Microclimate evaluation of strap-based wheelchair seating systems for persons with spinal cord injury: A pilot study.

STUDY PURPOSE: The purpose of this pilot study was to assess microclimate characteristics of two versions of a strap-based wheelchair seating system (perforated and solid straps) and to conduct preliminary microclimate comparisons of subjects' current wheelchair seating systems. MATERIALS AND METHODS: In this pilot study, the microclimate properties of two variations (solid and perforated) of a strap-based seating system were compared with two commonly used seating systems. Six subjects sat on three different seating systems each for 100-min test periods, while temperature and relative humidity were measured with a single sensor adjacent to the skin-seat interface. Additionally, thermal images of the seat interface were collected before and after each test period. RESULTS: The thermal images revealed that the maximum surface temperature of the solid-strap-based seating system was significantly lower than the other seating systems, -1.21 °C. (95% CI -2.11 to -0.30, p = 0.02), immediately following transfer out of the seat. Five minutes after transferring out of the seat, the perforated-strap seat was significantly cooler than the other seats -0.94 °C. (95% CI -1.59 to -0.30), p = 0.01, as was the solid-strap-based seat, -1.66 °C. (95% CI -2.69 to -0.63), p = 0.01. There were no significant differences in interface temperature or relative humidity measured with the single sensor near the skin-seat interface. CONCLUSION: This pilot study offers preliminary evidence regarding the microclimate of the strap-based seating systems compared with other common seating systems. Clinically, the strap-based seating system may offer another option for those who struggle with microclimate management.

Prognostic Value of Insulin-Like Growth Factor-Binding Protein 7 in Patients with Heart Failure and Preserved Ejection Fraction.

BACKGROUND: The prognostic merit of insulin-like growth factor-binding protein 7 (IGFBP7) is unknown in heart failure and preserved ejection fraction (HFpEF). METHODS AND RESULTS: Baseline IGFBP7 (BL-IGFBP7; n = 302) and 6-month change (Δ; n = 293) were evaluated in the Irbesartan in Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial. Primary outcome was all-cause mortality or cardiovascular hospitalization with median follow-up of 3.6 years; secondary outcomes included HF events. Median BL-IGFBP7 concentration was 218 ng/mL. BL-IGFBP7 was significantly correlated with age (R2 = 0.13; P < .0001), amino-terminal pro-B-type NP (R2 = 0.22; P < .0001), and estimated glomerular filtration rate (eGFR; R2 = 0.14; P < .0001), but not with signs/symptoms of HFpEF. BL-IGFBP7 was significantly associated with the primary outcome (hazard ratio [HR] = 1.007 per ng/mL; P < .001), all-cause mortality (HR = 1.008 per ng/mL; P < .001), and HF events (HR = 1.007 per ng/mL; P < .001). IGFBP7 remained significant for each outcome after adjustment for ln amino-terminal pro-B-type NP and eGFR but not all variables in the I-PRESERVE prediction model. After 6 months, IGFBP7 did not change significantly in either treatment group. ΔIGFBP7 was significantly associated with decrease in eGFR in patients randomized to irbesartan (R2 = 0.09; P = .002). ΔIGFBP7 was not independently associated with outcome. CONCLUSIONS: Higher concentrations of IGFBP7 were associated with increased risk of cardiovascular events, but after multivariable adjustment this association was no longer present. Further studies of IGFBP7 are needed to elucidate its mechanism. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT00095238.

Pharmacist-Led Chronic Disease Management: A Systematic Review of Effectiveness and Harms Compared With Usual Care.

BACKGROUND: Increased involvement of pharmacists in patient care may increase access to health care and improve patient outcomes. PURPOSE: To determine the effectiveness and harms of pharmacist-led chronic disease management for community-dwelling adults. DATA SOURCES: MEDLINE, Cochrane Library, CINAHL, and International Pharmaceutical Abstracts from 1995 through February 2016, and reference lists of systematic reviews and included studies. STUDY SELECTION: 65 patient populations in 63 studies conducted in the United States of any design reported outcomes of pharmacist-led chronic disease management versus a comparator for community-dwelling adults in the United States. Studies set in retail pharmacies were excluded. DATA EXTRACTION: Data extraction done by a single investigator was confirmed by a second investigator; risk of bias was assessed by 2 investigators; and strength of evidence was determined by consensus. DATA SYNTHESIS: Pharmacist-led care was associated with similar numbers of office visits, urgent care or emergency department visits, and hospitalizations (moderate-strength evidence) and medication adherence (low-strength evidence) compared with usual care (typically continuing a prestudy visit schedule). Pharmacist-led care increased the number or dose of medications received and improved study-selected glycemic, blood pressure, and lipid goal attainment (moderate-strength evidence). Mortality and clinical events were similar (low-strength evidence). Evidence on patient satisfaction was mixed and insufficient. The reporting of harms was limited. LIMITATIONS: Interventions were heterogeneous. Studies were typically short-term and designed to assess physiologic intermediate outcomes rather than clinical events. Reporting of many clinical outcomes of interest was limited, and often they were not the study-defined primary end points. CONCLUSION: Pharmacist-led chronic disease management was associated with effects similar to those of usual care for resource utilization and may improve physiologic goal attainment. Further research is needed to determine whether increased medication utilization and goal attainment improve clinical outcomes. PRIMARY FUNDING SOURCE: Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative.

Longer Withdrawal Time Is Associated With a Reduced Incidence of Interval Cancer After Screening Colonoscopy.

BACKGROUND & AIMS: Withdrawal times and adenoma detection rates are widely used quality indicators for screening colonoscopy. More rapid withdrawal times have been associated with undetected adenomas, which can increase risk for interval colorectal cancer. METHODS: We analyzed records of 76,810 screening colonoscopies performed between 2004 and 2009, by 51 gastroenterologists practicing in Minneapolis and St Paul, MN. Colonoscopy records were linked electronically to the state cancer registry (Minnesota Cancer Surveillance System) to identify incident interval cancers that were diagnosed within 5.5 years after the screening examination. RESULTS: The physicians' mean ± SD withdrawal time was 8.6 ± 1.7 minutes and adenoma detection rates were 25% ± 9%. Longer mean withdrawal times were associated with higher adenoma detection rates (3.6% per minute; 95% confidence interval: 2.4% to 4.8%; P < .0001). We identified 78 cancers during 410,687 person-years of follow-up, for an annual rate of 0.19/1000 person-years. Physicians' mean annual withdrawal times were inversely associated with cancer incidence (P < .0001). Compared with withdrawal times ≥6 minutes, the adjusted incidence rate ratio for withdrawal times of <6 minutes was 2.3 (95% confidence interval: 1.5-3.4; P < .0001). CONCLUSIONS: Shorter mean annual withdrawal times during screening colonoscopies were independently associated with lower adenoma detection rates and increased risk of interval colorectal cancer.

Extended Follow-Up of Patients With Heart Failure Receiving Autonomic Regulation Therapy in the ANTHEM-HF Study.

OBJECTIVE: Evaluate the effects of a novel autonomic regulation therapy (ART) via vagus nerve stimulation (VNS) in patients with chronic heart failure (HF) and reduced left ventricular ejection fraction during a 12-month follow-up period. METHODS: The Autonomic Regulation Therapy for the Improvement of Left Ventricular Function and Heart Failure Symptoms (ANTHEM-HF) study enrolled 60 subjects with New York Heart Association class II-III HF and low left ventricular ejection fraction (≤40%), who received open-loop ART using VNS randomized to left or right cervical vagus nerve placement and followed for 6 months after titration to a therapeutic output current (2.0 ± 0.6 mA). Patients received chronic stimulation at a frequency of 10 Hz and pulse duration of 250 µsec. Forty-nine subjects consented to participate in an extended follow-up study for an additional 6 months (12 months total posttitration) to determine whether the effects of therapy were maintained. RESULTS: During the 6-month extended follow-up period, there were no device malfunctions or device-related serious adverse effects. There were 7 serious adverse effects unrelated to the device, including 3 deaths (2 sudden cardiac deaths, 1 worsening HF death). There were 5 nonserious adverse events that were adjudicated to be device-related. Safety and tolerability were similar, and there were no significant differences in efficacy between left- and right-sided ART. Overall, mean efficacy measure values at 12 months were not significantly different from mean values at 6 months. CONCLUSIONS: Chronic open-loop ART via left- or right-sided VNS continued to be feasible and well-tolerated in patients with HF with reduced EF. Improvements in cardiac function and HF symptoms seen after 6 months of ART were maintained at 12 months.

Examination of CK2α and NF-κB p65 expression in human benign prostatic hyperplasia and prostate cancer tissues.

Protein kinase CK2 plays a critical role in cell growth, proliferation, and suppression of cell death. CK2 is overexpressed, especially in the nuclear compartment, in the majority of cancers, including prostate cancer (PCa). CK2-mediated activation of transcription factor nuclear factor kappa B (NF-κB) p65 is a key step in cellular proliferation, resulting in translocation of NF-κB p65 from the cytoplasm to the nucleus. As CK2 expression and activity are also elevated in benign prostatic hyperplasia (BPH), we sought to increase the knowledge of CK2 function in benign and malignant prostate by examination of the relationships between nuclear CK2 and nuclear NF-κB p65 protein expression. The expression level and localization of CK2α and NF-κB p65 proteins in PCa and BPH tissue specimens was determined. Nuclear CK2α and NF-κB p65 protein levels are significantly higher in PCa compared with BPH, and these proteins are positively correlated with each other in both diseases. Nuclear NF-κB p65 levels correlated with Ki-67 or with cytoplasmic NF-κB p65 expression in BPH, but not in PCa. The findings provide information that combined analysis of CK2α and NF-κB p65 expression in prostate specimens relates to the disease status. Increased nuclear NF-κB p65 expression levels in PCa specifically related to nuclear CK2α levels, indicating a possible CK2-dependent relationship in malignancy. In contrast, nuclear NF-κB p65 protein levels related to both Ki-67 and cytoplasmic NF-κB p65 levels exclusively in BPH, suggesting a potential separate impact for NF-κB p65 function in proliferation for benign disease as opposed to malignant disease.

Evaluation of a Potential Interaction Between New Regimens to Treat Hepatitis C and Warfarin.

OBJECTIVE: New regimens to treat hepatitis C virus infection have expanded the eligible patient population to include more patients receiving concurrent warfarin. The primary objective of this study was to assess whether a drug interaction occurs when these regimens are added to warfarin therapy. METHODS: This was a retrospective cohort design using a nationwide database of the Veterans Affairs Health System. Patients on warfarin therapy treated with sofosbuvir or ombitasvir, paritaprevir-ritonavir, and dasabuvir (OBV-PTV/r-DSV) from March 2014 through October 2015 were identified. The warfarin dose response was calculated using a warfarin sensitivity index (WSI) defined as the steady-state INR divided by the mean daily warfarin dose. The primary outcome was the change in WSI from hepatitis C treatment initiation to completion. RESULTS: The final sample consisted of 271 patients. The WSI decreased 23% from a mean baseline value of 0.53 to 0.39 (decrease of 0.14; 95% CI = 0.11 to 0.16; P < 0.001). OBV-PTV/r-DSV produced a significantly greater decrease than any sofosbuvir regimen. Concurrent ribavirin accounted for an additional decrease in warfarin sensitivity of -0.09 (95% CI = -0.06 to -0.12; P < 0.001). The percentage of subtherapeutic INR results increased from 26% prior to hepatitis C treatment to 58% during treatment. CONCLUSIONS: Results indicate a clinically significant reduction in warfarin dose-response when hepatitis C treatment regimens were added to warfarin. They were most profound with OBV-PTV/r-DSV. Ribavirin was associated with an additive effect. Clinicians should be aware of this potential drug interaction to closely monitor and minimize subtherapeutic levels of anticoagulation.

High-resolution wrist-worn overnight oximetry has high positive predictive value for obstructive sleep apnea in a sleep study referral population.

BACKGROUND: Reducing the need for diagnostic sleep studies for obstructive sleep apnea (OSA) would reduce direct and opportunity costs while expediting time to treatment for this common and morbid disorder. We sought to determine if an established sleep apnea screening questionnaire (STOP-BANG) and wrist-worn overnight oximetry data could provide high positive predictive value for the presence of OSA. METHODS: We conducted a prospective observational study of consecutive unattended sleep study patients at a single facility. Patients were referred for sleep testing after chart review by a sleep physician. We assessed area under the receiver-operating characteristic curve (ROC AUC) and positive predictive value (PPV) of STOP-BANG score and oxygen desaturation index (ODI) for a respiratory disturbance index (RDI) ≥15/h. RESULTS: Among 234 test patients, 65 % had an RDI ≥15/h. STOP-BANG had poor ability to discriminate these patients (ROC AUC 0.62). ODI added significant diagnostic information to the STOP-BANG score, increasing the ROC AUC to 0.86. Having the ODI, the STOP-BANG score no longer contributed significant diagnostic information, and the ODI alone discriminated as well as the combination (ROC AUC 0.86). Forty nine percent had an ODI ≥7/h, which had PPV of 92 % (95 % confidence interval (CI), 86 to 96 %). In the validation sample of 1,196 consecutive patients, ODI ≥ 7/h had a PPV of 97 % (95 % CI, 95 to 97 %). CONCLUSIONS: Among patients with a high prevalence of OSA, high ODI is common and its presence has high PPV for OSA. These data suggest that overnight oximetry prior to sleep testing could significantly reduce the number of patients requiring sleep studies, thereby reducing costs and time to treatment.

Mortality prediction using a modified Seattle Heart Failure Model may improve patient selection for ventricular tachycardia ablation.

BACKGROUND: Catheter ablation is frequently used as a palliative option to reduce shock burden in patients with ventricular tachycardia (VT). A risk prediction tool that accurately predicts short-term survival could improve patient selection for VT ablation. OBJECTIVE: The objective of the study is to assess utility of the Seattle Heart Failure Model (SHFM) to predict 6-month mortality in patients undergoing VT ablation. METHODS: Data on patients who underwent VT ablation at 2 tertiary institutions were retrospectively compiled. The SHFM score at the time of ablation, including 2 added VT variables, was used to predict 6-month mortality. The predicted number of deaths was compared to the observed number to assess model calibration. Model discrimination of those who died within 6 months was assessed by both K- and C-statistics. RESULTS: Mean age of the 243 patients was 63 ± 12 years; 89% were male. Mean SHFM score for the cohort was 1.3 ± 1.3. The Kaplan-Meier probability of death within 6 months was 14% (34 patients). The number of deaths estimated by the SHFM at 6 months was 31 (13%) giving a predicted to observed ratio of 0.91 (95% CI 0.64-1.30). The K-statistic for 6-month mortality predictions was 0.77 (95% CI 0.73-0.81), whereas the C-statistic was 0.84 (95% CI 0.78-0.92). Patients with an SHFM score ≥4.0 had an estimated positive predictive value of 80% (95% CI 28%-99%) for dying within 6 months of VT ablation. CONCLUSION: The SHFM was well calibrated to a sample of patients who underwent VT ablation and provided good discrimination of short-term deaths. This model could be useful as a prognostic tool to improve patient selection for VT ablation.

Are there racial/ethnic disparities in VA PTSD treatment retention?

BACKGROUND: Chronic posttraumatic stress disorder (PTSD) can result in significant social and physical impairments. Despite the Department of Veterans Affairs' (VA) expansion of mental health services into primary care clinics to reach larger numbers of Veterans with PTSD, many do not receive sufficient treatment to clinically benefit. This study explored whether the odds of premature mental health treatment termination varies by patient race/ethnicity and, if so, whether such variation is associated with differential access to services or beliefs about mental health treatments. METHODS: Prospective national cohort study of VA patients who were recently diagnosed with PTSD (n = 6,788). Self-administered surveys and electronic VA databases were utilized to examine mental health treatment retention across racial/ethnic groups in the 6 months following the PTSD diagnosis controlling for treatment need, access factors, age, gender, treatment beliefs, and facility factors. RESULTS: African American and Latino Veterans were less likely to receive a minimal trial of pharmacotherapy and African American Veterans were less likely to receive a minimal trial of any treatment in the 6 months after being diagnosed with PTSD. Controlling for beliefs about mental health treatments diminished the lower odds of pharmacotherapy retention among Latino but not African American Veterans. Access factors did not contribute to treatment retention disparities. CONCLUSIONS: Even in safety-net healthcare systems like VA, racial and ethnic disparities in mental health treatment occur. To improve treatment equity, clinicians may need to more directly address patients' treatment beliefs. More understanding is needed to address the treatment disparity for African American Veterans.

Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial.

OBJECTIVE: ANTHEM-HF evaluated a novel autonomic regulation therapy (ART) via either left or right vagus nerve stimulation (VNS) in patients with heart failure (HF) and reduced ejection fraction (HFrEF). METHODS AND RESULTS: Sixty subjects (New York Heart Association [NYHA] functional class II-III, left ventricular ejection fraction (LVEF) ≤ 40%, left ventricular end-diastolic diameter ≥ 50 mm to < 80 mm) receiving optimal pharmacologic therapy were randomized at 10 sites. VNS systems were randomly implanted on the left (n = 31) or right (n = 29) side. All patients were successfully implanted and 59 were titrated over 10 weeks to a well tolerated stimulation intensity. One patient died 3 days after an embolic stroke that occurred during implantation. Common device-related adverse events after VNS titration were transient mild dysphonia, cough, and oropharyngeal pain, which were similar for left- and right-side VNS. After 6 months of ART, the adjusted left-right differences in LVEF, left ventricular end-systolic volume (LVESV), and left ventricular end-systolic diameter (LVESD) were 0.2% (95% CI -4.4 to 4.7), 3.7 mL (95% CI -7.0 to 14.4), and 1.3 mm (95% CI -0.9 to 3.6), respectively. In the combined population, absolute LVEF improved by 4.5% (95% CI 2.4-6.6), LVESV improved by -4.1 mL (95% CI -9.0 to 0.8), and LVESD improved by -1.7 mm (95% CI -2.8 to -0.7). Heart rate variability improved by 17 ms (95% CI 6.5-28) with minimal left-right difference. Six-minute walk distance improved an average of 56 m (95% CI 37-75); however, improvement was greater for right-side ART (77 m [95% CI 49-105]). NYHA functional class improved in 77% of patients (baseline to 6 months). CONCLUSIONS: Chronic open-loop ART via left- or right-side VNS is feasible and well tolerated in HFrEF patients. Safety and efficacy measures are encouraging and warrant further study.

Differential effects of professional leaders on health care teams in chronic disease management groups.

BACKGROUND: Leadership by health care professionals is likely to vary because of differences in the social contexts within which they are situated, socialization processes and societal expectations, education and training, and the way their professions define and operationalize key concepts such as teamwork, collaboration, and partnership. This research examines the effect of the nurse and physician leaders on interdependence and encounter preparedness in chronic disease management practice groups. PURPOSE: The aim of this study was to examine the effect of complementary leadership by nurses and physicians involved in jointly producing a health care service on care team functioning. METHODOLOGY: The design is a retrospective observational study based on survey data. The unit of analysis is heart failure care groups in U.S. Veterans Health Administration medical centers. Survey and administrative data were collected in 2009 from 68 Veterans Health Administration medical centers. Key variables include nurse and physician leadership, interdependence, psychological safety, coordination, and encounter preparedness. Reliability and validity of survey measures were assessed with exploratory factor analysis and Cronbach alphas. Multivariate analyses tested hypotheses. FINDINGS: Professional leadership by nurses and physicians is related to encounter preparedness by different paths. Nurse leadership is associated with greater team interdependence, and interdependence is positively associated with respect. Physician leadership is positively associated with greater psychological safety, respect, and shared goals but is not associated with interdependence. Respect is associated with involvement in learning activities, and shared goals are associated with coordination. Coordination and involvement in learning activities are positively associated with encounter preparedness. PRACTICE IMPLICATIONS: By focusing on increasing interdependence and a constructive climate, nurse and physician leaders have the opportunity to increase care coordination and involvement in learning activities.

Synchronous and metachronous malignancies: analysis of the Minneapolis Veterans Affairs (VA) tumor registry.

PURPOSE: Multiple primary malignancies (MPMs) are increasing as cancer survivorship improves. A large analysis of the SEER database estimates that approximately 16 % of new cancers reported to their registry represent a second or higher order malignancy. The purpose of this study is to estimate the number of MPM diagnoses and to define differences in synchronous and metachronous cancers in the Veterans Affairs (VA) population. METHODS: The primary objective of this study was to determine the proportion of second or higher order cancers diagnosed at the Minneapolis VA Medical Center from 1 January 2005 to 31 December 2009. The secondary objectives were to analyze and compare correlative demographic, exposure, clinical, and tumor data among those with synchronous and metachronous malignancies. We included any patient with a diagnosis of a malignant cancer during the study period. RESULT: A total of 4,449 patients were diagnosed with malignancies during the study period. Of these, 506 patients (11.4 % of cancer diagnoses) had a diagnosis of a second or higher order malignancy. Of the 506 patients, 124 (24.3 %) had synchronous malignancies and 383 (75.5 %) had metachronous malignancies. The most common malignancy pairing was prostate cancer with bladder/ureter cancer (12 %) of MPM diagnoses. Differences between patients with synchronous and metachronous second occurrences were identified. CONCLUSION: Multiple primary malignancies are a growing area of interest in cancer survivorship. At our institution, approximately 1 in 9 new cancer diagnoses during the 5-year study period represented second-order malignancies. Our data suggest that the VA population is at risk of developing second primary cancers. Further analysis of this population to identify unique risk factors is warranted.

Management of hyperglycemia, dyslipidemia, and albuminuria in patients with diabetes and CKD: a systematic review for a KDOQI clinical practice guideline.

BACKGROUND: In 2007, the National Kidney Foundation (NKF) published clinical practice guidelines and recommendations for treating patients with diabetes and kidney diseases. Given recent studies that may enhance our understanding of the benefits and harms of glycemic, lipid, and albuminuria management in patients with diabetes and chronic kidney disease (CKD), the NKF commissioned a systematic review to evaluate data on the management of these patients. STUDY DESIGN: Systematic review and evidence synthesis. SETTING & POPULATION: Patients with type 1 or 2 diabetes with or without CKD. SELECTION CRITERIA FOR STUDIES: English-language publications indexed in the MEDLINE database from January 2003 to October 2010, as well as cited references in these publications and publications identified after consultation with the NKF Diabetes Work Group were screened. Randomized controlled trials providing evidence for the management of hyperglycemia, dyslipidemia, and albuminuria in individuals with diabetes were included. INTERVENTIONS: (1) Intensive glycemic control; (2) lipid management; (3) interventions aimed at prevention of incident albuminuria and/or progression of albuminuria in normotensive patients. OUTCOMES: For all interventions, all-cause mortality was the primary outcome and secondary clinical outcomes included death from cardiovascular causes, incident kidney failure, and nonfatal cardiovascular events. Intermediate outcomes included changes in albuminuria and measures of kidney function. For intensive glycemic control only, severe and mild hypoglycemia were secondary and intermediate outcomes, respectively. RESULTS: 5 studies (n=27,159) assessed the impact of intensive versus conventional glycemic control strategies on clinical outcomes in type 2 diabetes. Intensive glycemic control reduced the development of micro- and macroalbuminuria, but did not reduce the incidence of primary or secondary clinical outcomes and was associated with a 2.5-fold increase in severe hypoglycemia. 11 studies (n=7,539) assessed lipid management. Statins did not reduce all-cause mortality or stroke compared to placebo in adults with diabetes and CKD. Fenofibrate increased regression of microalbuminuria to normoalbuminuria compared to placebo. 3 studies reported inconsistent effects of different angiotensin II receptor blockers on the incidence of microalbuminuria, and one study reported that telmisartan reduced macroalbuminuria in normotensive participants. No study demonstrated a benefit on primary or secondary clinical outcomes. LIMITATIONS: Patients with CKD constituted a subgroup in most studies. Substantial heterogeneity with respect to population, interventions, outcome measures, and duration of follow-up. CONCLUSIONS: Intensive glycemic control and lipid interventions did not improve clinical outcomes in patients with type 2 diabetes. Although interventions typically improved albuminuria, evidence was insufficient to determine whether treatment of albuminuria in normotensive patients provides beneficial effects on clinical outcomes. More intensive clinical management of patients with diabetes and CKD has inherent risks, including severe hypoglycemia, which should be considered when formulating treatment strategies.

Chapter 12: systematic review of prognostic tests.

A number of new biological markers are being studied as predictors of disease or adverse medical events among those who already have a disease. Systematic reviews of this growing literature can help determine whether the available evidence supports use of a new biomarker as a prognostic test that can more accurately place patients into different prognostic groups to improve treatment decisions and the accuracy of outcome predictions. Exemplary reviews of prognostic tests are not widely available, and the methods used to review diagnostic tests do not necessarily address the most important questions about prognostic tests that are used to predict the time-dependent likelihood of future patient outcomes. We provide suggestions for those interested in conducting systematic reviews of a prognostic test. The proposed use of the prognostic test should serve as the framework for a systematic review and to help define the key questions. The outcome probabilities or level of risk and other characteristics of prognostic groups are the most salient statistics for review and perhaps meta-analysis. Reclassification tables can help determine how a prognostic test affects the classification of patients into different prognostic groups, hence their treatment. Review of studies of the association between a potential prognostic test and patient outcomes would have little impact other than to determine whether further development as a prognostic test might be warranted.

Comparative effectiveness of Clostridium difficile treatments: a systematic review.

BACKGROUND: Clostridium difficile infection is increasing in incidence and severity. The optimal treatment is unknown. PURPOSE: To determine whether, among adults with C. difficile infection, treatment with certain antibiotics compared with others results in differences in initial cure, recurrence, and harms. DATA SOURCES: MEDLINE, AMED, ClinicalTrials.gov, and Cochrane databases (search dates: inception through August 2011, limited to English-language reports); bibliography review. STUDY SELECTION: Randomized, controlled trials of adults with C. difficile infection, independent of outcomes, who were treated with medications available in the United States. Observational studies reporting strain were included. DATA EXTRACTION: Study design, inclusion and exclusion criteria, quality and strength of evidence as assessed by 2 reviewers, study definitions, and duration of treatment and follow-up. Outcomes included initial cure, recurrence, and treatment harms. DATA SYNTHESIS: 11 trials that included 1463 participants were identified. Three trials compared metronidazole with vancomycin; 8 compared metronidazole or vancomycin with another agent, combined agents, or placebo. Strain was analyzed in 1 trial and 2 cohort studies. No study comparing 2 antimicrobial agents demonstrated a statistically significant difference for initial cure; all comparisons were of low to moderate strength of evidence. Moderate-strength evidence from 1 study demonstrated that recurrence was decreased with fidaxomicin versus vancomycin (15% vs. 25%; difference, -10 percentage points [95% CI, -17 to -3 percentage points]; P=0.005). Subgroup analysis of a single study comparing metronidazole with vancomycin for patients who have severe C. difficile infection showed no difference by intention-to-treat analysis; this was rated as insufficient-strength evidence. Harms, when reported, did not differ between treatments in any study. LIMITATIONS: Definitions of diarrhea, C. difficile infection, initial cure, and relapse varied. Some studies reported insufficient detail to allow assessment of all randomly assigned participants or of harms. CONCLUSION: No antimicrobial agent is clearly superior for the initial cure of C. difficile infection. Recurrence is less frequent with fidaxomicin than with vancomycin. PRIMARY FUNDING SOURCE: U.S. Department of Health and Human Services.

Serial measurement of growth-differentiation factor-15 in heart failure: relation to disease severity and prognosis in the Valsartan Heart Failure Trial.

BACKGROUND: Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic biomarker in patients with coronary artery disease. Little is known about GDF-15 as a biomarker in patients with heart failure. METHODS AND RESULTS: The circulating concentration of GDF-15 was measured at baseline (n=1734) and at 12 months (n=1517) in patients randomized in the Valsartan Heart Failure Trial (Val-HeFT). GDF-15 levels at baseline ranged from 259 to 25 637 ng/L and were abnormally high (>1200 ng/L) in 85% of patients. Higher levels were associated with features of worse heart failure and biomarkers of neurohormonal activation, inflammation, myocyte injury, and renal dysfunction. Baseline GDF-15 levels (per 100 ng/L) were associated with the risks of mortality (hazard ratio, 1.017; 95% confidence interval, 1.014 to 1.019; P<0.001) and first morbid event (hazard ratio, 1.020; 95% confidence interval, 1.017 to 1.023; P<0.001). In a comprehensive multiple-variable Cox regression model that included clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T, GDF-15 remained independently associated with mortality (hazard ratio, 1.007; 95% confidence interval, 1.001 to 1.014; P=0.02) but not first morbid event. At 12 months, the GDF-15 levels had increased by a similar amount in the placebo and valsartan groups (P=0.94). Increases in GDF-15 over 12 months were independently associated with the risks of future mortality and first morbid event also after adjustment for clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T and their changes. CONCLUSIONS: GDF-15 reflects information from several pathological pathways and provides independent prognostic information in heart failure. GDF-15 levels increase over time, suggesting that GDF-15 reflects a pathophysiological axis that is not completely addressed by the therapies prescribed in Val-HeFT.

Telephone titration of heart failure medications.

BACKGROUND: In clinical practice, heart failure (HF) medications are underused and prescribed at lower than recommended doses. Telephone care is an option that could help to titrate HF medication in a timely manner. We describe our experience of a nurse-run, cardiologist- or nurse practitioner-supervised clinic to up-titrate HF medications via telephone. METHODS: Patients with the diagnosis of HF, New York Heart Association classes I to III, were referred to a registered nurse-run, cardiologist-/nurse practitioner-supervised HF medication titration clinic. Clinical and medication data collected at enrollment to the clinic and at 3 to 6 months after optimization of HF medications in patients who did or did not reach the target doses were compared. Effect on left ventricular (LV) function was also evaluated. RESULTS: There were 79 patients in the evaluation: 64 with HF and LV systolic dysfunction (LVSD) and the remaining 15 with HF and preserved ejection fraction (EF). Seventy-two percent of patients with LVSD were on an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and 61% were on a ß-blocker at baseline, and this increased to 98% and 97%, respectively, after optimization. Target doses was achieved in 50% of patients for ACEI or ARB, and in 41% for ß-blockers. The median time to optimization was 54 days (interquartile range, 20-97 days). The average number of phone calls at the time of optimization were 5.4 (SD, 3.7), and the average number of clinic visits was 1.9 (SD, 1.3). Reasons for not reaching the target doses included hypotension, hyperkalemia, and renal dysfunction for ACEI and bradycardia for ß-blockers. Overall, the EF increased by 10% (SD, 10%) after 6 months, and 35% or greater in 42% of patients whose baseline EF was less than 35%. There were no adverse events related to the dose up-titration. CONCLUSION: Telephonic titration of HF medications was feasible and safe and was achieved in 97% patients on ACEI/ARB and ß-blockers. Medication titration was associated with significant improvement in LV function, avoiding the need for device therapy in many patients.

Proteinuria, chronic kidney disease, and the effect of an angiotensin receptor blocker in addition to an angiotensin-converting enzyme inhibitor in patients with moderate to severe heart failure.

BACKGROUND: Chronic kidney disease (CKD) is an established risk factor for poor outcomes in heart failure (HF). Whether proteinuria provides additional prognostic information is not known. Renin-angiotensin blockade medications improve outcomes in HF but are underutilized in HF patients with renal dysfunction because of safety concerns and a lack of evidence of their effectiveness. METHODS AND RESULTS: In the Valsartan in Heart Failure Trial (Val-HeFT), 5010 patients with class II, III, or IV heart failure were randomly assigned to receive valsartan or placebo. The 2 primary outcomes were death and first morbid event, defined as death, sudden death with resuscitation, hospitalization for HF, or administration of intravenous inotropic or vasodilator drugs for 4 hours or more without hospitalization. The study cohort was divided into subgroups according to the presence of CKD (estimated glomerular filtration rate <60 mL x min(-1) x 1.73 m(-2)) and proteinuria (positive dipstick). Multivariable Cox proportional hazards regression models were used to examine the relationships between study outcomes and proteinuria, including its interaction with CKD. The interaction between valsartan and CKD was also tested. The effect of valsartan on estimated glomerular filtration rate was estimated by generalized linear models, including tests of interactions between treatment and CKD. At baseline, CKD was found in 58% and dipstick-positive proteinuria in 8% of patients. Dipstick-positive proteinuria was independently associated with mortality (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.01 to 1.62, P=0.05) and first morbid event (HR 1.28, 95% CI 1.06 to 1.55, P=0.01). The increased risk of death associated with dipstick-positive proteinuria was similar for those with and without CKD (HR 1.26, 95% CI 0.96 to 1.66 versus HR 1.37, 95% CI 0.83 to 2.26; P=0.94), as was the hazard for first morbid event (HR 1.26, 95% CI 1.01 to 1.57 versus HR 1.42, 95% CI 0.98 to 2.07; P=0.71). Valsartan reduced estimated glomerular filtration rate compared with placebo to a similar extent (P=0.52) in the subgroups with CKD (mean reduction -3.6 mL x min(-1) x 1.73 m(-2)) and without CKD (mean reduction -4.0 mL x min(-1) x 1.73 m(-2)) and by -3.8 mL x min(-1) x 1.73 m(-2) in both groups combined. The beneficial effect of valsartan on first morbid events was similar in those with and without CKD (HR 0.86, 95% CI 0.74 to 0.99 versus HR 0.91, 95% CI 0.73 to 1.12; P=0.23) and was significant in the subgroup with CKD. The effect of valsartan on mortality did not differ in patients with and without CKD (HR 1.01, 95% CI 0.85 to 1.20 versus HR 0.91, 95% CI 0.69 to 1.25; P=0.08). CONCLUSIONS: CKD was common and dipstick-positive proteinuria was infrequent in this sample of patients with HF. After controlling for other risk factors, including CKD, the relatively small subgroup with dipstick-positive proteinuria did have worse outcomes. Valsartan reduced the estimated glomerular filtration rate by the same amount in patients with and without CKD and reduced the risk of the first morbid event in patients with CKD, which suggests its beneficial effects in patients with HF and CKD.

Does quality of care for cardiovascular disease and diabetes differ by gender for enrollees in managed care plans?

PURPOSE: To assess gender differences in the quality of care for cardiovascular disease and diabetes for enrollees in managed care plans. METHODS: We obtained data from 10 commercial and 9 Medicare plans and calculated performance on 6 Health Employer Data and Information Set (HEDIS) measures of quality of care (beta-blocker use after myocardial infarction [MI], low-density lipoprotein cholesterol [LDL-C] check after a cardiac event, and in diabetics, whether glycosylated hemoglobin [HgbA1c], LDL cholesterol, nephropathy, and eyes were checked) and a 7th HEDIS-like measure (angiotensin-converting enzyme [ACE] inhibitor use for congestive heart failure). A smaller number of plans provided HEDIS scores on 4 additional measures that require medical chart abstraction (control of LDL-C after cardiac event, blood pressure control in hypertensive patients, and HgbA1c and LDL-C control in diabetics). We used logistic regression models to adjust for age, race/ethnicity, socioeconomic status, and plan. MAIN FINDINGS: Adjusting for covariates, we found significant gender differences on 5 of 11 measures among Medicare enrollees, with 4 favoring men. Similarly, among commercial enrollees, we found significant gender differences for 8 of 11 measures, with 6 favoring men. The largest disparity was for control of LDL-C among diabetics, where women were 19% less likely to achieve control among Medicare enrollees (relative risk [RR] = 0.81; 95% confidence interval [CI] = 0.64-0.99) and 16% less likely among commercial enrollees (RR = 0.84; 95%CI = 0.73-0.95). CONCLUSION: Gender differences in the quality of cardiovascular and diabetic care were common and sometimes substantial among enrollees in Medicare and commercial health plans. Routine monitoring of such differences is both warranted and feasible.