biliary excretion. Based on our understanding of the decarboxylation of carboxy-dabrafenib, a low pH-driven, nonenzymatic mechanism involving participation of the aryl nitrogen is proposed to allow prediction of metabolic oxidation and decarboxylation of drugs containing an aryl nitrogen positioned α to an alkyl (ethyl or t-butyl) side chain.

Concomitant oral and intravenous pharmacokinetics of dabrafenib, a BRAF inhibitor, in patients with BRAF V600 mutation-positive solid tumors.

Dabrafenib is an orally bioavailable, potent, and selective inhibitor of human wild-type BRAF and CRAF kinases as well as mutant forms of BRAF kinase. The aim of this phase 1, single-center, open-label study in four patients with BRAF mutation-positive solid tumors was to determine the absolute bioavailability of a 150 mg oral dose of dabrafenib. A microtracer study approach, in which a 50 µg radiolabeled intravenous (IV) microdose of dabrafenib was given concomitantly with a 150 mg oral dose, was used to simultaneously recover IV and oral pharmacokinetic parameters. The least squares mean (90% CI) absolute bioavailability of dabrafenib (HPMC capsules) was 94.5% (81.3%, 109.7%). Median T(max) after oral administration was 2.0 hours and the geometric mean terminal half-life was 4.8 hours. The geometric mean clearance and volume of distribution after IV administration were 12.0 L/h and 45.5 L, respectively. Human clearance and volume of distribution at steady state were in agreement with predictions made using allometric scaling of pharmacokinetic parameters from four preclinical species. In conclusion, dabrafenib absolute bioavailability was high, whereas first-pass metabolism was low. Furthermore, the microtracer approach provided an innovative and efficient method for assessing the absolute bioavailability of dabrafenib in patients with advanced cancer.

Effect of health insurance on the use and provision of maternal health services and maternal and neonatal health outcomes: a systematic review.

Financial barriers can affect timely access to maternal health services. Health insurance can influence the use and quality of these services and potentially improve maternal and neonatal health outcomes. We conducted a systematic review of the evidence on health insurance and its effects on the use and provision of maternal health services and on maternal and neonatal health outcomes in middle- and low-income countries. Studies were identified through a literature search in key databases and consultation with experts in healthcare financing and maternal health. Twenty-nine articles met the review criteria of focusing on health insurance and its effect on the use or quality of maternal health services, or maternal and neonatal health outcomes. Sixteen studies assessed demand-side effects of insurance, eight focused on supply-side effects, and the remainder addressed both. Geographically, the studies provided evidence from sub-Saharan Africa (n = 11), Asia (n = 9), Latin America (n = 8), and Turkey. The studies included examples from national or social insurance schemes (n = 7), government-run public health insurance schemes (n = 4), community-based health insurance schemes (n = 11), and private insurance (n = 3). Half of the studies used econometric analyses while the remaining provided descriptive statistics or qualitative results. There is relatively consistent evidence that health insurance is positively correlated with the use of maternal health services. Only four studies used methods that can establish this causal relationship. Six studies presented suggestive evidence of over-provision of caesarean sections in response to providers' payment incentives through health insurance. Few studies focused on the relationship between health insurance and the quality of maternal health services or maternal and neonatal health outcomes. The available evidence on the quality and health outcomes is inconclusive, given the differences in measurement, contradictory findings, and statistical limitations. Consistent with economic theories, the studies identified a positive relationship between health insurance and the use of maternal health services. However, more rigorous causal methods are needed to identify the extent to which the use of these services increases among the insured. Better measurement of quality and the use of cross-country analyses would solidify the evidence on the impact of insurance on the quality of maternal health services and maternal and neonatal health outcomes.

Overcoming autopsy barriers in pediatric cancer research.

BACKGROUND: More than 13,000 children annually in the United States and Canada under the age of 20 will be diagnosed with cancer at a mortality approaching 20% 1,2. Tumor samples obtained by autopsy provide an innovative way to study tumor progression, potentially aiding in the discovery of new treatments and increased survival rates. The purpose of this study was to identify barriers to autopsies and develop guidelines for requesting autopsies for research purposes. PROCEDURE: Families of children treated for childhood cancer were referred by patient advocacy groups and surveyed about attitudes and experiences with research autopsies. From 60 interviews, barriers to autopsy and tumor banking were identified. An additional 14 interviews were conducted with medical and scientific experts. RESULTS: Ninety-three percent of parents of deceased children did or would have consented to a research autopsy if presented with the option; however, only half of these families were given the opportunity to donate autopsy tissue for research. The most significant barriers were the physicians' reluctance to ask a grieving family and lack of awareness about research opportunities. CONCLUSIONS: The value of donating tumor samples to research via an autopsy should be promoted to all groups managing pediatric cancer patients. Not only does autopsy tumor banking offer a potentially important medical and scientific impact, but the opportunity to contribute this Legacy Gift of autopsy tumor tissue also creates a positive outlet for the grieving family. Taking these findings into account, our multidisciplinary team has developed a curriculum addressing key barriers.

Reveal Salmonella enteritidis test for detection of Salmonella enteritidis in shell eggs and environmental samples.

Reveal Salmonella Enteritidis (SE) is a lateral flow-based immunodiagnostic assay used for rapid detection of Salmonella enterica serovar Enteritidis from pooled shell eggs and environmental samples. This assay uses highly specific antibodies to accurately detect S. Enteritidis. Studies were conducted to compare the performance of this test against reference procedures for detection of S. Enteritidis from both pooled shell eggs and environmental samples. Pooled shell eggs were inoculated with low levels ofS. Enteritidis and were enriched according to the procedure prescribed by the U.S. Food and Drug Administration. Uninoculated samples were included in each trial. Reveal SE exhibited 100% sensitivity and 100% specificity in comparison to the reference method in all trials. An abbreviated 48 h/(no hold) enrichment procedure was also developed and validated for detection ofS. Enteritidis from pooled shell egg samples. This shortened enrichment procedure can be used in conjunction with the Reveal SE test and offers a significant enrichment time savings of 96 h. Chi-square analysis revealed that there was no significant difference between the abbreviated Reveal method and the reference procedure for detection ofS. Enteritidis from pooled shell egg samples. Out of 245 natural drag swabs screened internally, only three samples tested Reveal SE positive and were confirmed by the reference procedure, resulting in 100% sensitivity and 100% specificity. An external laboratory screened 147 poultry house environmental samples and obtained 35 Reveal SE confirmed positives for Reveal SE sensitivity of 100% and specificity of 90%. Inoculation trials with drag swabs resulted in 96% sensitivity and 100% specificity. Thus, these data demonstrate that Reveal SE is a highly sensitive and specific assay for the detection of S. Enteritidis from both pooled shell eggs and environmental samples.

Evaluation of a new disinfection approach: efficacy of chlorine and bromine halogenated contact disinfection for reduction of viruses and microcystin toxin.

Contaminated drinking water is responsible for causing diarrheal diseases that kill millions of people a year. Additionally, toxin-producing blue-green algae associated with diarrhea and neurologic effects continues to be an issue for many drinking water supplies. Disinfection has been used to reduce these risks. A novel gravity-fed household drinking water system with canisters containing N-halamine bromine or chlorine media was challenged with MS2 bacteriophage and microcystin. Chlorine and bromine systems were effective against this virus, with an mean +/- SE reduction of 2.98 +/- 0.26 log(10) and 5.02 +/- 0.19 log(10), respectively. Microcystin toxin was reduced by 27.5% and 88.5% to overall mean +/- SE concentrations of 1,600 +/- 98 ng/L and 259 +/- 50 ng/L for the chlorine and bromine canisters, respectively. Only the bromine units consistently produced microcystin effluent < 1,000 ng/L (the World Health Organization recommended level) when challenged with 2,500 ng/L and consistently surpassed the U.S. Environmental Protection Agency virus reduction goal of 99.99%.