In high-income countries, medical interventions to address the known risks associated with pregnancy and birth have been largely successful and have resulted in very low levels of maternal and neonatal mortality. In this Series paper, we present the main care delivery models, with case studies of the USA and Sweden, and examine the main drivers of these models. Although nearly all births are attended by a skilled birth attendant and are in an institution, practice, cadre, facility size, and place of birth vary widely; for example, births occur in homes, birth centres, midwifery-led birthing units in hospitals, and in high intervention hospital birthing facilities. Not all care is evidenced-based, and some care provision may be harmful. Fear prevails among subsets of women and providers. In some settings, medical liability costs are enormous, human resource shortages are common, and costs of providing care can be very high. New challenges linked to alteration of epidemiology, such as obesity and older age during pregnancy, are also present. Data are often not readily available to inform policy and practice in a timely way and surveillance requires greater attention and investment. Outcomes are not equitable, and disadvantaged segments of the population face access issues and substantially elevated risks. At the same time, examples of excellence and progress exist, from clinical interventions to models of care and practice. Labourists (who provide care for all the facility's women for labour and delivery) are discussed as a potential solution. Quality and safety factors are informed by women's experiences, as well as medical evidence. Progress requires the ability to normalise birth for most women, with integrated services available if complications develop. We also discuss mechanisms to improve quality of care and highlight areas where research can address knowledge gaps with potential for impact. Evaluation of models that provide woman-centred care and the best outcomes without high costs is required to provide an impetus for change.
As healthcare costs continue to grow, hospitalists may be able to help patients and health system administrators make decisions that generate higher-value care. In this article, we discuss 3 ways hospitalists can contribute to the mission of delivering value-based healthcare: design innovative strategies to coordinate care, advocate for appropriate utilization of tests and treatments, and lead local value-improvement initiatives. We also describe specific tools hospitalists can use in their daily practice, including the Choosing Wisely lists and the COST (Culture, Oversight, Systems Change, Training) framework for value-improvement initiatives.
OBJECTIVE: To estimate cost per patient-year in response during 2 years following biologic initiation among patients with rheumatoid arthritis (RA).
METHODS: Adults newly initiating biologics for RA (etanercept, abatacept, adalimumab, certolizumab, golimumab, or infliximab) between January 2009 and July 2011 were identified in the MarketScan Commercial Database. Eligible patients were continuously enrolled 6 months before (pre-index) and 24 months after (post-index) their first (index) biologic claim. Biologic effectiveness was assessed using six criteria during 2-year follow-up: treatment adherence ≥80%, no biologic dose escalation, no biologic switch, no new disease-modifying anti-rheumatic drug, no new/increased glucocorticoid dose, and limited intra-articular joint injections (≤2). After a 90-day period of non-response for a treatment failure, effectiveness or failure of subsequent treatment was assessed again for the index biologic or new biologic (after switching). Post-index RA-related medical, pharmacy, and drug administration costs were attributed to the index biologic. Cost per patient-year in response was calculated as RA-related costs divided by duration of response.
RESULTS: Overall, 15.0% of patients (1229/8193) did not fail any criterion for 2 years and were effectively treated. Mean duration of response was highest for etanercept (538.3 days), followed by golimumab (537.0 days; p = 0.864), adalimumab (534.7 days; p = 0.301), certolizumab (524.0 days; p = 0.165), infliximab (480.0 days; p < 0.001), and abatacept (482.3 days; p < 0.001). Total disease-related cost per patient-year in response was lower for patients initiated on etanercept ($25,086) than for patients initiated on adalimumab ($25,960), certolizumab ($26,339), golimumab ($26,332), abatacept ($35,581), or infliximab ($36,107).
LIMITATIONS: This study was limited to employer-paid commercial insurance. Database analyses cannot determine reasons for failing criteria. The algorithm was not designed and validated for 2 years of follow-up.
CONCLUSIONS: An effectiveness algorithm estimated that initiating etanercept was the most effective treatment during 2 years of follow-up, with the lowest cost per patient-year in response.
INTRODUCTION: Genetic mutations in the β2 receptor could alter its functioning and the response to β2 agonists. The study was done to find out the effect of two commonly occurring polymorphisms-Arg16Gly and Gln27Glu, on cause of asthma and on response to nebulized salbutamol in South Indian subjects of asthma.
METHODS: After baseline measurements of Forced Expiratory Volume in 1st second (FEV1), Forced Vital Capacity (FVC) and Peak Expiratory Flow Rate (PEFR), five mg of nebulized salbutamol was administered and spirometry was repeated. The increase in these parameters was calculated and patients were included for genotyping if the percentage increase in FEV1 was ≥12%. The frequencies of these polymorphisms in patients were compared with those of healthy volunteers.
RESULTS: 112 patients and 127 healthy volunteers were genotyped. The frequencies of the polymorphisms were found to be similar to previously published Dravidian population frequencies. The frequencies of genotypes in asthmatics were similar to healthy volunteers. The increase in FEV1, FVC and PEFR was similar across various genotypes and haplotypes in both the polymorphisms. The GG-CG haplotype was associated with 3.1 times increased occurrence of asthma (p value = 0.02). The G allele of the Arg16Gly polymorphism was associated with lower baseline FEV1, FVC and PEFR values, but these were not statistically significant.
CONCLUSION: The Arg16Gly and Gln27Glu polymorphisms do not determine the occurrence of asthma individually, but the GG-CG haplotype is associated with an increased risk of asthma. There is no effect of the genotypes on the response to nebulized salbutamol.
Zeta-chain associated protein of 70 kDa (ZAP-70) and spleen tyrosine kinase (Syk) are non-receptor tyrosine kinases that are essential for T-cell and B-cell antigen receptor signalling respectively. They are recruited, via their tandem-SH2 (Src-homology domain 2) domains, to doubly phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) on invariant chains of immune antigen receptors. Because of their critical roles in immune signalling, ZAP-70 and Syk are targets for the development of drugs for autoimmune diseases. We show that three thiol-reactive small molecules can prevent the tandem-SH2 domains of ZAP-70 and Syk from binding to phosphorylated ITAMs. We identify a specific cysteine residue in the phosphotyrosine-binding pocket of each protein (Cys39 in ZAP-70, Cys206 in Syk) that is necessary for inhibition by two of these compounds. We also find that ITAM binding to ZAP-70 and Syk is sensitive to the presence of H2O2 and these two cysteine residues are also necessary for inhibition by H2O2. Our findings suggest a mechanism by which the reactive oxygen species generated during responses to antigen could attenuate signalling through these kinases and may also inform the development of ZAP-70 and Syk inhibitors that bind covalently to their SH2 domains.
IMPORTANCE: Based on older analyses, the World Health Organization (WHO) recommends that cesarean delivery rates should not exceed 10 to 15 per 100 live births to optimize maternal and neonatal outcomes.
OBJECTIVES: To estimate the contemporary relationship between national levels of cesarean delivery and maternal and neonatal mortality.
DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional, ecological study estimating annual cesarean delivery rates from data collected during 2005 to 2012 for all 194 WHO member states. The year of analysis was 2012. Cesarean delivery rates were available for 54 countries for 2012. For the 118 countries for which 2012 data were not available, the 2012 cesarean delivery rate was imputed from other years. For the 22 countries for which no cesarean rate data were available, the rate was imputed from total health expenditure per capita, fertility rate, life expectancy, percent of urban population, and geographic region.
EXPOSURES: Cesarean delivery rate.
MAIN OUTCOMES AND MEASURES: The relationship between population-level cesarean delivery rate and maternal mortality ratios (maternal death from pregnancy related causes during pregnancy or up to 42 days postpartum per 100,000 live births) or neonatal mortality rates (neonatal mortality before age 28 days per 1000 live births).
RESULTS: The estimated number of cesarean deliveries in 2012 was 22.9 million (95% CI, 22.5 million to 23.2 million). At a country-level, cesarean delivery rate estimates up to 19.1 per 100 live births (95% CI, 16.3 to 21.9) and 19.4 per 100 live births (95% CI, 18.6 to 20.3) were inversely correlated with maternal mortality ratio (adjusted slope coefficient, -10.1; 95% CI, -16.8 to -3.4; P = .003) and neonatal mortality rate (adjusted slope coefficient, -0.8; 95% CI, -1.1 to -0.5; P < .001), respectively (adjusted for total health expenditure per capita, population, percent of urban population, fertility rate, and region). Higher cesarean delivery rates were not correlated with maternal or neonatal mortality at a country level. A sensitivity analysis including only 76 countries with the highest-quality cesarean delivery rate information had a similar result: cesarean delivery rates greater than 6.9 to 20.1 per 100 live births were inversely correlated with the maternal mortality ratio (slope coefficient, -21.3; 95% CI, -32.2 to -10.5, P < .001). Cesarean delivery rates of 12.6 to 24.0 per 100 live births were inversely correlated with neonatal mortality (slope coefficient, -1.4; 95% CI, -2.3 to -0.4; P = .004).
CONCLUSIONS AND RELEVANCE: National cesarean delivery rates of up to approximately 19 per 100 live births were associated with lower maternal or neonatal mortality among WHO member states. Previously recommended national target rates for cesarean deliveries may be too low.
BACKGROUND: Reducing maternal and neonatal deaths are important global health priorities. We have previously shown that up to a country-level caesarean delivery rate (CDRs) of roughly 19·0%, cesarean delivery rates and maternal mortality ratio (MMR) and neonatal mortality rate (NMR) were inversely correlated. We investigated the absolute reductions in maternal and neonatal deaths if countries with low CDR increased their rates to a range of greater than 7·2% but less than or equal to 19·1%.
METHODS: We calculated maternal and neonatal deaths in 2013 and 2012, respectively, for countries with CDR 7·2% or less (N=45) with available data from the World Bank Development Indicators. We modelled the expected reduction in deaths in these countries if they had the 25th and 75th MMR and NMR percentiles observed for countries (N=48) with CDRs ranging from greater than 7·2% but less than or equal to 19·1%. This model assumes that if countries with low CDRs increased their rates of caesarean delivery to greater than 7·2% but less than or equal to 19·1%, they would achieve levels of MMR and NMR observed in countries with those CDRs.
FINDINGS: We estimate 176 078 (95% CI 163 258-188 898) maternal and 1 117 257 (95% CI 1 033 611-1 200 902) neonatal deaths occurred in 45 countries with low CDRs in 2013 and 2012, respectively. If these countries had the 25th and 75th MMR and NMR percentiles (MMR, IQR 36-190; NMR, 9-24) observed in countries (N=48) with a CDR ranging from greater than 7·2% but less than or equal to 19·1%, there would be a potential reduction of 109 762-163 513 and 279 584-803 129 maternal and neonatal deaths, respectively.
INTERPRETATION: Increasing caesarean delivery in countries with low CDRs could avert as many as 163 513 maternal deaths and 803 129 neonatal deaths annually. These findings assume that as health systems develop the capacity to deliver surgical care, there is a concurrent improvement in the quality of care and in the ability to rescue women and neonates who would otherwise die. Improving access to safe caesarean delivery should be a central focus in surgical care globally.
PROBLEM: Medical education has been cited as both part of the problems facing, and part of the solution to reforming, the increasingly challenging U.S. health care system which is fraught with concerns regarding the quality and affordability of care. To teach value in ways that are impactful, sustainable, and scalable, the best and brightest ideas need to be shared such that educators can build on successful existing innovations.
APPROACH: To identify the most promising innovations and bright ideas for teaching value to clinical trainees, the authors hosted the "Teaching Value and Choosing Wisely Challenge." The challenge used crowdsourcing methods to solicit scalable, pedagogical approaches from across North America, and then draw generalizable lessons.
OUTCOMES: The authors received 74 submissions (28 innovations; 46 bright ideas) from 14 students, 20 residents/fellows, 38 faculty members (ranging from instructors to full professors), and 2 nonclinical administrators. Submissions represented 14 clinical disciplines including internal medicine, emergency medicine, surgery, pediatrics, obstetrics-gynecology, laboratory medicine, and pharmacy. Thirty-nine abstracts focused on graduate medical education, 15 addressed undergraduate medical education, and 20 applied to both.
NEXT STEPS: The authors have solicited, shared, and described solutions for teaching high-value care to medical trainees. Challenge participants demonstrated commitment to improving value and ingenuity in addressing professional barriers to change. Further success requires strong local faculty champions and willing trainee participants. Additionally, the use of data to demonstrate the collective positive impact of these ideas and programs will be critical for sustaining pedagogical changes in the health professions.
Androgen ablation therapy causes a temporary reduction in tumor burden in patients with advanced prostate cancer. Unfortunately the malignancy will return to form lethal castration-recurrent prostate cancer (CRPC). The androgen receptor (AR) remains transcriptionally active in CRPC in spite of castrate levels of androgens in the blood. AR transcriptional activity resides in its N-terminal domain (NTD). Possible mechanisms of continued AR transcriptional activity may include, at least in part, expression of constitutively active splice variants of AR that lack the C-terminal ligand-binding domain (LBD). Current therapies that target the AR LBD, would not be effective against these AR variants. Currently no drugs are clinically available that target the AR NTD which should be effective against these AR variants as well as full-length AR. Niphatenones were originally isolated and identified in active extracts from Niphates digitalis marine sponge. Here we begin to characterize the mechanism of niphatenones in blocking AR transcriptional activity. Both enantiomers had similar IC50 values of 6 µM for inhibiting the full-length AR in a functional transcriptional assay. However, (S)-niphatenone had significantly better activity against the AR NTD compared to (R)-niphatenone. Consistent with niphatenones binding to and inhibiting transactivation of AR NTD, niphatenones inhibited AR splice variant. Niphatenone did not affect the transcriptional activity of the related progesterone receptor, but slightly decreased glucocorticoid receptor (GR) activity and covalently bound to GR activation function-1 (AF-1) region. Niphatenone blocked N/C interactions of AR without altering either AR protein levels or its intracellular localization in response to androgen. Alkylation with glutathione suggests that niphatenones are not a feasible scaffold for further drug development.