bluuebunny/crossref_metadata_2025 huggingface dataset:
Spikey: self-lensing flares from eccentric SMBH binaries
Authors: Hu Betty X , D’Orazio Daniel J , Haiman Zoltán , Smith Krista Lynne , Snios Bradford , Charisi Maria , Di Stefano Rosanne
Published: May 2020

We examine the light curves of two quasars, motivated by recent suggestions that a supermassive black hole binary (SMBHB) can exhibit sharp lensing spikes. We model the variability of each light curve as due to a combination of two relativistic effects: the orbital relativistic Doppler boost and gravitational binary self-lensing. In order to model each system, we extend previous Doppler plus self-lensing models to include eccentricity. The first quasar is identified in optical data as a binary candidate with a 20-yr period (Ark 120), and shows a prominent spike. For this source, we rule out the lensing hypothesis and disfavour the Doppler-boost hypothesis due to discrepancies in the measured versus recovered values of the binary mass and optical spectral slope. The second source, which we nickname Spikey, is the rare case of an active galactic nucleus identified in Kepler’s high-quality, high-cadence photometric data. For this source, we find a model, consisting of a combination of Doppler modulation and a narrow symmetric lensing spike, consistent with an eccentric SMBHB with a mass of $M_{\text{tot}} = 3\times 10^{7} {\, \mathrm{M}_{\odot }}$, rest-frame orbital period T = 418 d, eccentricity e = 0.5, and seen at an inclination of 8○ from edge-on. This interpretation can be tested by monitoring Spikey for periodic behaviour and recurring flares in the next few years. In preparation for such monitoring, we present the first X-ray observations of this object taken by the Neil Gehrels Swift Observatory.
Will COVID-19 fiscal recovery packages accelerate or retard progress on climate change?
Authors: Hepburn Cameron , O’Callaghan Brian , Stern Nicholas , Stiglitz Joseph , Zenghelis Dimitri
Published: May 2020

The COVID-19 crisis is likely to have dramatic consequences for progress on climate change. Imminent fiscal recovery packages could entrench or partly displace the current fossil-fuel-intensive economic system. Here, we survey 231 central bank officials, finance ministry officials, and other economic experts from G20 countries on the relative performance of 25 major fiscal recovery archetypes across four dimensions: speed of implementation, economic multiplier, climate impact potential, and overall desirability. We identify five policies with high potential on both economic multiplier and climate impact metrics: clean physical infrastructure, building efficiency retrofits, investment in education and training, natural capital investment, and clean R&D. In lower- and middle-income countries (LMICs) rural support spending is of particular value while clean R&D is less important. These recommendations are contextualized through analysis of the short-run impacts of COVID-19 on greenhouse gas curtailment and plausible medium-run shifts in the habits and behaviours of humans and institutions.
Effect of biologics on radiographic progression of peripheral joint in patients with psoriatic arthritis: meta-analysis
Authors: Wu Dongze , Li Chen , Zhang Shuo , Wong Priscilla , Cao Yihan , Griffith James F , Zhang Xinlu , Gu Jieruo , Tam Lai-Shan
Published: May 2020

Objectives

To determine the efficacy of biologics in preventing radiographic progression in peripheral joints of PsA patients.

Methods

Studies were searched in MEDLINE, Web of Science, and abstracts from the last three EULAR and ACR meetings up to 31 December 2019. Primary and secondary endpoints were the proportion of patients without radiographic progression and the mean change in total radiographic score at week 24.

Results

Eleven studies, involving 5382 patients, 9 drugs and 18 treatments, were included. Patients receiving biologics were more likely to achieve radiographic non-progression compared with placebo [odds ratio: pooled: 2.40, 95% CI: 2.00, 2.87; TNF inhibitors (TNFi): 2.94, 95% CI: 2.38, 3.63; IL inhibitors (ILi): 2.15, 95% CI: 1.69, 2.74; abatacept: 1.54, 95% CI: 1.03, 2.28] and have significantly lower radiographic progression [standardized mean difference (SMD): pooled: −2.16, 95% CI: −2.91, −1.41; TNFi: −2.82, 95% CI: −4.31, −1.33; ILi: −1.60, 95% CI: −2.49, −0.72; abatacept: −0.40, 95% CI: −0.59, −0.21]. Concomitant MTX therapy was not superior to monotherapy (SMD: pooled: 0.01, 95% CI: −0.07, 0.08; biologics: 0.01, 95% CI: −0.09, 0.11; placebo: −0.01, 95% CI: −0.13, 0.12). The effect of ustekinumab and secukinumab on radiographic progression was not influenced by prior anti-TNF therapy (SMD: −0.08, 95% CI: −0.25, 0.10).

Conclusion

Biologic agents may retard radiographic progression in PsA patients in terms of bone erosion and joint space narrowing compared with placebo. MTX seems to have no added effect. Prior anti-TNF therapy seems to not influence the radiographic efficacy of IL blockers.
A Systematic Approach to Demystifying the Unilateral Hyperlucent Lung
Authors: Chua Steven Siangkiat , Matta Eduardo Jose , Restrepo Carlos S. , Ocazionez Daniel
Published: May 2020

Causes of the unilateral hyperlucent lung consist of technical factors and congenital and acquired conditions. The goal of this article is to document the causes of the unilateral hyperlucent lung to increase the radiologist's familiarity with each of these conditions, ensure proper diagnosis, and help to guide appropriate treatment.
The Effect of High-Fidelity, Interprofessional Simulation on Teamwork Skills and Attitudes Toward Interprofessional Education
Authors: Lee Charlotte , Milbury Bernadette , Movius Maureen , Zhuang Jianrong
Published: May 2020

High-fidelity simulation is increasingly popular in interprofessional education (IPE). This study aimed to determine the effectiveness of high-fidelity simulation in teaching IPE content to prelicensure trainees. A quasi-experimental study took place at a simulation center in Southern California. It assessed medical and nursing students’ teamwork skills and attitudes toward IPE before and after high-fidelity simulation. Multivariate analysis of variance results revealed a decline in positive attitudes toward IPE postintervention in both medical and nursing students. No changes in teamwork skills and no differences between nursing and medical trainees were found. The implications of the study’s findings are discussed.
Development and Validation of a Marginality Index for Nursing Students
Authors: Englund Heather M.
Published: May 2020

AIM

The purpose of this study was to develop a marginality tool that speaks specifically to the domain of nursing education.

BACKGROUND

Minority nursing students in the United States have consistently reported feelings associated with the process of marginalization. Given the dearth of instruments that measure marginality directly, the concept has not been sufficiently investigated in nursing students

METHOD

The Englund Marginality Index (EMI) was administered to 323 nursing students currently enrolled in a baccalaureate nursing program in Wisconsin. A psychometric evaluation of the index was performed.

RESULTS

The EMI consists of 19 items and explained 70 percent of the variance. Cronbach’s α coefficient for the instrument was .90. Test-retest correlation was strong at r = .92, a strong support for the temporal stability of the instrument.

CONCLUSION

The findings from this study demonstrate that the EMI is a valid and reliable measure of marginality.
Which Psychological Factors Are Involved in the Onset and/or Persistence of Musculoskeletal Pain? An Umbrella Review of Systematic Reviews and Meta-Analyses of Prospective Cohort Studies
Authors: Martinez-Calderon Javier , Flores-Cortes Mar , Morales-Asencio Jose Miguel , Luque-Suarez Alejandro
Published: May 2020

Objective:

The objective of this study was to summarize the current status of knowledge about the longitudinal association between vulnerability or protective psychological factors and the onset and/or persistence of musculoskeletal (MSK) pain.

Methods:

PubMed, CINAHL, PsycINFO, PubPsych, Scopus, Web of Science, gray literature, and manual screening of references were searched from inception to June 15, 2019. Systematic reviews with or without meta-analysis that explored the longitudinal association between psychological factors and the onset and/or persistence of MSK pain were identified. The AMSTAR-2 tool was used to assess the risk of bias.

Results:

Fifty-nine systematic reviews that included 286 original research studies were included, with a total of 249,657 participants (127,370 with MSK pain and 122,287 without MSK pain at baseline). Overall, our results found that exposure to many psychological vulnerability factors such as depression, anxiety, psychological distress, and fear, among others, may increase the risk of the onset and persistence of MSK pain across time. In addition, our results also showed that a range of psychological factors considered to be “protective” such as self-efficacy beliefs, better mental health, active coping strategies, or favorable expectations of recovery may reduce the risk of the onset and persistence of MSK pain. However, all these systematic reviews were evaluated to have critically low confidence based on the AMSTAR-2 tool, indicating that findings from these reviews may be informative, but should be interpreted with caution.

Discussion:

The large number of methodological flaws found across reviews gives rise to a call to action to develop high-quality systematic reviews in this field.
Internal Version Compared With Pushing for Delivery of Cephalic Second Twins
Authors: Pauphilet Victoire , Goffinet François , Seco Aurélien , Azria Elie , Cordier Anne-Gaël , Deruelle Philippe , Kayem Gilles , Rozenberg Patrick , Sananès Nicolas , Sénat Marie-Victoire , Sentilhes Loic , Vayssière Christophe , Winer Norbert , Korb Diane , Schmitz Thomas ,   for the JUmeaux MODe d'Accouchement (JUMODA) Study Group and the Groupe de Recherche en Obstétrique et Gynécologie (GROG)
Published: May 2020

OBJECTIVE:

To assess neonatal morbidity and mortality according to whether cephalic second twins were born after internal version followed by total breech extraction or after instructions to push. We hypothesized that interval version would result in shorter intertwin delivery intervals and lower cesarean delivery rates for the second twin and therefore better neonatal outcomes.

METHODS:

These planned analyses of the JUMODA (JUmeaux MODe d'Accouchement) cohort, a national prospective population-based study of twin deliveries, examined births of cephalic second twins after vaginal birth of the first twin at or after 32 weeks of gestation. The internal version group of second twins born in breech presentation after obstetric maneuvers was compared with the pushing group, comprising those born in cephalic presentation. The primary outcome was a composite of neonatal morbidity and mortality. Multivariate modified Poisson regression models were used to control for potential confounders.

RESULTS:

Of 2,256 cephalic second twins, 487 (21.6%) were born in breech presentation after internal version and total breech extraction and 1,769 (78.4%) in cephalic presentation after pushing. Composite neonatal morbidity and mortality was not lower in the internal version (17/487 [3.5%]) compared with the pushing group (38/1,769 [2.1%]; adjusted relative risk [aRR] 1.73 [95% CI 0.98–3.05]), although median [quartile 1–quartile 3] intertwin delivery intervals were shorter (5 [4–8] vs 8 [5–12] minutes, P<.001) and the cesarean delivery rate for the second twin lower (5/487 [1.0%] vs 66/1,769 [3.7%], P=.002). Subgroup analyses showed no difference between groups at or after 37 weeks of gestation but higher composite neonatal morbidity and mortality after internal version before 37 weeks (14/215 [6.5%] vs 26/841 [3.1%]; aRR 2.18 [95% CI 1.15–4.13]). Secondary analyses according to center expertise in the overall population and stratified by gestational age yielded concordant results.

CONCLUSION:

Although our sample size precluded a robust assessment for small differences in outcomes between groups, internal version followed by total breech extraction of cephalic second twins was not associated with better neonatal outcomes than pushing.
Neonatal Seizures Among Low-Risk Pregnancies at Term
Authors: Doty Morgen S. , Chen Han-Yang , Chauhan Suneet P.
Published: May 2020

OBJECTIVE:

To examine risk factors and adverse outcomes for neonatal–maternal dyads among low-risk pregnancies at term with subsequent neonatal seizures.

METHODS:

United States vital statistics data sets were used for this retrospective study. Inclusion criteria were low-risk women (without hypertensive disease or diabetes) with nonanomalous singleton pregnancies, who delivered after labor at 37–41 weeks of gestation. The primary composite neonatal adverse outcome included 5-minute Apgar score less than 5, assisted ventilation longer than 6 hours, and neonatal death. A secondary outcome was composite maternal adverse outcome. Multivariable Poisson regression models with robust error variance were used, with adjusted relative risk (aRR) and 95% CI reported.

RESULTS:

Of 19.76 million live births during the study interval, 11.7 million (59.4%) met inclusion criteria. The rate of neonatal seizures after low-risk pregnancies delivered at term was 0.2 per 1,000 live births. The maternal risks factors associated with neonatal seizures included no prenatal care, smoking during pregnancy, being overweight or obese, and gestational age of 41 weeks. The strongest risk factors for neonatal seizures were chorioamnionitis (relative risk [RR] 5.04, 95% CI 4.40–5.77; aRR 3.27, 95% CI 2.84–3.76) and route of delivery, with operative vaginal (RR 3.62, 95% CI 3.20–4.09; aRR 3.02, 95% CI 2.66–3.43) and cesarean (RR 4.13, 95% CI 3.81–4.48; aRR 3.14, 95% CI 2.86–3.45) higher than spontaneous vaginal. Compared with neonates without seizures, those with seizures had higher risk of composite neonatal adverse outcome (RR 64.55, 95% CI 61.83–67.39; aRR 37.09, 95% CI 35.20–39.08). Compared with women who delivered neonates without seizures, those who delivered neonates with seizures had higher risk of composite maternal adverse outcome (RR 16.27, 95% CI 13.66–19.37; aRR 9.70, 95% CI 8.15–11.53).

CONCLUSION:

We identified modifiable maternal risk factors associated with neonatal seizures among low-risk pregnancies at term. Though infrequent, neonatal seizures are associated with higher risk of adverse outcomes in neonatal–maternal dyads.
Executive Summary of the Early-Onset Breast Cancer Evidence Review Conference
Authors: Chelmow David , Pearlman Mark D. , Young Amy , Bozzuto Laura , Dayaratna Sandra , Jeudy Myrlene , Kremer Mallory E. , Scott Dana Marie , O'Hara Julia Sage
Published: May 2020

The Centers for Disease Control and Prevention launched the Bring Your Brave campaign to increase knowledge about early-onset breast cancer, defined as breast cancer in women aged 18–45 years. The American College of Obstetricians and Gynecologists convened a panel of experts in breast disease from the Society for Academic Specialists in General Obstetrics and Gynecology to review relevant literature, validated tools, best practices, and practice guidelines as a first step toward developing educational materials for women's health care providers about early-onset breast cancer. Panel members conducted structured literature reviews, which were then reviewed by other panel members and discussed at an in-person meeting of stakeholder professional and patient advocacy organizations in April 2019. This article summarizes the relevant literature, existing guidance, and validated tools to guide health care providers in the prevention, early detection, and special considerations of early-onset breast cancer. Substantive knowledge gaps were noted and summarized to provide guidance for future research.
Screw Fixation Versus Hemiarthroplasty for Nondisplaced Femoral Neck Fractures in the Elderly: A Cost-Effectiveness Analysis
Authors: Yong Taylor M. , Austin Daniel C. , Molloy Ilda B. , Kunkel Samuel T. , Jevsevar David S. , Gitajn Ida L.
Published: May 2020

Objective:

To evaluate the cost-effectiveness of screw fixation versus hemiarthroplasty for nondisplaced femoral neck fractures in low-demand elderly patients.

Methods:

We constructed a Markov decision model using a low-demand, 80-year-old patient as the base case. Costs, health-state utilities, mortality rates, and transition probabilities were obtained from published literature. The simulation model was cycled until all patients were deceased to estimate lifetime costs and quality-adjusted life years (QALYs). The primary outcome was the incremental cost-effectiveness ratio with a willingness-to-pay threshold set at $100,000 per QALY. We performed sensitivity analyses to assess our parameter assumptions.

Results:

For the base case, hemiarthroplasty was associated with greater quality of life (2.96 QALYs) compared with screw fixation (2.73 QALYs) with lower cost ($23,467 vs. $25,356). Cost per QALY for hemiarthroplasty was $7925 compared with $9303 in screw fixation. Hemiarthroplasty provided better outcomes at lower cost, indicating dominance over screw fixation.

Conclusions:

Hemiarthroplasty is a cost-effective option compared with screw fixation for the treatment of nondisplaced femoral neck fractures in the low-demand elderly. Medical comorbidities and other factors that impact perioperative mortality should also be considered in the treatment decision.

Level of Evidence:

Economic Level III. See Instructions for Authors for a complete description of levels of evidence.
Compartment Syndrome: Evaluation of Skeletal Muscle Ischemia and Physiologic Biomarkers in Controlled Conditions Within Ex Vivo Isolated Muscle Bundles
Authors: Tatman Lauren M. , Upchurch Weston J. , Scholz Natalie , Wagstrom Emily , Smith Lauren L. , Bechtold Joan E. , Schmidt Andrew H. , Iaizzo Paul A.
Published: May 2020

Objectives:

To identify potential physiologic markers of muscle ischemia to serve as diagnostic indicators of compartment syndrome. We hypothesize that muscle bundles in hypoxic conditions will elicit decreases in potential hydrogen (pH) and increases in lactate and potassium that correlates with decreased muscle twitch forces.

Methods:

We performed an ex vivo evaluation of individual skeletal muscle bundles obtained from a swine's diaphragm that were exposed to hypoxic conditions and compared with control groups. Over a 4-hour period, we evaluated the following parameters for each muscle bundle: muscle twitch forces and levels of potassium, lactate, and pH. Comparisons between the hypoxic and control groups were calculated at each time point using the 2-tailed Wilcoxon rank sum test for nonparametric data. Longitudinal associations between biomarkers and muscle twitch forces were tested using repeated measures analyses.

Results:

The hypoxic group elicited more significant decreases in normalized muscle twitch forces than the control group at all time points (0.15 g vs. 0.55 g at 4 hours, P < 0.001). Repeated measures analyses of the hypoxic group demonstrated a statistically significant association between potassium, lactate, and normalized peak force over the course of time. Potassium demonstrated the strongest association with a 1 mmol/L unit increase in potassium associated with a 2.9 g decrease in normalized peak force (95% confidence interval −3.3 to −2.4, P < 0.001). The pH of all muscle baths increased over the course of time at similar rates between the study groups.

Conclusions:

This study used an ex vivo ischemic skeletal muscle model as a representation for pathophysiologic pathways associated with compartment syndrome. In this experimental approach we were unable to evaluate the pH of the muscle bundles due to continuous applied gassing. Our findings support further evaluations of potassium and lactate levels as potential diagnostic markers.
Accuracy of the Gutter Position in Cervical Double-door Laminoplasty Using Intraoperative Computed Tomography Navigation and the Factors Associated With C5 Palsy
Authors: Kudo Hitoshi , Wada Kanichiro , Kumagai Gentaro , Tanaka Sunao , Asari Toru , Araki Ryo , Takeuchi Kazunari , Yokoyama Toru , Ishibashi Yasuyuki
Published: May 2020

Study Design:

This was a prospective study.

Objective:

This study aimed to investigate the accuracy of the gutter position after cervical double-door laminoplasty (LP) using intraoperative computed tomography (CT) navigation and the factors associated with C5 palsy.

Summary of Background Data:

There were some reports in which the gutter position and the width of decompression in cervical LP were associated with C5 palsy; however, there were few reports about the accuracy of the gutter position.

Materials and Methods:

Thirty-three patients treated with cervical LP were enrolled. We marked our targeted gutter position on the lamina with a high-speed drill using intraoperative CT navigation and performed the LP procedure. The accuracy of the gutter position was evaluated with a postoperative CT scan. We measured the angle of the opened lamina (AOL), the proportion of the distance between the gutters and the distance of transverse diameter of spinal canal (PGSC) with a postoperative CT scan and spinal cord posterior shifting (SCPS) with preoperative and postoperative magnetic resonance imaging scans. We investigated the incidence of C5 palsy and analyzed AOL, PGSC, and SCPS between the C5 palsy (+) and (−) groups.

Results:

The accuracy of all gutter positions was 78.4% (182/232). The accuracy of the gutter position at the right C4 and right C7 was lower than that at the other levels. The AOL in all cases was ~60 degrees. The PGSC was 90.1%–97.2%. The SCPS at C5 was the largest with 2.2 mm. C5 palsy occurred in 3 of 33 patients (9.1%). There were no significant differences in the AOL, PGSC, or SCPS between the 2 groups.

Conclusions:

The accuracy of the gutter position using intraoperative CT navigation was good. The incidence of C5 palsy was higher in this study than in the previous reports.
Surgical Technique for Harvesting ECRL and ECRB Concurrently as Upper Extremity Tendon Autograft
Authors: Türker Tolga , Gosey Gregory M. , Kempton Darren M.
Published: May 2020

Upper extremity tendon autograft harvest has many indications and techniques. Many harvest sites provide only 1 single autograft and/or require surgical set up of more extremities than the primary one of interest. In this report, we describe an easily reproducible, quick, and low-morbidity technique using both the wrist extensors—extensor carpi radialis longus and extensor carpi radialis brevis, from near their distal attachments to their musculotendinous junctions proximally—as a source of tendon autograft for a variety of applications.
The Impact of Step-Down Unit Care on Patient Outcomes After ICU Discharge
Authors: Lekwijit Suparerk , Chan Carri W. , Green Linda V. , Liu Vincent X. , Escobar Gabriel J.
Published: May 2020

Objectives:

To examine whether and how step-down unit admission after ICU discharge affects patient outcomes.

Design:

Retrospective study using an instrumental variable approach to remove potential biases from unobserved differences in illness severity for patients admitted to the step-down unit after ICU discharge.

Setting:

Ten hospitals in an integrated healthcare delivery system in Northern California.

Patients:

Eleven-thousand fifty-eight episodes involving patients who were admitted via emergency departments to a medical service from July 2010 to June 2011, were admitted to the ICU at least once during their hospitalization, and were discharged from the ICU to the step-down unit or the ward.

Interventions:

None.

Measurements and Main Results:

Using congestion in the step-down unit as an instrumental variable, we quantified the impact of step-down unit care in terms of clinical and operational outcomes. On average, for ICU patients with lower illness severity, we found that availability of step-down unit care was associated with an absolute decrease in the likelihood of hospital readmission within 30 days of 3.9% (95% CI, 3.6–4.1%). We did not find statistically significant effects on other outcomes. For ICU patients with higher illness severity, we found that availability of step-down unit care was associated with an absolute decrease in in-hospital mortality of 2.5% (95% CI, 2.3–2.6%), a decrease in remaining hospital length-of-stay of 1.1 days (95% CI, 1.0–1.2 d), and a decrease in the likelihood of ICU readmission within 5 days of 3.6% (95% CI, 3.3–3.8%).

Conclusions:

This study shows that there exists a subset of patients discharged from the ICU who may benefit from care in an step-down unit relative to that in the ward. We found that step-down unit care was associated with statistically significant improvements in patient outcomes especially for high-risk patients. Our results suggest that step-down units can provide effective transitional care for ICU patients.
Development of Persistent Respiratory Morbidity in Previously Healthy Children After Acute Respiratory Failure*
Authors: Keim Garrett , Yehya Nadir , Spear Debbie , Hall Mark W. , Loftis Laura L. , Alten Jeffrey A. , McArthur Jennifer , Patwari Pallavi P. , Freishtat Robert J. , Willson Douglas F. , Straumanis John P. , Thomas Neal J. ,   for the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network
Published: May 2020

Objectives:

Acute respiratory failure is a common reason for admission to PICUs. Short- and long-term effects on pulmonary health in previously healthy children after acute respiratory failure requiring mechanical ventilation are unknown. The aim was to determine if clinical course or characteristics of mechanical ventilation predict persistent respiratory morbidity at follow-up.

Design:

Prospective cohort study with follow-up questionnaires at 6 and 12 months.

Setting:

Ten U.S. PICUs.

Patients:

Two-hundred fifty-five children were included in analysis after exclusion for underlying chronic disease or incomplete data. One-hundred fifty-eight and 130 children had follow-up data at 6 and 12 months, respectively.

Interventions:

None.

Measurements and Main Results:

Pulmonary dysfunction at discharge a priori defined as one of: mechanical ventilation, supplemental oxygen, bronchodilators or steroids at 28 days or discharge. Persistent respiratory morbidity a priori defined as a respiratory PedsQL, a pediatric quality of life measure, greater than or equal to 5 or asthma diagnosis, bronchodilator or inhaled steroids, or unscheduled clinical evaluation for respiratory symptoms. Multivariate backward stepwise regression using Akaike information criterion minimization determined independent predictors of these outcomes. Pulmonary dysfunction at discharge was present in 34% of patients. Positive bacterial respiratory culture predicted pulmonary dysfunction at discharge (odds ratio, 4.38; 95% CI, 1.66–11.56). At 6- and 12-month follow-up 42% and 44% of responders, respectively, had persistent respiratory morbidity. Pulmonary dysfunction at discharge was associated with persistent respiratory morbidity at 6 months, and persistent respiratory morbidity at 6 months was strongly predictive of 12-month persistent respiratory morbidity (odds ratio, 18.58; 95% CI, 6.68–52.67). Positive bacterial respiratory culture remained predictive of persistent respiratory morbidity in patients at both follow-up points.

Conclusions:

Persistent respiratory morbidity develops in up to potentially 44% of previously healthy children less than or equal to 24 months old at follow-up after acute respiratory failure requiring mechanical ventilation. This is the first study, to our knowledge, to suggest a prevalence of persistent respiratory morbidity and the association between positive bacterial respiratory culture and pulmonary morbidity in a population of only previously healthy children with acute respiratory failure.
Cutaneous Adenosquamous Carcinoma of the Scalp With Intestinal Phenotype
Authors: Alomran Husain , Cruel Thierry , Harrou Olivier , Kanitakis Jean , Balme Brigitte
Published: May 2020

Cutaneous adenosquamous carcinoma is a mixed, squamous and glandular, rare malignant tumor of the skin characterized by a mixed, squamous, and glandular differentiation. Few cases of this tumor have been so far reported, and even fewer have been thoroughly studied by immunohistochemistry. We report here an exceptional case of cutaneous adenosquamous carcinoma which showed immunohistochemically features of intestinal differentiation, namely because of the expression of keratin 20 and CDX2, a marker of gastrointestinal tumors.
Beyond Developmental Supports for a Child Refugee
Authors: Moore Jessica A. , Scharf Rebecca J. , Malik Fatima , Nyp Sarah S.
Published: May 2020

CASE:

Zahid is a 10-year-old boy who moved to the United States 18 months ago with his parents and 3 younger siblings. He and his family are refugees from Syria. Zahid was born in Syria after an uncomplicated pregnancy and delivery. Zahid's parents first became concerned about Zahid's development when he was 9 months old because he had not started cooing or babbling and did not respond to his name. At 3 years, a doctor in Syria expressed concern that Zahid may have autism spectrum disorder; however, his parents did not know what symptoms triggered the concern and believed his behavior was because of his ongoing exposure to trauma.

Zahid underwent a full evaluation 1 year ago in the United States and was found to meet the criteria for autism spectrum disorder. Coaching was provided to his parents in obtaining appropriate educational support for their son, and a referral was placed for applied behavior analysis (ABA) to be provided by an organization in the community. After several meetings between the parents and school administration, an Individualized Education Program was initiated. Despite acceptance into a community-based ABA program, Zahid has not begun the intervention because of transportation difficulties. In-home ABA was offered but was refused by the family.

The family is under significant stress. Zahid is nonverbal and has displayed behaviors affecting safety, including wandering/eloping and turning on kitchen appliances resulting in a kitchen fire. Zahid's mother completed high school, and his father completed sixth grade. Both parents speak limited English, and neither is employed. The family receives financial support through the government, but this will be ending soon. Zahid's father is concerned that employment outside of the home will further limit his ability to transport Zahid to necessary appointments. Zahid's mother does not drive. Zahid's father requests that the physician provide a letter requesting exemption from requirements to participate in work or training programs because of Zahid's needs. How would you respond to this overwhelmed father?
Mediators and Moderators of the Influences of Living Alone on Psychological Distress Among Japanese Older Adults
Authors: Sugisawa Hidehiro , Sugihara Yoko
Published: May 2020

This study explored gender differences in mediators and moderators of the association between living alone and psychological distress among 2556 Japanese older adults aged 65 years and older. Putative mediators and moderators were physical health, income, informal networks, and social support. Living alone was significantly related to psychological distress only in men. Significant mediators were income in both genders and social support only in men. Living alone in women was related to having more informal networks, which reduced psychological distress. This contributed to mitigating the effect of living alone on psychological distress among women. Effective moderators were not discovered.
Evaluation of Extrapolation Methods to Predict Trough Concentrations to Guide Therapeutic Drug Monitoring of Oral Anticancer Drugs
Authors: Janssen Julie M. , Dorlo Thomas P.C. , Beijnen Jos H. , Huitema Alwin D.R.
Published: May 2020

Background:

For oral anticancer drugs, trough concentration (Cmin) is usually used as a target in therapeutic drug monitoring (TDM). Recording of Cmin is highly challenging in outpatients, in whom there is typically a variability in sample collection time after dosing. Various methods are used to estimate Cmin from the collected samples. This simulation study aimed to evaluate the performance of 3 different methods in estimating the Cmin of 4 oral anticancer drugs for which TDM is regularly performed.

Methods:

Plasma concentrations of abiraterone, dabrafenib, imatinib, and pazopanib at a random time (Ct,sim) and at the end of the dosing interval (Cmin,sim) were simulated from population pharmacokinetic models including 1000 patients, and the values were converted into simulated observed concentrations (Ct,sim,obs and Cmin,sim,obs) by adding a residual error. From Ct, sim,obs, Cmin was predicted (Cmin,pred) by the Bayesian estimation (method 1), taking the ratio of the Ct,sim,obs and typical population concentration and multiplying this ratio with the typical population value of Cmin,sim (method 2), and log-linear extrapolation (method 3). Target attainment was assessed by comparing Cmin,pred with the proposed pharmacokinetic targets related to efficacy and calculating the positive predictive and negative predictive values.

Results:

The mean relative prediction error and root mean squared relative prediction error results showed that method 3 was out-performed by method 1 and 2. Target attainment was adequately predicted by all 3 methods (the respective positive predictive value of method 1, 2, and 3 was 92.1%, 92.5%, and 93.1% for abiraterone; 87.3%, 86.9%, and 99.1% for dabrafenib; 79.3%, 79.3%, and 75.9% for imatinib; and 72.5%, 73.5%, and 67.6% for pazopanib), indicating that dose adjustments were correctly predicted.

Conclusions:

Both method 1 and 2 provided accurate and precise individual Cmin,pred values. However, method 2 was easier to implement than method 1 to guide individual dose adjustments in TDM programs.
Phenotyping of Uracil and 5-Fluorouracil Metabolism Using LC-MS/MS for Prevention of Toxicity and Dose Adjustment of Fluoropyrimidines
Authors: Tafzi Naima , Woillard Jean-Baptiste , Fleytoux Aurélie , Picard Nicolas , Marquet Pierre
Published: May 2020

Background:

Plasma concentrations of fluoropyrimidine exhibit a wide interindividual variability that depends mainly on the activity of dihydropyrimidine dehydrogenase, its major catabolic enzyme. Patients with low dihydropyrimidine dehydrogenase activity are at an increased risk of overexposure and often severe, sometimes lethal, toxicity. This study aimed to develop a quick and easy bioanalytical method for the simultaneous determination of endogenous uracil (U), exogenous 5-fluorouracil (5-FU), and their respective 5,6-dihydro-metabolite in human plasma using Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).

Methods:

After protein precipitation, the compounds were purified using liquid–liquid extraction. Chromatographic separation was conducted using a Cortecs T3 column and binary gradient elution. Detection and quantification were performed in the positive electrospray ionization and selected the reaction monitoring mode after 2 transitions per analyte and 1 per internal standard. The data obtained with this technique were retrospectively gathered for uracil metabolism phenotyping before fluoropyrimidine treatment (as enforced by national regulations) in a large group of 526 patients.

Results:

The analytical response was linear (r > 0.99 for all compounds), and it yielded a lower limit of quantification of 2 ng·mL−1 for U and UH2 as well as 4 ng·mL−1 for 5-FU and 5,6-dihydro-5-FUH2. The median uracil concentration in 526 patients was 10.6 mcg/L, with extreme values of 3.9 and 81.6 mcg/L; 78 patients (15%) had uracil concentration ≥16 mcg/L, that is, above the threshold of decreased enzyme activity and initial dose reduction.
Usage of Tacrolimus and Mycophenolic Acid During Conception, Pregnancy, and Lactation, and Its Implications for Therapeutic Drug Monitoring: A Systematic Critical Review
Authors: Le Hoang Lan , Francke Marith I. , Andrews Louise M. , de Winter Brenda C. M. , van Gelder Teun , Hesselink Dennis A.
Published: May 2020

Background:

Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosuppressive drug combination after solid organ transplantation consists of tacrolimus (Tac) plus mycophenolic acid (MPA). Here, the effects of Tac and MPA on fertility, pregnancy, and lactation are systematically reviewed, and their implications for therapeutic drug monitoring (TDM) are discussed.

Methods:

A systematic literature search was performed (August 19, 2019) using Ovid MEDLINE, EMBASE, the Cochrane Central Register of controlled trials, Google Scholar, and Web of Science, and 102 studies were included. Another 60 were included from the reference list of the published articles.

Results:

As MPA is teratogenic, women who are trying to conceive are strongly recommended to switch from MPA to azathioprine. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes. Nevertheless, in 2015, the drug label was updated with additional risk minimization measures in a pregnancy prevention program. Data on MPA pharmacokinetics during pregnancy and lactation are limited. Tac treatment during conception, pregnancy, and lactation seems to be safe in terms of the health of the mother, (unborn) child, and allograft. However, Tac may increase the risk of hypertension, preeclampsia, preterm birth, and low birth weight. Infants will ingest very small amounts of Tac via breast milk from mothers treated with Tac. However, no adverse outcomes have been reported in children exposed to Tac during lactation. During pregnancy, changes in Tac pharmacokinetics result in increased unbound to whole-blood Tac concentration ratio. To maintain Tac concentrations within the target range, increased Tac dose and intensified TDM may be required. However, it is unclear if dose adjustments during pregnancy are necessary, considering the higher concentration of (active) unbound Tac.

Conclusions:

Tac treatment during conception, pregnancy and lactation seems to be relatively safe. Due to pharmacokinetic changes during pregnancy, a higher Tac dose might be indicated to maintain target concentrations. However, more evidence is needed to make recommendations on both Tac dose adjustments and alternative matrices than whole-blood for TDM of Tac during pregnancy. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes, whereas MPA use in women during conception and pregnancy is strongly discouraged.
High-Performance Liquid Chromatography for Therapeutic Drug Monitoring of Serum Lenvatinib
Authors: Watanabe Yusuke , Doki Kosuke , Sekine Ikuo , Hara Hisato , Homma Masato
Published: May 2020

Background:

Therapeutic drug monitoring (TDM) and dose adjustment of lenvatinib may be beneficial in the treatment of radioiodine-refractory thyroid cancer, by maximizing antitumor effects and minimizing adverse drug reactions. The aim of this study was, therefore, to develop and validate a high-performance liquid chromatography method using an ultraviolet detection system for routine serum lenvatinib detection in patients with thyroid cancer.

Methods:

Serum specimens, spiked with an internal standard, were treated by a solid-phase extraction through an octadecylsilyl silica cartridge. Lenvatinib and internal standard were concomitantly separated from serum using a conventional octadecylsilyl silica column through isocratic elution, using a mobile phase consisting of 0.02 mol/L sodium phosphate (pH 6.7) and acetonitrile (50/50, vol/vol) at a flow rate of 1.0 mL/min. The detection wavelength was set at 244 nm. Serum samples from 5 patients were used for clinical validation of the method.

Results:

The calibration curve for lenvatinib was linear (Pearson correlation coefficient, r = 0.9998) over the concentration range of 6.25–400 ng/mL, with a lower limit of quantification of 6.25 ng/mL. Extraction recoveries for lenvatinib were 97% or more, with coefficients of variation less than 2.2%. The coefficients of variation for intraday and interday assays were less than 4.7% and 6.0%, respectively.

Conclusions:

This sensitive high-performance liquid chromatography method can be used for lenvatinib therapeutic drug monitoring when liquid chromatography–tandem mass spectrometry facilities are unavailable.
Evaluation of Imatinib Concentrations in Samples Submitted for BCR-ABL1 or Imatinib Testing—Evidence to Support Therapeutic Drug Monitoring for Dose Optimization?
Authors: Smy Laura , Sadler Aaron J. , McMillin Gwendolyn A.
Published: May 2020

Background:

Imatinib is one of the first-line therapies for chronic myeloid leukemia. Achieving a major molecular response early in treatment, as indicated by a BCR-ABL1 major international scale result of ≤0.1% within 6 months, is associated with better patient outcomes and is statistically associated with a trough imatinib concentration of approximately 1000 ng/mL. Adherence to therapy, drug resistance, drug–drug interactions, and pharmacokinetic/pharmacodynamic factors may hinder attaining this target. Therapeutic drug monitoring of imatinib is not currently standard-of-care, but may help to evaluate adherence and optimize treatment of patients with chronic myeloid leukemia. This study aimed to evaluate imatinib concentrations in real-world patient plasma samples to identify the proportion of imatinib-treated patients who achieved the therapeutic target of 1000 ng/mL.

Methods:

This was a retrospective, observational study that measured imatinib in residual plasma samples used for BCR-ABL1 tests (n = 1022) and analyzed clinician-ordered imatinib tests for therapeutic drug monitoring (n = 116). Imatinib was measured by competitive immunoassay. The frequency of imatinib concentrations achieving the therapeutic target was determined and correlated with BCR-ABL1 major international scale, age, and sex.

Results:

Seventy-two percent of patients tested for BCR-ABL1 may not have been prescribed or were not adherent to imatinib therapy. In the 29% of patients who did not achieve major molecular response, but had quantifiable imatinib concentrations, the therapeutic concentration was not met. For clinician-ordered imatinib tests, 45% of samples did not exceed the therapeutic target and 4% had potentially toxic plasma concentrations (>3000 ng/mL).

Conclusions:

Therapeutic drug monitoring for imatinib may assist clinicians in the identification of patients who may not be adherent to therapy, display variable pharmacokinetics or pharmacodynamics, or may be experiencing toxicity or treatment failure.
Chronic exercise mediates epigenetic suppression of L-type Ca2+ channel and BKCa channel in mesenteric arteries of hypertensive rats
Authors: Zhang Yanyan , Chen Yu , Xu Zhaoxia , Wu Ying , Zhang Yimin , Shi Lijun
Published: May 2020

Background:

Regular exercise is a lifestyle intervention for controlling hypertension and has an improving effect on vascular function. Voltage-gated L-type Ca2+ (LTCC) and large-conductance Ca2+-activated K+ (BKCa) channels are two principal mediators of vascular smooth muscle cell contractility and arterial tone. The present study tested the hypothesis that DNA methylation dynamics plays a key role in exercise-induced reprogramming and downregulation of LTCC and BKCa channel in mesenteric arteries from spontaneously hypertensive rats (SHRs).

Methods:

SHRs and Wistar–Kyoto (WKY) rats were subjected to exercise training or kept sedentary, and vascular molecular and functional properties were evaluated.

Results:

Exercise inhibited hypertension-induced upregulation of LTCC and BKCa channel function in mesenteric arteries by repressing LTCC α1c and BKCa β1 subunit expression. In accordance, exercise triggered hypermethylation of α1c and β1 gene in SHR, with concomitant decreasing TET1, increasing DNMT1 and DNMT3b expression in mesenteric arteries, as well as altering peripheral α-KG and S-adenosylmethionine/ S-adenosylhomocysteine ratio. Acting synergistically, these exercise-induced functional and molecular amelioration could allow for attenuating hypertension-induced elevation in arterial blood pressure.

Conclusion:

Our results indicate that exercise suppresses LTCC and BKCa channel function via hypermethylation of α1c and β1 subunits, which contributes to the restoration of mesenteric arterial function and vasodilation during hypertension.
Effect of 3,3’-Diindolylmethane on Pulmonary Injury Following Thoracic Irradiation in CBA Mice
Authors: Laiakis Evagelia C. , McCart Elizabeth A. , Deziel Annabella , Rittase W. Bradley , Bouten Roxane M. , Jha Jyoti , Wilkins W. Louis , Day Regina M. , Fornace Albert J.
Published: May 2020

The molecule 3,3’-diindolylmethane (DIM) is small, a major bioactive metabolite of indole-3 carbinol (13C), and a phytochemical compound from cruciferous vegetables released upon exposure to the gut acid environment. DIM is a proposed anti-cancer agent and was previously demonstrated to prevent radiation damage in the bone marrow and the gastrointestinal tract. Here we investigated the effect of DIM on radiation-induced injury to the lung in a murine model through untargeted metabolomics and gene expression studies of select genes. CBA mice were exposed to thoracic irradiation (17.5 Gy). Mice were treated with vehicle or DIM (250 mg kg−1, subcutaneous injection) on days −1 pre-irradiation through +14 post-irradiation. DIM induced a significant improvement in survival by day 150 post-irradiation. Fibrosis-related gene expression and metabolomics were examined using lung tissue from days 15, 45, 60, 90, and 120 post-irradiation. Our qRT-PCR experiments showed that DIM treatment reduced radiation-induced late expression of collagen Iα and the cell cycle checkpoint proteins p21/waf1 (CDKN1A) and p16ink (CDKN2A). Metabolomic studies of lung tissue demonstrated a significant dampening of radiation-induced changes following DIM treatment. Metabolites associated with pro-inflammatory responses and increased oxidative stress, such as fatty acids, were suppressed by DIM treatment compared to irradiated samples. Together these data suggest that DIM reduces radiation-induced sequelae in the lung.
OPTICAL COHERENCE TOMOGRAPHY BIOMARKERS FOR REDUCTION OF DRUSENOID PIGMENT EPITHELIUM DETACHMENT
Authors: Kim Mirinae , Lee Yeo Jin , Park Wookyung , Park Young-Gun , Park Young-Hoon
Published: May 2020

Purpose:

To identify the optical coherence tomography biomarkers that can collectively predict the probability of collapse or reduction of drusenoid pigment epithelium detachment (PED).

Methods:

This consecutive observational case series reviewed the clinical data of 24 eyes with non-neovascular drusenoid PED. Among the study population, 17 eyes showed collapse or reduction of drusenoid PED. The mean follow-up duration was 44.8 ± 24.6 months. Optical coherence tomography–derived parameters were analyzed at baseline, at the last available visit before reduction of PED, at the first available visit after reduction of PED, and at the final visit.

Results:

The mean subfoveal choroidal thickness showed a significant decrease after PED reduction and at the most recent visit (P = 0.015). Migration of retinal pigment epithelium cells was detected in 15 (88.2%) after PED reduction; however, there was no significance in the frequency of migration of retinal pigment epithelium cells at each time point (P = 0.392). Non-neovascular subretinal fluid was detected in 7 (41.2%) before PED reduction, 2 (11.8%) after PED reduction, and 2 (11.8%) at the final visit. Interestingly, subretinal fluid appeared more frequently just before reduction of PED (P = 0.029).

Conclusion:

We found evidence of non-neovascular subretinal fluid and choroidal thinning before reduction in PED. This finding might be useful for detection and prediction of the progression of drusenoid PED.