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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.

A 36-year-old otherwise healthy man who presents with two weeks of sore throat and associated hoarse voice, followed by 5 days of odynophagia. He denies fevers or chills. He does not smoke tobacco. No medical or surgical history. No home medications. No allergies. BP: 135/83 mm Hg, heart rate: 61, temperature: 36.8°C, respirations: 16, SpO2: 100%. Young man resting comfortably in bed. Non-toxic appearing. The patient was noted to have a ‘hot potato’ voice. Examination apart from intraoral was benign. Oral examination was notable for bilateral erythematous and swollen peritonsillar regions, left greater than right (figure 1). Figure 1 Intra-oral physical exam findings. None were drawn. 1. What are the indications for performing a point-of-care ultrasound (POCUS) of the peritonsillar region? Indications for this examination include evaluating for peritonsillar abscess. A peritonsillar abscess typically progresses from tonsillitis to peritonsillar cellulitis and then grows into an abscess. As with most soft-tissue infections, ultrasound can be used as a medium for diagnosing abscesses.1 2. Which probe is most ideal in the assessment of peritonsillar region? Images are obtained by with the use of the endocavitary transducer. Remember to keep your thumb aligned with the marker dot when using the endocavitary probe and to …

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.

Although speech and language biomarker (SLB) research studies have shown methodological and clinical promise, some common limitations of these studies include small sample sizes, limited longitudinal data, and a lack of a standardized survey protocol. Here, we introduce the Voiceome Protocol and the corresponding Voiceome Dataset as standards which can be utilized and adapted by other SLB researchers. The Voiceome Protocol includes 12 types of voice tasks, along with health and demographic questions that have been shown to affect speech. The longitudinal Voiceome Dataset consisted of the Voiceome Protocol survey taken on (up to) four occasions, each separated by roughly three weeks (22.80 +/- 20.91 days). Of 6,650 total participants, 1,382 completed at least two Voiceome surveys. The results of the Voiceome Dataset are largely consistent with results from standard clinical literature, suggesting that the Voiceome Study is a high-fidelity, normative dataset and scalable protocol that can be used to advance SLB research.

A man aged 65 years with a history of polysubstance abuse, currently on 80 mg daily of methadone in addition to ongoing intravenous drug use (IVDU) presents with 1 week of left arm pain. Patient reports gradual onset of swelling, erythema and pain of the left arm that began shortly after ‘muscling’ heroin (injecting heroin into the muscle instead of into a vein) into that site. He denies fever, chills, palpitations, chest pain, shortness of breath or other symptoms on review of systems. Medical history: hepatitis, polysubstance abuse. No surgical history. Home medications: methadone 80 mg daily. No known allergies. ### Triage vital signs BP: 146/84 mm Hg, HR: 77 bpm, temperature: 36.8°C, RR: 18 per min, SpO2: 98%. ### Physical examination Non-toxic male lying in bed comfortably. Exam benign apart from left arm soft tissue exam. Left arm with swelling, erythema and tenderness overlying the lateral bicep. No visible lesion or ulceration. Full range of motion of the shoulder and elbow (figure 1). Figure 1 Left upper extremity examination findings. ### Laboratory data Laboratory data revealed a leucocytosis of 14.6 and elevated lactate of 2.3. The rest of the laboratory values were within normal limits. Figure 2 shows the point-of-care ultrasound (POCUS) in the diagnosis of left upper extremity. Figure 2 Left upper extremity short axis plane. 1. What are the indications for performing a POCUS of the soft tissue? If there is clinical concern based on warmth, erythema, pain, induration or fluctuance, POCUS can aid in the diagnosis of cellulitis and abscess. 2. What clinical questions can be answered when assessing the soft tissue with POCUS ? Are there sonographic findings pointing to cellulitis, abscess, pyomyositis or necrotising …

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. 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). 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). Physicians, including radiologists, demonstrated substantial interobserver variability when identifying HIBI on head CT soon after out-of-hospital cardiac arrest.

The ICH M7 guidance provides a series of flexible control options for the control of (potentially) mutagenic impurities (PMIs) that fully align with key risk-based principles. This includes option ...

Background: Alpha-1-antitrypsin (A1AT) deficiency (A1ATD) is characterized by accelerated degradation of lung function. We examined our experience with lung transplantation for chronic obstructive pulmonary disease (COPD) with and without A1ATD to compare survival and rates of postoperative surgical complications. Methods: Patients with A1ATD and non-A1ATD COPD undergoing lung transplantation from 1988−2015 at our institution were analyzed. Complications were categorized into non-gastroenteritis gastrointestinal (GI), wound, airway, and reoperation for bleeding. Overall and complication-free survival were evaluated using Kaplan-Meier curves and Cox proportional hazards models. Results: Three hundred and eighty-five patients underwent lung transplant for COPD (98 A1ATD). For A1ATD, 56.1% underwent single lung transplantation (80.6% for COPD). Early overall and complication-free survival was worse for A1ATD, but this trend reversed at longer follow up. Unadjusted estimated survival showed advantage for COPD at 90 days and 1 year, which attenuated by 5 years and reversed at 10 years (P

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.

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.

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.

We report the ability to extend lung preservation up to 24 hours (24H) by using autologous whole donor blood circulating within an ex vivo lung perfusion (EVLP) system. This approach facilitates donor lung reconditioning in a model of extended normothermic EVLP. We analyzed comparative responses to cellular and acellular perfusates to identify these benefits.Twelve pairs of swine lungs were retrieved after cardiac arrest and studied for 24H on the Organ Care System (OCS) Lung EVLP platform. Three groups (n = 4 each) were differentiated by perfusate: (1) isolated red blood cells (RBCs) (current clinical standard for OCS); (2) whole blood (WB); and (3) acellular buffered dextran-albumin solution (analogous to STEEN solution).Only the RBC and WB groups met clinical standards for transplantation at 8 hours; our primary analysis at 24H focused on perfusion with WB versus RBC. The WB perfusate was superior (vs RBC) for maintaining stability of all monitored parameters, including the following mean 24H measures: pulmonary artery pressure (6.8 vs 9.0 mm Hg), reservoir volume replacement (85 vs 1607 mL), and PaO2:FiO2 ratio (541 vs 223). Acellular perfusion was limited to 6 hours on the OCS system due to prohibitively high vascular resistance, edema, and worsening compliance.The use of an autologous whole donor blood perfusate allowed 24H of preservation without functional deterioration and was superior to both RBC and buffered dextran-albumin solution for extended lung preservation in a swine model using OCS Lung. This finding represents a potentially significant advance in donor lung preservation and reconditioning.

Preventing or reversing the pathological misfolding and self-association of alpha-synuclein (aSyn) can rescue a broad spectrum of pathological cellular insults that manifest in Parkinson’s Disease (PD), Dementia with Lewy bodies (DLB), and other alpha-synucleinopathies. We have developed a high-throughput, FRET-based drug discovery platform that combines high-resolution protein structural detection in living cells with an array of functional and biophysical assays to identify novel lead compounds that protect SH-SY5Y cells from aSyn induced cytotoxicity as well as inhibiting seeded aSyn aggregation, even at nanomolar concentrations.Our combination of cellular and cell-free assays allow us to distinguish between direct aSyn binding or indirect mechanisms of action (MOA). We focus on targeting oligomers with the requisite sensitivity to detect subtle protein structural changes that may lead to effective therapeutic discoveries for PD, DLB, and other alpha-synucleinopathies. Pilot high-throughput screens (HTS) using our aSyn cellular FRET biosensors has led to the discovery of the first nanomolar-affinity small molecules that disrupt toxic aSyn oligomers in cells and inhibit cell death. Primary neuron assays of aSyn pathology (e.g. phosphorylation of mouse aSyn PFF) show rescue of pathology for two of our tested compounds. Subsequent seeded thioflavin-t (ThioT) aSyn aggregation assays demonstrate these compounds deter or block aSyn fibril assembly. Other hit compounds identified in our HTS are known to modulate oxidative stress, autophagy, and ER stress, providing validation that our biosensor is sensitive to indirect MOA as well.

Currently, exercise-based cardiac rehabilitation (CR) is the only recommended secondary prevention strategy for cardiac patients that attempts to tackle stress and psychosocial wellbeing, but it is under-utilized and lacks a comprehensive curriculum for this purpose; hence there is a critical gap to address psychosocial needs of cardiac patients after an event. Mindfulness-based stress reduction (MBSR) has shown benefits in the general population but its role in cardiac patients is not clear. We conducted a pilot randomized controlled trial (RCT) of MBSR in CR-eligible cardiac patients during their initial year of recovery. Patients were allocated 2:1 (intervention:control) to an 8-week MBSR group intervention or usual care. Standard measures of depression, anxiety, perceived stress, health related quality of life (HRQOL), blood pressure, biomarkers (lipids, HbA1c, CRP) and 24-hour Holter monitoring were obtained at baseline, 3- and 9-months post-randomization. Sub-group analyses were performed for participants with at least mild depression (PHQ-9 ≥ 5). 47 patients [mean age 58.6 years; 38% female; 77% white] were enrolled in 2 cohorts. 87% of MBSR patients completed the intervention; study retention was >95% at each follow-up visit. At 3 months, compared to controls, MBSR patients showed improvements in depression [p = 0.01] and anxiety [p = 0.04] with a similar trend in HRQOL [p = 0.06]. The MBSR group showed greater improvement or less worsening of most CV risk factors, with an attenuation of treatment effects at 9 months. Participants with at PHQ-9 scores ≥5 at baseline showed greater improvement in psychosocial and CV outcomes, that persisted at 9 months. MBSR is a safe and well received secondary prevention strategy. This pilot RCT provides preliminary evidence of MBSR’s potential to improve short term psychosocial well-being in cardiac patients during their first year of recovery.

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

The new 802.11ah standard promises to considerably extend the range of Wi-Fi networks by operating in the 902–928 MHz ISM band in the US. While the narrower band results in a lower available data rate, the new standard offers a number of advantageous features such as the restricted access window, traffic indication maps, and target wake time. However, as 802.11ah hardware is still in development, empirical outdoor results for the new standards are missing. The goal of this research project was to implement a simple 802.11ah transmitter and receiver using two software defined radios running a GNU Radio model emulating the new standard. Tests were conducted at three different test sites simulating three different test environments. Results show that 802.11ah can more than keep its promise of Wi-Fi beyond one kilometer as acceptable packet drop rates were still achieved at a distance of 2.7 km.

Smartphone-based activity-travel surveys have enabled the collection of continuous, multi-day data on individuals’ trips and activities with high spatial and temporal resolution. However, the multi-dimensional nature of these data makes it challenging to compare activity-travel patterns and identify clusters of individuals with similar patterns and use them to study behaviors and forecast travel demands. To address this challenge, we adopt a discrete, step-based view on time and transform the episodic-based diary into a sequence of states observed at a sample interval. The resulting sequences can visually characterize variations in activity-travel patterns across days of a week and among different individuals. Motivated by techniques in genomics and data science, we apply sequence alignment methods to measure the pairwise similarity between these activity-trip sequences. To address its practical implementation in transportation studies, we define and compare four weighting schemas: (1) the unit-cost distance, which assigns equal weights to all substitution operations between states; (2) the fixed-flexible weighted distance based on the time geography framework, where costs differ for substitutions involving fixed and flexible activities; (3) the trip-activity weighted distance considering travel as a derived demand, where costs differ for substitutions between trips and activities; and (4) transition-based weighted distance, where costs are based on the global or time-varying activity and trip transition rates estimated from the data. Then, we calculate the pairwise distances between individuals’ sequences and use them as inputs to a hierarchical clustering algorithm to group individuals with similar sequences. We visualize the state distributions of the identified clusters to infer and compare behavior patterns, and use functional data regression methods to estimate the time-dependent probabilities of engaging in various activities and trips. To demonstrate our methods, we analyze a smartphone-based survey dataset collected in the Minneapolis-St. Paul metropolitan area. We also conduct sensitivity analysis on the selection of cost metrics and sample intervals to ensure the robustness of our methods and discuss their implications in practice. By identifying population subgroups with distinct daily activity-travel patterns and explaining how these patterns vary over one day and depend on user profiles, our weighted sequence alignment approach provides an intuitive and flexible method for extracting and characterizing individuals’ activity-travel behaviors for use in transportation planning.

Stability studies of pharmaceutical drug products and pharmaceutical active substances are important to research and development in order to fully understand and maintain product quality and safety throughout its shelf-life. Oxidative forced degradation studies are among the different types of stability studies performed by the pharmaceutical industry in order to understand the intrinsic stability of drug molecules. We have been comparing the use of electrochemistry as an alternative oxidative forced degradation method to traditional forced degradation and accelerated stability studies. Using the electrochemical degradation approach the substrate oxidation takes place in a commercially available electrochemical cell and the effluent of the cell can be either a) directly infused into the mass spectrometer or b) injected in a chromatographic column for separation of the different products formed prior to the mass spectrometry analysis. To enable the study of large numbers of different experimental conditions and molecules we developed a new dual pump automated electrochemical screening platform. This system used a HPLC pump and autosampler to load and wash the electrochemical cell and deliver the oxidized sample plug to a second injection loop. This system enabled the automatic sequential analyses of large numbers of different solutions under varied experimental conditions without need for operator intervention during the run sequence. Here we describe the system and evaluate its performance using a test molecule with well characterized stability and compare results to those obtained using an off-line electrochemistry approach.

Background and objectives Ambulatory BP is increasingly recognized as a better measure of the risk for adverse outcomes related to hypertension, an important comorbidity in patients with CKD. Varying definitions of white-coat and masked hypertension have made it difficult to evaluate differences in prevalence of these BP patterns across CKD cohorts. Design, setting, participants, & measurements The International Database of Ambulatory BP in Renal Patients collaborative group established a large database of demographic, clinical, and ambulatory BP data from patients with CKD from cohorts in Italy, Spain, the Chronic Renal Insufficiency Cohort (CRIC) and the African American Study of Kidney Disease and Hypertension Cohort Study (AASK) in the United States, and the CKD Japan Cohort (CKD-JAC). Participants (n=7518) with CKD were included in the present analyses. Cutoffs for defining controlled BP were 140/90 mm Hg for clinic and 130/80 mm Hg for 24-hour ambulatory BP. Results Among those with controlled clinic BP, compared with CKD-JAC, AASK participants were more likely to have masked hypertension (prevalence ratio [PR], 1.21; 95% confidence interval [95% CI], 1.04 to 1.41) whereas CRIC (PR, 0.82; 0.72 to 0.94), Italian (PR, 0.73; 0.56 to 0.95), and Spanish participants (PR, 0.75; 0.64 to 0.88) were less likely. Among those with elevated clinic BP, AASK participants were more likely to have sustained hypertension (PR, 1.22; 95% CI, 1.13 to 1.32) whereas Italian (PR, 0.78; 0.70 to 0.87) and Spanish participants (PR, 0.89; 0.82 to 0.96) were less likely, although CRIC participants had similar prevalence as CKD-JAC. Prevalence of masked and sustained hypertension was elevated in males, patients with diabetes, participants on four or more antihypertensives, and those with moderate-to-severe proteinuria. Conclusions In a large, multinational database, the prevalence of masked and sustained hypertension varied across cohorts independent of important comorbidities.

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.

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.

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.

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.

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 .

A new method for the fast and convenient synthesis of pharmaceutical oxidation products is described. Two oxidation products of fesoterodine were electrochemically synthesized, isolated, and characterized. The influence of synthetic operating parameters such as pH, percentage of organic solvent in diluent, initial electrolyte concentration, and substrate concentration on the oxidation product profile was investigated. This synthetic procedure proved to be rapid, clean, and efficient compared to traditional synthetic methods and may be particularly useful for generating milligram quantities of reference samples of degradation products used as markers in chromatographic methods.

Katelyn E Uithoven,1 Justin R Ryder,2 Roland Z Brown,3 Kyle D Rudser,3 Nicholas G Evanoff,1 Donald R Dengel,1,2 Aaron S Kelly2,4 1School of Kinesiology, University of Minnesota, 2Department of Pediatrics, University of Minnesota Medical School, 3Division of Biostatistics, School of Public Health, University of Minnesota, 4Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA Abstract: The carotid artery represents an ideal location for noninvasive assessment of subclinical atherosclerosis in youth. Examination of arterial structure and function is generally conducted in the left common carotid. However, if the left common carotid is inaccessible or provides a poor acoustic window, it is unknown if the right common carotid can provide comparable values. The symmetry of carotid arteries in youth with high-resolution ultrasound was compared. Participants (N=230 [121 females], 13.8±2.9 years old) were assessed for carotid intima media thickness (cIMT), carotid lumen diameter (cLD), carotid incremental elastic modulus (cIEM), carotid diameter compliance (cDC), carotid cross-sectional compliance (cCSC), carotid diameter distensibility (cDD), and carotid cross-sectional distensibility (cCSD). No significant differences (P>0.05 all) were found for cIMT (0.49±0.09 vs 0.49±0.08mm), cIEM (1095±382 vs 1116±346 mmHg), cDC (0.01±0.0 vs 0.01±0.0 mm/mmHg), cCSC (0.01±0.001/mmHg vs 0.01±0.001/mmHg), cDD (14.0%±3.16% vs 13.7%±3.18%), and cCSD (30.1%±7.37% vs 29.4%±7.36%). Significant differences were found for cLD (6.06±0.62 mm vs 6.33±0.64 mm, P

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.

Background We sought to clarify the effect of donor age as a continuous variable on morbidity and mortality in a single-institution experience. Methods From 1986 to 2016, 882 adult lung transplants were performed, including 396 in the lung allocation score era. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate the association of donor age with overall survival and bronchiolitis obliterans syndrome (BOS) score ≥1-free survival. Logistic regression was used to evaluate the association with primary graft dysfunction grade 3. Natural cubic splines were used to explore donor age in a continuous fashion to allow for nonlinear relationships. Results In the lung allocation score era, unadjusted 5-year survival was not significantly different between 3 a priori–defined donor age groups: age P = .8). Unadjusted 5-year freedom from BOS ≥1 was not significantly different (34%, 20%, and 33%, respectively, P = .1). After we adjusted for comorbidities, cubic spline analysis demonstrated no effect between donor age as a continuous variable and hazard for mortality at 5 years. Similarly, no interaction was seen between donor age and risk of BOS or primary graft dysfunction 3. Adjusted analysis of all 882 transplants pre- and postinception of the lung allocation score also showed no effect of age on 10-year survival. Conclusions Long-term survival of lung transplant recipients was not affected by the age of the donor. These findings support the notion that donor age could be relaxed.

Forced degradation studies are used to facilitate the development of analytical methodology, to gain a better understanding of active pharmaceutical ingredient (API) and drug product (DP) stability, and to provide information about degradation pathways and degradation products. In order to fulfill development and regulatory needs, this publication provides a roadmap for when and how to perform studies, helpful tools in designing rugged scientific studies, and guidance on how to record and communicate results.

The aim of this study was to evaluate the use of electrochemistry to generate oxidative degradation products of a model pharmaceutical compound. The compound was oxidized at different potentials using an electrochemical flow-cell fitted with a glassy carbon working electrode, a Pd/H2 reference electrode and a titanium auxiliary electrode. The oxidative products formed were identified and structurally characterized by LC-ESI-MS/MS using a high resolution Q-TOF mass spectrometer. Results from electrochemical oxidation using electrolytes of different pH were compared to those from chemical oxidation and from accelerated stability studies. Additionally, oxidative degradation products predicted using an in silico commercially available software were compared to those obtained from the various experimental methods. The electrochemical approach proved to be useful as an oxidative stress test as all of the final oxidation products observed under accelerated stability studies could be generated; previously reported reactive intermediate species were not observed most likely because the electrochemical mechanism differs from the oxidative pathway followed under accelerated stability conditions. In comparison to chemical degradation tests electrochemical degradation has the advantage of being much faster and does not require the use of strong oxidizing agents. Moreover, it enables the study of different operating parameters in short periods of time and optimisation of the reaction conditions (pH and applied potential) to achieve different oxidative products mixtures. This technique may prove useful as a stress test condition for the generation of oxidative degradation products and may help accelerate structure elucidation and development of stability indicating analytical methods.

The Moving Picture Company (MPC) is one of Europe's leading post-production facilities. MPC provides digital visua; effects and computer animation to the advertising, music, TV and feature film industries. In this article, Roland Brown and Peter Grecian tell us about special effects engineering at MPC.

This article has been made available through the Brunel Open Access Publishing Fund. This paper reports on some of the key outcomes of a 3 year £1.5. m Technology Strategy Board (TSB) funded research programme to develop a small footprint, versatile, counter-current chromatography purification technology and methodology which can be operated at a range of scales in both batch and continuous modes and that can be inserted into existing process plant and systems. Our consortium, integrates technology providers (Dynamic Extractions) and the scientific development team (Brunel) with end user needs (GSK & Pfizer), addressing major production challenges aimed at providing flexible, low capital platform technology driving substantial cost efficiency in both drug development and drug manufacturing processes. The aims of the Technology Strategy Board's high value manufacturing programme are described and how the academic/industry community were challenged to instigate step changes in the manufacturing of high value pharmaceuticals. This paper focusses on one of the themes of the TSB research programme, " Generate a Comprehensive Applications Portfolio" It outlines 15 applications from this portfolio that can be published in the public domain and gives four detailed case studies illustrating the range of application of the technology on the separation of (1) isomers, (2) polar compounds, (3) crude mixtures and (4) on the removal of impurities. Two of these case studies that were scaled up demonstrate between 10 and 20% lower solvent usage and were projected to have significant cost savings compared to conventional solid phase silica gel chromatography at procss scale demonstrating that the latest high performance countercurrent chromatography technology is a competitive platform technolgy for the pharmaceutical industry. © 2013 Elsevier B.V.

Summary This article considers the policies which a democratic government of South Africa should adopt towards inward foreign investment and what instruments should be sued to give effect to those policies. The article notes the change in attitude towards foreign investment that has occurred in the past 30 years and a number of very special features which characterize South Africa's political economy. The approach proposed would essentially treat foreign investors on level terms (concerning rights and obligations) with domestic investors, save in two areas. First, it is recognized that there are aspiring Black businessmen and businesswomen, previously repressed, who will need special encouragement and assistance and some protection from would-be immigrant entrepreneurs. Second, it is recognized that some foreign investors for major projects may need assurances concerning the remittability of funds, security of title, and access to international arbitration. the article opposes across-the-board incentives but envisages a class of ‘Special Status Investments’ which could be given exceptional assurances but which could be asked to accept exceptional obligations and responsibilities as well. Resume Le present article considere les politiques qu'un gouvernement democratique en Afrique du Sud devrait adopter en ce qui concerne les investissements dans ce pays de provenance a la fois etrangere et exterieure; et s'interroge sur la nature des instruments qu'il serait necessaire d'employer pour leur donner vigueur. Les auteurs constatent qu'au cours des 30 dernieres annees certains changements se sont produits en ce qui concerne les investissements de provenance etrangere et exterieure, tout en constatant que certains facteurs tres particuliers caracterisent l'economie politique sud-africaine. L'approche proposee traiterait les investisseurs etrangers sur une base essentiellement paritaire (en termes des droits et des obligations) relativement aux investisseurs internes, sauf dans deux domaines. Tout d'abord il y aurait lieu de reconnaitre qu'il existe d'aspirants hommes et femmes d'affaires noirs, jusqu'ici victimes de la repression, qui meriteront un encouragement et une assistance speciaux, ainsi qu'une protection contre les eventuels entrepreneurs immigres. En deuxieme lieu, il est admis que certains investisseurs etrangers auront besoin, avant de participer dans des projets majeurs, de recevoir certaines garanties concernant la disponibilite des fonds, la permanence de leur accueil, et l'acces a l'arbitrage international. Les auteurs s'opposent a ce que des primes d'encouragement soient offertes a tous sans distinction des cas mais ils envisagent, par contre, une categorie speciale d'Investissements a Statut special auxquels des garanties exceptionnelles pourraient etre accordees moyennant, reciproquement, l'acceptation de certaines obligations et responsabilites exceptionnelles. Resumen Este articulo considera las pautas que un gobierno democratico en Sudafrica deberia adoptar para la inversion extranjera proveniente del exterior, y los elementos que deberian ponerse en practica para hacerlas efectivas. Se senala el cambio positivo en la actitud hacia las inversiones extranjeras que han ocurrido en los ultimos 30 anos, y se mencionan una serie de rasgos especiales que caracterizan a la politica economica de Sudafrica. El enfoque que se propone esencialmente consideraria a los inversores extranjeros en los mismos terminos (derechos y obligaciones) que a los inversores locales, con dos notables excepciones. En primer lugar, se reconoce la existencia de ambiciosos hombres y mujeres de negocios de raza negra, anteriormente reprimidos en sus actividades, que ahora necesitaran apoyo y estimulo especiales y tambien proteccion frente a la posibles aparicion de empresarios inmigrantes. En segundo lugar, se reconoce que algunos inversores extranjeros en proyectos de gran envergadura pueden necesitar seguridades en asuntos como remision de fondos, fiabilidad de titulos y acceso al arbitraje internacional. El articulo rechaza la idea de incentivos globales, pero preve un tipo de ‘Inversiones de Status Especial’ que si bien recibiria seguridades especiales, deberia a su vez aceptar obligaciones y responsabilidades de excepcion.