Historical evaluation of the in vivo adventitious virus test and its potential for replacement with next generation sequencing (NGS).

The Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) collected historical data from 20 biopharmaceutical industry members on their experience with the in vivo adventitious virus test, the in vitro virus test, and the use of next generation sequencing (NGS) for viral safety. Over the past 20 years, only three positive in vivo adventitious virus test results were reported, and all were also detected in another concurrent assay. In more than three cases, data collected as a part of this study also found that the in vivo adventitious virus test had given a negative result for a sample that was later found to contain virus. Additionally, the in vivo adventitious virus test had experienced at least 21 false positives and had to be repeated an additional 21 times all while using more than 84,000 animals. These data support the consideration and need for alternative broad spectrum viral detection tests that are faster, more sensitive, more accurate, more specific, and more humane. NGS is one technology that may meet this need. Eighty one percent of survey respondents are either already actively using or exploring the use of NGS for viral safety. The risks and challenges of replacing in vivo adventitious virus testing with NGS are discussed. It is proposed to update the overall virus safety program for new biopharmaceutical products by replacing in vivo adventitious virus testing approaches with modern methodologies, such as NGS, that maintain or even improve the final safety of the product.

Blood volume expansion, normovolemia, and clinical outcomes in chronic human heart failure: more is better.

Expansion in blood volume (BV) is a well-recognized response to arterial underfilling secondary to impaired cardiac output in heart failure (HF). However, the effectiveness of this response in terms of outcomes remains inadequately understood. Prospective analysis was undertaken in 110 patients with HF hospitalized and treated for fluid overload. BVs were measured in a compensated state at the hospital discharge using the indicator-dilution methodology. Data were analyzed for composite 1-year HF-related mortality/first rehospitalization. Despite uniform standard of care, marked heterogeneity in BVs was identified across the cohort. The cohort was stratified by BV expansion greater than or equal to +25% above normal (51% of cohort), mild-moderate expansion (22%), and normal BV (27%). Kaplan-Meier (K-M) survival estimates and regression analyses revealed BV expansion (greater than or equal to +25%) to be associated with better event-free survival relative to normal BV (P = 0.038). Increased red blood cell mass (RBCm; RBC polycythemia) was identified in 43% of the overall cohort and 70% in BV expansion greater than or equal to +25%. K-M analysis demonstrated polycythemia to be associated with better outcomes compared with normal RBCm (P < 0.002). Persistent BV expansion to include RBC polycythemia is common and, importantly, associated with better clinical outcomes compared with normal total BV or normal RBCm in patients with chronic HF. However, compensatory BV expansion is not a uniform physiological response to the insult of HF with marked variability in BV profiles despite uniform standard of care diuretic therapy. Therefore, recognizing the variability in volume regulation pathophysiology has implications not only for impact on clinical outcomes and risk stratification but also potential for informing individualized volume management strategies.NEW & NOTEWORTHY The novel findings of this study demonstrate that intravascular volume profiles among the patients with chronic heart failure (HF) vary substantially even with similar clinical compensation. Importantly, a profile of blood volume (BV) expansion (compared with a normal BV) is associated with lower HF mortality/morbidity. Furthermore, RBC polycythemia is common and independently associated with improved outcomes. These observations support BV expansion with RBC polycythemia as a compensatory mechanism in chronic HF.

Diuresis-Related Weight Loss Reflects Interstitial Compartment Decongestion with Minimal Impact on Intravascular Volume Expansion or Outcomes in Post-Acute Heart Failure: Metrics of Decongestion and Volume Status.

BACKGROUND: Findings from heart failure (HF) studies linking diuresis-related weight loss to clinical decongestion and outcomes are mixed. Differential responses of interstitial and intravascular volume compartments to diuretic therapy and heterogeneity in volume profiles may confound the clinical interpretation of weight loss in patients with HF. METHODS AND RESULTS: Data were prospectively collected in hospitalized patients requiring diuresis. Plasma volume (PV) was measured using I-131-labelled albumin indicator-dilution methodology. The cohort was stratified by tertiles of weight loss and analyzed for interstitial fluid loss relative to changes in PV and HF-related morality or first rehospitalization. Among 92 patients, the admission PV was expanded +42% (4.7 ± 1.2 L) above normal with significant variability (14% normal PV, 18% mild-moderate expansion, and 68% with large PV expansion [>+25% above normal]). With diuresis there were proportional decreases in interstitial volume (-6.5 ± 4.4%) and PV (-7.5 ± 11%); however, absolute decreases in the PV (-254 mL, interquartile range -11 to -583 mL) were less than 10% of interstitial volume loss (-5040 mL, interquartile range -2800 to -7989 mL); greater interstitial fluid loss did not translate into better outcomes (log-rank P = .430). CONCLUSIONS: Diuresis-related decreases in weight reflect fluid loss from the interstitial compartment with only minor changes in the PV and without an impact on outcomes. Further, the degree of PV expansion at hospital admission does not drive the magnitude of the diuresis response, even with a wide spectrum of body weights; interstitial fluid overload is preferentially targeted and PV relatively preserved. Therefore, greater interstitial fluid loss reflects clinical decongestion, but not better outcomes, and a limited association with intravascular volume profiles potentially confounding weight loss as a prognostic metric in HF.

Pulmonary embolism rule out: positivity and factors affecting the yield of CT angiography.

OBJECTIVE: CT pulmonary angiography (CTPA) is one of the most commonly ordered CT imaging tests. It is often believed to be overutilised with few recent studies showing a yield of less than 2%. This study aimed to determine the overall positivity rate of CTPA examinations and understand the factors that affect the yield of the CTPA examination. METHODS: We retrospectively analysed 2713 patients who received the CTPA exam between 2016 and 2018. Type of study ordered (CTPA chest or CTPA chest with abdomen and pelvis CT), patient location (emergency department (ED), outpatient, inpatient, intensive care unit (ICU)) and patient characteristics-age, sex and body mass index (BMI) were recorded. A logistic regression analysis was performed to determine what factors affect the positivity rate of CT scans for pulmonary embolism (PE). RESULTS: With 296 positive test results, the overall CTPA positivity was 10.9%. Male sex was associated with higher CTPA positivity, gender difference was maximum in 18-year to 35-year age group. Overweight and obese patients had significantly higher positivity as compared with BMI<25 (p<0.05). Higher positivity rate was seen in the BMI 25-40 group (11.9%) as compared with BMI>40 (10.1%) (p<0.05). Significant difference (p<0.001) was also found in CTPA examination yield from ICU (15.3%) versus inpatients (other than ICU) (12.4%) versus ED (9.6%), and outpatients (8.5%). The difference in CTPA yield based on the type of CT order (CTPA chest vs CTPA chest with CT abdomen and pelvis), patient's age and sex was not significant. CONCLUSION: CTPA yield of 10.9% in this study is comparable to acceptable positivity rate for the USA and is higher than recent studies showing positivity of <2%. Patient characteristics like obesity and ICU or inpatient location are associated with higher rate of CT positivity.

Post Transcatheter Mitral Valve-In-Valve Repair Cardiac Pseudoaneurysm.

Online supplemental material is available for this article.

Post-imaging pulmonary nodule mathematical prediction models: are they clinically relevant?

OBJECTIVES: Post-imaging mathematical prediction models (MPMs) provide guidance for the management of solid pulmonary nodules by providing a lung cancer risk score from demographic and radiologists-indicated imaging characteristics. We hypothesized calibrating the MPM risk score threshold to a local study cohort would result in improved performance over the original recommended MPM thresholds. We compared the pre- and post-calibration performance of four MPM models and determined if improvement in MPM prediction occurs as nodules are imaged longitudinally. MATERIALS AND METHODS: A common cohort of 317 individuals with computed tomography-detected, solid nodules (80 malignant, 237 benign) were used to evaluate the MPM performance. We created a web-based application for this study that allows others to easily calibrate thresholds and analyze the performance of MPMs on their local cohort. Thirty patients with repeated imaging were tested for improved performance longitudinally. RESULTS: Using calibrated thresholds, Mayo Clinic and Brock University (BU) MPMs performed the best (AUC = 0.63, 0.61) compared to the Veteran's Affairs (0.51) and Peking University (0.55). Only BU had consensus with the original MPM threshold; the other calibrated thresholds improved MPM accuracy. No significant improvements in accuracy were found longitudinally between time points. CONCLUSIONS: Calibration to a common cohort can select the best-performing MPM for your institution. Without calibration, BU has the most stable performance in solid nodules ≥ 8 mm but has only moderate potential to refine subjects into appropriate workup. Application of MPM is recommended only at initial evaluation as no increase in accuracy was achieved over time. KEY POINTS: • Post-imaging lung cancer risk mathematical predication models (MPMs) perform poorly on local populations without calibration. • An application is provided to facilitate calibration to new study cohorts: the Mayo Clinic model, the U.S. Department of Veteran's Affairs model, the Brock University model, and the Peking University model. • No significant improvement in risk prediction occurred in nodules with repeated imaging sessions, indicating the potential value of risk prediction application is limited to the initial evaluation.

Intravascular Volume Profiles in Patients With Class I and II Systolic Heart Failure: Heterogeneity and Volume Overload Are Common Even in Mild Heart Failure.

BACKGROUND: Although volume overload is a commonly described clinical feature of advanced heart failure (HF), less is known regarding volume profiles of patients with less severe class I and II HF. METHODS: Intravascular volume was quantitated by radiolabeled-albumin indicator-dilution technique in clinic outpatients. RESULTS: Forty-six patients (age 61 ± 13years, left ventricular ejection fraction 30 ± 8%) were prospectively evaluated with 28 undergoing repeat evaluations at 1 year. There was no difference in averaged total blood volume (TBV) at baseline between class I (N = 26) and II (N = 20) patients (5.6 ± 1.6vs 6.0 ± 1.3 L, P = .368) and at 1-year of follow-up. However, there was marked heterogeneity in plasma volume (-13% to +69% of normal) and red cell mass (RBCM -31% to +50%) profiles with TBV expansion identified in 46% of the cohort, whereas only 48% had a normal TBV. RBCM deficit (true anemia) was common (39%), but a low hemoglobin concentration was accurate in identifying anemia in only 11% of the cohort. RBCM excess (polycythemia) also was identified in 20% of the cohort. CONCLUSIONS: Marked heterogeneity in plasma volume and RBCM volume profiles is present even in mild HF, and identifying volume overload, which was common in early HF, has the potential to help guide therapy in the reduction of HF progression. Intravascular volume as a modifiable risk factor in early HF warrants further study.

11C-Choline PET/CT for Detection and Localization of Parathyroid Adenomas.

OBJECTIVE: The purpose of this study is to determine the efficacy of 11C-choline PET/CT for the detection of parathyroid adenomas by retrospectively reviewing a large patient population. MATERIALS AND METHODS: In this single-institution retrospective study, 7088 11C-choline PET/CT scans performed of 2933 men with prostate cancer from January 2005 through February 2016 were evaluated. Patients with suspected parathyroid adenomas were identified through a review of the electronic medical record and relevant imaging. Patient demographics, laboratory results, and lesion characteristics were noted. Pathologically proven parathyroid adenomas and lesions in patients with imaging or laboratory findings consistent with the diagnosis were considered positive. RESULTS: Thirteen men (mean [± SD] age, 72 ± 7 years) with pathologically or laboratory-proven parathyroid adenomas were identified. All had abnormally elevated serum calcium and parathyroid hormone levels. All adenomas were tracer avid on 11C-choline PET/CT (maximum standardized uptake value, 5.6 ± 3.0), with activity averaging 4.2 times that of the blood pool and 2.1 times that of the adjacent thyroid. One case of an ectopic adenoma was identified. Of the six pathologically confirmed cases, none displayed high-grade features such as capsular, vascular, or adjacent tissue invasion. Three additional patients with possible parathyroid adenomas at 11C-choline PET/CT were ultimately found to have thyroid lesions on the basis of tissue diagnosis; however, none of these patients had abnormal calcium or parathyroid hormone levels. CONCLUSION: In our patient population, 11C-choline PET/CT identified parathyroid adenomas with high specificity. Prospective investigation is warranted to validate this result and delineate the utility of 11C-choline PET/CT relative to other modalities.

Simvastatin in the acute respiratory distress syndrome.

BACKGROUND: Studies in animals and in vitro and phase 2 studies in humans suggest that statins may be beneficial in the treatment of the acute respiratory distress syndrome (ARDS). This study tested the hypothesis that treatment with simvastatin would improve clinical outcomes in patients with ARDS. METHODS: In this multicenter, double-blind clinical trial, we randomly assigned (in a 1:1 ratio) patients with an onset of ARDS within the previous 48 hours to receive enteral simvastatin at a dose of 80 mg or placebo once daily for a maximum of 28 days. The primary outcome was the number of ventilator-free days to day 28. Secondary outcomes included the number of days free of nonpulmonary organ failure to day 28, mortality at 28 days, and safety. RESULTS: The study recruited 540 patients, with 259 patients assigned to simvastatin and 281 to placebo. The groups were well matched with respect to demographic and baseline physiological variables. There was no significant difference between the study groups in the mean (±SD) number of ventilator-free days (12.6±9.9 with simvastatin and 11.5±10.4 with placebo, P=0.21) or days free of nonpulmonary organ failure (19.4±11.1 and 17.8±11.7, respectively; P=0.11) or in mortality at 28 days (22.0% and 26.8%, respectively; P=0.23). There was no significant difference between the two groups in the incidence of serious adverse events related to the study drug. CONCLUSIONS: Simvastatin therapy, although safe and associated with minimal adverse effects, did not improve clinical outcomes in patients with ARDS. (Funded by the U.K. National Institute for Health Research Efficacy and Mechanism Evaluation Programme and others; HARP-2 Current Controlled Trials number, ISRCTN88244364.).

Effectiveness of an exercise programme on physical function in patients discharged from hospital following critical illness: a randomised controlled trial (the REVIVE trial).

OBJECTIVE: To investigate the effectiveness of a 6-week exercise programme in patients discharged home following critical illness compared with standard care. DESIGN: Multicentre prospective phase II randomised controlled trial, with blinded outcome assessment after hospital discharge, following the 6-week intervention and at 6 months. PARTICIPANTS: 60 patients (30 per group) aged ≥18 years, mechanically ventilated >96 hours, and not in other rehabilitation, that is, cardiac or pulmonary rehabilitation programmes. Participants in the intervention group completed an individually tailored (personalised) exercise programme. OUTCOME MEASURES: Primary outcome measure was SF-36 physical functioning following the intervention. Secondary outcomes included a range of performance-based and patient-reported measures. RESULTS: Improvements in the primary outcome did not differ significantly between groups (mean difference (95% CI) 3.0 (-2.2 to 8.2), p=0.26). The intervention group showed significant improvement compared with the control group (mean difference (95% CI)) in SF-36 role physical (6.6 (0.73 to 12.5), p=0.03); incremental shuttle walk test (83.1 m (8.3 to 157.9), p=0.03); functional limitations profile (-4.8 (-8.7 to -0.9), p=0.02); self-efficacy to exercise (2.2 (0.8 to 3.7), p=0.01) and readiness to exercise (1.3 (0.8 to 1.9), p<0.001). These improvements were not sustained at 6 months except readiness to exercise. Improvements in all other secondary outcome measures were not significant. CONCLUSIONS: There was no statistically significant difference in the primary outcome measure of self-reported physical function following this 6-week exercise programme. Secondary outcome results will help inform future studies. TRIAL REGISTRATION NUMBER: NCT01463579. (results), https://clinicaltrials.gov/.

A Multimodal Imaging Protocol, (123)I/(99)Tc-Sestamibi, SPECT, and SPECT/CT, in Primary Hyperparathyroidism Adds Limited Benefit for Preoperative Localization.

INTRODUCTION: Focused parathyroidectomy in primary hyperparathyroidism (1°HPT) is possible with accurate preoperative localization and intraoperative PTH monitoring (IOPTH). The added benefit of multimodal imaging techniques for operative success is unknown. METHOD: Patients with 1°HPT, who underwent parathyroidectomy in 2012-2014 at a single institution, were retrospectively reviewed. Only the patients who underwent the standardized multimodal imaging workup consisting of (123)I/(99)Tc-sestamibi subtraction scintigraphy, SPECT, and SPECT/CT were assessed. RESULTS: Of 360 patients who were identified, a curative operation was performed in 96%, using pre-operative imaging and IOPTH. Imaging analysis showed that (123)I/(99)Tc-sestamibi had a sensitivity of 86% (95% CI 82-90%), positive predictive value (PPV) 93%, and accuracy 81%, based on correct lateralization. SPECT had a sensitivity of 77% (95% CI 72-82%), PPV 92% and accuracy 72%. SPECT/CT had a sensitivity of 75% (95% CI 70-80%), PPV of 94%, and accuracy 71%. There were 3 of 45 (7%) patients with negative sestamibi imaging that had an accurate SPECT and SPECT/CT. Of 312 patients (87%) with positive uptake on sestamibi (93% true positive, 7% false positive), concordant findings were present in 86% SPECT and 84% SPECT/CT. In cases where imaging modalities were discordant, but at least one method was true-positive, (123)I/(99)Tc-sestamibi was significantly better than both SPECT and SPECT/CT (p < 0.001). The inclusion of SPECT and SPECT/CT in 1°HPT imaging protocol increases patient cost up to 2.4-fold. CONCLUSION: (123)I/(99)Tc-sestamibi subtraction imaging is highly sensitive for preoperative localization in 1°HPT. SPECT and SPECT/CT are commonly concordant with (123)I/(99)Tc-sestamibi and rarely increase the sensitivity. Routine inclusion of multimodality imaging technique adds minimal clinical benefit but increases cost to patient in high-volume setting.

Comparison of Blood Volume Profiles in Heart Failure With Preserved and Reduced Ejection Fractions: Sex Makes a Difference.

BACKGROUND: Blood volume (BV) profiles vary markedly in patients with heart failure (HF), but how HF phenotypes and patient sex impact volume profiles remain to be explored. The aim of the study was to differentiate BV, plasma volume, and red blood cell mass profiles by phenotypes of preserved and reduced left ventricular ejection fractions and assess the impact of patient sex on profile heterogeneity. METHODS: Retrospective analysis of clinical and BV data was undertaken in patients with chronic New York Heart Association II-III heart failure. BV was quantitated using the nuclear medicine indicator-dilution methodology. RESULTS: A total of 530 BV analyses (360 HF with reduced ejection fraction and 170 HF with preserved ejection fraction) were identified in 395 unique patients. Absolute BV was greater in HF with reduced ejection fraction (6.7±1.8 versus 5.9±1.6 liters: P<0.001); however, large variability in frequency distribution of volume profiles was observed in both phenotypes (-22% deficit to +109% excess relative to normal volumes). HF with reduced ejection fraction was characterized by a higher prevalence of BV expansion ≥+25% of normal (39% versus 26%; P=0.003), and HF with preserved ejection fraction was characterized a by more frequent normal BV (42% versus 24%; P<0.001). Male sex in both phenotypes was associated with a larger absolute BV (7.0±1.6 versus 5.1±1.3 liters; P<0.001) and higher frequency of large BV and plasma volume expansions above normal (both P<0.001), while females in both phenotypes demonstrated a higher prevalence of normal BV and plasma volume (both P<0.001). CONCLUSIONS: Findings support significant differences in BV, plasma volume, and red blood cell mass profile distributions between heart failure phenotypes, driven in large part by sex-specific factors. This underscores the importance of identifying and distinguishing individual patient volume profiles to help guide volume management strategies.

Differences in red blood cell mass profiles impact intravascular volume and outcome risk in chronic heart failure.

AIMS: To identify different red blood cell mass (RBCM) profiles, separate from haemoglobin concentrations, and their impact on blood volume expansion and clinical outcomes in chronic heart failure. METHODS AND RESULTS: RBCM was measured at hospital discharge using standardized nuclear medicine indicator-dilution methodology in patients following diuretic treatment for clinical congestion. Individual RBCM phenotypes were prospectively identified and analysed for heart failure-related mortality or first rehospitalization over 1 year. Of 132 patients, 42 (32%) demonstrated normal RBCM, 36 (27%) RBCM deficit (true anaemia), and 54 (41%) RBCM excess (erythrocythemia). Dilutional 'anaemia' defined by haemoglobin <12 g/dL with normal or an excess in RBCM with plasma volume expansion was identified in 37 (28%) patients. There were 61 composite outcome events, which included 38 deaths (29% of cohort) occurring over the 1 year follow-up period [14/36 (39%) in RBCM deficit, 12/42 (29%) in normal RBCM, and 12/54 (22%) in RBCM excess subgroups]. By Kaplan-Meier and multivariate analyses, RBCM excess was independently associated with the best event-free survival while RBCM deficit (true anaemia) the poorest outcomes; both compared with normal RBCM (P < 0.001). Dilutional 'anaemia' demonstrated a lower risk compared with true anaemia (P = 0.03). CONCLUSIONS: Markedly different RBCM profiles are identifiable among comparably compensated heart failure patients, and this variability carries significant implications for post-hospital outcomes. Novel to this analysis and in contrast to RBCM deficit is the independent association of RBCM excess with better event-free survival compared with normal RBCM. The distinction of RBCM profiles to guide risk stratification and individualized patient management strategies warrants further study.

Blood volume and chronic kidney disease in heart failure - Can volume expansion help balance the Cardio-Renal Axis for better clinical outcomes?

Intravascular volume is largely regulated by the kidneys but how differences in intravascular volume profiles interact with chronic kidney disease (CKD) to influence outcomes in chronic heart failure (HF) has not been explored. Our hypothesis was that a greater degree of volume expansion (VE) would moderate the impact of CKD on HF-related clinical outcomes. Quantitative blood volume (BV) data were available in 137 patients at the time of hospital discharge using a nuclear medicine radiolabeled albumin indicator-dilution technique. The study patients were stratified by the cohort median glomerular filtration rate (GFR, 44 ml/min/1.73 m2 ). An a priori cut-point of ≥+25% above normal BV was then used to further stratify the two GFR subgroups and prospectively analyzed for 1-year HF-related mortality or 1st re-hospitalization. Persistent BV expansions ≥+25% were present in 51% of the cohort. In the subgroup with GFR above the median (N = 68) greater or lesser BV expansion from +25% did not differentiate outcomes. However, in the subgroup with GFR below the median (N = 69), BV expansion-stratified risk (log-rank p = 0.022) with <+25% VE associated with poorer outcomes, while VE ≥ + 25% was associated with lower risk and comparable to GFR above the median. In patients with chronic HF, significant intravascular VE and CKD are common co-existing conditions. The presence of larger VE, however, appears to be a factor mitigating the impact of declining renal function on clinical outcomes, and as an element of volume pathophysiology warrants further study.

Impaired endothelium-dependent vasodilatation is a novel predictor of mortality in intensive care.

OBJECTIVE: Endothelial function may be impaired in critical illness. We hypothesized that impaired endothelium-dependent vasodilatation is a predictor of mortality in critically ill patients. DESIGN: Prospective observational cohort study. SETTING: Seventeen-bed adult intensive care unit in a tertiary referral university teaching hospital. PATIENTS: Patients were recruited within 24 hrs of admission to the intensive care unit. INTERVENTIONS: The SphygmoCor Mx system was used to derive the aortic augmentation index from radial artery pulse pressure waveforms. Endothelium-dependent vasodilatation was calculated as the change in augmentation index in response to an endothelium-dependent vasodilator (salbutamol). MEASUREMENTS AND MAIN RESULTS: Demographics, severity of illness scores, and physiological parameters were collected. Statistically significant predictors of mortality identified using single regressor analysis were entered into a multiple logistic regression model. Receiver operator characteristic curves were generated. Ninety-four patients completed the study. There were 80 survivors and 14 nonsurvivors. The Simplified Acute Physiology Score II, the Sequential Organ Failure Assessment score, leukocyte count, and endothelium-dependent vasodilatation conferred an increased risk of mortality. In logistic regression analysis, endothelium-dependent vasodilatation was the only predictor of mortality with an adjusted odds ratio of 26.1 (95% confidence interval [CI], 4.3-159.5). An endothelium-dependent vasodilatation value of 0.5% or less predicted intensive care unit mortality with a sensitivity of 79% (CI, 59-88%) and specificity of 98% (CI, 94-99%). CONCLUSIONS: In vivo bedside assessment of endothelium-dependent vasodilatation is an independent predictor of mortality in the critically ill. We have shown it to be superior to other validated severity of illness scores with high sensitivity and specificity.

Symptom improvement after upgrade from right ventricular apical to biventricular pacing: Role of right and left ventricular volumes assessed with single-photon emission computed tomographic equilibrium radionuclide angiocardiography.

BACKGROUND: In patients with heart failure and reduced left ventricular ejection fraction (LVEF), the effect of upgrading from right ventricular (RV) apical to biventricular pacing on RV and left ventricular (LV) volumes and ejection fraction (EF) is unknown. Also, the relationship of symptom improvement after biventricular upgrade to RV and LV volumes and EF has not been clarified. METHODS AND RESULTS: Nineteen patients with long-standing persistent RV apical pacing who had heart failure symptoms and echocardiographic LVEF of 0.40 or less underwent upgrade to biventricular pacing. Patients had single-photon emission computed tomographic equilibrium radionuclide angiocardiography immediately before and at 3-6 months after the upgrade procedure, to measure RV and LV volumes and EF. Biventricular upgrade was associated with increase in LVEF and decrease in LV end-diastolic and end-systolic volumes; right ventricular ejection fraction (RVEF) and end-diastolic and end-systolic volumes were unaltered. Patients with improvement in New York Heart Association heart failure class of I or more had larger initial LV end-diastolic volumes than patients without an improvement and had decreased LV end-diastolic and end-systolic volumes comparatively. Symptom improvement was not associated with RVEF and volume change. CONCLUSION: Symptom improvement with LV remodeling, but not RV remodeling, occurs 3-6 months after biventricular upgrade in patients with heart failure.

The incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 1996 to 2006.

BACKGROUND & AIMS: The epidemiology of gastroparesis is unknown. We aimed to determine the incidence, prevalence, and outcome of gastroparesis in the community. METHODS: Using the Rochester Epidemiology Project, a medical records linkage system in Olmsted County, Minnesota, we identified county residents with potential gastroparesis. The complete medical records were reviewed by a gastroenterologist. Three diagnostic definitions were used: (1) definite gastroparesis, delayed gastric emptying by standard scintigraphy and typical symptoms for more than 3 months; (2) probable gastroparesis, typical symptoms and food retention on endoscopy or upper gastrointestinal study; (3) possible gastroparesis, typical symptoms alone or delayed gastric emptying by scintigraphy without gastrointestinal symptoms. Poisson regression was used to assess the association of incidence rates with age, sex, and calendar period. RESULTS: Among 3604 potential cases of gastroparesis, 83 met diagnostic criteria for definite gastroparesis, 127 definite plus probable gastroparesis, and 222 any of the 3 definitions of gastroparesis. The age-adjusted (to the 2000 US white population) incidence per 100,000 person-years of definite gastroparesis for the years 1996-2006 was 2.4 (95% confidence interval [CI], 1.2-3.8) for men and 9.8 (95% CI, 7.5-12.1) for women. The age-adjusted prevalence of definite gastroparesis per 100,000 persons on January 1, 2007, was 9.6 (95% CI, 1.8-17.4) for men and 37.8 (95% CI, 23.3-52.4) for women. Overall survival was significantly lower than the age- and sex-specific expected survival computed from the Minnesota white population (P<.05). CONCLUSIONS: Gastroparesis is an uncommon condition in the community but is associated with a poor outcome.

Comparison of 18F-FDG and PiB PET in cognitive impairment.

UNLABELLED: The purpose of this study was to compare the diagnostic accuracy of glucose metabolism and amyloid deposition as demonstrated by (18)F-FDG and Pittsburg Compound B (PiB) PET to evaluate subjects with cognitive impairment. METHODS: Subjects were selected from existing participants in the Mayo Alzheimer's Disease Research Center or Alzheimer's Disease Patient Registry programs. A total of 20 healthy controls and 17 amnestic mild cognitive impairment (aMCI), 6 nonamnestic mild cognitive impairment (naMCI), and 13 Alzheimer disease (AD) subjects were imaged with both PiB and (18)F-FDG PET between March 2006 and August 2007. Global measures for PiB and (18)F-FDG PET uptake, normalized to cerebellum for PiB and pons for (18)F-FDG, were compared. Partial-volume correction, standardized uptake value (SUV), and cortical ratio methods of image analysis were also evaluated in an attempt to optimize the analysis for each test. RESULTS: Significant discrimination (P < 0.05) between controls and AD, naMCI and aMCI, naMCI and AD, and aMCI and AD by PiB PET measurements was observed. The paired groupwise comparisons of the global measures demonstrated that PiB PET versus (18)F-FDG PET showed similar significant group separation, with only PiB showing significant separation of naMCI and aMCI subjects. CONCLUSION: PiB PET and (18)F-FDG PET have similar diagnostic accuracy in early cognitive impairment. However, significantly better group discrimination in naMCI and aMCI subjects by PiB, compared with (18)F-FDG, was seen and may suggest early amyloid deposition before cerebral metabolic disruption in this group.

Myocardial Energetics in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O2 consumption [MVO2]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O2 extraction. Lastly, we assessed whether coupling of MVO2 to EW (mechanical efficiency) was impaired in HFpEF. METHODS AND RESULTS: In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11C-acetate positron emission tomography assessing MVO2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO2, and MBF. With dobutamine, LV EW, MVO2, and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. CONCLUSIONS: In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O2 supply relative to demand, and is associated with reserve dysfunction.

18F-FDG PET in the management of patients with anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid tumors in humans. The use of positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) in ATC has not been studied, and only a few case reports have been published. The objective of this study was to investigate the potential contribution of 18F-FDG PET to the clinical management of patients with ATC. METHODS: All patients with ATC studied with 18F-FDG PET from August 2001 through March 2007 were included. The PET results were correlated with computed tomography, ultrasound, magnetic resonance imaging, bone scan, histology, and clinical follow-up. The FDG uptake was semiquantified as maximum standard uptake value. Any change in the treatment plan as a direct result of the PET findings as documented in the clinical notes was recorded. RESULTS: Sixteen patients were included. True-positive PET findings were seen for all primary tumors, in all nine patients with lymph node metastases, in five out of eight patients with lung metastases, and in two patients with distant metastases other than lung metastases. In 8 of the 16 patients, the medical records reported a direct impact of the PET findings on the clinical management. CONCLUSIONS: ATC demonstrates intense uptake on 18F-FDG PET images. In 8 of the 16 patients (50%), the medical records reported a direct impact of the PET findings on the management of the patient. PET may improve disease detection and have an impact on the management of patients with ATC relative to other imaging modalities.