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Sphingosine 1 phosphate (S1P), S1P receptors (S1PRs) and their signaling pathways play an important role in the fate of cancer cells. The expression pattern of S1PR subtypes (S1PR1–S1PR5) may alter in cancer development stages, depending on the origin and the pathologic features of tumors. The present study aimed to examine the relationship between plasma S1P levels and the expression of S1PR subtypes in bladder tumors.
These changes were evaluated in terms of the pathologic grades and stages of human bladder cancer samples. For this, tumor biopsies from 41 new bladder cancer patients as well as 26 normal-looking bladder tissues were collected and processed for immunohistochemistry (IHC) and quantitative real-time RT-PCR of S1PR subtypes. Plasma S1P level was measured using liquid chromatography–tandem mass spectrometry (LC–MS/MS).
The results show that tissue S1PR1, S1PR2 and S1PR3 are over-expressed in all tumors regardless of their pathological grade (~ 3, ~ 6 and ~ 104 folds, respectively). These results were corroborated by IHC data showing accumulation of S1PR subtypes 1 and 2 in the tissues. Plasma S1P in the plasma samples from patients was in the range of control samples (Controls; 256 ± 47; patients, 270 ± 41).
Overexpression of S1PR1, S1PR2 and S1PR3 in bladder tumor biopsies which were corroborated with the pathological grades and stages may suggest that S1PR profile in tumor biopsies is a promising marker in the diagnosis of bladder carcinoma.
After decades of hype, cell-based therapies are emerging into the clinical arena for the purposes of promoting recovery after stroke. In this review, we discuss the most recent science behind the role of cell-based therapies in ischemic stroke and the efforts to translate these therapies into human clinical trials.
Preclinical data support numerous beneficial effects of cell-based therapies in both small and large animal models of ischemic stroke. These benefits are driven by multifaceted mechanisms promoting brain repair through immunomodulation, trophic support, circuit reorganization, and cell replacement.
Cell-based therapies offer tremendous potential for improving outcomes after stroke through multimodal support of brain repair. Based on recent clinical trials, cell-based therapies appear both feasible and safe in all phases of stroke. Ongoing translational research and clinical trials will further refine these therapies and have the potential to transform the approach to stroke recovery and rehabilitation.
Parotid tumors are rare, and no clinical trial data exists to guide postoperative radiation therapy (PORT) usage. We sought to determine the impact of PORT on the overall survival (OS) of patients with parotid malignancies.
Patient data was queried from the National Cancer Database. Patients with surgical resection of parotid gland carcinomas from 2004 to 2012 were analyzed. Kaplan-Meier and Cox proportional hazards were used to assess OS among those receiving PORT or not. Additionally, variables affecting OS and use of PORT were evaluated.
A total of 12,439 patients were identified for analysis. Increasing T stage, N stage, tumor grade, and positive margin status were predictive of PORT. Survival for patients receiving PORT versus surgery only at 5 and 10 years was 65.5% and 50.3% versus 74.4% and 61.2% for surgery only (p ≤ 0.001). After multivariable adjustment, PORT improved OS (adjusted hazard ratio 0.79, 95% confidence interval 0.70–0.89). In subgroup analysis, PORT provided benefit for certain histologic subtypes and all other patient groups except those with T1 tumors and undifferentiated/anaplastic tumor grades.
Our data suggests that PORT was associated with improved survival. Additionally, some subgroups may receive additional benefit and patients with small (T1), low-grade disease may be able to forgo PORT.
Annals of the American Thoracic Society, Volume 16, Issue 2, Page 175-181, February 2019.
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Annals of the American Thoracic Society, Volume 16, Issue 2, Page 161-170, February 2019.
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Annals of the American Thoracic Society, Volume 16, Issue 2, Page 217-224, February 2019.
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Annals of the American Thoracic Society, Volume 16, Issue 2, Page 187-188, February 2019.
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Annals of the American Thoracic Society, Volume 16, Issue 2, Page 197-199, February 2019.
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Annals of the American Thoracic Society, Volume 16, Issue 2, Page 191-192, February 2019.
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Annals of the American Thoracic Society, Volume 16, Issue 2, Page 240-247, February 2019.
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Annals of the American Thoracic Society, Volume 16, Issue 2, Page 225-230, February 2019.
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Annals of the American Thoracic Society, Volume 16, Issue 2, Page 258-264, February 2019.
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Annals of the American Thoracic Society, Volume 16, Issue 2, Page 231-239, February 2019.
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Introduction
Genetic testing for hypertrophic cardiomyopathy (HCM) in the era of genomics brings unique challenges for genetic counselling. The number of genes routinely included in an HCM gene panel has increased markedly, many with minimal if any robust evidence of gene–disease association. Subsequently, there is a greater chance of uncertain genetic findings. The responsibility of communicating this information with at-risk relatives lies with the index case (proband). We have developed a communication aid to assist with the delivery of genetic results to the proband. We have previously shown the aid is feasible and acceptable and have now developed a study protocol for a randomised controlled trial of a genetic counsellor-led intervention incorporating the communication aid.
Methods and analysisThis is a prospective randomised controlled trial. We will investigate the impact of a genetic counsellor-led intervention to return proband genetic results using a custom-designed communication aid. We aim to improve knowledge and empowerment. The primary outcome of this trial is the ability and confidence of the proband to communicate genetic results to at-risk relatives. Secondary outcomes will assess genetic knowledge, satisfaction with services, outcomes from genetic counselling and psychological adaptation to genetic information.
Ethics and disseminationThis study has been approved by and is in strict accordance with the Sydney Local Health District Ethics Review Committee (X16-0030; 22/01/2016; version 1). Results from this trial will be prepared as a manuscript and submitted to peer-reviewed journals for publication as well as submission for presentation at national and international meetings.
Trial registration numberACTRN12617000706370.
Objectives
12-hour shifts worked by nurses on acute hospital wards have been associated with increased rates of missed care reported by nurses. This study aimed to measure the association between nurses working shifts of at least 12 hours and an objective measure of missed care: vital signs observations taken on time according to an acuity-based surveillance protocol.
DesignA retrospective observational study using routinely collected data from March 2012 to March 2015.
Setting32 general inpatient wards at a large acute hospital in England.
Participants658 628 nursing shifts nested in 24 069 ward days.
Outcome measuresThe rate of daily delayed and missed vital signs observations. We focused on situations where vital signs observations were required at least every 4 hours and measured the number of instances where observations were delayed or missed, per 24-hour period. For each ward and each day, shift patterns were characterised in terms of proportion of care hours per patient day deriving from 'long' shifts (≥12 hours) for both registered nurses and healthcare assistants.
ResultsOn 99 043 occasions (53%), observations were significantly delayed, and on 81 568 occasions (44%), observations were missed. Observations were more likely to be delayed when a higher proportion of the hours worked by healthcare assistants were part of long shifts (IRR=1.05; 95% CI 1.00 to 1.10). No significant association was found in relation to the proportion of hours registered nurses worked as long shifts.
ConclusionOn days when a higher proportion of hours worked by healthcare assistants are from long shifts, the risk of delaying vital signs observations is higher, suggesting lower job performance. While longer shifts are thought to require fewer staff resources to maintain nurse-to-patient ratios, any benefits may be lost if staff become less productive.
Objective
To assess existing literature on the effectiveness of mental health training courses for non-specialist health workers, based on the WHO guidelines (2008).
DesignA systematic review was carried out, complying with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist.
Data sourcesAfter examination of key studies in the literature, a comprehensive search was performed within the following electronic databases on 31 May 2017: PubMed, PsycINFO, CINAHL (using EBSCOHost interface), Cochrane, Web of Science.
Eligibility criteriaSearches were conducted for articles published in English from January 2008 to May 2017, using search terms related to mental health, training, community care and evaluation/outcome, following the Participants, Interventions, Comparators and Outcomes process for evidence-based practice.
OutcomesData were collected across the following categories: trainees (number and background), training course (curriculum, teaching method, length), evaluation method (timing of evaluation, collection method and measures assessed) and evaluation outcome (any improvement recorded from baseline). In addition, studies were assessed for their methodological quality using the framework established by Liu et al (2016).
Results29 studies with relevant training courses met the inclusion criteria. These were implemented across 16 countries since 2008 (over half between 2014 and 2017), with 10 in three high-income countries. Evaluation methods and outcomes showed high variability across studies, with courses assessing trainees' attitude, knowledge, clinical practice, skills, confidence, satisfaction and/or patient outcome. All 29 studies found some improvement after training in at least one area, and 10 studies found this improvement to be significant.
ConclusionsTraining non-specialist workers in mental healthcare is an effective strategy to increase global provision and capacity, and improves knowledge, attitude, skill and confidence among health workers, as well as clinical practice and patient outcome. Areas for future focus include the development of standardised evaluation methods and outcomes to allow cross-comparison between studies, and optimisation of course structure.
PROSPERO registration numberCRD42016033269
Objective
To estimate the association between the use of sodium glucose co-transporter-2 (SGLT2) inhibitors and postmarket harms as identified by drug regulatory agencies.
DesignWe conducted a systematic review and meta-analysis of randomised controlled trials (RCT). Six large databases were searched from inception to May 2018. Random effects models were used to estimate pooled relative risks (RRs).
InterventionSGLT2 inhibitors, compared with placebo or active comparators.
Primary outcomesAcute kidney injury (AKI), diabetic ketoacidosis (DKA), urinary tract infections (UTI), bone fractures and lower limb amputations.
ResultsWe screened 2418 citations of which 109 were included. Most studies included one of four SGLT2 inhibitors, dapagliflozin, canagliflozin, empagliflozin and ipragliflozin. When compared with placebo, SGLT2 inhibitors were found to be significantly protective against AKI (RR=0.59; 95% CI 0.39 to 0.89; I2=0.0%), while no difference was found for DKA (RR 0.66; 95% CI 0.30 to 1.45, I2=0.0%), UTI (RR 1.02; 95% CI 0.95 to 1.09, I2=0.0%) or bone fracture (RR 0.87; 95% CI 0.69 to 1.09, I2=1.3%). Three studies reported on amputation, with one finding a significant increase risk. No increased risk for either outcome was found when compared with active controls. Subgroup analysis did show an increased risk of UTI with dapagliflozin only (RR 1.21; 95% CI 1.02 to 1.43, I2=0.0%), but no other analysis supported an increased risk of AKI, DKA, UTI or fracture.
ConclusionsCurrent evidence from RCTs does not suggest an increased risk of harm with SGLT2 inhibitors as a class over placebo or active comparators with respect to AKI, DKA, UTI or fracture. However, wide CIs for many comparisons suggest limited precision, and therefore clinically important adverse events cannot be ruled out. Dapagliflozin, appears to independently increase the risk of UTI, although the mechanism for this intraclass variation in risk is unclear.
PROSPERO registration numberCRD42016038715.
Objectives
Community-Based Rehabilitation (CBR) is a multi-sectoral approach working to equalise opportunities and include people with disabilities in all aspects of life. The complexity of CBR and often limited resources lead to challenges when attempting to quantify its effectiveness, with randomisation and longitudinal data rarely possible. Statistical methods, such as propensity score matching (PSM), offer an alternative approach to evaluate a treatment when randomisation is not feasible. The aim of this study is to examine whether PSM can be an effective method to facilitate evaluations of results in CBR when data are cross-sectional.
DesignCross-sectional survey.
Setting and participantsData were collected using the WHO's CBR Indicators in Vietnam, with treatment assignment (participating in CBR or not) determined by province of residence. 298 participants were selected through government records.
ResultsPSM was conducted using one-to-one nearest neighbour method on 10 covariates. In the unmatched sample, significant differences between groups were found for six of the 10 covariates. PSM successfully adjusted for bias in all covariates in the matched sample (74 matched pairs). A paired t-test compared the outcome of 'community inclusion' (a score based on selected indicators) between CBR and non-CBR participants for both the matched and unmatched samples, with CBR participants found to have significantly worse community inclusion scores (mean=17.86, SD=6.30, 95% CI 16.45 to 19.32) than non-CBR participants (mean=20.93, SD=6.16, 95% CI 19.50 to 22.35); t(73)=3.068, p=0.001. This result did not differ between the matched and unmatched samples.
ConclusionPSM successfully reduced bias between groups, though its application did not affect the tested outcome. PSM should be considered when analysing cross-sectional CBR data, especially for international comparisons where differences between populations may be greater.
Introduction
The University of Utah (UofU) Health intensive outpatient clinic (IOC) is a primary care clinic for medically complex (high-cost, high-need) patients with Medicaid. The clinic consists of a multidisciplinary care team aimed at providing coordinated, comprehensive and patient-centred care. The protocol outlines the quantitative design of an evaluation study to determine the IOC's effects on reducing healthcare utilisation and costs, as well as improving patient-reported health outcomes and quality of care.
Methods and analysisHigh-risk patients, with high utilisation and multiple chronic illnesses, were identified in the Medicaid ACO population managed by the UofU Health plans for IOC eligibility. A prospective, case-control study design is being used to match 100 IOC patients to 200 control patients (receiving usual care within the UofU) based on demographics, health utilisation and medical complexity for evaluating the primary outcome of change in healthcare utilisation and costs. For the secondary outcomes of patient health and care quality, a prepost design will be used to examine within-person change across the 18 months of follow-up (ie, before and after IOC intervention). Logistic regression and hierarchical, longitudinal growth modelling are the two primary modelling approaches.
Ethics and disseminationThis work has received ethics approval by the UofU Institutional Review Board. Results from the evaluation of primary and secondary outcomes will be disseminated in scientific research journals and presented at national conferences.
Objective
After a decade of increase, the preterm birth (PTB) rate has declined in the USA since 2006, with the largest decline at late preterm (34–36 weeks). We described concomitant changes in gestational age-specific rates of neonatal mortality and morbidity following spontaneous and clinician-initiated PTB among singleton infants.
Design, setting and participantsThis retrospective population-based study included 754 763 singleton births in Washington State, USA, 2004–2013, using data from birth certificates and hospitalisation records. PTB subtypes included preterm premature rupture of membranes (PPROM), spontaneous onset of labour and clinician-initiated delivery.
Outcome measuresThe primary outcomes were neonatal mortality and a composite outcome including death or severe neonatal morbidity. Temporal trends in the outcomes and individual morbidities were assessed by PTB subtype. Logistic regression yielded adjusted odds ratios (AOR) per 1 year change in outcome and 95% CI.
ResultsThe rate of PTB following PPROM and spontaneous labour declined, while clinician-initiated PTB increased (all p<0.01). Overall neonatal mortality remained unchanged (1.3%; AOR 0.99, CI 0.95 to 1.02), though gestational age-specific mortality following clinician-initiated PTB declined at 32–33 weeks (AOR 0.85, CI 0.74 to 0.97) and increased at 34–36 weeks (AOR 1.10, CI 1.01 to 1.20). The overall rate of the composite outcome increased (from 7.9% to 11.9%; AOR 1.06, CI 1.05 to 1.08). Among late preterm infants, combined mortality or severe morbidity increased following PPROM (AOR 1.13, CI 1.08 to 1.18), spontaneous labour (AOR 1.09, CI 1.06 to 1.13) and clinician-initiated delivery (AOR 1.10, CI 1.07 to 1.13). Neonatal sepsis rates increased among all preterm infants (AOR 1.09, CI 1.08 to 1.11).
ConclusionsTiming of obstetric interventions is associated with infant health outcomes at preterm. The temporal decline in late PTB among singleton infants was associated with increased mortality among late preterm infants born following clinician-initiated delivery and increased combined mortality or severe morbidity among all late preterm infants, mainly due to increased rate of sepsis.
Objective
To elicit perspectives of family physicians and patients with knee osteoarthritis (KOA) on KOA, its treatment/management and the use of a mobile health application (app) to help patients self-manage their KOA.
DesignA qualitative study using Cognitive Task Analysis for physician interviews and peer-to-peer semistructured interviews for patients according to the Patient and Community Engagement Research (PaCER) method.
SettingPrimary care practices and patient researchers at an academic centre in Southern Alberta.
ParticipantsIntentional sampling of family physicians (n=4; 75% women) and patients with KOA who had taken part in previous PaCER studies and had experienced knee pain on most days of the month at any time in the past (n=5; 60% women).
ResultsPhysician and patient views about KOA were starkly contrasting. Patient participants expressed that KOA seriously impacted their lives and lifestyles, and they wanted their knee pain to be considered as important as other health problems. In contrast, physicians uniformly conceptualised KOA as a relatively minor health problem, although they still recognised it as a painful condition that often limits patients' activities. Consequently, physicians did not regard KOA as a condition to be proactively and aggressively managed. The gap between physicians' and patients' conceptualisation of KOA and its treatment extended to the use of an app for self-management. While patients were supportive of the app, physicians were sceptical of its use and focused more on accountability and patient resources.
ConclusionsThe clear discord between physicians' mental models and patients' lived experience and perceived needs around KOA emphasised a gap in understanding and communication about treatment and management of KOA. As such, this preliminary and formative research will inform a codesign approach to develop an app that will act as a communications tool between patients and physicians, enabling patient–physician discussions regarding modifiable self-management options based on a patient's perspectives and needs.
Introduction
Mortality among children hospitalised for complicated severe acute malnutrition (SAM) remains high despite the implementation of WHO guidelines, particularly in settings of high HIV prevalence. Children continue to be at high risk of morbidity, mortality and relapse after discharge from hospital although long-term outcomes are not well documented. Better understanding the pathogenesis of SAM and the factors associated with poor outcomes may inform new therapeutic interventions.
Methods and analysisThe Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM) study is a longitudinal observational cohort that aims to evaluate the short-term and long-term clinical outcomes of HIV-positive and HIV-negative children with complicated SAM, and to identify the risk factors at admission and discharge from hospital that independently predict poor outcomes. Children aged 0–59 months hospitalised for SAM are being enrolled at three tertiary hospitals in Harare, Zimbabwe and Lusaka, Zambia. Longitudinal mortality, morbidity and nutritional data are being collected at admission, discharge and for 48 weeks post discharge. Nested laboratory substudies are exploring the role of enteropathy, gut microbiota, metabolomics and cellular immune function in the pathogenesis of SAM using stool, urine and blood collected from participants and from well-nourished controls.
Ethics and disseminationThe study is approved by the local and international institutional review boards in the participating countries (the Joint Research Ethics Committee of the University of Zimbabwe, Medical Research Council of Zimbabwe and University of Zambia Biomedical Research Ethics Committee) and the study sponsor (Queen Mary University of London). Caregivers provide written informed consent for each participant. Findings will be disseminated through peer-reviewed journals, conference presentations and to caregivers at face-to-face meetings.
Objectives
Despite feedback being an extensively researched and essential component of teaching and learning, there is a paucity of research examining feedback within a medical education e-portfolio setting including feedback-seeking behaviours (FSBs). FSBs can be understood within a cost–value perspective. The objective of this research is to explore the factors that influence postgraduate year 1 (PGY1) trainee doctors' FSBs via e-portfolios.
SettingPostgraduate education provision in the largest teaching hospital in Taiwan.
ParticipantsSeventy-one PGY1s (66% male).
MethodsA qualitative semistructured one-to-one interview method was adopted. Interviews were audio recorded, transcribed verbatim, anonymised and checked for completeness. Data were analysed inductively via thematic framework analysis and deductively informed using FSB theory. The process comprised data familiarisation, identification of the themes, charting and data interpretation.
ResultsTwo main themes of FSB related and e-portfolio related were identified. We present the theme focussing on FSB here to which n=32 (22 males, 10 females) of the n=71 participants contributed meaningfully. Subthemes include factors variously affecting PGY1s' positive and negative FSBs via e-portfolios at the individual, process and technological levels. These factors include learner-related (internal values vs social influence, forced reflection); teacher-related (committed educators vs superficial feedback); technology-related (face-saving vs lagging systems; inadequate user-interface) and process-related (delayed feedback, too frequent feedback) factors.
ConclusionsOur findings reveal the complexity of PGY1s' FSBs in an e-portfolio context and the interaction of numerous facilitating and inhibiting factors. Further research is required to understand the range of facilitating and inhibiting factors involved in healthcare learners' FSBs across different learning, social, institutional and national cultural settings.
Introduction
The upsurge in the use of clinical prediction models in general medical practice is a result of evidence-based practice. However, the total number of clinical prediction rules (CPRs) currently being used or undergoing impact analysis in the management of patients who have sustained spinal cord injuries (SCIs) is unknown. This scoping review protocol will describe the current CPRs being used and highlight their possible strengths and weaknesses in SCI management.
Methods and analysisArksey and O'Malley's scoping review framework will be used. The following databases will be searched to identify relevant literature relating to the use of CPRs in the management of patients who have sustained an SCI: PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), ScienceDirect, EBSCOhost, Medline, OvidMedline and Google Scholar. Grey literature as well as reference lists of included studies will be searched. All studies relating to the use of CPRs in the management of patients with SCIs will be included. Literature searches and data extraction will be performed independently by two groups of reviewers.
Ethics and disseminationEthical clearance is not required for this scoping review study since only secondary data sources will be used. The findings of this review will be disseminated by means of peer-reviewed publication and conference proceedings. The final paper will be submitted for publication. Results of this review will also be presented at relevant conferences and disseminated to important stakeholders such as practicing physicians within specialised spinal care facilities within South Africa.
Objective
The aim of this review was to collate all available evidence on the impact of point-of-care C reactive protein (CRP) testing on patient-relevant outcomes in children and adults in ambulatory care.
DesignThis was a systematic review to identify controlled studies assessing the impact of point-of-care CRP in patients presenting to ambulatory care services. Ovid Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, DARE, Science Citation Index were searched from inception to March 2017.
Eligibility criteria for selecting studiesControlled studies assessing the impact of point-of-care CRP in patients presenting to ambulatory care services, measuring a change in clinical care, including but not limited to antibiotic prescribing rate, reconsultation, clinical recovery, patient satisfaction, referral and additional tests. No language restrictions were applied.
Data extractionData were extracted on setting, date of study, a description of the intervention and control group, patient characteristics and results. Methodological quality of selected studies and assessment of potential bias was assessed independently by two authors using the Cochrane Risk of Bias tool.
Results11 randomised controlled trials and 8 non-randomised controlled studies met the inclusion criteria, reporting on 16 064 patients. All included studies had a high risk of performance and selection bias. Compared with usual care, point-of-care CRP reduces immediate antibiotic prescribing (pooled risk ratio 0.81; 95% CI 0.71 to 0.92), however, at considerable heterogeneity (I2=72%). This effect increased when guidance on antibiotic prescribing relative to the CRP level was provided (risk ratios of 0.68; 95% CI 0.63 to 0.74 in adults and 0.56; 95% CI 0.33 to 0.95 in children). We found no significant effect of point-of-care CRP testing on patient satisfaction, clinical recovery, reconsultation, further testing and hospital admission.
ConclusionsPerforming a point-of-care CRP test in ambulatory care accompanied by clinical guidance on interpretation reduces the immediate antibiotic prescribing in both adults and children. As yet, available evidence does not suggest an effect on other patient outcomes or healthcare processes.
PROSPERO registration numberCRD42016035426; Results.
The strength of presurgical language mapping using electrocorticography (ECoG) is its outstanding signal fidelity and temporal resolution, but the weakness includes limited spatial sampling at an individual patient level. By averaging naming‐related high‐gamma activity at nonepileptic regions across a large number of patients, we provided the functional cortical atlases animating the neural dynamics supporting visual‐object and auditory‐description naming at the whole brain level.
We studied 79 patients who underwent extraoperative ECoG recording as epilepsy presurgical evaluation, and generated time‐frequency plots and animation videos delineating the dynamics of naming‐related high‐gamma activity at 70‐110 Hz.
Naming task performance elicited high‐gamma augmentation in domain‐specific lower‐order sensory areas and inferior‐precentral gyri immediately after stimulus onset. High‐gamma augmentation subsequently involved widespread neocortical networks with left hemisphere dominance. Left posterior temporal high‐gamma augmentation at several hundred milliseconds before response onset exhibited a double dissociation; picture naming elicited high‐gamma augmentation preferentially in regions medial to the inferior‐temporal gyrus, whereas auditory naming elicited high‐gamma augmentation more laterally. The left lateral prefrontal regions including Broca's area initially exhibited high‐gamma suppression subsequently followed by high‐gamma augmentation at several hundred milliseconds before response onset during both naming tasks. Early high‐gamma suppression within Broca's area was more intense during picture compared to auditory naming. Subsequent lateral‐prefrontal high‐gamma augmentation was more intense during auditory compared to picture naming.
This study revealed contrasting characteristics in the spatiotemporal dynamics of naming‐related neural modulations between tasks. The dynamic atlases of visual and auditory language might be useful for planning of epilepsy surgery. Differential neural activation well explains some of the previously reported observations of domain‐specific language impairments following resective epilepsy surgery. Video materials might be beneficial for the education of lay people about how the brain functions differentially during visual and auditory naming.
CpG rewires macrophage metabolism to bypass inhibitory CD47 signals and enhance antitumor activity.
ctDNA analysis of CSF recapitulates the genomic evolution of brain tumors.
Autophagic cell death during replicative crisis prevents further accumulation of genomic instability.
Draft guidelines from the USPSTF suggest that women at high risk for the disease consider using the drugs.
AJP Rep 2019; 09: e23-e26
DOI: 10.1055/s-0038-1675631
Cytomegalovirus(CMV) associated thrombosis has been reported sporadically in the medical literature; however, its antenatal scenario has not been documented. We herein present the antenatal, Doppler's ultrasound and magnetic resonance angiographic features of thrombosis in the aortic arch showing extension toward the medial lumen of the brachiocephalic trunk with critical occlusion of the left common carotid artery and left subclavian artery in a term fetus to raise obstetricians'/ neonatologists'/pediatric cardiologists' awareness for the association between CMV viremia and intrauterine thrombosis that caused cerebral injury, neurodevelopmental impairment, and permanent sequela.
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FRIDAY, Feb. 1, 2019 -- Physicians who receive direct pharmaceutical payments for opioid prescribing prescribe more opioids, especially hydrocodone and oxycodone, according to a study published online Jan. 22 in Addiction. Thuy D. Nguyen, Ph.D.,...
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FRIDAY, Feb. 1, 2019 -- A shortage of the anti-anxiety drug buspirone in the United States has patients and doctors concerned. Buspirone is among one of the generic drugs for which prices have fallen so low that many manufacturers claim they cannot...
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FRIDAY, Feb. 1, 2019 -- Discontinuing tumor necrosis factor inhibitors (TNFi) before gestational week 20 in women with well-controlled rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA) is not associated with disease worsening in late...
http://bit.ly/2TtcLUb
FRIDAY, Feb. 1, 2019 -- Improving clinic capacity to respond to patients' social needs may reduce primary care physician burnout, according to a study published in the January-February issue of the Journal of the American Board of Family...
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Boron neutron capture therapy and Y-90 radioembolization are emerging therapeutic methods for uncontrolled brain cancers and hepatic cancers, respectively. These advanced radiation therapies are heavily relied on theranostic nuclear medicine imaging before the therapy for the eligibility of patients and the prescribed-dose simulation, as well as the post-therapy scanning for assessing the treatment efficacy. In Taiwan, the Taipei Veterans General Hospital is the only institute performing the BNCT and also the leading institute performing Y-90 radioembolization. In this article, we present our single institute experiences and associated theranostic nuclear medicine approaches for these therapies.
Renal dysfunction increases risk of death for patients with cirrhosis. We investigated whether mortality differs significantly among patients with acute kidney injury (AKI), chronic kidney disease (CKD), and both.
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It is important to rapidly identify patients with advanced liver disease. Routine tests to assess liver function and fibrosis provide data that can be used to determine patients' prognoses. We tested the validated the ability of combined data from the ALBI and FIB-4 scoring systems to identify patients with compensated cirrhosis at highest risk for decompensation.
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Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE).
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Current clinical-pathologic stratification factors do not allow clear identification of high-risk stage II colorectal cancer (CRC) patients. Therefore, the identification of additional prognostic markers is desirable. Toll-like receptor (TLR)-4 is activated during tumorigenesis and matrix metalloproteases (MMPs) are involved in invasion and metastasis. We aimed to evaluate the expression and clinical relevance of TLR4, MMP11 and MMP13 for patients with stage II CRC. Immunohistochemistry was used to study the expression of TLR4, MMP11 and MMP13 in 96 patients with stage II CRC. We measured the global expression and the expression by different cell types (tumor cells, cancer-associated fibroblasts (CAFs) and mononuclear inflammatory cells (MICs)). The potential relationship between expressions of factors and different prognostic variables were evaluated. Our results show significant relationships between either TLR4 expression by tumor cells and MMP11 expression by CAFs and high risk of tumor recurrence. In addition, the concurrence of age ≥ 75 years and the non-expression of MMP11 by CAFs identify a subgroup of patients with a good prognosis. Our results show that TLR4 expression by tumor cells and MMP11 expression by CAFs may to improve the identification of patients with stage II CRC with a high-risk of relapse.
Colonic endoscopic submucosal dissection (ESD) is more difficult than rectal ESD because of poor maneuverability of the endoscope due to physiological flexion, peristalsis and respiratory movements. The aim of this study is to assess the usefulness of the pocket-creation method (PCM) for colonic ESD compared with the conventional method (CM) regardless of lesion shape or location.
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Older (≥67 years) breast cancer survivors diagnosed in 2009 and treated with 1 of 5 local-therapy options [lumpectomy plus whole breast irradiation, brachytherapy, or endocrine therapy (Lump+WBI, Lump+Brachy, or Lump-alone) or mastectomy -/+ radiation (Mast-alone or Mast+RT)] were surveyed to examine their local-therapy treatment-related decisional regret 6-years after diagnosis. Local-therapy regret afflicted nearly one-quarter of our cohort and was associated with black race, less education, and more extensive nodal dissection but not breast surgery.
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Risk estimation of genitourinary (GU) toxicity after prostate radiotherapy is generally based on bladder dose-volume histograms (DVHs), disregarding any spatial dose-distribution information. We used a voxel-based approach to explore dosimetric regional differences in the bladder and the urethra associated with GU toxicity. The dose delivered to specific subregions of the urethra and the bladder was predictive of specific urinary symptoms, whereas the dose delivered to the whole bladder was less or not predictive.
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It is currently unknown whether increasing radiotherapy volume has a negative impact on the health-related quality of life (HRQoL) of low-grade glioma (LGG) patients in the short-term. The aim was to examine if the size of the target volume is independently associated with HRQoL.
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The objectives of this systematic review and meta-analysis are to appraise the evidence in regard to the diagnostic accuracy of a low-risk History, ECG, Age, Risk Factors, and Troponin (HEART) score for prediction of major adverse cardiac events in emergency department (ED) patients. These included 4 subgroup analyses: by geographic region, the use of a modified low-risk HEART score (traditional HEART score [0 to 3] in addition to negative troponin results), using conventional versus high-sensitivity troponin assays in the HEART score, and a comparison of different post–ED-discharge patient follow-up intervals.
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We have developed a whole-cortical electrocorticographic array for the common marmoset that continuously covers almost the entire lateral surface of cortex, from the occipital pole to the temporal and frontal poles. This protocol describes a chronic implantation procedure of the array in the epidural space of the marmoset brain.
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Leptomeningeal collaterals play a pivotal role in acute ischemic stroke. While most collateral scores rely on subjective visual analysis, an objective quantification is possible using dynamic computed tomography (CT) angiography (dynCTA). The aim was to determine the value of collateral filling delay (CFD) as assessed by dynCTA for predicting subacute stroke complications.
All subjects with isolated prebifurcation middle cerebral artery M1 occlusions were selected from an initial cohort of 2635 patients who underwent multiparametric CT for suspected stroke. The CFD was defined as the difference in time to peak enhancement between M2 segments of both hemispheres. Logistic regression analysis of CFD for space-occupying infarction (≥5 mm shift of brain tissue over the midline), parenchymal hematoma, and hemorrhagic transformation on follow-up imaging was performed.
In this study 78 patients (47 female, median age 74 years) were included. The median CFD was 6.31 s (interquartile range [IQR] 4.00–8.64). The CFD values were correlated with qualitative collateral scores (p < 0.05). Higher CFD was associated with the development of space-occupying infarction in univariable (odds ratio, OR = 1.28; p = 0.002) and multivariable regression analysis (OR = 1.48; p = 0.004). The CFD had no association with parenchymal hematoma or hemorrhagic transformation (p > 0.05).
A high CFD may serve as reproducible measure for collateralization and indicate development of increased risk of space-occupying infarction.
Authors: Kundert, Kale / Kortemme, Tanja
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Authors: Harzer, Klaus / Yildiz, Yildiz / Beck-Wödl, Stefanie
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Authors: Dickopf, Steffen / Lauer, Matthias E. / Ringler, Philippe / Spick, Christian / Kern, Peter / Brinkmann, Ulrich
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Gasdermin E (GSDME) has an important role in inducing secondary necrosis/pyroptosis. Upon apoptotic stimulation, it can be cleaved by activated caspase-3 to generate its N-terminal fragment (GSDME-NT), which executes pyroptosis by perforating the plasma membrane. GSDME is expressed in many human lung cancers including A549 cells. Paclitaxel and cisplatin are two representative chemotherapeutic agents for lung cancers, which induce apoptosis via different action mechanisms. However, it remains unclear whether they can induce GSDME-mediated secondary necrosis/pyroptosis in lung A549 cancer cells. Here we showed that both paclitaxel and cisplatin evidently induced apoptosis in A549 cells as revealed by the activation of multiple apoptotic markers. Notably, some of the dying cells displayed characteristic morphology of secondary necrosis/pyroptosis, by blowing large bubbles from the cellular membrane accompanied by caspase-3 activation and GSDME-NT generation. But the ability of cisplatin to induce this phenomenon was much stronger than that of paclitaxel. Consistent with this, cisplatin triggered much higher activation of caspase-3 and generation of GSDME-NT than paclitaxel, suggesting that the levels of secondary necrosis/pyroptosis correlated with the levels of active caspase-3 and GSDME-NT. Supporting this, caspase-3 specific inhibitor (Ac-DEVD-CHO) suppressed cisplatin-induced GSDME-NT generation and concurrently reduced the secondary necrosis/pyroptosis. Besides, GSDME knockdown significantly inhibited cisplatin- but not paclitaxel-induced secondary necrosis/pyroptosis. These results indicated that cisplatin induced higher levels of secondary necrosis/pyroptosis in A549 cells than paclitaxel, suggesting that cisplatin may provide additional advantages in the treatment of lung cancers with high levels of GSDME expression.
Here, we present a protocol for a novel gap junction intercellular communication assay designed for the high-throughput screening of gap junction-modulating chemicals for drug discovery and toxicological assessment.
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Authors: Poletti, Venerino / Ravaglia, Claudia
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Authors: Mindt, Sonani / Aida, Sihem / Merx, Kirsten / Müller, Annette / Gutting, Tobias / Hedtke, Maren / Neumaier, Michael / Hofheinz, Ralf-Dieter
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Authors: Hollestelle, Martine J. / Ruinemans-Koerts, Janneke / Idema, René N. / Meijer, Piet / de Maat, Moniek P.M.
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Authors: Kavsak, Peter A. / Roy, Chantele / Malinowski, Paul / Clark, Lorna / Lamers, Shana / Bamford, Karen / Hill, Stephen / Worster, Andrew / Jaffe, Allan S.
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Authors: Zakaria, Rosita / Allen, Katrina J. / Koplin, Jennifer J. / Crinis, Nick / De Rosa, Lidia / Roche, Peter / Greaves, Ronda F.
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Authors: Bogaert, Laura / Van den Bremt, Stefanie / Schouwers, Sofie / Bossuyt, Xavier / Van Hoovels, Lieve
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Authors: Laserna-Mendieta, Emilio J. / Lucendo, Alfredo J.
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Gender nonconforming behavior (GNB) is a risk factor for poorer psychological adjustment, but little is known about whether preschool-age children displaying GNB are at risk for depressive symptoms during adolescence. We examined maternal report of GNB at age 4–5 years-old as a predictor of adolescents' depressive symptoms at age 16–17 years-old in a longitudinal study of U.S. children from a predominantly low SES (61% received Aid to Families with Dependent Children) and African American (90%) sample. Youth with GNB in early childhood (n = 10) reported more depressive symptoms during adolescence than did their peers without GNB (n = 115), and this relationship remained after controlling for covariates (environmental risk, prenatal exposure, and neonatal medical problems). Our findings suggest that early GNB may be a risk factor for the development of depressive symptoms in adolescence. Further research is needed to replicate the current findings with a larger sample and to identify the underlying mechanisms by which GNB may increase risk for depressive symptoms. If replicated, the findings further highlight the need for both professionals and parents to become aware of the potential challenges that children with GNB face and to become knowledgeable about ways to facilitate healthy adjustment among gender nonconforming youth.
FRIDAY, Feb. 1, 2019 -- Four maternal characteristics can predict 12-month trajectories for women with postpartum depression with 72.8 percent accuracy, according to a study published online Jan. 15 in Depression & Anxiety. Sheehan D. Fisher,...
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FRIDAY, Feb. 1, 2019 -- For older men, hearing loss is associated with subjective cognitive function (SCF) decline, according to a study published online Jan. 29 in Alzheimer's & Dementia. Sharon G. Curhan, M.D., from Brigham and Women's...
http://bit.ly/2Be8flI
FRIDAY, Feb. 1, 2019 -- For patients with chronic pain (CP), both mindfulness-based stress reduction (MBSR) and cognitive behavioral therapy (CBT) improve physical functioning, pain intensity, and depression, according to a review published online...
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FRIDAY, Feb. 1, 2019 -- In utero exposure to higher levels of maternal glucose is associated with higher glucose levels and insulin resistance during childhood, according to a study published online Jan. 7 in Diabetes Care. Denise M. Scholtens,...
http://bit.ly/2Tr4wZ0
FRIDAY, Feb. 1, 2019 -- More black index patients diagnosed with HIV are interviewed for partner services than all index patients combined, according to research published in the Feb. 1 issue of the U.S. Centers for Disease Control and Prevention...
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FRIDAY, Feb. 1, 2019 -- Recommendations have been developed to improve accuracy, precision, and reproducibility in the interpretation of human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) results for breast cancer with use of...
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FRIDAY, Feb. 1, 2019 -- Educational videos in pediatric clinics can increase rates of human papillomavirus (HPV) vaccination among adolescents, according to a study published in the January issue of Pediatrics. Brian E. Dixon, Ph.D., from Indiana...
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FRIDAY, Feb. 1, 2019 -- A personalized web-based decision aid about prolonged mechanical ventilation does not improve prognostic concordance between clinicians and surrogate decision makers, according to a study published online Jan. 29 in the...
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Here are what the editors at HealthDay consider to be the most important developments in Psychiatry for January 2019. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are...
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Here are what the editors at HealthDay consider to be the most important developments in Ophthalmology for January 2019. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that...
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Here are what the editors at HealthDay consider to be the most important developments in Critical Care for January 2019. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that...
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Here are what the editors at HealthDay consider to be the most important developments in Pathology for January 2019. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are...
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Here are what the editors at HealthDay consider to be the most important developments in Allergy for January 2019. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are the...
http://bit.ly/2TpCRYn
Here are what the editors at HealthDay consider to be the most important developments in Otolaryngology for January 2019. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that...
http://bit.ly/2BhFQLp
Introduction
A 55-year-old woman was referred for investigation of an incidental iron deficiency anaemia (haemoglobin 97 g/L; ferritin 10 ug/L and mean cell volume 71.3 fL). The patient had no gastrointestinal symptoms. Upper gastrointestinal endoscopy was normal, with no evidence of coeliac disease on duodenal biopsies. Colonoscopy showed diverticulosis.
A capsule endoscopy was then performed, using a new generation dual camera capsule (Mirocam MC2000, Intromedic, Seoul, Korea). This utilises a charge coupled device camera at each end of the capsule, with software that allows the images from each camera to be viewed individually or in combination. Each camera records at three frames per second, and each has a 170° field of view. Compared with a single camera capsule endoscope, dual camera devices generate twice the coverage area of the small bowel, with faster frame acquisition rates.1
Small bowel images from capsule camera 1 were entirely normal (figure 1). A small bowel...
Objective
Evaluate the cost-effectiveness of laparoscopic ileocaecal resection compared with infliximab in patients with ileocaecal Crohn's disease failing conventional therapy.
DesignA multicentre randomised controlled trial was performed in 29 centres in The Netherlands and the UK. Adult patients with Crohn's disease of the terminal ileum who failed >3 months of conventional immunomodulators or steroids without signs of critical strictures were randomised to laparoscopic ileocaecal resection or infliximab. Outcome measures included quality-adjusted life-years (QALYs) based on the EuroQol (EQ) 5D-3L Questionnaire and the Inflammatory Bowel Disease Questionnaire (IBDQ). Costs were measured from a societal perspective. Analyses were performed according to the intention-to-treat principle. Missing cost and effect data were imputed using multiple imputation. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated to show uncertainty.
ResultsIn total, 143 patients were randomised. Mean Crohn's disease total direct healthcare costs per patient at 1 year were lower in the resection group compared with the infliximab group (mean difference –8931; 95% CI –12 087 to –5097). Total societal costs in the resection group were lower than in the infliximab group, however not statistically significant (mean difference –5729, 95% CI –10 606 to 172). The probability of resection being cost-effective compared with infliximab was 0.96 at a willingness to pay (WTP) of 0 per QALY gained and per point improvement in IBDQ Score. This probability increased to 0.98 at a WTP of 20 000/QALY gained and 0.99 at a WTP of 500/point of improvement in IBDQ Score.
ConclusionLaparoscopic ileocaecal resection is a cost-effective treatment option compared with infliximab.
Clinical trial registration numberDutch Trial Registry NTR1150; EudraCT number 2007-005042-20 (closed on 14 October 2015).
Here we describe a protocol for the generation of cationic nanoliposomes, which is based on the dry-film method and can be used for the safe and efficient delivery of in vitro transcribed messenger RNA.
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Cancers, Vol. 11, Pages 170: Integrating Small Animal Irradiators withFunctional Imaging for Advanced Preclinical Radiotherapy Research
Cancers doi: 10.3390/cancers11020170
Authors: Ghita Brown Kelada Graves Butterworth
Translational research aims to provide direct support for advancing novel treatment approaches in oncology towards improving patient outcomes. Preclinical studies have a central role in this process and the ability to accurately model biological and physical aspects of the clinical scenario in radiation oncology is critical to translational success. The use of small animal irradiators with disease relevant mouse models and advanced in vivo imaging approaches offers unique possibilities to interrogate the radiotherapy response of tumors and normal tissues with high potential to translate to improvements in clinical outcomes. The present review highlights the current technology and applications of small animal irradiators, and explores how these can be combined with molecular and functional imaging in advanced preclinical radiotherapy research.
Cancers, Vol. 11, Pages 171: Antimicrobial Peptide TP4 Induces ROS-Mediated Necrosis by Triggering Mitochondrial Dysfunction in Wild-Type and Mutant p53 Glioblastoma Cells
Cancers doi: 10.3390/cancers11020171
Authors: Su Pan Chen
Antimicrobial peptide tilapia piscidin 4 (TP4) from Oreochromis niloticus exhibits potent bactericidal and anti-tumorigenic effects. In a variety of cancers, the mutation status of p53 is a decisive factor for therapeutic sensitivity. Therefore, we investigated the impact of p53 status on TP4-induced cytotoxicity in glioblastoma cell lines and the molecular mechanisms that govern cytotoxic effects. Both U87MG (wild-type/WT p53) and U251 (mutant p53) glioblastoma cell lines were sensitive to TP4-induced cytotoxicity. The necrosis inhibitors Necrostatin-1 and GSK’872 attenuated TP4-induced cytotoxicity, and TP4 treatment induced the release of cyclophilin A, a biomarker of necrosis. Moreover, TP4 induced mitochondrial hyperpolarization and dysfunction, which preceded the elevation of intracellular reactive oxygen species, DNA damage, and necrotic cell death in both U87MG and U251 glioblastoma cells. p38 was also activated by TP4, but did not contribute to cytotoxicity. SB202190, a specific p38 inhibitor, enhanced TP4-induced oxidative stress, mitochondrial dysfunction, and cytotoxicity, suggesting a protective role of p38. Furthermore, TP4-induced cytotoxicity, oxidative stress, phosphorylation of p38, and DNA damage were all attenuated by the mitochondrial-targeted reactive oxygen species (ROS) scavenger MitoTEMPO, or the reactive oxygen species scavenger N-acetyl-L-cysteine. Based on these data, we conclude that TP4 induces necrosis in both WT and mutant p53 glioblastoma cells through a mitochondrial ROS-dependent pathway.
Cancers, Vol. 11, Pages 173: Association between Paclitaxel Clearance and Tumor Response in Patients with Esophageal Cancer
Cancers doi: 10.3390/cancers11020173
Authors: Eelke L.A. Toxopeus Femke M. de Man Nanda Krak Katharina Biermann Annemieke J.M. Nieuweboer Lena E. Friberg Esther Oomen-de Hoop Jan J.B. van Lanschot Joel Shapiro Bas P.L. Wijnhoven Ron H.J. Mathijssen
Inter-individual variability in paclitaxel pharmacokinetics may play a role in the response to chemotherapy. Therefore, we studied the association between paclitaxel clearance and treatment response in patients with esophageal cancer. All patients who received paclitaxel (plus carboplatin) treatment for esophageal cancer between 2007 and 2013 were included. The treatment was given as neoadjuvant chemoradiotherapy (nCRT), induction chemotherapy (iCT), or palliative chemotherapy (pCT). The treatment response was assessed by the tumor regression grade (TRG) or by the RECIST1.1 criteria, respectively. The unbound paclitaxel clearance (CL) was estimated with NONMEM. The log-transformed clearance was related to response with ANOVA and independent sample t-tests. A total of 166 patients were included, of whom 113 received nCRT, 23 iCT and 30 pCT. In patients receiving nCRT, paclitaxel clearance was not associated with tumor regression grade (p-value = 0.25), nor with pathologically complete response (geometric mean 561.6 L/h) and residual disease (geometric mean 566.1 L/h, p-value = 0.90). In patients who underwent iCT or pCT, also no association between paclitaxel clearance and RECIST outcome was identified (iCT: p-value = 0.08 and pCT: p-value = 0.81, respectively). In conclusion, systemic paclitaxel exposure was not associated with response to common paclitaxel-based treatment regimens for esophageal cancer. Future studies should focus on tumor exposure in relation to systemic exposure and treatment outcome.
Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare ( ≤ 0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes (C1S, DNASE1L3, DNASE1, IFIH1, and RNASEH2A) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported.
American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 384-386, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 313-320, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 386-389, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 255-256, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 286-301, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 389-390, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 260-261, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 377-379, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page e5-e23, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 258-259, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page P5-P6, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 352-361, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 261-263, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 392-394, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 390-392, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 362-376, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 380-380, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page 302-312, February 1, 2019.
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American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 3, Page e24-e25, February 1, 2019.
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Personality in a Hierarchical Model of Psychopathology
Thomas A. Widiger, Martin Sellbom, Michael Chmielewski, Lee Anna Clark, Colin G. DeYoung, Roman Kotov, Robert F. Krueger, Donald R. Lynam, Joshua D. Miller, Stephanie Mullins-Sweatt, Douglas B. Samuel, Susan C. South, Jennifer L. Tackett, Katherine M. Thomas, David Watson, and Aidan G. C. Wright
Traditional classifications of psychopathology (e.g., the Diagnostic and Statistical Manual of Mental Disorders, or DSM) categorize different combinations of symptoms onto syndromes and suggest treatments for each syndrome. The Hierarchical Taxonomy of Psychopathology (HiTOP) is an alternative that considers different domains of psychopathology (e.g., internalizing, detachment) that derive from empirical research and thus organize psychopathology along these domains. Widiger et al. discuss the role of personality within the HiTOP. Different personality-trait configurations contribute differently to the development and evolution of psychopathology. Therefore, the structure of personality provides a fundamental base for the HiTOP, and personality should perhaps become the focus of preventive interventions, before the onset of psychopathology. Consistent with this idea, developing preventions and treatment protocols for domains of personality rather than (or in addition to) treating disorders and syndromes might contribute to improvements in quality of life and health.
Is Worse Attention a Risk Factor for or a Consequence of Depression, or Are Worse Attention and Depression Better Accounted for by Stress? A Prospective Test of Three Hypotheses
Naoise Mac Giollabhui, Thomas M. Olino, Johanna Nielsen, Lyn Y. Abramson, and Lauren B. Alloy
Impaired cognitive functioning (e.g., attention deficits) usually accompanies depression, but is it caused by depression, a cause for depression, or are both caused by a third process (e.g., stress)? For 3 years, Giollabhui et al. collected data from adolescents and their caregivers regarding depressive diagnosis, depressive symptoms, stressful life events, emotional maltreatment, and attention — sustained attention (i.e., focusing on one task for a long period of time), divided attention (i.e., focusing on two or more different tasks), selective attention (i.e., focusing on one task while ignoring distractions), and switching attention (i.e., switching back and forth between tasks). Giollabhui and colleagues found that the relationship between depression and attention is complex and not confined to depressive episodes. Only decreases in divided attention predicted future depressive symptoms, but switching attention declined before the first episode of depression and recovered after the episode. In fact, decreases in switching attention predicted increases in depressive symptoms, which in turn predicted worse selective and switching attention. Childhood stress, but not recent maltreatment, was associated with increases in depressive symptoms and decreases in switching attention. Overall, these results suggest the importance of considering the role of external risk factors that might increase depression and impaired cognition.
Social Anxiety and Social Behavior: A Test of Predictions From an Evolutionary Model
Erin B. Tone, Eddy Nahmias, Roger Bakeman, Trevor Kvaran, Sarah F. Brosnan, Negar Fani, and Elizabeth A. Schroth
How does social anxiety — fear and avoidance of social situations— influence social behavior in competitive contexts? Participants reported their social anxiety levels and completed a Prisoner's Dilemma game in which they selected whether they wanted to cooperate with or defect from a coplayer. The coplayer, which was always a computer, although participants were informed of it only in some of the trials, used an algorithm to decide whether to cooperate or defect. Afterward, participants reported their experiences and their goals during the game. Participants with higher social anxiety reported (a) more competitive goals than cooperative or individualistic goals and (b) greater nervousness and anger toward the coplayer during the game. Participants with higher social anxiety also tended to defect after the coplayer was cooperative. So, social anxiety predicted a tendency to respond aversively to positive behavior from others. This tendency may reflect self-protection and a lack of trust in others or an unwillingness to reciprocate positive behavior.
In the metadata of the original publication of the article.
Heterozygous germline TP53 gene mutations result in Li-Fraumeni Syndrome (LFS). Breast cancer (BC) is the most frequent tumor in young women with LFS. An important issue related to BC in the Mexican population is the average age at diagnosis, which is approximately 11 years younger than that of patients in the United States (U.S.) and Europe. The aim of this study was to determine the prevalence of germline mutations in TP53 among young Mexican BC patients.
We searched for germline mutations in the TP53 gene using targeted next-generation sequencing (NGS) in 78 BC patients younger than 45 years old (yo) who tested negative for BRCA1/2 mutations. A group of 509 Mexican women aged 45yo or older without personal or family BC history (parents/grandparents) was used as a control.
We identified five patients with pathogenic variants in the TP53 gene, equivalent to 6.4% (5/78). Among patients diagnosed at age 36 or younger, 9.4% (5/55) had pathogenic TP53 mutations. Three of these variants were missense mutations (c.844C > T, c.517G > A, and c.604C > T), and the other two mutations were frameshifts (c.291delC and c.273dupC) and had not been reported previously. We also identified a variant of uncertain clinical significance (VUS), c.672G > A, which causes a putative splice donor site mutation. All patients with TP53 mutations had high-grade and HER2-positive tumors. None of the 509 patients in the healthy control group had mutations in TP53.
Among Mexican BC patients diagnosed at a young age, we identified a high proportion with germline mutations in the TP53 gene. All patients with the TP53 mutations had a family history suggestive of LFS. To establish the clinical significance of the VUS found, additional studies are needed. Pathogenic variants of TP53 may explain a substantial fraction of BC in young women in the Mexican population. Importantly, none of these mutations or other pathological variants in TP53 were found in the healthy control group.
Patients with advanced disease experience high levels of psychological distress, yet there is low uptake of psychosocial services offered to patients who screened positive for distress. In this study we aimed to identify predictors for use of psychosocial services in patients with metastatic colorectal cancer (mCRC) receiving first line chemotherapy enrolled in a prospective cluster randomized trial (CRT).
Patients completed measures on psychological distress, physical distress, and quality of life at baseline. Demographics, clinical characteristics at baseline and clinical events during treatment (e.g. severe adverse events, clinical benefit) were extracted from patient records. Patients reported psychosocial service utilization in- and outside the hospital after 10, 24 and 48 weeks of treatment. Multivariable logistic regression models were used to identify predictors for the use of psychosocial services.
Out of 349 patients, seventy patients (20.0%) used psychosocial support services during the follow-up period. Use of psychosocial services was associated with younger age, a higher educational level, presence of more pain (at baseline), and the expressed need to talk to a professional (at baseline). In addition, patients without progressive disease within the first ten weeks of treatment were more likely to use psychosocial services .
One in five patients with mCRC receiving first line palliative treatment used psychosocial services during this prospective longitudinal CRT. Sociodemographic factors (age, education), clinical factors (pain and no progressive disease) and the expressed need to talk to a professional predicted use of psychosocial services. Identification of these predictors may contribute to the understanding of factors that determine the need for psychosocial services.
Netherlands Trial Register NTR4034.
Synovial sarcoma is a relatively rare type of soft tissue sarcoma. The commonly observed symptom is a deep-seated palpable mass accompanied by pain or tenderness. Thus, it is considered a soft tissue sarcoma and rarely occurs primarily in bone. However, only few studies have been reported on intraosseous synovial sarcoma, and reports on cases with cytogenetic or molecular confirmation are even rarer. We report a case of intraosseous synovial sarcoma of the distal ulna that has been confirmed using histopathological examination and molecular analysis.
A 77-year-old female was referred to our hospital with a 1-month history of right wrist pain after housework. Clinical and imaging findings suggested a benign bone tumor that was enhanced by Gd-DTPA. It was thought that the tumor was possibly an enchondroma. Initially, we planned to evaluate the benignancy of the tumor with intraoperative frozen section, followed by curettage and bone graft at one stage However, when considering carefully, characteristics of the tumor did not perfectly match those of any diagnostic categories including enchondroma. Therefore, an incisional biopsy was performed and revealed that the tumor was synovial sarcoma. Following an elaborate plan, the patient underwent a wide resection of the tumor at the distal part of the right ulna. Reverse transcription-polymerase chain reaction (RT-PCR) from the resected specimen and sequencing of RT-PCR products demonstrated a chimeric SYT-SSX1 transcript, confirming the diagnosis of synovial sarcoma.
Synovial sarcoma is seldom considered in differential diagnosis of bone tumors because it is difficult to line up such an unusual diagnosis as a differential diagnosis. When the lesion does not perfectly fit into any diagnostic category, when the initial image diagnosis appears unconvincing, biopsy and pathology are indicated, recalling Jaffe's triangle. According to these diagnostic processes, the patient successfully completed the treatment for this rare intraosseous synovial sarcoma, following a careful plan based on the preoperative diagnosis.
Little is known about the spectrum of mitochondrial DNA (mtDNA) mutations across pediatric malignancies. In this study, we analyzed matched tumor and normal whole genome sequencing data from 616 pediatric patients with hematopoietic malignancies, solid tumors, and brain tumors. We identified 391 mtDNA mutations in 284 tumors including 45 loss-of-function mutations, which clustered at 4 statistically significant hotspots in MT-COX3, MT-ND4, and MT-ND5, and at a mutation hotspot in MT-tRNA-MET. A skewed ratio (4.83) of non-synonymous versus synonymous (dN/dS) mtDNA mutations with high statistical significance was identified based on Monte Carlo simulations in the tumors. By comparison, opposite ratios of 0.44 and 0.93 were observed in 616 matched normal tissues and in 249 blood samples from children without cancer, respectively. mtDNA mutations varied by cancer type and mtDNA haplogroup. Collectively, these results suggest that deleterious mtDNA mutations play a role in the development and progression of pediatric cancers.
http://bit.ly/2SfJ5gd
The formation of new lymphatic vessels (lymphangiogenesis) and remodeling of existing lymphatics are thought to facilitate the entry and transport of tumor cells into lymphatic vessels and on to distant organs. The migration of lymphatic endothelial cells (LEC) toward guidance cues is critical for lymphangiogenesis. While chemokines are known to provide directional navigation for migrating immune cells, their role in mediating LEC migration during tumor-associated lymphangiogenesis is not well defined. Here we undertook gene profiling studies to identify chemokine-chemokine receptor pairs that are involved in tumor lymphangiogenesis associated with lymph node metastasis. CCL27 and CCL28 were expressed in tumor cells with metastatic potential, while their cognate receptor, CCR10, was expressed by LEC and upregulated by the lymphangiogenic growth factor VEGF-D and the pro-inflammatory cytokine TNF-α. LEC were attracted to both CCL27 and CCL28 in a CCR10-dependent manner. Abnormal lymphatic vessel patterning in CCR10-deficient mice confirmed the role of CCR10 in lymphatic patterning. In vivo analyses showed that LEC are recruited to a CCL27 or CCL28 source, while VEGF-D was required in combination with these chemokines to enable formation of coherent lymphatic vessels. Moreover, tumor xenograft experiments demonstrated that even though CCL27 expression by tumors enhanced LEC recruitment, the ability to metastasize was dependent on the expression of VEGF-D. These studies demonstrate that CCL27 and CCL28 act through CCR10 to cooperate with inflammatory mediators and VEGF-D during tumor lymphangiogenesis.
http://bit.ly/2GmbOtt
Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in non-coding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM, 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P<5.69×10-6, we identified 31 genes, including GALNT6 at 12q13.33, as a candidate novel risk locus for GBM (mean Z=4.43, P=5.68×10-6). GALNT6 resides at least 55 Mb away from any previously-identified glioma risk variant, while all other 30 significantly-associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis.
http://bit.ly/2SfIxa9
Although cell cycle arrest, senescence, and apoptosis are established mechanisms of tumor suppression, accumulating evidence reveals that ferroptosis, an iron-dependent, non-apoptotic form of cell death, represents a new regulatory pathway in suppressing tumor development. Ferroptosis is triggered by lipid peroxidation and is tightly regulated by SLC7A11, a key component of the cystine-glutamate antiporter. Although many studies demonstrate the importance of transcriptional regulation of SLC7A11 in ferroptotic responses, it remains largely unknown how the stability of SLC7A11 is controlled in human cancers. In this study, we utilized biochemial purification to identify the ubiquitin hydrolase OTUB1 as a key factor in modulating SLC7A11 stability. OTUB1 directly interacted with and stabilized SLC7A11; conversely, OTUB1 knockdown diminished SLC7A11 levels in cancer cells. OTUB1 was overexpressed in human cancers, and inactivation of OTUB1 destabilized SLC7A11 and led to growth suppression of tumor xenografts in mice, which was associated with reduced activation of ferroptosis. Notably, overexpression of the cancer stem cell marker CD44 enhanced the stability of SLC7A11 by promoting the interaction between SLC7A11 and OTUB1; depletion of CD44 partially abrogated this interaction. CD44 expression suppressed ferroptosis in cancer cells in an OTUB1-dependent manner. Together, these results show that OTUB1 plays an essential role in controlling the stability of SLC7A11 and the CD44-mediated effects on ferroptosis in human cancers.
http://bit.ly/2GmbFWX
Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Immunotherapy targeting inhibitory pathways to unleash the anti-leukemia T cell response is a promising strategy for the treatment of leukemia, but we must first understand the underlying molecular mechanisms. Eomesodermin (Eomes) and T-bet are both T-box transcription factors that regulate CD8+ T cell responses in a context-specific manner. Here we examined the role of these transcription factors in CD8+ T cell immunity in AML patients. We report that the frequency of Eomes+T-betlow CD8+ T cells increased in newly diagnosed AML. This cell subset produced less cytokines and displayed reduced killing capacity, whereas depletion of Eomes by siRNA reversed these functional defects. Furthermore, Eomes bound the promoter of T cell immunoglobulin and ITIM domain (TIGIT) and positively regulated the expression of this inhibitory receptor on patient-derived T cells. A high frequency of Eomes+T-betlow CD8+ T cells was associated with poor response to induction chemotherapy and shorter overall survival in AML patients. These findings have significant clinical implications as they not only identify a predictive and prognostic biomarker for AML, but they also provide an important target for effective leukemia therapeutics.
http://bit.ly/2SfIqLL
American Journal of Respiratory Cell and Molecular Biology, Volume 60, Issue 2, Page 144-157, February 2019.
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American Journal of Respiratory Cell and Molecular Biology, Volume 60, Issue 2, Page 232-243, February 2019.
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American Journal of Respiratory Cell and Molecular Biology, Volume 60, Issue 2, Page 189-197, February 2019.
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American Journal of Respiratory Cell and Molecular Biology, Volume 60, Issue 2, Page 141-143, February 2019.
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American Journal of Respiratory Cell and Molecular Biology, Volume 60, Issue 2, Page 139-140, February 2019.
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American Journal of Respiratory Cell and Molecular Biology, Volume 60, Issue 2, Page 167-178, February 2019.
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American Journal of Respiratory Cell and Molecular Biology, Volume 60, Issue 2, Page 209-220, February 2019.
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American Journal of Respiratory Cell and Molecular Biology, Volume 60, Issue 2, Page 135-136, February 2019.
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American Journal of Respiratory Cell and Molecular Biology, Volume 60, Issue 2, Page 244-247, February 2019.
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American Journal of Respiratory Cell and Molecular Biology, Volume 60, Issue 2, Page 221-231, February 2019.
http://bit.ly/2S2OpUP