We investigate the effects of territorial government fragmentation on the quality of public services. We argue that an increase in the number of regional governments has two effects: (1) it ...redistributes fiscal and administrative resources to underserved regions and (2) encourages yardstick competition. Extreme government fragmentation, however, limits efficiency gains by reducing administrative capacity, economies of scale, and enabling capture. We test this argument using original data on the number of regional governments in sub-Saharan Africa (1960–2012). Consistent with our theoretical expectations, we find robust evidence for an initial increase in the quality of services provision following regional government splits, which levels off at high levels of regional fragmentation. Three distinct difference-in-difference analyses of microlevel, georeferenced data on health outcomes in Malawi, Nigeria, and Uganda further support our theoretical argument.
Transcription factors are DNA-binding proteins that have key roles in gene regulation
. Genome-wide occupancy maps of transcriptional regulators are important for understanding gene regulation and ...its effects on diverse biological processes
. However, only a minority of the more than 1,600 transcription factors encoded in the human genome has been assayed. Here we present, as part of the ENCODE (Encyclopedia of DNA Elements) project, data and analyses from chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) experiments using the human HepG2 cell line for 208 chromatin-associated proteins (CAPs). These comprise 171 transcription factors and 37 transcriptional cofactors and chromatin regulator proteins, and represent nearly one-quarter of CAPs expressed in HepG2 cells. The binding profiles of these CAPs form major groups associated predominantly with promoters or enhancers, or with both. We confirm and expand the current catalogue of DNA sequence motifs for transcription factors, and describe motifs that correspond to other transcription factors that are co-enriched with the primary ChIP target. For example, FOX family motifs are enriched in ChIP-seq peaks of 37 other CAPs. We show that motif content and occupancy patterns can distinguish between promoters and enhancers. This catalogue reveals high-occupancy target regions at which many CAPs associate, although each contains motifs for only a minority of the numerous associated transcription factors. These analyses provide a more complete overview of the gene regulatory networks that define this cell type, and demonstrate the usefulness of the large-scale production efforts of the ENCODE Consortium.
Objective
To disentangle the relationships among food insecurity, health care utilization, and health care expenditures.
Data Sources/Study Setting
We use national data on 13 465 adults (age ≥ 18) ...from the 2016 Medical Expenditure Panel Survey (MEPS), the first year of the food insecurity measures.
Study Design
We employ two‐stage empirical models (probit for any health care use/expenditure, ordinary least squares, and generalized linear models for amount of utilization/expenditure), controlling for demographics, health insurance, poverty status, chronic conditions, and other predictors.
Principal Findings
Our results show that the likelihood of any health care expenditure (total, inpatient, emergency department, outpatient, and pharmaceutical) is higher for marginal, low, and very low food secure individuals. Relative to food secure households, very low food secure households are 5.1 percentage points (P < .001) more likely to have any health care expenditure, and have total health care expenditures that are 24.8 percent higher (P = .011). However, once we include chronic conditions in the models (ie, high blood pressure, heart disease, stroke, emphysema, high cholesterol, cancer, diabetes, arthritis, and asthma), these underlying health conditions mitigate the differences in expenditures by food insecurity status (only the likelihood of any having any health care expenditure for very low food secure households remains statistically significant).
Conclusions
Policy makers and government agencies are focused on addressing deficiencies in social determinants of health and the resulting impacts on health status and health care utilization. Our results indicate that chronic conditions are strongly associated with food insecurity and higher health care spending. Efforts to alleviate food insecurity should consider the dual burden of chronic conditions. Finally, future research can address specific mechanisms underlying the relationships between food security, health, and health care.
Biosimilar drugs-lower-cost alternatives to expensive biologic drugs-have the potential to slow the growth of US drug spending. However, rates of biosimilar uptake have varied across hospital ...outpatient providers. We investigated whether the 340B Drug Pricing Program, which offers eligible hospitals substantial discounts on drug purchases, inhibits biosimilar uptake. Almost one-third of US hospitals participate in the 340B program. Using a regression discontinuity design and two high-volume biologics with biosimilar competitors, filgrastim and infliximab, we estimated that 340B program eligibility was associated with a 22.9-percentage-point reduction in biosimilar adoption. In addition, 340B program eligibility was associated with 13.3 more biologic administrations annually per hospital and $17,919 more biologic revenue per hospital. Our findings suggest that the program inhibited biosimilar uptake, possibly as a result of financial incentives making reference drugs more profitable than biosimilar medications.
Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) supports blood-based genomic profiling but is not yet routinely implemented in the setting of a phase I trials clinic. TARGET is a ...molecular profiling program with the primary aim to match patients with a broad range of advanced cancers to early phase clinical trials on the basis of analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated-gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumor and results were turned round within a clinically acceptable timeframe for Molecular Tumor Board (MTB) review. When a 2.5% variant allele frequency (VAF) threshold was applied, actionable mutations were identified in 41 of 100 patients, and 11 of these patients received a matched therapy. These data support the application of ctDNA in this early phase trial setting where broad genomic profiling of contemporaneous tumor material enhances patient stratification to novel therapies and provides a practical template for bringing routinely applied blood-based analyses to the clinic.
The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and ...traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Here, we show that olaparib combines synergistically with the ATR-inhibitor AZD6738 (ceralasertib), in vitro, leading to selective cell death in ATM-deficient cells. We observe that 24 h olaparib treatment causes cells to accumulate in G2-M of the cell cycle, however, co-administration with AZD6738 releases the olaparib-treated cells from G2 arrest. Selectively in ATM-knockout cells, we show that combined olaparib/AZD6738 treatment induces more chromosomal aberrations and achieves this at lower concentrations and earlier treatment time-points than either monotherapy. Furthermore, single-agent olaparib efficacy in vitro requires PARP inhibition throughout multiple rounds of replication. Here, we demonstrate in several ATM-deficient cell lines that the olaparib and AZD6738 combination induces cell death within 1-2 cell divisions, suggesting that combined treatment could circumvent the need for prolonged drug exposure. Finally, we demonstrate in vivo combination activity of olaparib and AZD6738 in xenograft and PDX mouse models with complete ATM loss. Collectively, these data provide a mechanistic understanding of combined PARP and ATR inhibition in ATM-deficient models, and support the clinical development of AZD6738 in combination with olaparib.
This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The ...objectives were to investigate the safety, tolerability, and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity.
Patients were aged ≥18 years with World Health Organization (WHO) performance status of 0 to 1. Dose escalation was conducted within separate continuous and intermittent 4 days/week (4/7) or 2 days/week (2/7) schedules with safety, pharmacokinetic, and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in
-mutant breast and gynecologic cancers.
MTDs were 320, 480, and 640 mg for continuous (
= 47), 4/7 (
= 21), and 2/7 (
= 22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II dose (480 mg bid, 4/7 intermittent) was assessed in
-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the prespecified 20% response rate; therefore, the criteria to stop further recruitment to the
-mutant cohort were met.
At the recommended phase II dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with
-mutant cancers treated with AZD5363.
.
Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to ...determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K-mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor-positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K-mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio HR, 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.
Assisting smokers to quit before surgery reduces surgical site infection (SSI) risk. The short-term economic benefits of reducing SSIs by embedding tobacco dependence treatment in Australian ...hospitals are unknown. Estimated annual number of SSIs prevented, and hospital bed-days (HBD) and costs saved from reducing smoking before surgery are calculated.
The most recent number of surgical procedures and SSI rates for Australia were sourced. The number of smokers and non-smokers having a SSI were calculated using the UK Royal College of Physicians reported adjusted odds ratio (1.79), and the proportion of SSIs attributable to smoking calculated. The potential impact fraction was used to estimate reductions in SSIs and associated HBDs and costs from reducing the smoking rates among surgical patients from 23.9% to 10% or 5% targets. Uncertainty around the final estimates was calculated using probabilistic sensitivity analysis.
In 2016-17, approximately 40,593 (95% UI 32,543, 50,239) people having a surgical procedure in Australia experienced a SSI leading to 101,888 extra days (95% UI 49,988, 200,822) in hospital. If the smoking rate among surgical patients was reduced to 10%, 3,580 (95% UI 2,312, 5,178) SSIs would be prevented, and 8,985 (95% UI 4,094, 19,153) HBDs and $19.1M (95% UI $7.7M, $42.5M) saved in one year. If the smoking rate was reduced to 5%, 4,867 (95% UI 3,268, 6,867) SSIs would be prevented, and 12,217 (95% UI 5,614, 25,642) HBDs and $26.0M (95% UI $10.8M, $57.0M) would be saved.
The findings suggest achieving smoking rate targets of 10% or 5% would provide substantial short-term health and economic benefits through reductions in SSIs. Embedding tobacco dependence treatment in Australian hospitals would provide value for money by reducing costs and improving clinical quality and safety. A more comprehensive, modelled economic evaluation synthesising the best available evidence is needed to confirm findings.
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