Study design and baseline profile for adults with type 2 diabetes in the once-weekly subcutaneous SEmaglutide randomized PRAgmatic (SEPRA) trial.

INTRODUCTION: Once-weekly subcutaneous semaglutide, a glucagon-like peptide-1 analog, is approved in the USA as an adjunct to diet and exercise for adults with inadequately controlled type 2 diabetes (T2D) to improve glycemic control and reduce the risk of major adverse cardiovascular events in people with T2D and established cardiovascular disease. The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) phase III clinical trial program demonstrated the efficacy and safety of once-weekly subcutaneous semaglutide; however, determining its effectiveness in a real-world setting could support decision-making by clinicians, payers and policy makers in routine clinical practice. RESEARCH DESIGN AND METHODS: SEmaglutide PRAgmatic (SEPRA) is an ongoing open-label, randomized, pragmatic clinical trial designed to compare the effects of once-weekly subcutaneous semaglutide versus standard of care in US health-insured adults with T2D and physician-determined inadequate glycemic control. The primary end point is the proportion of participants achieving glycated hemoglobin (HbA1c) <7.0% at year 1; other key outcomes include glycemic control, weight loss, healthcare utilization, and patient-reported outcomes. Individual-level data will be collected from routine clinical practice and health insurance claims. The last patient last visit is expected by June 2023. RESULTS: Between July 2018 and March 2021, 1278 participants were enrolled from 138 study sites across the USA. At baseline, 54% were male with mean±SD age 57.4±11.1 years and body mass index 35.7±8.0 kg/m2. Mean diabetes duration was 7.4±6.0 years and mean HbA1c was 8.5±1.6%. At baseline, concomitant antidiabetes medications included metformin, sulfonylureas, sodium-glucose co-transporter-2 inhibitors, and dipeptidyl peptidase-4 inhibitors. The majority of participants had hypertension and dyslipidemia. The trial design was self-assessed using the PRagmatic Explanatory Continuum Indicator Summary-2 tool by the study steering group and was scored 4-5 in all domains suggesting a highly pragmatic study. CONCLUSIONS: SEPRA, a highly pragmatic ongoing study, will provide data on the effects of once-weekly subcutaneous semaglutide in a real-world setting when used during routine management of T2D. TRIAL REGISTRATION NUMBER: NCT03596450.

A new wearable diagnostic home sleep testing platform: comparison with available systems and benefits of multinight assessments.

STUDY OBJECTIVES: We assessed the real-world performance of the ANNE Sleep system against 2 Food and Drug Administration-cleared home sleep testing platforms and the intraindividual night-to-night variability of respiratory event index measured by ANNE Sleep. METHODS: We evaluated the home performance of the ANNE Sleep system compared with 2 Food and Drug Administration-cleared home sleep testing platforms (WatchPAT: n = 29 and Alice NightOne: n = 46) during a synchronous night with unsupervised patient application. Additionally, we evaluated night-to-night variability of respiratory event index and total sleep time using the ANNE Sleep system (n = 30). RESULTS: For the diagnosis of moderate and severe obstructive sleep apnea, the ANNE Sleep system had a positive percent agreement of 58% (95% confidence interval, 28-85%) and a negative percent agreement of 100% (95% confidence interval, 80-100%) compared to WatchPAT. The positive and negative percent agreement for ANNE Sleep vs Alice NightOne was 85% (95% confidence interval, 66-96%) and 95% (95% confidence interval, 74-100%). There were no differences in mean total sleep time or respiratory event index across multiple nights of monitoring with ANNE. There were no differences consistent with a first-night effect but testing multiple nights reclassified obstructive sleep apnea severity in 5 (17%) individuals and detected 3 additional cases of moderate disease, with only a 12% (standard deviation, 28%) mean fluctuation in respiratory event index from the first night of testing compared to a mean of multiple nights. Overall, 80% of users found ANNE comfortable and easy to use. CONCLUSIONS: ANNE Sleep exhibited stronger concordance with Alice NightOne compared to WatchPAT. While we illustrated low night-to-night variability for ANNE Sleep, the results suggest multiple nights increased detection of moderate or severe obstructive sleep apnea. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: ANNE Diagnostic Agreement With Home Sleep Testing; URL: https://clinicaltrials.gov/ct2/show/NCT05421754; Identifier: NCT05421754. CITATION: Walter J, Lee JY, Blake S, et al. A new wearable diagnostic home sleep testing platform: comparison with available systems and benefits of multinight assessments. J Clin Sleep Med. 2023;19(5):865-872.

A single-arm, open-label, multicenter, and comparative study of the ANNE sleep system vs polysomnography to diagnose obstructive sleep apnea.

STUDY OBJECTIVES: Evaluate per-patient diagnostic performance of a wireless dual-sensor system (ANNE sleep) compared with reference standard polysomnography (PSG) for the diagnosis of moderate and severe obstructive sleep apnea (OSA) with a minimum prespecified threshold of 80% for both sensitivity and specificity. METHODS: A multicenter clinical trial was conducted to evaluate ANNE sleep vs PSG to diagnose moderate and severe OSA in individuals 22 years or older. For each testing approach, apnea-hypopnea index (AHI) was manually scored and averaged by 3 registered sleep technologists blinded to the other system. Average variations > 15% were adjudicated by a sleep medicine physician. RESULTS: In a total of n = 225 participants (mean age 53 years, range 22-88 years), PSG diagnosed 30% (n = 68) of participants with moderate or severe OSA (AHI ≥ 15 events/h) compared to 29% (n = 65) diagnosed by ANNE sleep (P = .55). The sensitivity and specificity for ANNE sleep were 90% (95% confidence interval: 80-96%) and 98% (95% confidence interval: 94-99%), respectively. Strong correlation was shown in terms of final AHI (r = .93), with an average AHI bias of 0.5 (95% limits of agreement: -12.8 to 11.8). The majority of users noted comfort with using the ANNE sleep in the home setting. No adverse events were noted. CONCLUSIONS: Using PSG as the gold standard, ANNE sleep demonstrated high sensitivity and specificity for the diagnosis of moderate or severe OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Comparative Study of the ANNE™ One System to Diagnose Obstructive Sleep Apnea; URL: https://clinicaltrials.gov/ct2/show/NCT04643782; Identifier: NCT04643782. CITATION: Davies C, Lee JY, Walter J et al. A single-arm, open-label, multicenter, and comparative study of the ANNE sleep system vs polysomnography to diagnose obstructive sleep apnea. J Clin Sleep Med. 2022;18(12):2703-2712.

Effectiveness of Combining Antiobesity Medication With an Employer-Based Weight Management Program for Treatment of Obesity: A Randomized Clinical Trial.

Importance: The clinical efficacy of antiobesity medications (AOMs) as adjuncts to lifestyle intervention is well characterized, but data regarding their use in conjunction with workplace wellness plans are lacking, and coverage of AOMs by US private employers is limited. Objective: To determine the effect of combining AOMs with a comprehensive, interdisciplinary, employer-based weight management program (WMP) compared with the WMP alone on weight loss, treatment adherence, and work productivity and limitations. Design, Setting, and Participants: This 1-year, single-center, open-label, parallel-group, real-world, randomized clinical trial was conducted at the Cleveland Clinic's Endocrinology and Metabolism Institute in Cleveland, Ohio, from January 7, 2019, to May 22, 2020. Participants were adults with obesity (body mass index [BMI; calculated as weight in kilograms divided by height in meters squared] ≥30) enrolled in the Cleveland Clinic Employee Health Plan. Interventions: In total, 200 participants were randomized 1:1, 100 participants to WMP combined with an AOM (WMP+Rx), and 100 participants to WMP alone. The WMP was the Cleveland Clinic Endocrinology and Metabolism Institute's employer-based integrated medical WMP implemented through monthly multidisciplinary shared medical appointments. Participants in the WMP+Rx group initiated treatment with 1 of 5 US Food and Drug Administration-approved medications for chronic weight management (orlistat, lorcaserin, phentermine/topiramate, naltrexone/bupropion, and liraglutide, 3.0 mg) according to standard clinical practice. Main Outcomes and Measures: The primary end point was the percentage change in body weight from baseline to month 12. Results: The 200 participants were predominately (177 of 200 [88.5%]) women, had a mean (SD) age of 50.0 (10.3) years, and a mean (SD) baseline weight of 105.0 (19.0) kg. For the primary intention-to-treat estimand, the estimated mean (SE) weight loss was -7.7% (0.7%) for the WMP+Rx group vs -4.2% (0.7%) for the WMP group, with an estimated treatment difference of -3.5% (95% CI, -5.5% to -1.5%) (P < .001). The estimated percentage of participants achieving at least 5% weight loss was 62.5% for WMP+Rx vs 44.8% for WMP (P = .02). The rate of attendance at shared medical appointments was higher for the WMP+Rx group than for the WMP group. No meaningful differences in patient-reported work productivity or limitation measures were observed. Conclusions and Relevance: Clinically meaningful superior mean weight loss was achieved when access to AOMs was provided in the real-world setting of an employer-based WMP, compared with the WMP alone. Such results may inform employer decisions regarding AOM coverage and guide best practices for comprehensive, interdisciplinary employer-based WMPs. Trial Registration: ClinicalTrials.gov Identifier: NCT03799198.

Objective and Subjective Measures of Premature Ejaculation: How Closely Do They Correspond and How Well Are the Subjective Measures Recalled?

BACKGROUND: Clinical trials evaluating new treatments for premature ejaculation (PE) should ideally include both objective end points and patient reported outcomes (PROs), but there is no consensus currently over the optimal measures or combination of outcomes. In addition, many PROs use a 1-month recall period, despite concerns about potential recall bias. AIMS: Data from a clinical trial of men with lifelong PE were used to examine the consistency of 2 core items of the Premature Ejaculation Profile (PEP), a widely used PRO for assessing subjective aspects of PE. The specific aim was to assess the level of agreement between the original 1-month recall version compared with a new event-based version of the scale in men meeting current definitions of lifelong PE. A further aim was to investigate the convergent validity between an objective end point of intravaginal ejaculatory latency time (IELT), subjective PEP responses, and a patient's Clinical Global Impression of Change (CGIC) measure. METHODS: For assessment of consistency of PEP responses (short-term [ie, sexual event driven] vs 1-month recall), descriptive statistics, correlation coefficients (Pearson and Spearman), and Bland-Altman plots are presented for each time interval. For assessment of convergent validity, descriptive statistics and correlation coefficients (Pearson and Spearman) are presented for each assessment with geometric mean IELT values. Results are also depicted graphically. Geometric mean IELT over the last 4 weeks of treatment and change from baseline (absolute and fold change) were estimated via a general linear model for each category of change in PEP and CGIC, adjusting for baseline IELT. OUTCOMES: PEP items administered via 1-month recall and short-term event-driven responses gave virtually identical results. There was a strong correlation (very good convergent validity) between IELT and responses to PEP and the CGIC. CLINICAL TRANSLATION: Men with lifelong PE can accurately recall their level of sexual functioning over the previous month. The PEP and CGIC are appropriate instruments to measure the subjective response of men with PE to new treatments. STRENGTHS AND LIMITATIONS: Our analyses address gaps in previously published research on PE assessment methodology. Men with acquired PE, men without partners, and men in homosexual relationships were not studied. CONCLUSIONS: In a clinical trial setting, PEP and CGIC are appropriate end points and are likely the optimal combination of PROs for use with IELT to enable a global assessment of patient response to new PE treatments. Althof S, Rosen R, Harty B, et al. Objective and Subjective Measures of Premature Ejaculation: How Closely Do They Correspond and How Well Are the Subjective Measures Recalled? J Sex Med 2020;17:634-644.

The Oxytocin Antagonist Cligosiban Prolongs Intravaginal Ejaculatory Latency and Improves Patient-Reported Outcomes in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Proof-of-Concept Trial (PEPIX).

INTRODUCTION: Cligosiban is an orally administered oxytocin receptor antagonist being developed to treat premature ejaculation (PE). AIM: To determine the safety and efficacy of cligosiban capsules (dose range 400-800 mg) to improve intravaginal ejaculation latency time (IELT) and patient-reported outcomes in men with severe lifelong PE. METHODS: Patients recorded details of at least 4 sexual intercourse events during a 4-week run-in period, after which they underwent baseline assessments. Patients were eligible for the study if they rated their control of ejaculation as poor/very poor and their stopwatch-assessed IELT was ≤1 minute in ≥75% of intercourse attempts. Eligible patients were randomized to an 8-week treatment period with double-blind cligosiban or placebo (to be taken 1 to 6 hours prior to sexual activity). The starting dose was 400 mg (not more than 1 dose per day) which could be increased to 800 mg after 2 and/or 4 weeks of treatment. Assessments were conducted at 2, 4, and 8 weeks. MAIN OUTCOME MEASURE: Efficacy measures were comprised of IELT, self-rating of ejaculation control and ejaculation-related distress (recorded in an electronic diary after each intercourse attempt), premature ejaculation profile, and the Clinical Global Impression of Change. RESULTS: The mean ratio of fold change from baseline in IELT to the last 4 weeks of treatment (cligosiban/placebo) was 1.9 compared to a baseline of 1.0 (P = .0079). The mean increase in IELT from baseline to the last 4 weeks of treatment was 61.0 seconds for cligosiban, which was significantly different from (and 3.6-fold greater than) the mean increase of 16.4 seconds for placebo (P = .0086). Statistically significant improvements in ejaculation control and ejaculation-related personal distress scores were also observed for cligosiban compared to little or no change with placebo. Cligosiban was generally well tolerated, with no serious or severe adverse events or other safety parameters. CLINICAL IMPLICATIONS: This proof-of-concept study demonstrated the potential for cligosiban, an oxytocin antagonist, to successfully treat symptoms of severe lifelong PE. STRENGTHS AND LIMITATIONS: This was a Phase II, randomized, double-blind, placebo-controlled study that was adequately powered to detect a clinically meaningful difference in change in IELT between cligosiban and placebo. Larger studies will be needed to confirm these findings, determine the optimal dose of cligosiban and assess efficacy in men with acquired PE. CONCLUSIONS: Cligosiban was well tolerated, and resulted in significant benefits in both objective and subjective measures of ejaculatory control in men with lifelong PE and therefore offers significant potential as an on-demand, orally administered agent for the treatment of PE. McMahon C, Althof S, Rosen R, et al. The Oxytocin Antagonist Cligosiban Prolongs Intravaginal Ejaculatory Latency and Improves Patient-Reported Outcomes in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Proof-of-Concept Trial (PEPIX). J Sex Med 2019; 16:1178-1187.

Comparison of Outcomes in Patients With Diabetes Mellitus Treated With Versus Without Insulin + Heart Failure With Preserved Left Ventricular Ejection Fraction (from the TOPCAT Study).

We aimed to evaluate the impact of diabetes mellitus (DM) and insulin treatment on clinical outcomes in patients with heart failure and preserved left ventricular ejection fraction enrolled in the TOPCAT study. We investigated the influence of DM status (insulin-treated [ITDM], non-insulin treated [NITDM], and no diabetes [non-DM]) at baseline on time to development of the primary end point, a composite of cardiovascular (CV) mortality, heart failure hospitalization, and aborted cardiac arrest. Secondary end points included the individual components of the primary end point, myocardial infarction, stroke, all-cause mortality, hyperkalemia, and worsened renal function. Due to marked regional differences in characteristics and outcomes of the TOPCAT patients, with much lower events in patients enrolled in Russia/Georgia, we restricted our analyses on findings from patients enrolled from the Americas. Compared to patients without DM, patients with ITDM had approximately 2-fold increased risk for the primary end point, heart failure hospitalization, and myocardial infarction (hazard ratios: 1.80, 1.97, and 2.27, respectively) and approximately 50% increases in all-cause and CV mortality. The risks for these outcomes were also increased in patients with ITDM in comparison to patients with NITDM as well (hazard ratios: 1.63, 1.65, and 2.73, respectively, and approximately 40% increases in all-cause and CV mortality). Patients with NITDM had similar risks for the primary end point and all secondary end points as patients without DM. In conclusion, the apparent increased risk of adverse outcomes in patients with heart failure and preserved left ventricular ejection fraction and ITDM merits future research to improve the prognosis of these high-risk patients.

The stability of HIV-1 nucleic acid in whole blood and improved detection of HIV-1 in alternative specimen types when compared to Dried Blood Spot (DBS) specimens.

BACKGROUND: Commercially-available kits for HIV-1 detection include instructions for detecting HIV-1 in plasma and DBS, but don't support other specimen types. OBJECTIVES: Show quantitative stability of HIV-1 total nucleic acid (TNA) in blood and improved HIV-1 detection in alternative specimen types. STUDY DESIGN: Whole blood and DBS specimens, tested as part of an external quality assurance program for qualitative HIV-1 detection, were used to evaluated error rates (false negative [FN], false positive [FP] and indeterminant [IND] results) across assays (internally developed [IH], Roche Amplicor [RA], and Roche TaqMan Qual [TQ]) and specimen types (frozen whole blood [BLD], DBS and cell pellets [PEL]). A modified Roche TaqMan HIV-1 assay was used to quantify HIV-1 TNA. RESULTS: Significantly higher error rates were noted in DBS across all of the assays (4% vs. 0% for DBS and PEL, IH, p = 0.005; 4% vs. 0.1% for DBS and PEL, RA, p < 0.001; 10% vs. 1% for DBS and PEL or BLD, TQ, p < 0.001). HIV TNA concentration is stable in BLD (day 1 vs. day 10, p = 0.39) and higher than DBS (p < 0.001). CONCLUSIONS: Transporting refrigerated whole blood for centralized processing into alternative specimen types will improve the sensitivitiy of HIV-1 detection in samples with low virus loads.

Overall Postneonatal Mortality and Rates of SIDS.

BACKGROUND: Reductions in sudden infant death syndrome (SIDS) are commonly attributed to modifications in infant sleep environments. Approaches to diagnosis in sudden infant death, death scene investigations, the prevalence of intrinsic risk factors for SIDS, and the potential influence of treatment-related factors on infant vulnerability have also changed. Understanding all contributory factors may help reduce residual SIDS rates. METHODS: We analyzed US Mortality Multiple Causes Records for 1983 to 2012 to compare SIDS postneonatal mortality rates with a projection applying non-SIDS mortality changes, using those changes as a proxy measure for alterations in intrinsic risk. Composites of neglect-related, unknown, and circumstantial respiratory diagnoses were measured, as was a cumulative composite of unexplained infant death diagnoses. Cluster analysis with leading causes of postneonatal mortality and SIDS mortality rates for low birth weight infants were also examined. RESULTS: SIDS and non-SIDS postneonatal mortality rates were concordant over time. Important variance was seen 1994 to 1996, coinciding with Back-to-Sleep initiation. Other variance, eliminated in the cumulative composite, appeared related to differences in diagnostic practices. Changes in SIDS rates resembled changes in mortality from congenital malformations, respiratory distress of the newborn, and diseases of the circulatory system. SIDS rates for low birth weight infants followed broader postneonatal trends. CONCLUSIONS: SIDS mortality followed trends in overall postneonatal mortality, including effects of changes in the infant sleep environment and diagnostic classification. Preventing asphyxia risk in the sleep environment must be coupled with efforts to understand intrinsic biological pathways, some potentially associated with other categories of infant and perinatal mortality.

Online self-administered training of PTSD treatment providers in cognitive-behavioral intervention skills: results of a randomized controlled trial.

Despite potential advantages in scalability and efficiency of web-based training for trauma providers, few controlled trials of feasibility and effectiveness of web-based mental health training have been performed. Our study compared web-based training in 3 intervention skills (motivation enhancement [ME], goal setting [GS], behavioral task assignment [BTA]) with web-based training plus telephone consultation, and a no-training control. The primary outcome measures included objective measures of skills acquisition (standardized patient assessments). Results showed significant differences among the training conditions. The overall tests of differences among the groups were statistically significant for ME and BTA skills (p < .001 and p = .005, respectively), but not for GS (p = .245). The web training plus consultation group improved in ME skills by 0.35 units compared to 0.12 units in the web only group (p < .001) and no change in the control group (p = .001). For BTA skills, the web training plus consultation improved by 0.27 units compared to 0.17 units in the web only group (p = .175) and no change in the control group (p = .004). Overall, these findings support the use of web-based dissemination for large-scale training programs for trauma providers in health care delivery systems. Further studies are needed to clarify the specific role of consultation as an adjunct to web-based training.

Spironolactone for heart failure with preserved ejection fraction.

BACKGROUND: Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction. METHODS: In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. RESULTS: With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P=0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P=0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 µmol per liter) or higher, or dialysis. CONCLUSIONS: In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. (Funded by the National Heart, Lung, and Blood Institute; TOPCAT ClinicalTrials.gov number, NCT00094302.).

Serotonin metabolites in the cerebrospinal fluid in sudden infant death syndrome.

Forensic biomarkers are needed in sudden infant death syndrome (SIDS) to help identify this group among other sudden unexpected deaths in infancy. Previously, we reported multiple serotonergic (5-HT) abnormalities in nuclei of the medulla oblongata that help mediate protective responses to homeostatic stressors. As a first step toward their assessment as forensic biomarkers of medullary pathology, here we test the hypothesis that 5-HT-related measures are abnormal in the cerebrospinal fluid (CSF) of SIDS infants compared with those of autopsy controls. Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), the degradative products of 5-HT and dopamine, respectively, were measured by high-performance liquid chromatography in 52 SIDS and 29 non-SIDS autopsy cases. Tryptophan (Trp) and tyrosine (Tyr), the substrates of 5-HT and dopamine, respectively, were also measured. There were no significant differences in 5-HIAA, Trp, HVA, or Tyr levels between the SIDS and non-SIDS groups. These data preclude the use of 5-HIAA, HVA, Trp, or Tyr measurements as CSF autopsy biomarkers of 5-HT medullary pathology in infants who have died suddenly and unexpectedly. They do, however, provide important information about monoaminergic measurements in human CSF at autopsy and their developmental profile in infancy that is applicable to multiple pediatric disorders beyond SIDS.

Baseline characteristics of patients in the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial.

BACKGROUND: Treatment of Preserved Cardiac Function with an Aldosterone Antagonist (TOPCAT) is an ongoing randomized controlled trial of spironolactone versus placebo for heart failure with preserved ejection fraction (HFpEF). We sought to describe the baseline clinical characteristics of subjects enrolled in TOPCAT relative to other contemporary observational studies and randomized clinical trials of HFpEF. METHODS AND RESULTS: Between August 2006 and January 2012, 3445 patients with symptomatic HFpEF from 270 sites in 6 countries were enrolled in TOPCAT. At the baseline study visit, all subjects provided a detailed medical history and underwent physical examination, electrocardiography, quality of life, and laboratory assessment. Key parameters were compared with other large, contemporary HFpEF studies. The mean age was 68.6±9.6 years with a slight female predominance (52%); mean body mass index was 32 kg/m2; and comorbidities were common. History of hypertension (91% prevalence in TOPCAT) exceeded all other major HFpEF clinical trials. However, baseline blood pressure was well controlled (129/76 mm Hg; systolic blood pressure 7-16 mm Hg lower than other similar trials). Other common comorbidities included coronary artery disease (57%), atrial fibrillation (35%), chronic kidney disease (38%) and diabetes mellitus (32%). Self-reported activity levels were low, quality of life scores were comparable with those reported for patients with end-stage renal disease, and the prevalence of moderate or greater depression was 27%. CONCLUSIONS: TOPCAT subjects share many common characteristics with contemporary HFpEF cohorts. Low activity level, significantly decreased quality of life, and depression were common at baseline in TOPCAT, underscoring the continued unmet need for evidence-based treatment strategies in HFpEF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT00094302.

Cross-platform analysis of HIV-1 RNA data generated by a multicenter assay validation study with wide geographic representation.

HIV-1 RNA quantitation continues to be extremely important for monitoring patients infected with HIV-1, and a number of assays have been utilized for this purpose. Differences in assay performance with respect to log(10) recovery and HIV-1 subtype specificity have been well documented for commercially available assays, although comparisons are usually limited to one or two assay platforms. Two new FDA-approved assays, the Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test (RT) and the Abbott RealTime HIV-1 assay (AR), that utilize real-time PCR have replaced previous HIV-1 RNA platforms. Inadequate detection of some strains of HIV-1 resulted in the addition of a new primer/probe set and the introduction of a second version of the RT assay. In this study, comparisons of assay performance between the different FDA-approved HIV-1 RNA assay platforms (both new and existing) were performed by using validation data that included both well-characterized virus stock and locally collected clinical samples. Laboratories across diverse geographical regions performed the validation testing and submitted data to the Virology Quality Assurance program (VQA) for analysis. Correlation values for clinical sample testing varied across the assay platforms (r = 0.832 to 0.986), and average log(10) recoveries for HIV-1 RNA controls (compared to the nominal value) ranged from -0.215 to 0.181. These data demonstrate the need for use of one assay platform for longitudinal patient monitoring, but the data also reinforce the notion that no one assay is superior and that testing across platforms may be required for discordance reconciliation.

The Cognitive Change in Women study (CCW): informant ratings of cognitive change but not self-ratings are associated with neuropsychological performance over 3 years.

The value of self-reported memory complaints for identifying or predicting future cognitive decline or dementia is controversial, but observations from a third party, or "informant," may prove more useful. The relationship between Informant and Self-ratings of cognitive status and neuropsychological test scores was examined in a cohort of 384 nondemented, community-dwelling women, aged 60 years and older, participating in a single-site Women's Health Initiative ancillary study. Each participant and her respective informant separately completed the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Participants also underwent neuropsychological testing and responded to questionnaires on depression and functioning in complex activities of daily living. All neuropsychological test scores were significantly correlated (P values <0.05 to <0.01) with IQCODE ratings whereas Self-ratings overestimated cognitive functioning in some domains. Furthermore, the Self and Informant ratings were both positively correlated with depression and negatively correlated with participants' activity level. Therefore, informant judgments of functional abilities are robust predictors of cognitive status in high functioning nondemented women. These results suggest that informants may be sensitive to changes that are not clinically significant but that may represent an incipient trend for decline.

Monounsaturated, trans, and saturated Fatty acids and cognitive decline in women.

OBJECTIVES: To prospectively assess effects of select dietary fats on cognitive decline. DESIGN: Prospective observational; 3-year follow-up. SETTING: Northwestern University. PARTICIPANTS: Four hundred eighty-two women aged 60 and older who participated in the Women's Health Initiative (WHI) Observational Study or in the control group of the WHI Diet Modification arm. MEASUREMENTS: Dietary intake from a validated food frequency questionnaire (FFQ) administered twice (mean 2.7 years apart) before baseline cognitive assessment (mean 2.9 years after second FFQ) was averaged. Testing of memory, vision, executive function, language, and attention was performed twice, 3 years apart. A global Z-score was created for both time points by averaging all Z-scores for each participant, and global cognitive change was defined as the difference between follow-up and baseline Z-scores. RESULTS: Median intake of saturated fat (SFA), trans-fat, (TFA), dietary cholesterol (DC), and monounsaturated fat (MUFA) was 18.53, 3.45, 0.201, and 19.39 g/d, respectively. There were no associations between degree of cognitive decline and intake of SFA (P=.69), TFA (P=.54), or DC (P=.64) after adjusting for baseline cognition, total energy intake, age, education, reading ability, apolipoprotein E ɛ4 allele, body mass index, estrogen and beta-blocker use, and intake of caffeine and other fatty acids. In contrast, MUFA intake was associated with lower cognitive decline in fully adjusted linear regression models, with mean decline (standard error) of 0.21 (0.05) in the lowest and 0.05 (0.05) in the highest quartiles (P=.02). This effect of MUFA intake was primarily in the visual and memory domains (P=.03 for both). CONCLUSION: Greater intake of SFA, TFA, and DC was not associated with cognitive decline, whereas greater MUFA intake was associated with less cognitive decline.

Mucosal priming of simian immunodeficiency virus-specific cytotoxic T-lymphocyte responses in rhesus macaques by the Salmonella type III secretion antigen delivery system.

Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested DeltaphoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01(+) macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag(181-189) epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag(181-189)-specific CD8(+) T-cell responses in peripheral blood. A significant percentage of the Gag(181-189)-specific T-cell population in each animal also expressed the intestinal homing receptor alpha4beta7. Additionally, Gag(181-189)-specific CD8(+) T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model.