Five-year Impact of a Commercial Accountable Care Organization on Health Care Spending, Utilization, and Quality of Care.

BACKGROUND: Accountable Care Organizations (ACOs) have proliferated after the passage of the Affordable Care Act in 2010. Few longitudinal ACO studies with continuous enrollees exist and most are short term. OBJECTIVE: The objective of this study was to evaluate the long-term impact of a commercial ACO on health care spending, utilization, and quality outcomes among continuously enrolled members. RESEARCH DESIGN: Retrospective cohort study design and propensity-weighted difference-in-differences approach were applied to examine performance changes in 2 ACO cohorts relative to 1 non-ACO cohort during the commercial ACO implementation in 2010-2014. SUBJECTS: A total of 40,483 continuously enrolled members of a commercial health maintenance organization from 2008 to 2014. MEASURES: Cost, use, and quality metrics for various type of services in outpatient and inpatient settings. RESULTS: The ACO cohorts had (1) increased inpatient and outpatient total spending in the first 2 years of ACO operation, but insignificant differential changes for the latter 3 years; (2) decreased outpatient spending in the latter 2 years through reduced primary care visits and lowered spending on specialists, testing, and imaging; (3) no differential changes in inpatient hospital spending, utilization, and quality measures for most of the 5 years; (4) favorable results for several quality measures in preventive and diabetes care domains in at least one of the 5 years. CONCLUSIONS: The commercial ACO improved outpatient process quality measures modestly and slowed outpatient spending growth by the fourth year of operation, but had a negligible impact on inpatient hospital cost, use, and quality measures.

Risk of death following admission to a UK hospital with diabetic ketoacidosis.

AIMS/HYPOTHESIS: The aim of this study was to assess the risk of death during hospital admission for diabetic ketoacidosis (DKA) and, subsequently, following discharge. In addition, we aimed to characterise the risk factors for multiple presentations with DKA. METHODS: We conducted a retrospective cohort study of all DKA admissions between 2007 and 2012 at a university teaching hospital. All patients with type 1 diabetes who were admitted with DKA (628 admissions of 298 individuals) were identified by discharge coding. Clinical, biochemical and mortality data were obtained from electronic patient records and national databases. Follow-up continued until the end of 2014. RESULTS: Compared with patients with a single DKA admission, those with recurrent DKA (more than five episodes) were diagnosed with diabetes at an earlier age (median 14 [interquartile range 9-23] vs 24 [16-34] years, p < 0.001), had higher levels of social deprivation (p = 0.005) and higher HbA1c values (103 [89-108] vs 79 [66-96] mmol/mol; 11.6% [10.3-12.0%] vs 9.4% [8.2-10.9%], p < 0.001), and tended to be younger (25 [22-36] vs 31 [23-42] years, p = 0.079). Antidepressant use was greater in those with recurrent DKA compared with those with a single episode (47.5% vs 12.6%, p = 0.001). The inpatient DKA mortality rate was no greater than 0.16%. A single episode of DKA was associated with a 5.2% risk of death (4.1 [2.8-6.0] years of follow-up) compared with 23.4% in those with recurrent DKA admissions (2.4 [2.0-3.8] years of follow-up) (HR 6.18, p = 0.001). CONCLUSIONS/INTERPRETATION: Recurrent DKA is associated with substantial mortality, particularly among young, socially disadvantaged adults with very high HbA1c levels.

Clinical audit results in earlier nutritional intervention in malnourished children with cystic fibrosis with improved outcome.

AIM: The association between nutritional status, pulmonary function and survival in cystic fibrosis (CF) is well established. A previous case series from the Royal Children's Hospital, Melbourne (RCH), demonstrated suboptimal referral practices and highlighted the importance of early nutritional interventions in children with CF. Various qualitative changes were made to our CF service, and this study assesses the effects of these practice changes timing of gastrostomy and clinical outcome in patients who underwent gastrostomy insertion. METHOD: Clinical audit of all CF patients who had undergone gastrostomy insertion from 2002 to 2010 at Royal Children's Hospital. Clinical data, including nutritional parameters, respiratory function and survival, were collected at 2 years prior and 2 years post gastrostomy insertion. Data were compared with the previous study from 1989 to 1997. RESULTS: Patients with CF who underwent gastrostomy insertion between 2002 and 2010 (n = 22) had higher weight-for-age scores (-1.5 ± 0.68 vs. -2.67 ± 1.06; P = 0.0001) and higher forced expiratory volume in 1 s (68% ± 22 vs. 52% ± 18.5; P = 0.006), compared with the cohort from 1989 to 1997 (n = 37). These differences were maintained at 2-year follow-up. Pseudomonas aeruginosa colonisation rate was 100% in 1989-1997 vs. 41% in 2002-2010; P = 0.0001. The 2-year survival post-gastrostomy insertion improved from 70% to 100%; P = 0.004. CONCLUSION: Earlier referral of patients in the recent cohort resulted in sustained improvements in weight-for-age and lung function. Survival at 2 years post-procedure was significantly improved. This study confirms the value of clinical audits and subsequent re-evaluation of clinical services.

The lived experience of participation in student nursing associations and leadership behaviors: a phenomenological study.

The purpose of this qualitative phenomenological research study was to obtain vivid descriptions of the lived experience of nurses who participated in a student nursing association (SNA) as students. Nursing graduates from five nursing programs in Long Island, New York were identified using a purposive sampling strategy. During individual interviews, the themes of the lived experiences of the participants emerged: (1) leadership: communication, collaboration and resolving conflict, (2) mentoring and mutual support, (3) empowerment and ability to change practice, (4) professionalism, (5) sense of teamwork, and (6) accountability and responsibility. Recommendations from the study included an orientation and mentoring of new students to the SNA by senior students and faculty. Additionally, nursing faculty could integrate SNA activities within the classroom and clinical settings to increase the awareness of the benefits of participation in a student nursing organization. Recommendations for future research include a different sample and use of different research designs.

VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo.

The Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumors, and lead to aneuploidy and tumorigenesis. Here we report the discovery of a highly potent and selective small-molecule inhibitor of Aurora kinases, VX-680, that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types. This compound causes profound inhibition of tumor growth in a variety of in vivo xenograft models, leading to regression of leukemia, colon and pancreatic tumors at well-tolerated doses. Our data indicate that Aurora kinase inhibition provides a new approach for the treatment of multiple human malignancies.

Findings From a Commercial ACO Patient Experience Survey.

Accountable care organizations (ACO) emerge each year aiming to improve care quality while controlling rising health care costs. This cross-sectional study examined whether ACO arrangements within a Preferred Provider Organization and a Health Maintenance Organization (HMO) effected patient experience. A modified Consumer Assessment of Healthcare Providers and Systems ACO survey was used to assess care domain differences overall and by product. The association between ACO and non-ACO populations and items in each significant care domain, flu vaccination, and delayed and emergency department care are explored using multivariable logistic regression. Accountable care organizations patients were more likely to report it was easy to get a specialist appointment (adjusted odds ratio [AOR], 1.54; 95% CI = 1.11-2.13), less likely to report visiting the emergency department for care (AOR, 0.70; 95% CI = 0.55-0.90) and communicating with their provider using technology (AOR, 0.79; 95% CI = 0.65-0.96). Reported experience differed for Access to Specialists between ACO and non-ACO groups among overall and HMO respondents (79.4% vs 74.7% and 79.9% vs 75.5%, P < .05, respectively). The ACO patient experience was not substantially better. Strategies incorporating satisfaction and experience, whether linked to contracts or not, should be encouraged given ACOs goal to optimize patient care. Survey instruments must be improved to capture nuances of provider care and patient bond that is vital in ACO integrated systems.

Impact of a commercial accountable care organization on prescription drugs.

OBJECTIVE: To determine the long-run impact of a commercial accountable care organization (ACO) on prescription drug spending, utilization, and related quality of care. DATA SOURCES/STUDY SETTING: California Public Employees' Retirement System (CalPERS) health maintenance organization (HMO) member enrollment data and pharmacy benefit claims, including both retail and mail-order generic and brand-name prescription drugs. STUDY DESIGN: We applied a longitudinal retrospective cohort study design and propensity-weighted difference-in-differences regression models. We examined the relative changes in outcome measures between two ACO cohorts and one non-ACO cohort before and after the ACO implementation in 2010. The ACO directed provider prescribing patterns toward generic substitution for brand-name prescription drugs to maximize shared savings in pharmacy spending. DATA COLLECTION/EXTRACTION METHODS: The study sample included members continuously enrolled in a CalPERS commercial HMO from 2008 through 2014 in the Sacramento area. PRINCIPAL FINDINGS: The cohort differences in baseline characteristics of 40 483 study participants were insignificant after propensity-weighting adjustment. The ACO enrollees had no significant differential changes in either all or most of the five years of the ACO operation for the following measures: (1) average total spending and (2) average total scripts filled and days supplied on either generic or brand-name prescription drugs, or the two combined; (3) average generic shares of total prescription drug spending, scripts filled or days supplied; (4) annual rates of 10 outpatient process quality of care metrics for medication prescribing or adherence. CONCLUSIONS: Participation in the commercial ACO was associated with negligible differential changes in prescription drug spending, utilization, and related quality of care measures. Capped financial risk-sharing and increased generics substitution for brand names are not enough to produce tangible performance improvement in ACOs. Measures to increase provider financial risk-sharing shares and lower brand-name drug prices are needed.

Preclinical characterization of PF-00868554, a potent nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase.

PF-00868554 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase, which exerts its inhibitory effect by binding to the thumb base domain of the protein. It is a potent and selective inhibitor, with a mean 50% inhibitory concentration of 0.019 microM against genotype 1 polymerases and a mean 50% effective concentration (EC(50)) of 0.075 microM against the genotype 1b-Con1 replicon. To determine the in vitro antiviral activity of PF-00868554 against various HCV strains, a panel of chimeric replicons was generated, in which polymerase sequences derived from genotype 1a and 1b clinical isolates were cloned into the 1b-Con1 subgenomic reporter replicon. Our results indicate that PF-00868554 has potent in vitro antiviral activity against a majority (95.8%) of genotype 1a and 1b replicons, with an overall mean EC(50) of 0.059 microM. PF-00868554 showed no cytotoxic effect in several human cell lines, up to the highest concentration evaluated (320 microM). Furthermore, the antiviral activity of PF-00868554 was retained in the presence of human serum proteins. An in vitro resistance study of PF-00868554 identified M423T as the predominant resistance mutation, resulting in a 761-fold reduction in susceptibility to PF-00868554 but no change in susceptibility to alpha interferon and a polymerase inhibitor that binds to a different region. PF-00868554 also showed good pharmacokinetic properties in preclinical animal species. Our results demonstrate that PF-00868554 has potent and broad-spectrum antiviral activity against genotype 1 HCV strains, supporting its use as an oral antiviral agent in HCV-infected patients.

Development of intergenotypic chimeric replicons to determine the broad-spectrum antiviral activities of hepatitis C virus polymerase inhibitors.

To address the need for broad-spectrum antiviral activity characterization of hepatitis C virus (HCV) polymerase inhibitors, we created a panel of intergenotypic chimeric replicons containing nonstructural (NS) protein NS5B sequences from genotype 2b (GT2b), GT3a, GT4a, GT5a, and GT6a HCV isolates. Viral RNA extracted from non-GT1 HCV patient plasma was subjected to reverse transcription. The NS5B region was amplified by nested PCR and introduced into the corresponding region of the GT1b (Con-1) subgenomic reporter replicon by Splicing by Overlap Extension (SOEing) PCR. Stable cell lines were generated with replication-competent chimeras for in vitro antiviral activity determination of HCV nonnucleoside polymerase inhibitors (NNIs) that target different regions of the protein. Compounds that bind to the NNI2 (thiophene carboxylic acid) or NNI3 (benzothiadiazine) allosteric sites showed 8- to >1,280-fold reductions in antiviral activity against non-GT1 NS5B chimeric replicons compared to that against the GT1b subgenomic replicon. Smaller reductions in susceptibility, ranging from 0.2- to 33-fold, were observed for the inhibitor binding to the NNI1 (benzimidazole) site. The inhibitor binding to the NNI4 (benzofuran) site showed broad-spectrum antiviral activity against all chimeric replicons evaluated in this study. In conclusion, evaluation of HCV NNIs against intergenotypic chimeric replicons showed differences in activity spectrum for inhibitors that target different regions of the enzyme, some of which could be associated with specific residues that differ between GT1 and non-GT1 polymerases. Our study demonstrates the utility of chimeric replicons for broad-spectrum activity determination of HCV inhibitors.

Supplementation with iron and riboflavin enhances dark adaptation response to vitamin A-fortified rice in iron-deficient, pregnant, nightblind Nepali women.

BACKGROUND: Nightblindness affects 16-52% of pregnant women in areas of Nepal and in some cases persists after vitamin A treatment. Iron and riboflavin affect vitamin A utilization and photoreceptor function, respectively, and pilot data in the study population showed a high prevalence of iron and riboflavin deficiencies. OBJECTIVE: The objective was to assess the effect of supplemental iron and riboflavin on pupillary threshold (PT) and plasma retinol in nightblind, pregnant Nepali women given vitamin A-fortified rice. DESIGN: Nightblind pregnant women were randomly assigned to receive, 6 d/wk under supervision for 6 wk, a vitamin A-fortified rice curry dish providing 850 microg retinal activity equivalents/d with either a 30-mg Fe and 6-mg riboflavin (FeR + VA) capsule or a placebo control (VA only) capsule. Hemoglobin, erythrocyte riboflavin, and plasma ferritin and retinol were measured before and after the intervention. Dark adaptation was assessed by PT score. RESULTS: Women who were iron deficient at baseline (n=38) had significantly greater improvement in PT score with iron and riboflavin supplementation than without (P=0.05). Iron and riboflavin supplements significantly reduced the prevalences of riboflavin deficiency (from 60% to 6%; P<0.0001), iron deficiency anemia (from 35% to 15%; P<0.007), and abnormal PT (from 87% to 30%; P<0.05) from baseline. Mean increases in erythrocyte riboflavin (P<0.0001) and plasma ferritin (P=0.01) were greater in the FeR + VA group than in the VA only group. CONCLUSIONS: Iron deficiency may limit the efficacy of vitamin A to normalize dark adaptation in pregnant Nepali women. Further studies are needed to assess the effect of simultaneous delivery of iron and vitamin A for the treatment of nightblindness.

Cooperative activity of cytotoxic chemotherapy with antiangiogenic thrombospondin-I peptides, ABT-526 in pet dogs with relapsed lymphoma.

PURPOSE: Thrombospondin-I (TSP-I) is a natural antiangiogenic protein that enhances apoptosis of activated endothelial cells. A modified nonapeptide from TSP-I, ABT-526, has been found to be active in mouse cancer models and in dogs with naturally occurring cancers. To further assist in the development of ABT-526, we report herein on its evaluation in combination with cytotoxic chemotherapy in pet dogs with relapsed non-Hodgkin's lymphoma (NHL). EXPERIMENTAL DESIGN: Ninety-four pet dogs with naturally occurring first-relapse NHL were entered into a prospective randomized placebo controlled double-blinded trial of ABT-526 plus CeeNu (Bristol-Myers Squibb, New York, NY) versus CeeNu alone. Endpoints included response rate, duration of response, time to progression, and incidence of toxicoses. RESULTS: No significant ABT-526-specific toxicities were seen. CeeNu-associated toxicities, including neutropenia, thrombocytopenia, gastroenteritis, and elevated alanine transaminase, were similar. No significant difference in objective response rate was seen (ABT-526 + CeeNu versus placebo + CeeNu, 23/49 versus 23/37; P > 0.25). Cooperative activity between ABT-526 and CeeNu chemotherapy was evident based on a significant increase in the median response duration of dogs receiving ABT-526 plus CeeNu compared with placebo plus CeeNu (35 versus 15 days; P < 0.05). The time to progression for responding cases was also significantly greater in dogs receiving ABT-526 plus CeeNu compared with placebo plus CeeNu (41 versus 21 days; P < 0.05). CONCLUSIONS: Results of this preclinical trial suggest that the activity of ABT-526 is sustained when combined with cytotoxic chemotherapy; furthermore, the activity seems to be associated with the maintenance of CeeNu-induced treatment responses. Further studies of TSP-I peptide antiangiogenic therapy in pet dogs and humans with NHL are warranted.

In vitro selection of mutations in human immunodeficiency virus type 1 reverse transcriptase that confer resistance to capravirine, a novel nonnucleoside reverse transcriptase inhibitor.

Capravirine (CPV; formerly AG1549 and S-1153) is a novel, nonnucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) that has demonstrated potent in vitro antiviral activity against several HIV-1 laboratory strains and clinical isolates with EC50 values ranging from 0.7 to 10.3 nM. In this study, we evaluated the resistance and cross-resistance profiles of CPV through selection of resistant HIV-1 variants from in vitro serial passage of HIV-1 NL4-3 and HIV-1 IIIB and by performing susceptibility assays on HIV-1 variants constructed to contain CPV-specific amino acid substitutions in reverse transcriptase (RT). Results demonstrate that HIV-1 variants selected at increasing CPV concentrations contained multiple substitutions in diverse patterns including L100I, Y181C, G190E and/or L234I in various combinations with K101R/E, K103T, V106A/I, V108I, E138K, T139K, A158T, V179D/I/G, Y188D, V189I, G190A, F227C, W229R, L234F, M230I/L and P236H/T. Interestingly, HIV-1 variants constructed to contain the T215Y zidovudine (AZT)-resistance associated substitution with CPV-resistance associated substitutions V106A, Y181C, F227C, F227L, L234I or V106A/F227L demonstrated 2.4-5.4-fold increased susceptibility to CPV. Results also demonstrate that the CPV-resistance associated substitutions Y181C, F227C, F227L and L234I reverse the phenotypic resistance to AZT conferred by the T215Y substitution.

Retrospective evaluation of adjunctive doxorubicin for the treatment of feline mammary gland adenocarcinoma: 67 cases.

Medical records for 67 cats with histologically confirmed mammary gland adenocarcinomas treated with adjunctive doxorubicin from June 1994 through December 2002 were reviewed. Data were examined to evaluate factors influencing disease-free interval (DFI) and survival time. The Kaplan-Meier median survival time of cats that received surgery and doxorubicin was 448 days. The Kaplan-Meier median DFI was 255 days. Significant univariate prognostic factors for DFI included histological subtype, completion of initial chemotherapy, development of metastatic disease, and location of metastatic disease. Significant univariate prognostic factors for survival included tumor volume, the development of metastatic disease, and location of metastatic disease.

Recovery from impaired dark adaptation in nightblind pregnant Nepali women who receive small daily doses of vitamin A as amaranth leaves, carrots, goat liver, vitamin A-fortified rice, or retinyl palmitate.

BACKGROUND: It is not known whether daily consumption of vitamin A-containing foods is efficacious for treating nightblindness. OBJECTIVE: We assessed the effect of supplementation with vitamin A from food or synthetic sources on dark adaptation and plasma retinol concentrations in nightblind pregnant Nepali women. DESIGN: Nightblind pregnant women were randomly assigned to 1 of 6 treatment groups to receive 6 d/wk for 6 wk either 850 microg retinol equivalents/d as retinyl palmitate, vitamin A-fortified rice, goat liver, amaranth leaves, or carrots or 2000 microg retinol equivalents/d as retinyl palmitate. Dark adaptation was assessed weekly by using the pupillary threshold (PT) test; plasma retinol concentrations were measured before and after the intervention. These outcomes were also assessed in a comparison group of nonnightblind pregnant women. RESULTS: In the nightblind women, the mean PT improved significantly (P<0.0001) from -0.71+/-0.04 to -1.42+/-0.02 log cd/m2, and the final mean PT did not differ significantly from that in the nonnightblind women (-1.43+/-0.04; P=0.55). Improvement in dark adaptation was greater in the liver group than in the vitamin A-fortified rice group (P<0.02). Plasma retinol concentrations increased significantly (P<0.0001) from 0.95+/-0.05 to 1.07+/-0.05 micromol/L. The plasma retinol response was greater in the higher-dose capsule and liver groups than in the vegetable groups and significantly greater in the liver group than in the vitamin A-fortified rice group (both: P<0.05). CONCLUSION: Improvement in dark adaptation did not differ significantly between women who received vitamin A as liver, amaranth leaves, carrots, or retinyl palmitate.

In vitro resistance study of AG-021541, a novel nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase.

A novel class of nonnucleoside hepatitis C virus (HCV) polymerase inhibitors characterized by a dihydropyrone core was identified by high-throughput screening. Crystallographic studies of these compounds in complex with the polymerase identified an allosteric binding site close to the junction of the thumb and finger domains, approximately 30 A away from the catalytic center. AG-021541, a representative compound from this series, displayed measurable in vitro antiviral activity against the HCV genotype 1b subgenomic replicon with a mean 50% effective concentration of 2.9 muM. To identify mutations conferring in vitro resistance to AG-021541, resistance selection was carried out using HCV replicon cells either by serial passages in increasing concentrations of AG-021541 or by direct colony formation at fixed concentrations of the compound. We identified several amino acid substitutions in the AG-021541-binding region of the polymerase, including M423(T/V/I), M426T, I482(S/T), and V494A, with M423T as the predominant change observed. These mutants conferred various levels of resistance to AG-021541 and structurally related compounds but remained sensitive to interferon and HCV polymerase inhibitors known to interact with the active site or other allosteric sites of the protein. In addition, dihydropyrone polymerase inhibitors retained activity against replicons that contain signature resistance changes to other polymerase inhibitors, including S282T, C316N, M414T, and P495(S/L), indicating their potential to be used in combination therapies with these polymerase inhibitors. AG-021541-resistant replicon cell lines provide a valuable tool for mechanism-of-action studies of dihydropyrone polymerase inhibitors. The clinical relevance of in vitro resistance to HCV polymerase inhibitors remains to be investigated.

Identification and characterization of UK-201844, a novel inhibitor that interferes with human immunodeficiency virus type 1 gp160 processing.

More than 10(6) compounds were evaluated in a human immunodeficiency virus type 1 (HIV-1) high-throughput antiviral screen, resulting in the identification of a novel HIV-1 inhibitor (UK-201844). UK-201844 exhibited antiviral activity against HIV-1 NL4-3 in MT-2 and PM1 cells, with 50% effective concentrations of 1.3 and 2.7 microM, respectively, but did not exhibit measurable antiviral activity against the closely related HIV-1 IIIB laboratory strain. UK-201844 specifically inhibited the production of infectious virions packaged with an HIV-1 envelope (Env), but not HIV virions packaged with a heterologous Env (i.e., the vesicular stomatitis virus glycoprotein), suggesting that the compound targets HIV-1 Env late in infection. Subsequent antiviral assays using HIV-1 NL4-3/IIIB chimeric viruses showed that HIV-1 Env sequences were critical determinants of UK-201844 susceptibility. Consistent with this, in vitro resistant-virus studies revealed that amino acid substitutions in HIV-1 Env are sufficient to confer resistance to UK-201844. Western analysis of HIV Env proteins expressed in transfected cells or in isolated virions showed that UK-201844 inhibited HIV-1 gp160 processing, resulting in the production of virions with nonfunctional Env glycoproteins. Our results demonstrate that UK-201844 represents the prototype for a unique HIV-1 inhibitor class that directly or indirectly interferes with HIV-1 gp160 processing.