Iterated multisource exchangeability models for individualized inference with an application to mobile sensor data.

Researchers are increasingly interested in using sensor technology to collect accurate activity information and make individualized inference about treatments, exposures, and policies. How to optimally combine population data with data from an individual remains an open question. Multisource exchangeability models (MEMs) are a Bayesian approach for increasing precision by combining potentially heterogeneous supplemental data sources into analysis of a primary source. MEMs are a potentially powerful tool for individualized inference but can integrate only a few sources; their model space grows exponentially, making them intractable for high-dimensional applications. We propose iterated MEMs (iMEMs), which identify a subset of the most exchangeable sources prior to fitting a MEM model. iMEM complexity scales linearly with the number of sources, and iMEMs greatly increase precision while maintaining desirable asymptotic and small sample properties. We apply iMEMs to individual-level behavior and emotion data from a smartphone app and show that they achieve individualized inference with up to 99% efficiency gain relative to standard analyses that do not borrow information.

Structure Driven Prediction of Chromatographic Retention Times: Applications to Pharmaceutical Analysis.

Pharmaceutical drug development relies heavily on the use of Reversed-Phase Liquid Chromatography methods. These methods are used to characterize active pharmaceutical ingredients and drug products by separating the main component from related substances such as process related impurities or main component degradation products. The results presented here indicate that retention models based on Quantitative Structure Retention Relationships can be used for de-risking methods used in pharmaceutical analysis and for the identification of optimal conditions for separation of known sample constituents from postulated/hypothetical components. The prediction of retention times for hypothetical components in established methods is highly valuable as these compounds are not usually readily available for analysis. Here we discuss the development and optimization of retention models, selection of the most relevant structural molecular descriptors, regression model building and validation. We also present a practical example applied to chromatographic method development and discuss the accuracy of these models on selection of optimal separation parameters.

Need for tracheostomy after lung transplant predicts decreased mid- and long-term survival.

BACKGROUND: Tracheostomy is an important adjunct for lung transplant patients requiring prolonged ventilation. We explored the effects of post-transplant tracheostomy on survival and bronchiolitis obliterans syndrome after lung transplant. METHODS: A retrospective, single center analysis was performed on all lung transplant recipients during the Lung Allocation Score (LAS) era. Risk factors for post-transplant tracheostomy or death within 30 days were assessed. Kaplan-Meier estimates and Cox proportional hazards models were used to examine the association between tracheostomy within 30 days after transplant and survival at 1 and 3 years. A total of 403 patients underwent single or bilateral lung transplant between May 2005 and February 2016 with complete data for 352 cases, and 35 patients (9.9%) underwent tracheostomy or died (N = 10, 2.8%) within 30 days. RESULTS: In adjusted analyses, primary graft dysfunction grade 3 (PGD3) was associated with a composite end point of tracheostomy or death within 30 days (HR 3.11 (1.69, 5.71), P-value < .001). Tracheostomy within 30 days was associated with decreased survival at 1(HR 4.25 [1.75, 10.35] P-value = .001) and 3 years (HR 2.74 [1.30, 5.76], P-value = .008), as well as decreased bronchiolitis obliterans (BOS)-free survival at 1 (HR 1.87 [1.02, 3.41] P-value = .042) and 3 years (HR 2.15 [1.33, 3.5], P-value = .002). CONCLUSION: Post-transplant tracheostomy is a marker for advanced lung allograft dysfunction with significant reduction in long-term overall and BOS-free survival.

Interobserver Variability in the Recognition of Hypoxic-Ischemic Brain Injury on Computed Tomography Soon After Out-of-Hospital Cardiac Arrest.

BACKGROUND: Cerebral edema and loss of gray-white matter differentiation on head computed tomography (CT) after cardiac arrest generally portend a poor prognosis. The interobserver variability in physician recognition of hypoxic-ischemic brain injury (HIBI) on early CT after out-of-hospital cardiac arrest has not been studied. METHODS: In this survey study, participating physicians and a neuroradiologist reviewed 20 randomly selected head CTs obtained within 2 h of out-of-hospital cardiac arrest and decided if HIBI was present. All participants were blinded to clinical details. Interobserver agreement on the presence of HIBI (primary outcome) and pairwise agreement between participants and the neuroradiologist (secondary outcome) were determined using multi- and dual-rater kappa statistics with 95% confidence intervals (CIs). RESULTS: Agreement among physicians regarding the presence of HIBI on head CT was fair (kappa 0.34; 95% CI 0.19-0.49). Individual physician agreement with the neuroradiologist varied from poor to moderate (kappa 0.0-0.48), with 8 of 10 physicians having no more than fair agreement. Regarding the perceived severity of HIBI on head CT, physician agreement was moderate (ICC = 0.56; 95% CI 0.38-0.77). CONCLUSION: Physicians, including radiologists, demonstrated substantial interobserver variability when identifying HIBI on head CT soon after out-of-hospital cardiac arrest.

Early characteristics of bone deficits in children with Fontan palliation.

BACKGROUND: This is a cross-sectional study aiming to understand the early characteristics and background of bone health impairment in clinically well children with Fontan circulation. METHODS: We enrolled 10 clinically well children with Fontan palliation (operated >5 years before study entrance, Tanner stage ≤3, age 12.1 ± 1.77 years, 7 males) and 11 healthy controls (age 12.0 ± 1.45 years, 9 males) at two children's hospitals. All patients underwent peripheral quantitative CT. For the Fontan group, we obtained clinical characteristics, NYHA class, cardiac index by MRI, dual x-ray absorptiometry, and biochemical studies. Linear regression was used to compare radius and tibia peripheral quantitative CT measures between Fontan patients and controls. RESULTS: All Fontan patients were clinically well (NYHA class 1 or 2, cardiac index 4.85 ± 1.51 L/min/m2) and without significant comorbidities. Adjusted trabecular bone mineral density, cortical thickness, and bone strength index at the radius were significantly decreased in Fontan patients compared to controls with mean differences -30.13 mg/cm3 (p = 0.041), -0.31 mm (p = 0.043), and -6.65 mg2/mm4 (p = 0.036), respectively. No differences were found for tibial measures. In Fontan patients, the mean height-adjusted lumbar bone mineral density and total body less head z scores were -0.46 ± 1.1 and -0.63 ± 1.1, respectively, which are below the average, but within normal range for age and sex. CONCLUSIONS: In a clinically well Fontan cohort, we found significant bone deficits by peripheral quantitative CT in the radius but not the tibia, suggesting non-weight-bearing bones may be more vulnerable to the unique haemodynamics of the Fontan circulation.

Single Versus Bilateral Lung Transplantation for Idiopathic Pulmonary Fibrosis in the Lung Allocation Score Era.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease. Lung transplantation is the only therapy associated with prolonged survival. The ideal transplant procedure for IPF is unclear. Outcomes after single transplantation (SLTx) versus bilateral lung transplantation (BLTx) in IPF patients after introduction of the Lung Allocation Score were examined. METHODS: Records of patients undergoing lung transplantation for IPF at our institution between May 2005 and March 2017 were reviewed to examine the effect of transplant laterality. Primary outcomes were overall, rejection-free, and bronchiolitis obliterans (BOS)-free survival at 1 and 5 years post-transplant. RESULTS: Lung transplantation was performed in 151 IPF patients post-Lung Allocation Score. Most recipients were male with average age 59 ± 8 years. SLTx was performed in 94 patients (62%). In the overall cohort, comparative survival between SLTx and BLTx was similar at 1 and 5 years before and after adjusting for age and pulmonary hypertension (PH). SLTx was associated with shorter ventilator time and intensive care unit stay and trended toward improved survival over BLTx in patients without PH. CONCLUSIONS: The use of SLTx versus BLTx in IPF did not correspond to significantly different survival adjusting for age and PH. BLTx was associated with prolonged postoperative ventilation and length of stay compared with SLTx. Patients without PH, all older patients, and patients with PH and advanced disease should be considered for SLTx for IPF.

Laryngeal Mask Airway for Surfactant Administration in Neonates: A Randomized, Controlled Trial.

OBJECTIVE: To determine if preterm infants with moderate respiratory distress syndrome on continuous positive airway pressure (CPAP) who received surfactant via a laryngeal mask airway (LMA) would have a decreased rate of intubation and mechanical ventilation compared with those on CPAP who did not receive surfactant. STUDY DESIGN: In this prospective, multicenter, randomized controlled trial, 103 premature infants 280/7-356/7 weeks gestation, ≥1250 g and ≤36 hours old on CPAP requiring fraction of inspired oxygen 0.30-0.40 were assigned to receive surfactant administered through an LMA then placed back on CPAP (LMA group) or maintained on CPAP with no surfactant administered (control group). The primary outcome was treatment failure necessitating intubation and mechanical ventilation in the first 7 days of life. RESULTS: Surfactant administration through an LMA (n = 50) significantly decreased the rate of intubation and mechanical ventilation compared with controls (n = 53): 38% vs 64%, respectively, OR 0.30 (95% CI 0.13, 0.70), P = .006, number needed to treat: 4). There were no serious adverse events associated with placement of the LMA or surfactant administration. CONCLUSIONS: In premature neonates with moderate respiratory distress syndrome, surfactant administered through an LMA decreased the rate of intubation and mechanical ventilation. This intervention may have significant impact on clinical care in both high and low resource settings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01116921.

Lung transplant after prolonged ex vivo lung perfusion: predictors of allograft function in swine.

Portable normothermic EVLP has been evaluated in clinical trials using standard and extended-criteria donor lungs. We describe a swine model of lung transplant following donation after circulatory death using prolonged normothermic EVLP to assess the relationship between EVLP data and acute lung allograft function. Adult swine were anesthetized and heparinized. In the control group (n = 4), lungs were procured, flushed, and transplanted. Treatment swine underwent either standard procurement (n = 3) or agonal hypoxia followed by 1 (n = 4) or 2 hours (H) (n = 4) of ventilated warm ischemia. Lungs were preserved for 24H using normothermic blood-based EVLP then transplanted. Recipients were monitored for 4 H. After 24H of preservation, mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and dynamic compliance (Cdyn ) were improved in all EVLP groups. After transplant, EVLP groups showed similar allograft oxygenation. EVLP PVR, mPAP, and lung block weights had significant negative correlations with post-transplant allograft oxygenation. EVLP P:F ratio did not correlate with acute post-transplant allograft function until 24H of preservation. Data measured in the first 8H of EVLP were sufficient for predicting acute post-transplant allograft function. This study provides a benchmark and platform for evaluation of therapies for donor-related allograft injury in injured lungs treated with prolonged normothermic EVLP.

Gender differences in long-term survival post-transplant: A single-institution analysis in the lung allocation score era.

The purpose of this study was to clarify the significance of recipient gender status on lung transplant outcomes in a large single-institution experience spanning three decades, we analyzed data from all lung transplants performed in our institution since 1986. Kaplan-Meier curves and Cox proportional hazard models were used to evaluate the effect of recipient characteristics on survival and BOS score ≥1-free survival. Logistic regression analysis was used to explore the association of gender with short-term graft function. About 876 lung transplants were performed between 1986 and 2016. Kaplan-Meier survival estimates at 5 years post-transplant for females vs males in the LAS era were 71% vs 58%. In the LAS era, females showed greater unadjusted BOS≥1-free survival than males (35% vs 25%, P=.02) over 5 years. Female gender was the only factor in the LAS era significantly associated with improved adjusted 5-year survival [HR 0.56 (95% CI 0.33, 0.95) P=.03]. Conversely, in the pre-LAS era female gender was not associated with improved survival. Female recipients showed significantly improved survival over 5 years compared to males in the LAS era. A prospective analysis of biologic and immunologic differences is warranted.

An experimental study of the recovery of injured porcine lungs with prolonged normothermic cellular ex vivo lung perfusion following donation after circulatory death.

Donation after circulatory death (DCD) is an underused source of donor lungs. Normothermic cellular ex vivo lung perfusion (EVLP) is effective in preserving standard donor lungs but may also be useful in the preservation and assessment of DCD lungs. Using a model of DCD and prolonged EVLP, the effects of donor warm ischemia and postmortem ventilation on graft recovery were evaluated. Adult male swine underwent general anesthesia and heparinization. In the control group (n = 4), cardioplegic arrest was induced and the lungs were procured immediately. In the four treatment groups, a period of agonal hypoxia was followed by either 1 h of warm ischemia with (n = 4) or without (n = 4) ventilation or 2 h of warm ischemia with (n = 4) or without (n = 4) ventilation. All lungs were studied on an EVLP platform for 24 h. Hemodynamic measures, compliance, and oxygenation on EVLP were worse in all DCD lungs compared with controls. Hemodynamics and compliance normalized in all lungs after 24 h of EVLP, but DCD lungs demonstrated impaired oxygenation. Normothermic cellular EVLP is effective in preserving and monitoring of DCD lungs. Early donor postmortem ventilation and timely procurement lead to improved graft function.

A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies.

The ICH M7 Option 4 control of (potentially) mutagenic impurities is based on the use of scientific principles in lieu of routine analytical testing. This approach can reduce the burden of analytical testing without compromising patient safety, provided a scientifically rigorous approach is taken which is backed up by sufficient theoretical and/or analytical data. This paper introduces a consortium-led initiative and offers a proposal on the supporting evidence that could be presented in regulatory submissions.

Comparison of laryngeal mask airway and endotracheal tube placement in neonates.

OBJECTIVE: We hypothesize that the time, number of attempts, and physiologic stability of placement of an LMA would be superior compared to ETT. STUDY DESIGN: Videotape and physiologic parameters of LMA (n = 36) and ETT (n = 31) placement procedures for infants 28-36 weeks gestation were reviewed. RESULTS: Duration of attempts (32 vs 66 s, p < 0.001) and mean total airway insertion time (88 vs 153 s, p = 0.06) was shorter for LMA compared to ETT. Mean number of attempts for successful placement was fewer for LMA (1.5 vs 1.9, p = 0.11). Physiologic parameters remained near baseline in both groups despite very different degrees of premedication. CONCLUSION: Placement of an LMA required less time and fewer number of attempts compared to ETT. Physiologic stability of an LMA was maintained without the use of an analgesic and muscle relaxant. Use of an LMA is a favorable alternative to ETT placement for surfactant delivery in neonates. TRIAL REGISTRATION: NCT01116921.

Longitudinal comparison of the self-administered ALSFRS-RSE and ALSFRS-R as functional outcome measures in ALS.

Objective: Test the feasibility, adherence rates and optimal frequency of digital, remote assessments using the ALSFRS-RSE via a customized smartphone-based app. Methods: This fully remote, longitudinal study was conducted over a 24-week period, with virtual visits every 3 months and weekly digital assessments. 19 ALS participants completed digital assessments via smartphone, including a digital version of the ALSFRS-RSE and mood survey. Interclass correlation coefficients (ICC) and Bland-Altman plots were used to assess agreement between staff-administered and self-reported ALSFRS-R pairs. Longitudinal change was evaluated using ANCOVA models and linear mixed models, including impact of mood and time of day. Impact of frequency of administration of the ALSFRS-RSE on precision of the estimate slope was tested using a mixed effects model. Results: In our ALS cohort, digital assessments were well-accepted and adherence was robust, with completion rates of 86%. There was excellent agreement between the digital self-entry and staff-administered scores computing multiple ICCs (ICC range = 0.925-0.961), with scores on the ALSFRS-RSE slightly higher (1.304 points). Digital assessments were associated with increased precision of the slope, resulting in higher standardized response mean estimates for higher frequencies, though benefit appeared to diminish at biweekly and weekly frequency. Effects of participant mood and time of day on total ALSFRS-RSE score were evaluated but were minimal and not statistically significant. Conclusion: Remote collection of digital patient-reported outcomes of functional status such as the ALSFRS-RSE yield more accurate estimates of change over time and provide a broader understanding of the lived experience of people with ALS.

Comparison of Laryngeal Mask Airway and Endotracheal Tube Placement in Neonates.

Objective: We hypothesize that the time, number of attempts and physiologic stability of placement of an LMA would be superior compared to ETT. Study Design: Videotape and physiologic parameters of LMA (n = 36) and ETT (n = 31) placement procedures for infants 28-36 weeks gestation were reviewed. Results: Duration of attempts (32 vs 66 sec, p < 0.001) and mean total procedure time (88 vs 153 sec, p = 0.06) was shorter for LMA compared to ETT. Mean number of attempts for successful placement was fewer for LMA (1.5 vs 1.9, p = 0.11). Physiologic parameters remained near baseline in both groups despite very different degrees of premedication. Conclusion: Placement of an LMA required less time and fewer number of attempts compared to ETT. Physiologic stability of an LMA was maintained without the use of an analgesic and muscle relaxant. Use of an LMA is a favorable alternative to ETT placement for surfactant delivery in neonates. Trial registration: NCT01116921.

Impact of structural similarity on the accuracy of retention time prediction.

Quantitative Structure-Retention Relationships offer a valuable tool for de-risking chromatographic methods in relation to newly formed or hypothetical compounds, arising from synthetic processes or formulation activities. They can also be used to identify optimal separation conditions, or in support of structural elucidation. In this contribution, we provide a systematic study of the relationship between the accuracy of the retention model, the size of the training set and its structural similarity to the predicted compound. We compare structural similarity expressed either on a fingerprint basis (e.g., Tanimoto index), or by Euclidean distance calculated from of subset of molecular descriptors. The results presented indicate that accurate and predictive models can be built from a small dataset containing as few as 25 compounds, provided that the training set is structurally similar to the test compound. When the training set contains compounds selected by minimizing the Euclidean distance calculated from 3 descriptors most correlated with the retention time, root mean square error of 0.48 min and correlation coefficient of 0.9464 were observed for the test sets of 104 compounds. Moreover, these models meet the Tropsha predictivity criteria. These findings potentially bring the prediction of retention times within the practical reach of pharmaceutical analysts involved in chromatographic method development. We also present an optimisation approach to select algorithm settings in order to minimize the prediction error and ensure model predictivity.

Guanidinium solvents with exceptional hydrogen bond donating abilities.

Guanidinium chloride-based solvents have been prepared using deep eutectic solvent principles. Strong hydrogen-bond (H-bond) donating abilities are established based on a range of measures of solvent polarity, including a novel 31P NMR chemical shift method. The physical properties and origin of the strong H-bonding ability of these solvents have been explored.

Incidental coronary calcium in cancer patients treated with anthracycline and/or trastuzumab.

AIMS: Cancer patients are at increased risk of cardiovascular disease (CVD) after treatment with potentially cardiotoxic treatments. Many cancer patients undergo non-gated chest computed tomography (NCCT) for cancer staging prior to treatment. We aimed to assess whether coronary artery calcification on NCCT predicts CVD risk in cancer patients. METHODS AND RESULTS: Six hundred and three patients (mean age: 61.3 years, 30.8% male) with either breast cancer, lymphoma, or sarcoma were identified retrospectively. Primary endpoint was a major adverse cardiac event (MACE) composite including non-fatal myocardial infarction, new heart failure (HF) diagnosis, HF hospitalization, and cardiac death, with Fine-Gray analysis for non-cardiac death as competing risk. Secondary endpoints included a coronary composite and a HF composite. Coronary artery calcification was present in 194 (32.2%) and clinically reported in 85 (43.8%) patients. At a median follow-up of 5.3 years, 256 (42.5%) patients died of non-cardiac causes. Coronary artery calcification presence or extent was not an independent predictor of MACE [sub-distribution hazards ratio (SHR) 1.28; 0.73-2.27]. Coronary artery calcification extent was a significant predictor of the coronary composite outcome (SHR per two-fold increase 1.14; 1.01-1.28), but not of the HF composite outcome (SHR per two-fold increase 1.04; 0.95-1.14). CONCLUSION: Coronary artery calcification detected incidentally on NCCT scans in cancer patients is prevalent and often not reported. Coronary artery calcification presence or extent did not independently predict MACE. Coronary artery calcification extent was independently associated with increased risk of CAD events but not HF events.

Potent inhibitors of toxic alpha-synuclein identified via cellular time-resolved FRET biosensors.

We have developed a high-throughput drug discovery platform, measuring fluorescence resonance energy transfer (FRET) with fluorescent alpha-synuclein (αSN) biosensors, to detect spontaneous pre-fibrillar oligomers in living cells. Our two αSN FRET biosensors provide complementary insight into αSN oligomerization and conformation in order to improve the success of drug discovery campaigns for the treatment of Parkinson's disease. We measure FRET by fluorescence lifetime, rather than traditional fluorescence intensity, providing a structural readout with greater resolution and precision. This facilitates identification of compounds that cause subtle but significant conformational changes in the ensemble of oligomeric states that are easily missed using intensity-based FRET. We screened a 1280-compound small-molecule library and identified 21 compounds that changed the lifetime by >5 SD. Two of these compounds have nanomolar potency in protecting SH-SY5Y cells from αSN-induced death, providing a nearly tenfold improvement over known inhibitors. We tested the efficacy of several compounds in a primary mouse neuron assay of αSN pathology (phosphorylation of mouse αSN pre-formed fibrils) and show rescue of pathology for two of them. These hits were further characterized with biophysical and biochemical assays to explore potential mechanisms of action. In vitro αSN oligomerization, single-molecule FRET, and protein-observed fluorine NMR experiments demonstrate that these compounds modulate αSN oligomers but not monomers. Subsequent aggregation assays further show that these compounds also deter or block αSN fibril assembly.

Patients with Gaucher disease display systemic oxidative stress dependent on therapy status.

Gaucher disease is an autosomal recessive metabolic disorder caused by mutations in GBA1, which encodes for the lysosomal hydrolase enzyme, ß-glucocerebrosidase. The resulting misfolded protein can trigger endoplasmic reticulum stress and an unfolded protein response within the affected cells. The enzyme deficiency leads to accumulation of its substrates, glucosylceramide and glucosylsphingosine, within macrophage lysosomes and with prominent disease manifestations in macrophage rich tissues. Resultant lysosomal pathology and impaired autophagy leads to redox imbalance, mitochondrial dysfunction and intracellular oxidative stress. Here we have systematically examined a role for oxidative stress in individuals affected by Gaucher disease. We compared multiple oxidative stress biomarkers in plasma and red blood cell samples from patients who are currently untreated, with those who are stable on standard-of-care therapy, and with healthy controls. We found significant differences in key oxidative stress biomarkers in untreated patients compared to healthy control. In treated patients, results generally fell between the controls and the untreated patients. Interestingly, even asymptomatic and minimally symptomatic untreated patients had evidence of significant systemic oxidative stress. We conclude that underlying oxidative stress may contribute to Gaucher disease pathophysiology including long-term adverse outcomes such as Parkinsonism and malignancies. Therapies targeting oxidative stress may prove useful as adjuvant treatments for Gaucher disease and other lysosomal storage disorders.

White matter microstructure relates to lassitude but not diagnosis in adolescents with depression.

The neurobiology of adolescent depression remains poorly understood. Initial studies suggested impaired white matter microstructure in adults and adolescents, but findings have not been consistent. Challenges in this literature have included small samples, medication confounds and inconsistent correction for type I error. This study addressed these issues in a new examination of fractional anisotropy (FA) in adolescents with major depressive disorder (MDD) using diffusion tensor imaging. We examined FA in 81 adolescents aged 12-19 (44 MDD [all unmedicated], 37 controls). We conducted logistic regression analyses to examine the odds of MDD versus control based on FA within standard white matter tracts that were delineated by probabilistic tractography. We also examined relationships between FA and disease severity (overall depression and dimensions of illness). Finally, we conducted a voxel-wise group comparison of FA. All analyses covaried for age, sex and socioeconomic status, and applied rigorous corrections for multiple testing. Logistic regression did not reveal significant associations between diagnosis and FA within white matter tracts defined by probabilistic tractography. Dimensional analyses revealed that greater lassitude was associated with higher FA in right cingulum bundle and bilateral corticospinal tracts, but with lower FA in right anterior thalamic radiation. Voxel-wise group comparisons of FA did not reveal significant group differences. The current findings do not support low FA as a neurobiological marker of adolescent depression. Dimensional results suggest that FA relates to lassitude but not overall depression. Given the clinical and neurobiological heterogeneity of depression, future work utilizing dimensional approaches may help elucidate the role of white matter microstructure in adolescent depression neurobiology.