The Comprehensive Primary Care Plus Model and Health Care Spending, Service Use, and Quality.

Importance: Implemented in 18 regions, Comprehensive Primary Care Plus (CPC+) was the largest US primary care delivery model ever tested. Understanding its association with health outcomes is critical in designing future transformation models. Objective: To test whether CPC+ was associated with lower health care spending and utilization and improved quality of care. Design, Setting, and Participants: Difference-in-differences regression models compared changes in outcomes between the year before CPC+ and 5 intervention years for Medicare fee-for-service beneficiaries attributed to CPC+ and comparison practices. Participants included 1373 track 1 (1 549 585 beneficiaries) and 1515 track 2 (5 347 499 beneficiaries) primary care practices that applied to start CPC+ in 2017 and met minimum care delivery and other eligibility requirements. Comparison groups included 5243 track 1 (5 347 499 beneficiaries) and 3783 track 2 (4 507 499 beneficiaries) practices, matched, and weighted to have similar beneficiary-, practice-, and market-level characteristics as CPC+ practices. Interventions: Two-track design involving enhanced (higher for track 2) and alternative payments (track 2 only), care delivery requirements (greater for track 2), data feedback, learning, and health information technology support. Main Outcomes and Measures: The prespecified primary outcome was annualized Medicare Part A and B expenditures per beneficiary per month (PBPM). Secondary outcomes included expenditure categories, utilization (eg, hospitalizations), and claims-based quality-of-care process and outcome measures (eg, recommended tests for patients with diabetes and unplanned readmissions). Results: Among the CPC+ patients, 5% were Black, 3% were Hispanic, 87% were White, and 5% were of other races (including Asian/Other Pacific Islander and American Indian); 85% of CPC+ patients were older than 65 years and 58% were female. CPC+ was associated with no discernible changes in the total expenditures (track 1: $1.1 PBPM [90% CI, -$4.3 to $6.6], P = .74; track 2: $1.3 [90% CI, -$5 to $7.7], P = .73), and with increases in expenditures including enhanced payments (track 1: $13 [90% CI, $7 to $18], P < .001; track 2: $24 [90% CI, $18 to $31], P < .001). Among secondary outcomes, CPC+ was associated with decreases in emergency department visits starting in year 1, and in acute hospitalizations and acute inpatient expenditures in later years. Associations were more favorable for practices also participating in the Medicare Shared Savings Program and independent practices. CPC+ was not associated with meaningful changes in claims-based quality-of-care measures. Conclusions and Relevance: Although the timing of the associations of CPC+ with reduced utilization and acute inpatient expenditures was consistent with the theory of change and early focus on episodic care management of CPC+, CPC+ was not associated with a reduction in total expenditures over 5 years. Positive interaction between CPC+ and the Shared Savings Program suggests transformation models might be more successful when provider cost-reduction incentives are aligned across specialties. Further adaptations and testing of primary care transformation models, as well as consideration of the larger context in which they operate, are needed.

Phase separation of an actin nucleator by junctional microtubules regulates epithelial function.

Liquid-liquid phase separation (LLPS) is involved in various dynamic biological phenomena. In epithelial cells, dynamic regulation of junctional actin filaments tethered to the apical junctional complex (AJC) is critical for maintaining internal homeostasis against external perturbations; however, the role of LLPS in this process remains unknown. Here, after identifying a multifunctional actin nucleator, cordon bleu (Cobl), as an AJC-enriched microtubule-associated protein, we conducted comprehensive in vitro and in vivo analyses. We found that apical microtubules promoted LLPS of Cobl at the AJC, and Cobl actin assembly activity increased upon LLPS. Thus, microtubules spatiotemporally regulated junctional actin assembly for epithelial morphogenesis and paracellular barriers. Collectively, these findings established that LLPS of the actin nucleator Cobl mediated dynamic microtubule-actin cross-talk in junctions, which fine-tuned the epithelial barrier.

Long-Term Effects of the Comprehensive Primary Care Model on Health Care Spending and Utilization.

BACKGROUND: The Centers for Medicare & Medicaid Services launched the 4-year Comprehensive Primary Care Initiative (CPC Classic) in 2012 and its 5-year successor, CPC Plus (CPC+), in 2017 to test whether improving primary care delivery in five areas-and providing practices with financial and technical support-reduced spending and improved quality. This is the first study to examine long-term effects of a primary care practice transformation model. OBJECTIVE: To test whether long-term primary care transformation-the 4-year CPC Classic and the first 2 years of its successor, CPC+-reduced hospitalizations, emergency department (ED) visits, and spending over 6 years. DESIGN: We used a difference-in-differences analysis to compare outcomes for beneficiaries attributed to CPC Classic practices with outcomes for beneficiaries attributed to comparison practices during the year before and 6 years after CPC Classic began. PARTICIPANTS: The study involved 565,674 Medicare fee-for-service beneficiaries attributed to 502 CPC Classic practices and 1,165,284 beneficiaries attributed to 908 comparison practices, with similar beneficiary-, practice-, and market-level characteristics as the CPC Classic practices. INTERVENTIONS: The interventions required primary care practices to improve 5 care areas and supported their transformation with substantially enhanced payment, data feedback, and learning support and, for CPC+, added health information technology support. MAIN MEASURES: Hospitalizations (all-cause), ED visits (outpatient and total), and Medicare Part A and B expenditures. KEY RESULTS: Relative to comparison practices, beneficiaries in intervention practices experienced slower growth in hospitalizations-3.1% less in year 5 and 3.5% less in year 6 (P < 0.01) and roughly 2% (P < 0.1) slower growth each year in total ED visits during years 3 through 6. Medicare Part A and B expenditures (excluding care management fees) did not change appreciably. CONCLUSIONS: The emergence of favorable effects on hospitalizations in years 5 and 6 suggests primary care transformation takes time to translate into lower hospitalizations. Longer tests of models are needed.

RNA Sequencing Reveals Key Metabolic Pathways Are Modified by Short-Term Whole Egg Consumption.

Eggs are protein-rich, nutrient-dense, and contain bioactive ingredients that have been shown to modify gene expression and impact health. To understand the effects of egg consumption on tissue-specific mRNA and microRNA expression, we examined the role of whole egg consumption (20% protein, w/w) on differentially expressed genes (DEGs) between rat (n = 12) transcriptomes in the prefrontal cortex (PFC), liver, kidney, and visceral adipose tissue (VAT). Principal component analysis with hierarchical clustering was used to examine transcriptome profiles between dietary treatment groups. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis as well as genetic network and disease enrichment analysis to examine which metabolic pathways were the most predominantly altered in each tissue. Overall, our data demonstrates that whole egg consumption for 2 weeks modified the expression of 52 genes in the PFC, 22 genes in VAT, and two genes in the liver (adj p < 0.05). Additionally, 16 miRNAs were found to be differentially regulated in the PFC, VAT, and liver, but none survived multiple testing correction. The main pathways influenced by WE consumption were glutathione metabolism in VAT and cholesterol biosynthesis in the PFC. These data highlight key pathways that may be involved in diseases and are impacted by acute consumption of a diet containing whole eggs.

Proximal fibular nerve conduction studies to tibialis anterior: Optimal E2 (reference electrode) placement.

BACKGROUND: Several E2 (reference electrode) positions are described for fibular (peroneal) nerve conduction studies to tibialis anterior (TA). METHODS: This study compared the contribution of different E2 sites to the TA motor response, using remote referential recordings and different bipolar montages. RESULTS: The medial knee contributes minimal electrical activity to the bipolar TA recordings, whereas tibial, ankle, and toe references resulted in very similar, moderate amplitude contributions consistent with far field potentials. These observations were very similar in controls and in patients with lower leg symptoms and signs. CONCLUSIONS: Standard montages using distal leg or foot E2 sites result in lower amplitudes with distortion arising from the E2 electrode, compared with the TA-Knee montage. Optimal measurement of the TA motor response is achieved using a medial knee reference, without compromising measures of fibular nerve conduction across the knee.

Ivermectin inhibits extracellular vesicle secretion from parasitic nematodes.

Lymphatic filariasis (LF) is a disease caused by parasitic filarial nematodes that is endemic in 49 countries of the world and affects or threatens over 890 million people. Strategies to control LF rely heavily on mass administration of anthelmintic drugs including ivermectin (IVM), a macrocyclic lactone drug considered an Essential Medicine by the WHO. However, despite its widespread use the therapeutic mode of action of IVM against filarial nematodes is not clear. We have previously reported that filarial nematodes secrete extracellular vesicles (EVs) and that their cargo has immunomodulatory properties. Here we investigate the effects of IVM and other anti-filarial drugs on parasitic nematode EV secretion, motility, and protein secretion. We show that inhibition of EV secretion was a specific property of IVM, which had consistent and significant inhibitory effects across nematode life stages and species, with the exception of male parasites. IVM inhibited EV secretion, but not parasite motility, at therapeutically relevant concentrations. Protein secretion was inhibited by IVM in the microfilariae stage, but not in any other stage tested. Our data provides evidence that inhibiting the secretion of immunomodulatory EVs by parasitic nematodes could explain, at least in part, IVM mode of action and provides a phenotype for novel drug discovery.

Whole egg consumption increases gene expression within the glutathione pathway in the liver of Zucker Diabetic Fatty rats.

Nutrigenomic evidence supports the idea that Type 2 Diabetes Mellitus (T2DM) arises due to the interactions between the transcriptome, individual genetic profiles, lifestyle, and diet. Since eggs are a nutrient dense food containing bioactive ingredients that modify gene expression, our goal was to examine the role of whole egg consumption on the transcriptome during T2DM. We analyzed whether whole egg consumption in Zucker Diabetic Fatty (ZDF) rats alters microRNA and mRNA expression across the adipose, liver, kidney, and prefrontal cortex tissue. Male ZDF (fa/fa) rats (n = 12) and their lean controls (fa/+) (n = 12) were obtained at 6 wk of age. Rats had ad libitum access to water and were randomly assigned to a modified semi-purified AIN93G casein-based diet or a whole egg-based diet, both providing 20% protein (w/w). TotalRNA libraries were prepared using QuantSeq 3' mRNA-Seq and Lexogen smallRNA library prep kits and were further sequenced on an Illumina HighSeq3000. Differential gene expression was conducted using DESeq2 in R and Benjamini-Hochberg adjusted P-values controlling for false discovery rate at 5%. We identified 9 microRNAs and 583 genes that were differentially expressed in response to 8 wk of consuming whole egg-based diets. Kyto Encyclopedia of Genes and Genomes/Gene ontology pathway analyses demonstrated that 12 genes in the glutathione metabolism pathway were upregulated in the liver and kidney of ZDF rats fed whole egg. Whole egg consumption primarily altered glutathione pathways such as conjugation, methylation, glucuronidation, and detoxification of reactive oxygen species. These pathways are often negatively affected during T2DM, therefore this data provides unique insight into the nutrigenomic response of dietary whole egg consumption during the progression of T2DM.

Systematic review and meta-analysis of patient race/ethnicity, socioeconomics, and quality for adult type 2 diabetes.

OBJECTIVE: To review the evidence of the association between performance in eight indicators of diabetes care and a patient's race/ethnicity and socioeconomic characteristics. DATA SOURCE: Studies of adult patients with type 2 diabetes in MEDLINE published between January 1, 2000, and December 31, 2018. STUDY DESIGN: Systematic review and meta-analysis of regression-based studies including race/ethnicity and income or education as explanatory variables. Meta-analysis was used to quantify differences in performance associated with patient race/ethnicity or socioeconomic characteristics. The systematic review was used to identify potential mechanisms of disparities. DATA COLLECTION: Two coauthors separately conducted abstract screening, study exclusions, data extraction, and scoring of retained studies. Estimates in retained studies were extracted and, where applicable, were standardized and converted to odds ratios and standard errors. PRINCIPAL FINDINGS: Performance in intermediate outcomes and process measures frequently exhibited differences by race/ethnicity even after adjustment for socioeconomic, lifestyle, and health factors. Meta-analyses showed black patients had lower odds of HbA1c and blood pressure (BP) control (OR range: 0.67-0.68, P < .05) but higher odds of receiving eye or foot examination (OR range: 1.22-1.47, P < .05) relative to white patients. A high school degree or more was associated with higher odds of HbA1c control and receipt of eye examinations compared to patients without a degree. Meta-analyses of income included a handful of studies and were inconsistently associated with diabetes care performance. Differences in diabetes performance appear to be related to access-related factors such as uninsurance or lacking a usual source of care; food insecurity and trade-offs at very low incomes; and lower adherence among younger and healthier diabetes patients. CONCLUSIONS: Patient race/ethnicity and education were associated with differences in diabetes quality measures. Depending on the approach used to rate providers, not adjusting for these patient characteristics may penalize or reward providers based on the populations they serve.

Primary Care Practice Transformation Introduces Different Staff Roles.

PURPOSE: Practices in the 4-year Comprehensive Primary Care (CPC) initiative changed staffing patterns during 2012-2016 to improve care delivery. We sought to characterize these changes and to compare practice patterns with those in similar non-CPC practices in 2016. METHODS: We conducted an online survey among selected US primary care practices. We statistically tested 2012-2016 changes in practice-reported staff composition among 461 CPC practices using 2-tailed t tests. Using logistic regression analysis, we compared differences in staff types between the CPC practices and 358 comparison practices that participated in the survey in 2016. RESULTS: In 2012, most CPC practices reported having physicians (100%), administrative staff (99%), and medical assistants (90%). By 2016, 84% reported having care managers/care coordinators (up from 24% in 2012), and 29% reported having behavioral health professionals, clinical psychologists, or social workers (up from 19% in 2014). There were also smaller increases (of less than 10 percentage points) in the share of practices having pharmacists, nutritionists, registered nurses, quality improvement specialists, and health educators. Larger and system-affiliated practices were more likely to report having care managers/care coordinators and behavioral health professionals. In 2016, relative to comparison practices, CPC practices were more likely to report having various staff types-notably, care managers/care coordinators (84% of CPC vs 36% of comparison practices), behavioral health professionals (29% vs 12%), and pharmacists (18% vs 4%). CONCLUSIONS: During the CPC initiative, CPC practices added different staff types to a fairly traditional staffing model of physicians with medical assistants. They most commonly added care managers/care coordinators and behavioral health staff to support the CPC model and, at the end of CPC, were more likely to have these staff members than comparison practices.

Novel ACTG1 mutations in patients identified by massively parallel DNA sequencing cause progressive hearing loss.

Human ACTG1 mutations are associated with high-frequency hearing loss, and patients with mutations in this gene are good candidates for electric acoustic stimulation. To better understand the genetic etiology of hearing loss cases, massively parallel DNA sequencing was performed on 7,048 unrelated Japanese hearing loss probands. Among 1,336 autosomal dominant hearing loss patients, we identified 15 probands (1.1%) with 13 potentially pathogenic ACTG1 variants. Six variants were novel and seven were previously reported. We collected and analyzed the detailed clinical features of these patients. The average progression rate of hearing deterioration in pure-tone average for four frequencies was 1.7 dB/year from 0 to 50 years age, and all individuals over 60 years of age had severe hearing loss. To better understand the underlying disease-causing mechanism, intracellular localization of wild-type and mutant gamma-actins were examined using the NIH/3T3 fibroblast cell line. ACTG1 mutants p.I34M p.M82I, p.K118M and p.I165V formed small aggregates while p.R37H, p.G48R, p.E241K and p.H275Y mutant gamma-actins were distributed in a similar manner to the WT. From these results, we believe that some part of the pathogenesis of ACTG1 mutations may be driven by the inability of defective gamma-actin to be polymerized into F-actin.

In vivo-directed evolution of adeno-associated virus in the primate retina.

Efficient adeno-associated virus-mediated (AAV-mediated) gene delivery remains a significant obstacle to effective retinal gene therapies. Here, we apply directed evolution - guided by deep sequencing and followed by direct in vivo secondary selection of high-performing vectors with a GFP-barcoded library - to create AAV viral capsids with the capability to deliver genes to the outer retina in primates. A replication-incompetent library, produced via providing rep in trans, was created to mitigate risk of AAV propagation. Six rounds of in vivo selection with this library in primates - involving intravitreal library administration, recovery of genomes from outer retina, and extensive next-generation sequencing of each round - resulted in vectors with redirected tropism to the outer retina and increased gene delivery efficiency to retinal cells. These viral vectors expand the toolbox of vectors available for primate retina, and they may enable less invasive delivery of therapeutic genes to patients, potentially offering retina-wide infection at a similar dosage to vectors currently in clinical use.

Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-Onset Progressive Hearing Loss.

MYO6 is known as a genetic cause of autosomal dominant and autosomal recessive inherited hearing loss. In this study, to clarify the frequency and clinical characteristics of hearing loss caused by MYO6 gene mutations, a large-scale genetic analysis of Japanese patients with hearing loss was performed. By means of massively parallel DNA sequencing (MPS) using next-generation sequencing for 8074 Japanese families, we found 27 MYO6 variants in 33 families, 22 of which are novel. In total, 2.40% of autosomal dominant sensorineural hearing loss (ADSNHL) in families in this study (32 out of 1336) was found to be caused by MYO6 mutations. The present study clarified that most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age. The estimated hearing deterioration was found to be 0.57 dB per year; when restricted to change after 40 years of age, the deterioration speed was accelerated to 1.07 dB per year. To obtain supportive evidence for pathogenicity, variants identified in the patients were introduced to MYO6 cDNA by site-directed mutagenesis and overexpressed in epithelial cells. They were then assessed for their effects on espin1-induced microvilli formation. Cells with wildtype myosin 6 and espin1 co-expressed created long microvilli, while co-expression with mutant constructs resulted in severely shortened microvilli. In conclusion, the present data clearly showed that MYO6 is one of the genes to keep in mind with regard to ADSNHL, and the molecular characteristics of the identified gene variants suggest that a possible pathology seems to result from malformed stereocilia of the cochlear hair cells.

Optimal reference electrode placement for accessory and axillary nerve conduction studies.

BACKGROUND: Various techniques are described for proximal motor nerve conduction studies (NCSs). We investigated alternative reference electrode (E2) locations for accessory and axillary NCSs. METHODS: Multi-channel recordings were made from trapezius or deltoid referred to different sites, and from those sites referred to a remote electrode. Responses were compared using grouped statistics, and correlation analysis. RESULTS: For accessory NCSs, all belly:E2 montages showed comparable responses but axillary NCSs were more variable. Low amplitude contamination was seen at the sternum and contralateral acromion but greater distortion using other potential E2 sites. In both accessory and axillary studies, the ipsilateral acromion showed moderate activity, which correlated with the belly:remote response. CONCLUSIONS: Variation in E2 electrode sites may significantly distort the measured compound muscle action potential (CMAP). For accessory and axillary NCS, a sternal reference has favorable characteristics. Other sites, such as ipsilateral acromion or deltoid insertion, may not yield a representative CMAP.

Making Evidence Actionable: Interactive Dashboards, Bayes, and Health Care Innovation.

The results of many large-scale federal or multi-site evaluations are typically compiled into long reports which end up sitting on policymaker's shelves. Moreover, the information policymakers need from these reports is often buried in the report, may not be remembered, understood, or readily accessible to the policymaker when it is needed. This is not a new challenge for evaluators, and advances in statistical methodology, while they have created greater opportunities for insight, may compound the challenge by creating multiple lenses through which evidence can be viewed. The descriptive evidence from traditional frequentist models, while familiar, are frequently misunderstood, while newer Bayesian methods provide evidence which is intuitive, but less familiar. These methods are complementary but presenting both increases the amount of evidence stakeholders and policymakers may find useful. In response to these challenges, we developed an interactive dashboard that synthesizes quantitative and qualitative data and allows users to access the evidence they want, when they want it, allowing each user a customized, and customizable view into the data collected for one large-scale federal evaluation. This offers the opportunity for policymakers to select the specifics that are most relevant to them at any moment, and also apply their own risk tolerance to the probabilities of various outcomes.

Effects of a Behavioral Health and Chronic Illness Care Intervention on Patient Outcomes in Primary Care Practices in the Dakotas.

From 2012 to 2015, Sanford Health, a large health care system, integrated behavioral health services and chronic condition care management in some of its primary care practices in the Dakotas and rural Minnesota. Using difference-in-differences analyses for fee-for-service Medicare beneficiaries attributed to 22 participating practices and 91 matched comparison practices, we found that the program increased the receipt of four recommended diabetes care processes by 8.6% (p=.048) and, by slowing the increase in emergency department (ED) visits, reduced them by 4.9% (p=.07) relative to the comparison group. However, the findings are mixed: the program did not affect hospital admissions, readmissions, or Medicare spending. In addition, the program increased admissions for ambulatory care-sensitive conditions by 13.6% (p=.07) relative to the comparison group. Sanford's program provides a concrete example of how to incorporate behavioral health services in primary care in underserved areas with some positive results on quality-of-care processes and ED utilization.

Dual Targeting of EGFR and IGF1R in the TNFAIP8 Knockdown Non-Small Cell Lung Cancer Cells.

Aberrant regulation of EGFR is common in non-small cell lung carcinomas (NSCLC), and tumor resistance to targeted therapies has been attributed to emergence of other co-occurring oncogenic events, parallel bypass receptor tyrosine kinase pathways including IGF1R, and TNFα-driven adaptive response via NF-κB. TNFAIP8, TNFα-inducible protein 8, is an NF-κB-activated prosurvival and oncogenic molecule. TNFAIP8 expression protects NF-κB-null cells from TNFα-induced cell death by inhibiting caspase-8 activity. Here, we demonstrate that knockdown of TNFAIP8 inhibited EGF and IGF-1-stimulated migration in NSCLC cells. TNFAIP8 knockdown cells showed decreased level of EGFR and increased expression of sorting nexin 1 (SNX1), a key regulator of the EGFR trafficking through the endosomal compartments, and treatment with SNX1 siRNA partially restored EGFR expression in these cells. TNFAIP8 knockdown cells also exhibited downregulation of IGF-1-induced pIGF1R and pAKT, and increased expression of IGF-1-binding protein 3 (IGFBP3), a negative regulator of the IGF-1/IGF1R signaling. Consistently, treatment of TNFAIP8 knockdown cells with IGFBP3 siRNA restored pIGF1R and pAKT levels. TNFAIP8 knockdown cells had enhanced sensitivities to inhibitors of EGFR, PI3K, and AKT. Furthermore, IHC expression of TNFAIP8 was associated with poor prognosis in NSCLC. These findings demonstrate TNFAIP8-mediated regulation of EGFR and IGF1R via SNX1 and IGFBP3, respectively. We posit that TNFAIP8 is a viable, multipronged target downstream of the TNFα/NF-κB axis, and silencing TNFAIP8 may overcome adaptive response in NSCLC. IMPLICATIONS: TNFAIP8 and its effectors SNX1 and IGFBP3 may be exploited to improve the efficacy of molecular-targeted therapies in NSCLC and other cancers.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/5/1207/F1.large.jpg.

The Effects of a Primary Care Transformation Initiative on Primary Care Physician Burnout and Workplace Experience.

BACKGROUND: Physician burnout is associated with deleterious effects for physicians and their patients and might be exacerbated by practice transformation. OBJECTIVE: Assess the effect of the Comprehensive Primary Care (CPC) initiative on primary care physician experience. DESIGN: Prospective cohort study conducted with about 500 CPC and 900 matched comparison practices. Mail surveys of primary care physicians, selected using cross-sectional stratified random selection 11 months into CPC, and a longitudinal design with sample replacement 44 months into CPC. PARTICIPANTS: Primary care physicians in study practices. INTERVENTION: A multipayer primary care transformation initiative (October 2012-December 2016) that required care delivery changes and provided enhanced payment, data feedback, and learning support. MAIN MEASURES: Burnout, control over work, job satisfaction, likelihood of leaving current practice within 2 years. KEY RESULTS: More than 1000 physicians responded (over 630 of these in CPC practices) in each round (response rates 70-81%, depending on round and research group). Physician experience outcomes were similar for physicians in CPC and comparison practices. About one third of physician respondents in CPC and comparison practices reported high levels of burnout in each round (32 and 29% in 2013 [P = 0.59], and 34 and 36% in 2016 [P = 0.63]). Physicians in CPC and comparison practices reported some to moderate control over work, with an average score from 0.50 to 0.55 out of 1 in 2013 and 2016 (CPC-comparison differences of - 0.04 in 2013 [95% CI - 0.08-0.00, P = 0.07], and - 0.03 in 2016 [95% CI - 0.03-0.02, P = 0.19]). In 2016, roughly three quarters of CPC and comparison physicians were satisfied with their current job (77 and 74%, P = 0.77) and about 15% planned to leave their practice within 2 years (14 and 15%, P = 0.17). CONCLUSIONS: Despite requiring substantial practice transformation, CPC did not affect physician experience. Research should track effects of other transformation initiatives on physicians and test new ways to address burnout. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02320591.

Patient experience during a large primary care practice transformation initiative.

OBJECTIVES: To determine how the multipayer Comprehensive Primary Care (CPC) initiative that transformed primary care delivery affected patient experience of Medicare fee-for-service beneficiaries. The study examines whether patient experience changed during the 4-year initiative, whether ratings of CPC practices changed relative to ratings of comparison practices, and areas in which practices still have an opportunity to improve patient experience. STUDY DESIGN: Prospective study using 2 cross-sectional samples of more than 25,000 Medicare fee-for-service beneficiaries attributed to 490 CPC practices and more than 8000 beneficiaries attributed to 736 comparison practices. METHODS: We analyzed patient experience 8 to 12 months and 45 to 48 months after CPC began, measured using 5 domains of the Consumer Assessment of Healthcare Providers and Systems Clinician and Group survey with Patient-Centered Medical Home items, version 2.0. A regression-adjusted analysis compared differences in the proportion of beneficiaries giving the best responses (and, as a sensitivity test, mean responses) to survey questions over time and between CPC and comparison practices. RESULTS: Patient ratings of care over time were generally comparable for CPC and comparison practices. CPC had favorable effects on measures of follow-up care after hospitalizations and emergency department visits. CONCLUSIONS: Practice transformation did not alter patient experience. The lack of favorable findings raises questions about how future efforts in primary care can succeed in improving patient experience.

Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy.

Conventional approaches for antiparasitic drug discovery center upon discovering selective agents that adversely impact parasites with minimal host side effects. Here, we show that agents with a broad polypharmacology, often considered 'dirtier' drugs, can have unique efficacy if they combine deleterious effects on the parasite with beneficial actions in the host. This principle is evidenced through a screen for drugs to treat schistosomiasis, a parasitic flatworm disease that impacts over 230 million people. A target-based screen of a Schistosoma serotoninergic G protein coupled receptor yielded the potent agonist, ergotamine, which disrupted worm movement. In vivo, ergotamine decreased mortality, parasite load and intestinal egg counts but also uniquely reduced organ pathology through engagement of host GPCRs that repressed hepatic stellate cell activation, inflammatory damage and fibrosis. The unique ability of ergotamine to engage both host and parasite GPCRs evidences a future strategy for anthelmintic drug design that coalesces deleterious antiparasitic activity with beneficial host effects.