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Objectives: To develop and test quality indicators for assessing care in pediatric hospital settings for common respiratory illnesses., Patients: A sample of 2796 children discharged from the emergency department or inpatient setting at 1 of the 3 participating hospitals with a primary diagnosis of asthma, bronchiolitis, croup, or community-acquired pneumonia (CAP) between January 1, 2010, and December 31, 2011., Setting: Three tertiary care children's hospitals in the United States., Methods: We developed evidence-based quality indicators for asthma, bronchiolitis, croup, and CAP. Expert panel-endorsed indicators were included in the P ediatric R espiratory I llness Me asurement S ystem (PRIMES). This new set of pediatric quality measures was tested to assess feasibility of implementation and sensitivity to variations in care. Medical records data were extracted by trained abstractors. Quality measure scores (0-100 scale) were calculated by dividing the number of times indicated care was received by the number of eligible cases. Score differences within and between hospitals were determined by using the Student's t -test or analysis of variance., Results: CAP and croup condition-level PRIMES scores demonstrated significant between-hospital variations ( P < .001). Asthma and bronchiolitis condition-level PRIMES scores demonstrated significant within-hospital variation with emergency department scores (means [SD] 82.2(6.1)-100.0 (14.4)] exceeding inpatient scores (means [SD] 71.1 (2.0)-90.8 (1.3); P < .001)., Conclusions: PRIMES is a new set of measures available for assessing the quality of hospital-based care for common pediatric respiratory illnesses., (Copyright © 2017 by the American Academy of Pediatrics.)

Just as online shopping is supplanting visits to the mall, and distance learning is part of the new wave in higher education, so is health care coming to a computer or mobile device near you. In the next few years, telehealth will increasingly become part of psychiatric and neurological care. Still to overcome is an unwieldy health care system that will need to adapt to practices that have the potential to lower costs and improve care .

In this paper we report new data on peat carbon (C), nitrogen (N) and phosphorus (P) concentrations and accumulation rates for 15 sites in the UK. Concentrations of C, N and P measured in peat from five ombrotrophic blanket mires, spanning 4000-10,000years to present were combined with existing nutrient data from ten Scottish ombrotrophic peat bogs to provide the first UK perspective on millennial scale macronutrient concentrations in ombrotrophic peats. Long-term average C, N and P concentrations (0-1.25m) for the UK are 54.8, 1.56 and 0.039wt%, of similar magnitude to the few published comparable sites worldwide. The uppermost peat (0-0.2m) is enriched in P and N (51.0, 1.86, and 0.070wt%) relative to the deeper peat (0.5-1.25m, 56.3, 1.39, and 0.027wt%). Long-term average (whole core) accumulation rates of C, N and P are 25.3±2.2gCm -2 year - 1 (mean±SE), 0.70±0.09gNm -2 year -1 and 0.018±0.004gPm -2 year -1 , again similar to values reported elsewhere in the world. The two most significant findings are: 1) that a regression model of N concentration on P concentration and mean annual precipitation, based on global meta data for surface peat samples, can explain 54% of variance in N concentration in these UK peat profiles; and 2) budget calculations for the UK peat cores yield an estimate for long-term average N-fixation of 0.8gm -2 year -1 . Our UK results, and comparison with others sites, corroborate published estimates of N storage in northern boreal peatlands through the Holocene as ranging between 8 and 15Pg N. However, the observed correlation of N% with both mean annual precipitation and P concentration allows a potential bias in global estimates that do not take this into account. The peat sampling data set has been deposited at the NERC Data Centre (Toberman et al., 2016)., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

To predict ecosystem responses to anthropogenic change it is important to understand how and where plant productivity is limited by macronutrient availability. Nitrogen (N) is required in large quantities for plant growth, and is readily lost through leaching or gas fluxes, but reactive nitrogen can be obtained through dinitrogen fixation, and phosphorus (P) is often considered a more fundamental long-term constraint to growth and carbon sequestration in terrestrial ecosystems. Phosphorus limitation may be becoming more prevalent due to widespread pollution by atmospheric N. Assessments of the effects of macronutrient availability on productivity in natural ecosystems are however scarce. We measured standing biomass of bracken Pteridium aquilinum as a proxy for productivity across sites with similar climate but varied geology. Total above-ground biomass varied from 404 to 1947gm -2 , yet despite 12-fold to 281-fold variation in soil macronutrient stocks these were remarkably poor at explaining variation in productivity. Soil total nitrogen, organic phosphorus, calcium, magnesium and zinc had no relationship with productivity, whether expressed as concentrations, stocks or element/C ratios, and nor did foliar N/P. Soil potassium (K) and molybdenum stocks both showed weak relationships with productivity. The stock of K in bracken biomass was considerably greater as a proportion of soil stock than for other nutrient elements, suggesting that this nutrient element can be important in determining productivity. Moisture availability, as indicated by environmental trait scores for plant species present, explained considerably more of the variation in productivity than did K stock, with less production in wetter sites. Soil N/C ratio and organic P stock were relatively unimportant in determining productivity across these bracken sites. It is possible that more-direct measures of N and P availability would explain variation in productivity, but the study shows the importance of considering other essential elements and other environmental factors when predicting productivity., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To present a case study on how to compare various matching methods applying different measures of balance and to point out some pitfalls involved in relying on such measures., Data Sources: Administrative claims data from a German statutory health insurance fund covering the years 2004-2008., Study Design: We applied three different covariance balance diagnostics to a choice of 12 different matching methods used to evaluate the effectiveness of the German disease management program for type 2 diabetes (DMPDM2). We further compared the effect estimates resulting from applying these different matching techniques in the evaluation of the DMPDM2., Principal Findings: The choice of balance measure leads to different results on the performance of the applied matching methods. Exact matching methods performed well across all measures of balance, but resulted in the exclusion of many observations, leading to a change of the baseline characteristics of the study sample and also the effect estimate of the DMPDM2. All PS-based methods showed similar effect estimates. Applying a higher matching ratio and using a larger variable set generally resulted in better balance. Using a generalized boosted instead of a logistic regression model showed slightly better performance for balance diagnostics taking into account imbalances at higher moments., Conclusion: Best practice should include the application of several matching methods and thorough balance diagnostics. Applying matching techniques can provide a useful preprocessing step to reveal areas of the data that lack common support. The use of different balance diagnostics can be helpful for the interpretation of different effect estimates found with different matching methods., (© Health Research and Educational Trust.)

Wisconsin, like much of the nation, is currently suffering from a growing nursing shortage. The University of Wisconsin-Eau Claire College of Nursing and Health Sciences, in partnership with the University of Wisconsin-Madison, University of Wisconsin-Milwaukee, and University of Wisconsin Oshkosh nursing programs, took advantage of a University of Wisconsin System Incentive Grant for economic and workforce development to address this problem. With a $3.2 million award, the Nurses for Wisconsin goal is to increase the number of baccalaureate registered nurses by expanding the nursing education capacity within the University of Wisconsin System. Nurses for Wisconsin is accelerating the preparation of nursing faculty by supporting nurses to enroll in doctor of nursing practice or nursing doctor of philosophy programs with pre- and postdoctoral fellowship awards ranging from $21,500 to $90,000 and the recruitment of faculty with a loan repayment program of up to $50,000. In exchange for the financial support, fellows and faculty must make a 3-year commitment to teach in a UW System nursing program. Two conferences for program participants are also funded through the award. The first conference was held in October 2014. The second conference is scheduled for summer 2015. With the first year of the 2-year project completed, this article describes Nurses for Wisconsin from inception to implementation and midterm assessment with a focus on lessons learned. A follow-up article addressing final outcomes and next steps is planned., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Little is known about factors associated with unmet needs for symptom management in patients with cancer., Methods: Patients with a new diagnosis of lung and colorectal cancer from the diverse nationally representative Cancer Care Outcomes Research and Surveillance cohort completed a survey approximately 5 months after diagnosis (N = 5,422). We estimated the prevalence of unmet need for symptom management, defined as patients who report that they wanted help for at least one common symptom (pain, fatigue, depression, nausea/vomiting, cough, dyspnea, diarrhea) during the 4 weeks before the survey but did not receive it. We identified patient factors associated with unmet need by using logistic regression with random effects to account for clustering within study sites., Results: Overall, 15% (791 of 5,422) of patients had at least one unmet need for symptom management. Adjusting for sociodemographic and clinical factors, African American race, being uninsured or poor, having early-stage lung cancer, and the presence of moderate to severe symptoms were associated with unmet need (all P < .05). Furthermore, patients who rated their physician's communication score < 80 (on a 0 to 100 scale) had adjusted rates of an unmet need for symptom management that were more than twice as high as patients who rated their physicians with a perfect communication score (23.1% v 10.0%; P < .001)., Conclusion: A significant minority of patients with newly diagnosed lung and colorectal cancer report unmet needs for symptom management. Interventions to improve symptom management should consider the importance of physician communication to the patient's experience of disease., (Copyright © 2016 by American Society of Clinical Oncology.)

Interventions with multivalued treatments are common in medical and health research, such as when comparing the efficacy of competing drugs or interventions, or comparing between various doses of a particular drug. In recent years, there has been a growing interest in the development of multivalued treatment effect estimators using observational data. In this paper, we compare the performance of commonly used regression-based methods that estimate multivalued treatment effects based on the unconfoundedness assumption. These estimation methods fall into three general categories: (i) estimators based on a model for the outcome variable using conventional regression adjustment; (ii) weighted estimators based on a model for the treatment assignment; and (iii) 'doubly-robust' estimators that model both the treatment assignment and outcome variable within the same framework. We assess the performance of these models using Monte Carlo simulation and demonstrate their application with empirical data. Our results show that (i) when models estimating both the treatment and outcome are correctly specified, all adjustment methods provide similar unbiased estimates; (ii) when the outcome model is misspecified, regression adjustment performs poorly, while all the weighting methods provide unbiased estimates; (iii) when the treatment model is misspecified, methods based solely on modeling the treatment perform poorly, while regression adjustment and the doubly robust models provide unbiased estimates; and (iv) when both the treatment and outcome models are misspecified, all methods perform poorly. Given that researchers will rarely know which of the two models is misspecified, our results support the use of doubly robust estimation., (Copyright © 2015 John Wiley & Sons, Ltd.)

Very high baseline HIV-1 RNA viral loads require potent and robust antiretroviral regimens to achieve virological suppression. The coformulated single tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) is recommended by the US Department of Health and Human Services for the treatment of HIV-1 in treatment-naive adults and adolescents regardless of baseline CD4(+) T-cell count and viral load. We report two cases of HIV-infected, treatment-naive patients, with baseline HIV-1 RNA viral loads >1,000,000 copies/ml who were initiated on the single tablet regimen EVG/COBI/FTC/TDF, but failed to attain viral load suppression and developed resistance to the components of EVG/COBI/FTC/TDF.

The riverine transport of particulate organic matter (POM) is a significant flux in the carbon cycle, and affects macronutrients and contaminants. We used radiocarbon to characterise POM at 9 riverine sites of four UK catchments (Avon, Conwy, Dee, Ribble) over a one-year period. High-discharge samples were collected on three or four occasions at each site. Suspended particulate matter (SPM) was obtained by centrifugation, and the samples were analysed for carbon isotopes. Concentrations of SPM and SPM organic carbon (OC) contents were also determined, and were found to have a significant negative correlation. For the 7 rivers draining predominantly rural catchments, PO14C values, expressed as percent modern carbon absolute (pMC), varied little among samplings at each site, and there was no significant difference in the average values among the sites. The overall average PO14C value for the 7 sites of 91.2 pMC corresponded to an average age of 680 14C years, but this value arises from the mixing of differently-aged components, and therefore significant amounts of organic matter older than the average value are present in the samples. Although topsoil erosion is probably the major source of the riverine POM, the average PO14C value is appreciably lower than topsoil values (which are typically 100 pMC). This is most likely explained by inputs of older subsoil OC from bank erosion, or the preferential loss of high-14C topsoil organic matter by mineralisation during riverine transport. The significantly lower average PO14C of samples from the River Calder (76.6 pMC), can be ascribed to components containing little or no radiocarbon, derived either from industrial sources or historical coal mining, and this effect is also seen in the River Ribble, downstream of its confluence with the Calder. At the global scale, the results significantly expand available information for PO14C in rivers draining catchments with low erosion rates., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To examine how similar racial/ethnic disparities in clinical quality (Healthcare Effectiveness Data and Information Set [HEDIS]) and patient experience (Consumer Assessment of Healthcare Providers and Systems [CAHPS]) measures are for different measures within Medicare Advantage (MA) plans., Data Sources/study Setting: 5.7 million/492,495 MA beneficiaries with 2008-2009 HEDIS/CAHPS data., Study Design: Binomial (HEDIS) and linear (CAHPS) hierarchical mixed models generated contract estimates for HEDIS/CAHPS measures for Hispanics, blacks, Asian-Pacific Islanders, and whites. We examine the correlation of within-plan disparities for HEDIS and CAHPS measures across measures., Principal Findings: Plans with disparities for a given minority group (vs. whites) for a particular measure have a moderate tendency for similar disparities for other measures of the same type (mean r = 0.51/.21 and 53/34 percent positive and statistically significant for CAHPS/HEDIS). This pattern holds to a lesser extent for correlations of CAHPS disparities and HEDIS disparities (mean r = 0.05/0.14/0.23 and 4.4/5.6/4.4 percent) positive and statistically significant for blacks/Hispanics/API., Conclusions: Similarities in CAHPS and HEDIS disparities across measures might reflect common structural factors, such as language services or provider incentives, affecting several measures simultaneously. Health plan structural changes might reduce disparities across multiple measures., (© Health Research and Educational Trust.)

Purpose: The first purpose of this study was to explore the use of a whole class, test-teach-test, dynamic assessment of narratives for identifying participants. The second purpose was to examine the efficacy of a Tier 2 narrative language intervention for culturally and linguistically diverse preschoolers., Method: A dynamic assessment was conducted with students from 3 Head Start classrooms. On the basis of the results of the dynamic assessment, 22 children were randomly assigned to treatment (n = 12) and control (n = 10) groups for intervention. Participants received a small-group (4:1), differentiated, narrative intervention for 15-20 min, twice a week, for 9 weeks. Interventionists used weekly progress monitoring data to explicitly focus on individualized narrative and linguistic targets., Results: The treatment group showed significant improvement over the control group on proximal and distal measures of narrative retells, with large effect sizes. Group differences on a measure of children's language in the context of personal stories were not statistically significant., Conclusions: This early-stage study provides evidence that narrative language intervention is an effective approach to improving the language skills of preschoolers with diverse language needs. Furthermore, the evidence supports the use of dynamic assessment for reducing overidentification and identifying candidates for small-group language intervention.

Objective: To assess the extent to which patients self-refer to cancer specialists and whether self-referral is associated with better experiences and quality of care., Data Sources: Data from surveys and medical record abstraction collected through the Cancer Care Outcomes Research and Surveillance Consortium., Study Design: Observational study of patients with lung and colorectal cancer diagnosed from 2003 through 2005 in five geographically defined regions and five integrated health care delivery systems., Methods: Multivariable logistic regression models used to assess factors associated with self-referral and propensity score-weighted doubly robust models to test the association between self-referral and experiences/quality of care., Principal Findings: Among 5,882 patients, 9.7 percent of lung cancer patients and 14.9 percent of colorectal cancer patients self-referred to at least one cancer specialist. Black patients were less likely to self-refer than white patients (odds ratio: 0.48, 95 percent confidence interval: 0.35, 0.64); patients with high incomes (vs. low) and with a college degree (vs. non-high school graduates) were significantly more likely to self-refer. Self-referral was associated with lower ratings of overall physician communication for patients with lung cancer but, conversely, higher odds of curative surgery among patients with stage I/II lung cancer., Conclusions: A small but significant proportion of patients self-referred to their cancer specialists; rates varied by patient race and socioeconomic status. To the extent that self-referral is associated with quality, it may reinforce disparities in care., (© Health Research and Educational Trust.)

Purpose of the Study: The relationship between stress and smoking has been established, but there is little research on the effects of stress and coping on smoking in caregivers of Alzheimer's disease patients. This study examines how caregiver stressors and coping resources explain smoking status and recent smoking increase., Design and Methods: Data were obtained from the Resources for Enhancing Alzheimer's Caregivers Health (REACH II) study. Analyses identified differences between caregiver smokers and nonsmokers and between caregiver smokers who reported a recent smoking increase and those who did not. Variables that were significantly different between the groups were examined in two logistic regression analyses to explain smoking status and smoking increase., Results: Of 642 caregivers, nearly 40% reported smoking and 25% of smokers reported recent increase in smoking. Younger caregivers were more likely to report smoking. Explanatory variables for smoking increase were being Caucasian or African-American, higher depression scores, and less caregiving skills., Implications: This study demonstrates that smoking among caregivers is a valid public health concern. Further investigation of ways that explanatory variables affect smoking status and increase in caregivers, and incorporation of smoking cessation strategies that address depression and low caregiving skills, seem warranted in future caregiver interventions., (Published by Oxford University Press on behalf of the Gerontological Society of America 2013.)

We report a woman who presented with rapidly progressive dementia and hypoglycorrhachia and discuss the approach and differential diagnosis for her condition. Rapidly progressive dementia poses a variety of challenges to the treating clinician, not only due to the speed of disease progression, but also due to the poor prognosis if intervention is delayed. The differential diagnosis of a patient presenting with rapid cognitive and functional decline is broad and includes degenerative, infectious, toxic, and neoplastic etiologies, some of which can be identified clinically through history and physical examination. Diagnostic evaluation using gadolinium-enhanced MRI, electroencephalography, and serum and cerebrospinal fluid testing is often required. The utility of testing for cerebrospinal fluid 14-3-3 antigen and tau is also reviewed., (Published by Elsevier Ltd.)

Background: Depression is a major barrier to HIV treatment outcomes., Objective: To test whether antidepressant management decision support integrated into HIV care improves antiretroviral adherence and depression morbidity., Design: Pseudo-cluster randomized trial., Setting: Four US infectious diseases clinics., Participants: HIV-infected adults with major depressive disorder., Intervention: Measurement-based care (MBC) - depression care managers used systematic metrics to give HIV primary-care clinicians standardized antidepressant treatment recommendations., Measurements: Primary - antiretroviral medication adherence (monthly unannounced telephone-based pill counts for 12 months). Primary time-point - 6 months. Secondary - depressive severity, depression remission, depression-free days, measured quarterly for 12 months., Results: From 2010 to 2013, 149 participants were randomized to intervention and 155 to usual care. Participants were mostly men, Black, non-Hispanic, unemployed, and virally suppressed with high baseline self-reported antiretroviral adherence and depressive severity. Over follow-up, no differences between arms in antiretroviral adherence or other HIV outcomes were apparent. At 6 months, depressive severity was lower among intervention participants than usual care [mean difference -3.7, 95% confidence interval (CI) -5.6, -1.7], probability of depression remission was higher [risk difference 13%, 95% CI 1%, 25%), and suicidal ideation was lower (risk difference -18%, 95% CI -30%, -6%). By 12 months, the arms had comparable mental health outcomes. Intervention arm participants experienced an average of 29 (95% CI: 1-57) more depression-free days over 12 months., Conclusion: In the largest trial of its kind among HIV-infected adults, MBC did not improve HIV outcomes, possibly because of high baseline adherence, but achieved clinically significant depression improvements and increased depression-free days. MBC may be an effective, resource-efficient approach to reducing depression morbidity among HIV patients.

The regulatory approval of ipilimumab (Yervoy) in 2011 ushered in a new era of cancer immunotherapies with durable clinical effects. Most of these breakthrough medicines are monoclonal antibodies that block protein-protein interactions between T cell checkpoint receptors and their cognate ligands. In addition, genetically engineered autologous T cell therapies have also recently demonstrated significant clinical responses in haematological cancers. Conspicuously missing from this class of therapies are traditional small-molecule drugs, which have previously served as the backbone of targeted cancer therapies. Modulating the immune system through a small-molecule approach offers several unique advantages that are complementary to, and potentially synergistic with, biologic modalities. This Review highlights immuno-oncology pathways and mechanisms that can be best or solely targeted by small-molecule medicines. Agents aimed at these mechanisms--modulation of the immune response, trafficking to the tumour microenvironment and cellular infiltration--are poised to significantly extend the scope of immuno-oncology applications and enhance the opportunities for combination with tumour-targeted agents and biologic immunotherapies.

Study Objective: Experience with low-dose intermittent danazol or prolonged gonadotropin-releasing hormone agonist (GnRH-a) with and without add-back therapy in endometriosis-associated ureteral obstruction., Design: Retrospective case series (Canadian Task Force classification II-2)., Setting: University-affiliated teaching hospital., Patients: Three women with endometriosis-associated ureteral obstruction., Intervention: The regimen of GnRH-a alone or with add-back included (1) leuprolide acetate 3.75 mg intramuscularly monthly; (2) micronized 17α-estradiol 1 mg/day by mouth; (3) pulsed norethinedrone 0.35 mg/day by mouth, 2 days on and/or 2 days off; and (4) letrozole 2.5 mg by mouth for the first 5 days of the first GnRH-a injection. Danazol, 100 mg/day by mouth, was prescribed as a regimen of 3 months on, 3 months off, for 4 years., Measurements and Main Results: The first case was a 50-year-old woman, gravida 3, para 3, body mass index (BMI) 27 kg/m(2), with multiple surgeries, including hysterectomy and bilateral salpingo-oophorectomy (HBSO), and history of a stroke. She presented with right-sided pain and hydro-uretero-nephrosis. Magnetic resonance imaging identified a right adnexal cyst (4.5 × 3.4 × 2.4 cm). She was treated with leuprolide acetate monthly injections and a ureteric stent. The cyst, pain, and hydro-uretero-nephrosis resolved after 12 months. The second case was a 45-year-old woman, G2P2, BMI 28 kg/m(2) with multiple surgeries, including HBSO. She presented with left-sided pelvic pain. Ultrasound identified a left adnexal cyst and hydronephrosis. After 3 months of leuprolide acetate and add-back therapy, the cyst, pain, and hydronephrosis resolved. The third case was a 46-year-old woman, G2P2, BMI 25 kg/m(2), who presented with left flank and pelvic pain. Magnetic resonance imaging indicated moderate left hydronephrosis and left adnexal pelvic side-wall involvement with possible endometriosis. Due to many previous surgeries, this patient was a high-risk surgical candidate, and therefore, she was offered medical therapy. After a normal serum liver and lipid profile, she was started on danazol, 100 mg/day for 3 months. After 3 months of therapy, there was complete resolution of the patient's hydronephrosis and pain. She was then advised to continue with a 3-month on, 3-month off regimen. She discontinued the danazol and remained asymptomatic with no recurrence of hydronephrosis at 3 years., Conclusions: Low-dose intermittent danazol or GnRH-a alone or with add-back, may be effective long-term therapies in endometriosis-associated ureteral obstruction when surgery is contraindicated, refused, or difficult to perform., (Copyright © 2015 AAGL. Published by Elsevier Inc. All rights reserved.)

Introduction: Increased demand for expensive intensive care unit (ICU) services may contribute to rising health-care costs. A focus on appropriate use may offer a clinically meaningful way of finding the balance. We aimed to determine the extent and characteristics of perceived inappropriate treatment among ICU doctors and nurses, defined as an imbalance between the amount or intensity of treatments being provided and the patient's expected prognosis or wishes., Methods: This was a cross-sectional study of doctors and nurses providing care to patients in 56 adult ICUs in California between May and August 2013. In total, 1,363 doctors and nurses completed an anonymous electronic survey., Results: Thirty-eight percent of 1,169 respondents (95% confidence interval (CI) 35% to 41%, 51.1% of physicians and 35.8% of nurses) identified at least one patient as receiving inappropriate treatment. Respondents most commonly reported that the amount of treatment provided was disproportionate to the patient's expected prognosis or wishes-325 out of 429 (76%, 95% CI 72% to 80%)--and that treatment was 'too much' in 93% of cases. Factors associated with perceived inappropriateness of treatment were the belief that death in their ICU is seen as a failure (odds ratio (OR) 5.75, 95% CI 2.28 to 14.53, P = 0.000), profession (doctors more than nurses) (OR 2.50, 95% CI 1.58 to 3.97, P = 0.000), lack of collaboration between doctors and nurses (OR 1.84, 95% CI 1.21 to 2.80, P = 0.004), intent to leave their job (OR 1.73, 95% CI 1.18 to 2.55, P = 0.005), and the perceived responsibility to control health-care costs (OR 1.57, 95% CI 1.05 to 2.33, P = 0.026). Providers supported formal communication training (90%, 95% CI 88% to 92%) and mandatory family meetings (89%, 95% CI 87% to 91%) as potential solutions to reduce the provision of inappropriate treatment., Conclusions: Doctors and nurses working in California ICUs frequently perceive treatment to be inappropriate. They also identified measures that could reduce the provision of inappropriate treatment.

Background: Public report card designers aim to provide comprehensible provider performance information to consumers. Report cards often display classifications of providers into performance tiers that reflect whether performance is statistically significantly above or below average or not statistically significantly different from average. To further enhance the salience of public reporting to consumers, report card websites often allow a user to compare a subset of selected providers on tiered performance rather than direct statistical comparisons of the providers in a consumer's personal choice set., Objective: We illustrate the differences in conclusions drawn about relative provider performance using tiers versus conducing statistical tests to assess performance differences., Methods: Using publicly available cross-sectional data from Medicare Hospital Compare on three mortality and three readmission outcome measures, we compared each provider in the top or bottom performance tier with those in the middle tier and assessed the proportion of such comparisons that exhibited no statistically significant differences., Results: Across the six outcomes, 1.3-6.1% of hospitals were classified in the top tier. Each top-tier hospital did not statistically significantly differ in performance from at least one mid-tier hospital. The percentages of mid-tier hospitals that were not statistically significantly different from a given top-tier hospital were 74.3-81.1%. The percentages of hospitals classified as bottom tier were 0.6-4.0%. Each bottom-tier hospital showed no statistically significant difference from at least one mid-tier hospital. The percentage of mid-tier hospitals that were not significantly different from a bottom-tier hospital ranged from 60.4% to 74.8%., Conclusions: Our analyses illustrate the need for further innovations in the design of public report cards to enhance their salience for consumers., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Quality care for patients with cancer often requires access to specialty providers, but little is known about barriers to referring cancer patients for specialized care. Referral barriers may also lessen physician career satisfaction. The study was aimed at determining what factors are associated with these barriers and whether greater barriers are associated with low career satisfaction., Methods: This cross-sectional study examined 1562 primary care physicians (PCPs) and 2144 specialists responding to the multiregional Cancer Care Outcomes Research and Surveillance Consortium physician survey. The prevalence of physician-reported barriers to referring cancer patients for more specialized care (restricted provider networks, preauthorization requirements, patient inability to pay, lack of surgical subspecialists, and excessive patient travel time) was assessed. The 5 items were averaged to calculate a barrier score. A multivariate linear regression was used to determine physician and practice setting characteristics associated with the barrier score, and a multivariate logistic regression was used to analyze the association of the barrier score with physician career satisfaction., Results: Three in 5 physicians reported always, usually, or sometimes encountering any barrier to cancer patient specialty referrals. In adjusted analyses of PCPs and specialists, international medical graduates, physicians practicing in solo or government-owned practices, and physicians with <90% of their patients in managed care plans had higher barrier scores than others (P < .05). High barrier scores were associated with lower physician career satisfaction among PCPs and specialists (P < .05)., Conclusions: Many physicians experience barriers to specialty referral for cancer patients. Uniform systems for providing and tracking timely referrals may enhance care and promote physician career satisfaction., (© 2014 American Cancer Society.)

Advances in fluidics, electronics, and instrument design have enabled automation of complex molecular assays. The FilmArray Respiratory Panel (RP) is one such assay; it allows for rapid detection of multiple viral and bacterial respiratory targets via nested polymerase chain reaction (PCR), with all components contained within a single pouch. We performed a detailed comparison of workflow between the FilmArray RP and direct fluorescent antibody (DFA) staining. The FilmArray RP proved to be more efficient, with as few as 91 total touches needed and as little as 4 minutes 52 seconds hands-on time. This compares with as many as 502 total touches and 12 minutes 45 seconds hands-on time for DFA staining. FilmArray RP detected a greater number of organisms (20 viruses and bacteria vs 7 viruses for DFA staining) and required less training compared with DFA staining. The ease of use of the FilmArray RP makes this molecular assay amenable to operation 24 hours a day, 7 days a week in routine laboratory and point-of-care settings.

Chemokine receptor CCR5 plays an important role in the pro-inflammatory environment that aids in the proliferation of prostate cancer cells. Previously, a series of CCR5 antagonists containing a piperidine ring core skeleton were designed based upon the proposed CCR5 antagonist pharmacophore from molecular modeling studies. The developed CCR5 antagonists were able to antagonize CCR5 at a micromolar level and inhibit the proliferation of metastatic prostate cancer cell lines. In order to further explore the structure-activity-relationship of the pharmacophore identified, the molecular scaffold was expanded to contain a piperazine ring as the core. A number of compounds that were synthesized showed promising anti prostate cancer activity and reasonable cytotoxicity profiles based on the biological characterization., (Published by Elsevier Ltd.)

Background: An association between testosterone therapy (TT) and cardiovascular disease has been reported and TT use is increasing rapidly., Methods: We conducted a cohort study of the risk of acute non-fatal myocardial infarction (MI) following an initial TT prescription (N = 55,593) in a large health-care database. We compared the incidence rate of MI in the 90 days following the initial prescription (post-prescription interval) with the rate in the one year prior to the initial prescription (pre-prescription interval) (post/pre). We also compared post/pre rates in a cohort of men prescribed phosphodiesterase type 5 inhibitors (PDE5I; sildenafil or tadalafil, N = 167,279), and compared TT prescription post/pre rates with the PDE5I post/pre rates, adjusting for potential confounders using doubly robust estimation., Results: In all subjects, the post/pre-prescription rate ratio (RR) for TT prescription was 1.36 (1.03, 1.81). In men aged 65 years and older, the RR was 2.19 (1.27, 3.77) for TT prescription and 1.15 (0.83, 1.59) for PDE5I, and the ratio of the rate ratios (RRR) for TT prescription relative to PDE5I was 1.90 (1.04, 3.49). The RR for TT prescription increased with age from 0.95 (0.54, 1.67) for men under age 55 years to 3.43 (1.54, 7.56) for those aged ≥ 75 years (p trend = 0.03), while no trend was seen for PDE5I (p trend = 0.18). In men under age 65 years, excess risk was confined to those with a prior history of heart disease, with RRs of 2.90 (1.49, 5.62) for TT prescription and 1.40 (0.91, 2.14) for PDE5I, and a RRR of 2.07 (1.05, 4.11)., Discussion: In older men, and in younger men with pre-existing diagnosed heart disease, the risk of MI following initiation of TT prescription is substantially increased.

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.

Objective: To determine whether risk-adjusted colorectal SSI rates are statistically reliable as hospital quality measures., Background: Policymakers use surgical site infections (SSI) for public reporting of hospital quality and pay-for-performance because they are a relatively common and costly cause of patient morbidity., Methods: Patients who underwent a colorectal procedure in 2009 were identified from the American College of Surgeons National Surgical Quality Improvement Program. We developed hierarchical multivariate logistic models for (1) superficial SSI, (2) deep/organ-space SSI, and (3) "any SSI" and compared how each model ranked hospital-level risk-adjusted performance. Statistical reliability of hospital quality measurements was estimated on a scale from 0 to 1; with 0 indicating that apparent variation between a hospital's quality measurement and the average hospital is statistically unreliable, and 1 indicating that any observed variation is due to a real difference in performance., Results: Mean reliability of hospital-level quality measurements was 0.650 for superficial, 0.404 for deep/organ-space, and 0.586 for "any SSI." Lower reliability was accounted for by relatively little variation in risk-adjusted SSI rates between hospitals and insufficient numbers of colorectal cases submitted by individual hospitals. In 2009, we estimate that 22.1% of all US hospitals performed a sufficient number of colorectal cases to report superficial SSI rates at a high standard of statistical reliability and 1.0% did for deep/organ-space SSI., Conclusions: As currently constructed, colorectal SSI quality measures might not meet a high standard of statistical reliability for most hospitals, limiting their ability to confidently differentiate high and low performance. Despite an expectation of improving statistical power, combining superficial and deep/organ-space SSI into an "any SSI" measure worsens reliability.

Objectives: To describe first-dose and steady state pharmacokinetics (PKs) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy HIV-negative men., Design: A phase 1, open-label, PK study that enrolled 12 healthy men taking 50 mg DTG daily for 8 days., Methods: Eleven paired BP samples and 3 SF and RF samples were collected over 24 hours after first (PK1) and multiple (PK2) dosing. RT biopsies were collected at 1 of 6 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis was conducted with Phoenix WinNonlin v6.3, and Spearman rank correlations were determined using SAS v9.3., Results: BP area under the concentration-time curves (AUCs) were similar to previous reports, and concentrations at 24 hours (C24 h) were 6- to 34-fold greater than the protein-adjusted concentration required for 90% viral inhibition (PA-IC90) of 64 ng/mL. SF exposures were <7% of BP and below the PA-IC90. RT exposures were 17% of BP and ∼2-fold greater than the PA-IC90. RF AUCs were ∼2%-5% of RT and did not correlate with RT (rho = 0.43, P = 0.17). Accumulation of DTG with multiple dosing was observed in BP, SF, and RT., Conclusions: DTG BP PKs were consistent with previously published values. SF concentrations were <7% BP, with SF C24 h below the PA-IC90. However, SF protein binding was not measured. Although the AUC of DTG in RT was <20% BP, RT C24 h remained ∼2-fold higher than the PA-IC90. RF was not a strong surrogate for RT concentrations.

Background: The Centers for Medicare and Medicaid Services and many private health plans are encouraging patients to seek orthopedic care at hospitals designated as centers of excellence. No evaluations have been conducted to compare patient outcomes and costs at centers of excellence versus other hospitals. The objective of our study was to assess whether hospitals designated as spine surgery centers of excellence by a group of over 25 health plans provided higher quality care., Methods: Claims representing approximately 54 million commercially insured individuals were used to identify individuals aged 18-64 years with 1 of 3 types of spine surgery in 2007-2009: 1-level or 2-level cervical fusion (referred to as cervical simple fusion), 1-level or 2-level lumbar fusion (referred to as lumbar simple fusion), or lumbar discectomy and/or decompression without fusion. The primary outcomes were any complication (7 complications were captured) and 30-day readmission. The multivariate models controlled for differences in age, sex, and comorbidities between the 2 sets of hospitals., Results: A total of 29,295 cervical simple fusions, 27,214 lumbar simple fusions, and 28,911 lumbar discectomy/decompressions were identified, of which 42%, 42%, and 47%, respectively, were performed at a hospital designated as a spine surgery center of excellence. Designated hospitals had a larger number of beds and were more likely to be an academic center. Across the 3 types of spine surgery (cervical fusions, lumbar fusions, or lumbar discectomies/decompressions), there was no difference in the composite complication rate [OR 0.90 (95% CI, 0.72-1.12); OR 0.98 (95% CI, 0.85-1.13); OR 0.95 (95% CI, 0.82-1.07), respectively] or readmission rate [OR 1.03 (95% CI, 0.87-1.21); OR 1.01 (95% CI, 0.89-1.13); OR 0.91 (95%, CI 0.79-1.04), respectively] at designated hospitals compared with other hospitals., Conclusions: On average, spine surgery centers of excellence had similar complication rates and readmission rates compared with other hospitals. These results highlight the importance of empirical evaluations of centers of excellence programs.

Few data are available on physician perceptions of osteoporosis medication adherence. This study compared physician-estimated medication adherence with adherence calculated from their patients' pharmacy claims. Women aged ≥45 years, with an osteoporosis-related pharmacy claim between January 1, 2005 and August 31, 2008, and continuous coverage for ≥12 months before and after first (index) claim, were identified from a commercial health plan population. Prescribing physicians treating ≥5 of these patients were invited to complete a survey on their perception of medication adherence and factors affecting adherence in their patients. Pharmacy claims-based medication possession ratio (MPR) was calculated for the 12-month post-index period for each patient. Physicians who overestimated the percentage of adherent (MPR ≥0.8) patients by ≥10 points were considered "optimistic". Logistic regression assessed physician characteristics associated with optimistic perception of adherence. A total of 376 (17.2%) physicians responded to the survey; 62.0% were male, 58.2% were aged 45 to 60 years, 55.3% had ≥20 years of practice, and 35.4% practiced in an academic setting. Participating physicians prescribed osteoporosis medications for 2748 patients with claims data (mean [SD] age of 62.0 [10.6] years). On average, physicians estimated 67.2% of their patients to be adherent; however, only 40% of patients were actually adherent based on pharmacy data. Optimistic physicians (73.4%) estimated 71.9% of patients to be adherent while only 32.2% of their patients were adherent based on claims data. Physicians in academic settings were more likely to be optimistic than community-based physicians (odds ratio 1.69, 95% CI: 1.01, 2.85). Overestimation of medication adherence may impede physicians' ability to provide high quality care for their osteoporosis patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Ongoing efforts to profile physicians on their relative cost of care have been criticized because they do not account for differences in patients' socioeconomic status (SES). The importance of SES adjustment has not been explored in cost-profiling applications that measure costs using an episode of care framework., Objectives: We assessed the relationship between SES and episode costs and the impact of adjusting for SES on physicians' relative cost rankings., Research Design: We analyzed claims submitted to 3 Massachusetts commercial health plans during calendar years 2004 and 2005. We grouped patients' care into episodes, attributed episodes to individual physicians, and standardized costs for price differences across plans. We accounted for differences in physicians' case mix using indicators for episode type and a patient's severity of illness. A patient's SES was measured using an index of 6 indicators based on the zip code in which the patient lived. We estimated each physician's case mix-adjusted average episode cost and percentile rankings with and without adjustment for SES., Results: Patients in the lowest SES quintile had $80 higher unadjusted episode costs, on average, than patients in the highest quintile. Nearly 70% of the variation in a physician's average episode cost was explained by case mix of their patients, whereas the contribution of SES was negligible. After adjustment for SES, only 1.1% of physicians changed relative cost rankings >2 percentiles., Conclusions: Accounting for patients' SES has little impact on physicians' relative cost rankings within an episode cost framework.

Purpose: The American Society of Clinical Oncology Quality Oncology Practice Initiative (QOPI) has provided a method for measuring process-based practice quality since 2006. We sought to determine whether QOPI scores showed improvement in measured quality over time and, if change was demonstrated, which factors in either the measures or participants were associated with improvement., Methods: The analysis included 156 practice groups from a larger group of 308 that submitted data from 2006 to 2010. One hundred fifty-two otherwise eligible practices were excluded, most commonly for insufficient data submission. A linear regression model that controlled for varied initial performance was used to estimate the effect of participation over time and evaluate participant and measure characteristics of improvement., Results: Participants completed a mean of 5.06 (standard deviation, 1.94) rounds of data collection. Adjusted mean quality scores improved from 0.71 (95% CI, 0.42 to 0.91) to 0.85 (95% CI, 0.60 to 0.95). Overall odds ratio of improvement over time was 1.09 (P < .001). The greatest improvement was seen in measures that assessed newly introduced clinical information, in which the mean scores improved from 0.05 (95% CI, 0.01 to 0.17) to 0.69 (95% CI, 0.33 to 0.91; P < .001). Many measures showed no change over time., Conclusion: Many US oncologists have participated in QOPI over the past 6 years. Participation over time was highly correlated with improvement in measured performance. Greater and faster improvement was seen in measures concerning newly introduced clinical information. Some measures showed no change despite opportunity for improvement.

Objective: To produce reliable and informative health plan performance data by race/ethnicity for the Medicare beneficiary population and to consider appropriate presentation strategies., Data Sources: Patient experience data from the 2008-2009 Medicare Advantage (MA) and fee-for-service (FFS) CAHPS surveys and 2008-2009 HEDIS data (MA beneficiaries only)., Study Design: Mixed effects linear (and binomial) regression models estimated the reliability and statistical informativeness of CAHPS (HEDIS) measures., Principal Findings: Seven CAHPS and seven HEDIS measures were reliable and informative for four racial/ethnic subgroups-Whites, Blacks, Hispanics, and Asian/Pacific Islanders-at sample sizes of 100 beneficiaries (200 for prescription drug plans). Although many plans lacked adequate sample size for reporting group-specific data, reportable plans contained a large majority of beneficiaries from each of the four racial/ethnic groups., Conclusions: Statistically reliable and valid information on health plan performance can be reported by race/ethnicity. Many beneficiaries may have difficulty understanding such reports, however, even with careful guidance. Thus, it is recommended that health plan performance data by subgroups be reported as supplemental data and only for plans meeting sample size requirements., (© Health Research and Educational Trust.)

Unlabelled: We examined the association between osteoporosis treatment change and adherence, incident fractures, and healthcare costs among Medicare Advantage Prescription Drug (MAPD) plan members. Treatment change was associated with a small but significant increase in adherence, but was not associated with incident fracture or total healthcare costs. Overall adherence remained low., Introduction: We examined the association between osteoporosis treatment change and adherence, incident fractures, and healthcare costs among MAPD plan members in a large US health plan., Methods: We conducted a retrospective cohort study of MAPD plan members aged≥50 years newly initiated on an osteoporosis medication between 1 January 2006 and 31 December 2008. Members were identified as having or not having an osteoporosis treatment change within 12 months after initiating osteoporosis medication. Logistic regression analyses and difference-in-difference (DID) generalized linear models were used to investigate the association between osteoporosis treatment change and (1) adherence to treatment, (2) incident fracture, and (3) healthcare costs at 12 and 24 months follow-up., Results: Of the 33,823 members newly initiated on osteoporosis treatment, 3,573 (10.6%) changed osteoporosis treatment within 12 months. After controlling for covariates, osteoporosis treatment change was associated with significantly higher odds of being adherent (medication possession ratio [MPR]≥0.8) at 12 months (odds ratio [OR]=1.18) and 24 months (OR=1.13) follow-up. However, overall adherence remained low (MPR=0.59 and 0.51 for the change cohort and MPR=0.51 and 0.44 for the no-change cohort at 12 and 24 months, respectively). Osteoporosis treatment change was not significantly associated with incident fracture (OR=1.00 at 12 months and OR=0.98 at 24 months) or total direct healthcare costs (p>0.4) in the DID analysis, but was associated with higher pharmacy costs (p<0.004)., Conclusions: Osteoporosis treatment change was associated with a small but significant increase in adherence, but was not associated with incident fracture or total healthcare costs in the MAPD plan population. Overall adherence to therapy remained low.

Background: Evaluating large-scale disease management interventions implemented in actual health care settings is a complex undertaking for which universally accepted methods do not exist. Fundamental issues, such as a lack of control patients and limited generalizability, hamper the use of the 'gold-standard' randomized controlled trial, while methodological shortcomings restrict the value of observational designs. Advancing methods for disease management evaluation in practice is pivotal to learn more about the impact of population-wide approaches. Methods must account for the presence of heterogeneity in effects, which necessitates a more granular assessment of outcomes., Methods: This paper introduces multilevel regression methods as valuable techniques to evaluate 'real-world' disease management approaches in a manner that produces meaningful findings for everyday practice. In a worked example, these methods are applied to retrospectively gathered routine health care data covering a cohort of 105,056 diabetes patients who receive disease management for type 2 diabetes mellitus in the Netherlands. Multivariable, multilevel regression models are fitted to identify trends in clinical outcomes and correct for differences in characteristics of patients (age, disease duration, health status, diabetes complications, smoking status) and the intervention (measurement frequency and range, length of follow-up)., Results: After a median one year follow-up, the Dutch disease management approach was associated with small average improvements in systolic blood pressure and low-density lipoprotein, while a slight deterioration occurred in glycated hemoglobin. Differential findings suggest that patients with poorly controlled diabetes tend to benefit most from disease management in terms of improved clinical measures. Additionally, a greater measurement frequency was associated with better outcomes, while longer length of follow-up was accompanied by less positive results., Conclusions: Despite concerted efforts to adjust for potential sources of confounding and bias, there ultimately are limits to the validity and reliability of findings from uncontrolled research based on routine intervention data. While our findings are supported by previous randomized research in other settings, the trends in outcome measures presented here may have alternative explanations. Further practice-based research, perhaps using historical data to retrospectively construct a control group, is necessary to confirm results and learn more about the impact of population-wide disease management.

The global HIV epidemic cannot be controlled by current treatment or prevention strategies. Pre-exposure prophylaxis (PrEP) using antiretrovirals is a promising approach to curbing the spread of HIV transmission. Recently, four clinical trials demonstrated favorable results when antiretroviral PrEP was administered topically or orally. However, two additional trials were unable to demonstrate a benefit, indicating that further study is required to define the populations and conditions under which PrEP will be effective. Adherence is highly correlated with protection, yet the exact level of adherence required is unknown. Future studies may require increased drug exposure testing and more objective methods to monitor adherence in real-time. Although the development of drug resistance in the PrEP trials has been low, it remains a concern, as therapeutic options could be compromised for those who seroconvert while on PrEP.

Objective: To develop a reliable, robust, parsimonious, risk-adjusted 30-day composite colectomy outcome measure., Background: A fundamental aspect in the pursuit of high-quality care is the development of valid and reliable performance measures in surgery. Colon resection is associated with appreciable morbidity and mortality and therefore is an ideal quality improvement target., Methods: From 2010 American College of Surgeons National Surgical Quality Improvement Program data, patients were identified who underwent colon resection for any indication. A composite outcome of death or any serious morbidity within 30 days of the index operation was established. A 6-predictor, parsimonious model was developed and compared with a more complex model with more variables. National caseload requirements were calculated on the basis of increasing reliability thresholds., Results: From 255 hospitals, 22,346 patients were accrued who underwent a colon resection in 2010, most commonly for neoplasm (46.7%). A mortality or serious morbidity event occurred in 4461 patients (20.0%). At the hospital level, the median composite event rate was 20.7% (interquartile range: 15.8%-26.3%). The parsimonious model performed similarly to the full model (Akaike information criterion: 19,411 vs 18,988), and hospital-level performance comparisons were highly correlated (R = 0.97). At a reliability threshold of 0.4, 56 annual colon resections would be required and achievable at an estimated 42% of US and 69% of American College of Surgeons National Surgical Quality Improvement Program hospitals. This 42% of US hospitals performed approximately 84% of all colon resections in the country in 2008., Conclusions: It is feasible to design a measure with a composite outcome of death or serious morbidity after colon surgery that has a low burden for data collection, has substantial clinical importance, and has acceptable reliability.

Background: The active metabolites of tenofovir (TFV) and emtricitabine (FTC) in peripheral blood mononuclear cells (PBMCs) have been used as markers of long-term antiretroviral (ARV) adherence. However, the process of isolating PBMCs is expensive, complex, and not feasible in many settings. We compared concentrations of TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in the upper layer packed cells (ULPCs) obtained after whole blood centrifugation to isolated PBMCs as a possible alternative marker of adherence., Methods: Ten HIV+ adults with HIV RNA <50 copies/mL on a TDF/FTC-containing regimen provided 5 paired PBMC and ULPC samples over 6 hours. TFV-DP and FTC-TP concentrations were analyzed by liquid chromatography/mass spectrometry. Partial areas under the curve were calculated using noncompartmental methods and Spearman Rank Correlations (rho) between PBMC and ULPC were determined., Results: The median (25th-75th percentile) concentration of TFV-DP in PBMCs was 143 (103-248) fmol/10(6) cells and in ULPC was 227 (160-394) fmol/10(6) cells (rho = 0.65; P < 0.0001). The concentration of FTC-TP in PBMCs was 6660 (5650-10,000) fmol/10(6) cells and in ULPC was 19.0 (12.0-27.8) fmol/10(6) cells (rho = 0.55; P < 0.0001). Compared to PBMCs, ULPC TFV-DP was 64% higher and FTC-TP was 99.7% lower. ULPC concentrations of TFV-DP and FTC-TP in one additional subject receiving a single dose of TDF/FTC were only 0.05% and 25%, of the other 10 subjects, respectively., Conclusions: ULPC concentrations significantly correlated with PBMC concentrations. Preliminary single-dose data suggest some discrimination between intermittent versus consistent dosing. ULPC concentrations of TFV-DP and FTC-TP should be further investigated as a simply collected surrogate measure of ARV adherence.

Rationale, Aims and Objectives: Multiple treatments are available for osteoporosis; however, little is known about treatment change patterns and associated factors. Osteoporosis treatment change patterns, discontinuation and factors associated with treatment change in members of a large national health plan were examined., Methods: A retrospective cohort study was conducted in 7315 commercial and 34 146 Medicare Advantage Prescription Drug (MAPD) members newly initiated on an osteoporosis medication between 2006 and 2008. Osteoporosis treatment change, discontinuation and re-initiation patterns were assessed. Multivariate logistic regression was used to examine factors associated with treatment change. Commercial and MAPD members were assessed separately because of differences in demographics and insurance benefits., Results: Approximately 12% of members had a change in index therapy within 12 months. Almost 60% of members discontinued the index medication at least once, based on a 90-day refill gap. Over 40% of members discontinued all osteoporosis medications by the end of 12 months post-index. Among MAPD and commercial members, women and those with risedronate, ibandronate or calcitonin at index, index therapy in 2008 and an osteoporosis diagnosis were more likely to have a treatment change while members with health plans other than health maintenance organizations and generic alendronate at index were less likely to have a treatment change., Conclusions: Osteoporosis treatment change occurred in approximately 12% of members, while a greater proportion of members discontinued treatment completely within 12 months. Member characteristics may be used to predict therapy change for evaluation and quality initiatives within a health plan., (© 2011 Blackwell Publishing Ltd.)

Background: Antiretrovirals that achieve adequate concentrations in anatomical sites of transmission are of interest for HIV prevention. A Phase I open-label pharmacokinetic (PK) study was performed to describe first dose (PK1) and steady-state (PK2) PKs of the integrase inhibitor dolutegravir (DTG) in blood plasma (BP), cervicovaginal fluid (CVF), cervical tissue (CT) and vaginal tissue (VT) in HIV type-1-negative women., Methods: A total of 8 healthy females given DTG 50 mg daily for 5-7 days had 11 paired BP and CVF samples collected over 24 h following the first dose (PK1) and multiple dosing (PK2). Each woman underwent CT and VT biopsies at 1/4 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analysed by validated liquid chromatography-tandem mass spectrometry methods. Non-compartmental PK analysis was performed and Spearman rank correlations determined between matrices., Results: BP areas under the concentration-time curve (AUCs) were similar to previous reports and concentrations remained greater than the protein-adjusted (PA) 90% inhibitory concentration (IC90) for wild-type HIV (64 ng/ml). CVF exposures were approximately 6% of BP with low inter-individual variability. CT and VT exposures were 7% of BP at PK1, and 9-10% of BP at PK2 with 94% of samples >PA-IC90. CT and VT concentrations were correlated to each other (ρ=0.70, P=0.003), and to CVF at steady state (ρ=0.52, P=0.04). Accumulation of DTG from PK1 to PK2 occurred in BP, CT and VT, but only marginally in CVF., Conclusions: DTG BP PK were consistent with previously published values. CVF, CT and VT exposures were highly correlated. At PK2, DTG accumulated to a greater extent in tissue than in BP or CVF, suggesting increased tissue affinity.

People living with HIV/AIDS (PLWHA) suffer increased depression prevalence compared to the general population, which negatively impacts antiretroviral (ART) adherence and HIV-related outcomes leading to morbidity and mortality. Yet depression in this population often goes undiagnosed and untreated. The current project sought to design an evidence-based approach to integrate depression care in HIV clinics. The model chosen, measurement-based care (MBC), is based on existing guidelines and the largest randomized trial of depression treatment. MBC was adapted to clinical realities of HIV care for use in a randomized controlled effectiveness trial of depression management at three academic HIV clinics. The adaptation accounts for drug-drug interactions critical to ongoing ART effectiveness and can be delivered by a multidisciplinary team of nonmental health providers. A treatment algorithm was developed that enables clinically supervised, nonphysician depression care managers (DCMs) to track and monitor antidepressant tolerability and treatment response while supporting nonpsychiatric prescribers with antidepressant choice and dosing. Quality of care is ensured through weekly supervision of DCMs by psychiatrists. Key areas of flexibility that have been important in implementation have included flexibility in timing of assessments, accommodation of divergence between algorithm recommendations and provider decisions, and accommodation of delays in implementing treatment plans. This adaptation of the MBC model to HIV care has accounted for critical antidepressant-antiretroviral interactions and facilitated the provision of quality antidepressant management within the HIV medical home.

Health plans and Medicare are using cost profiles to identify which physicians account for more health care spending than others. By identifying the costliest physicians, health plans and Medicare hope to craft policy interventions to reduce total health care spending. To identify which physician types, if any, might be costlier than others, we analyzed cost profiles created from health plan claims for physicians in Massachusetts. We found that physicians with fewer than ten years of experience had 13.2 percent higher overall costs than physicians with forty or more years of experience. We found no association between costs and other physician characteristics, such as having had malpractice claims or disciplinary actions, board certification status, and the size of the group in which the physician practices. Although winners and losers are inevitable in any cost-profiling effort, physicians with less experience are more likely to be negatively affected by policies that use cost profiles, unless they change their practice patterns. For example, these physicians could be excluded from high-value networks or receive lower payments under Medicare's planned value-based payment program. We cannot fully explain the mechanism by which more-experienced physicians have lower costs, but our results suggest that the more costly practice style of newly trained physicians may be a driver of rising health care costs overall.

Background: Estimating effectiveness of clinical interventions depends on detecting differences between the responses of intervention and control groups. The outcome, intervention, and moderating factors all may influence the between group change. The absence of a clinically or statistically meaningful difference may also result from control group improvement due to nonspecific factors such as participants' perception of attention, positive regard, expectations, desire to please, and therapeutic alliance with the care provider., Purpose: We examined perceived benefit and sources of benefit for control caregivers who participated in the CONNECT randomized controlled trial of a dementia caregiving intervention., Methods: After the final scheduled data collection in CONNECT, control group participants were asked whether they believed they benefited from study participation. Those who reported benefit were asked to describe the benefit received. Data were analyzed qualitatively., Results: Of 60 available control caregivers, 82% reported a perceived benefit from study participation in five areas: getting information about dementia and caregiving; having someone to talk to and feeling supported; receiving understanding and validation of feelings; knowledge that others were in similar situations; and perceived appreciation of own abilities. Control caregivers who reported benefit were less burdened and depressed and spent less time on duty at baseline than those who did not report benefit. From caregivers' responses, we have identified the assessment battery, both content and time spent in data collection, as a possible mechanism of action for benefit., Limitations: Study limitations include the better baseline characteristics of the control caregivers who reported benefit, the sample size of benefit control caregivers, the possibility of perceptions of benefit being a function of social desirability, and the lack of a similar question about benefit being asked of intervention caregivers., Conclusions: These findings suggest that the outcome assessment questionnaires used in this and similar trials may be an intervention of sorts for caregiver participants in the control group. Caregivers who are less distressed may benefit more from the attention provided during assessment. These findings underscore the importance of asking caregivers how they are doing. For researchers, there is a need to develop innovative ways to assess outcomes to avoid unintended benefit of assessments.

Purpose of Review: The purpose of this study is to review recent and relevant pharmacology data for three HIV integrase inhibitors: raltegravir (marketed), dolutegravir, and elvitegravir (both in phase III drug development)., Recent Findings: Data from January 2011 to April 2012 were evaluated. These data better characterized integrase inhibitor pharmacokinetics, assessed dosing regimens, and investigated previously undescribed drug-drug interactions. Due to formulation challenges, raltegravir inter-patient and intra-patient pharmacokinetic variability is high. Twice-daily 400  mg dosing has been shown to be clinically superior to 800  mg once-daily dosing. A pediatric formulation of raltegravir with less variable pharmacokinetics and greater bioavailability was US Food and Drug Administration (US FDA)-approved in December 2011. Cobicistat-boosted elvitegravir, and the second-generation integrase inhibitor dolutegravir, have lower pharmacokinetic variability and are dosed once daily. Dolutegravir drug interactions are similar to raltegravir, whereas boosted elvitegravir participates in additional CYP3A-mediated interactions., Summary: Raltegravir's potent antiretroviral activity has resulted in widespread use in both treatment-naïve and experienced patients. Dolutegravir and cobicistat-boosted elvitegravir have some pharmacokinetic advantages. Pharmacokinetic data in special populations (pregnancy, pediatrics) to optimize dosing are still required.