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/.