bluuebunny/crossref_metadata_2025 huggingface dataset:
Photometry and performance of SPECULOOS-South
Authors: Murray C A , Delrez L , Pedersen P P , Queloz D , Gillon M , Burdanov A , Ducrot E , Garcia L J , Lienhard F , Demory B O , Jehin E , McCormac J , Sebastian D , Sohy S , Thompson S J , Triaud A H M J , Grootel V V , Günther M N , Huang C X
Published: May 2020

SPECULOOS-South, an observatory composed of four independent 1-m robotic telescopes, located at ESO Paranal, Chile, started scientific operation in 2019 January. This Southern hemisphere facility operates as part of the Search for Habitable Planets EClipsing ULtra-cOOl Stars (SPECULOOS), an international network of 1-m-class telescopes surveying for transiting terrestrial planets around the nearest and brightest ultracool dwarfs (UCDs). To automatically and efficiently process the observations of SPECULOOS-South, and to deal with the specialized photometric requirements of UCD targets, we present our automatic pipeline. This pipeline includes an algorithm for automated differential photometry and an extensive correction technique for the effects of telluric water vapour, using ground measurements of the precipitable water vapour. Observing very red targets in the near-infrared can result in photometric systematics in the differential light curves, related to the temporally-varying, wavelength-dependent opacity of the Earth’s atmosphere. These systematics are sufficient to affect the daily quality of the light curves, the longer time-scale variability study of our targets and even mimic transit-like signals. Here we present the implementation and impact of our water vapour correction method. Using the 179 nights and 98 targets observed in the I + z′ filter by SPECULOOS-South since 2019 January, we show the impressive photometric performance of the facility (with a median precision of ∼1.5 mmag for 30-min binning of the raw, non-detrended light curves) and assess its detection potential. We compare simultaneous observations with SPECULOOS-South and TESS, to show that we readily achieve high-precision, space-level photometry for bright, UCDs, highlighting SPECULOOS-South as the first facility of its kind.
A Likelihood Approach for Uncovering Selective Sweep Signatures from Haplotype Data
Authors: Harris Alexandre M , DeGiorgio Michael
Published: May 2020

Selective sweeps are frequent and varied signatures in the genomes of natural populations, and detecting them is consequently important in understanding mechanisms of adaptation by natural selection. Following a selective sweep, haplotypic diversity surrounding the site under selection decreases, and this deviation from the background pattern of variation can be applied to identify sweeps. Multiple methods exist to locate selective sweeps in the genome from haplotype data, but none leverages the power of a model-based approach to make their inference. Here, we propose a likelihood ratio test statistic T to probe whole-genome polymorphism data sets for selective sweep signatures. Our framework uses a simple but powerful model of haplotype frequency spectrum distortion to find sweeps and additionally make an inference on the number of presently sweeping haplotypes in a population. We found that the T statistic is suitable for detecting both hard and soft sweeps across a variety of demographic models, selection strengths, and ages of the beneficial allele. Accordingly, we applied the T statistic to variant calls from European and sub-Saharan African human populations, yielding primarily literature-supported candidates, including LCT, RSPH3, and ZNF211 in CEU, SYT1, RGS18, and NNT in YRI, and HLA genes in both populations. We also searched for sweep signatures in Drosophila melanogaster, finding expected candidates at Ace, Uhg1, and Pimet. Finally, we provide open-source software to compute the T statistic and the inferred number of presently sweeping haplotypes from whole-genome data.
Lead-seq: transcriptome-wide structure probing in vivo using lead(II) ions
Authors: Twittenhoff Christian , Brandenburg Vivian B , Righetti Francesco , Nuss Aaron M , Mosig Axel , Dersch Petra , Narberhaus Franz
Published: May 2020

The dynamic conformation of RNA molecules within living cells is key to their function. Recent advances in probing the RNA structurome in vivo, including the use of SHAPE (Selective 2′-Hydroxyl Acylation analyzed by Primer Extension) or kethoxal reagents or DMS (dimethyl sulfate), provided unprecedented insights into the architecture of RNA molecules in the living cell. Here, we report the establishment of lead probing in a global RNA structuromics approach. In order to elucidate the transcriptome-wide RNA landscape in the enteric pathogen Yersinia pseudotuberculosis, we combined lead(II) acetate-mediated cleavage of single-stranded RNA regions with high-throughput sequencing. This new approach, termed ‘Lead-seq’, provides structural information independent of base identity. We show that the method recapitulates secondary structures of tRNAs, RNase P RNA, tmRNA, 16S rRNA and the rpsT 5′-untranslated region, and that it reveals global structural features of mRNAs. The application of Lead-seq to Y. pseudotuberculosis cells grown at two different temperatures unveiled the first temperature-responsive in vivo RNA structurome of a bacterial pathogen. The translation of candidate genes derived from this approach was confirmed to be temperature regulated. Overall, this study establishes Lead-seq as complementary approach to interrogate intracellular RNA structures on a global scale.
PseudoChecker: an integrated online platform for gene inactivation inference
Authors: Alves Luís Q , Ruivo Raquel , Fonseca Miguel M , Lopes-Marques Mónica , Ribeiro Pedro , Castro L Filipe C
Published: May 2020

The rapid expansion of high-quality genome assemblies, exemplified by ongoing initiatives such as the Genome-10K and i5k, demands novel automated methods to approach comparative genomics. Of these, the study of inactivating mutations in the coding region of genes, or pseudogenization, as a source of evolutionary novelty is mostly overlooked. Thus, to address such evolutionary/genomic events, a systematic, accurate and computationally automated approach is required. Here, we present PseudoChecker, the first integrated online platform for gene inactivation inference. Unlike the few existing methods, our comparative genomics-based approach displays full automation, a built-in graphical user interface and a novel index, PseudoIndex, for an empirical evaluation of the gene coding status. As a multi-platform online service, PseudoChecker simplifies access and usability, allowing a fast identification of disruptive mutations. An analysis of 30 genes previously reported to be eroded in mammals, and 30 viable genes from the same lineages, demonstrated that PseudoChecker was able to correctly infer 97% of loss events and 95% of functional genes, confirming its reliability. PseudoChecker is freely available, without login required, at http://pseudochecker.ciimar.up.pt.
SYNERGxDB: an integrative pharmacogenomic portal to identify synergistic drug combinations for precision oncology
Authors: Seo Heewon , Tkachuk Denis , Ho Chantal , Mammoliti Anthony , Rezaie Aria , Madani Tonekaboni Seyed Ali , Haibe-Kains Benjamin
Published: May 2020

Drug-combination data portals have recently been introduced to mine huge amounts of pharmacological data with the aim of improving current chemotherapy strategies. However, these portals have only been investigated for isolated datasets, and molecular profiles of cancer cell lines are lacking. Here we developed a cloud-based pharmacogenomics portal called SYNERGxDB (http://SYNERGxDB.ca/) that integrates multiple high-throughput drug-combination studies with molecular and pharmacological profiles of a large panel of cancer cell lines. This portal enables the identification of synergistic drug combinations through harmonization and unified computational analysis. We integrated nine of the largest drug combination datasets from both academic groups and pharmaceutical companies, resulting in 22 507 unique drug combinations (1977 unique compounds) screened against 151 cancer cell lines. This data compendium includes metabolomics, gene expression, copy number and mutation profiles of the cancer cell lines. In addition, SYNERGxDB provides analytical tools to discover effective therapeutic combinations and predictive biomarkers across cancer, including specific types. Combining molecular and pharmacological profiles, we systematically explored the large space of univariate predictors of drug synergism. SYNERGxDB constitutes a comprehensive resource that opens new avenues of research for exploring the mechanism of action for drug synergy with the potential of identifying new treatment strategies for cancer patients.
Adult immuno-oncology: using past failures to inform the future
Authors: Rahman Maryam , Sawyer W Gregory , Lindhorst Scott , Deleyrolle Loic P , Harrison Jeffrey K , Karachi Aida , Dastmalchi Farhad , Flores-Toro Joseph , Mitchell Duane A , Lim Michael , Gilbert Mark R , Reardon David A
Published: May 2020

In oncology, “immunotherapy” is a broad term encompassing multiple means of utilizing the patient’s immune system to combat malignancy. Prominent among these are immune checkpoint inhibitors, cellular therapies including chimeric antigen receptor T-cell therapy, vaccines, and oncolytic viruses. Immunotherapy for glioblastoma (GBM) has had mixed results in early trials. In this context, the past, present, and future of immune oncology for the treatment of GBM was discussed by clinical, research, and thought leaders as well as patient advocates at the first annual Remission Summit in 2019. The goal was to use current knowledge (published and unpublished) to identify possible causes of treatment failures and the best strategies to advance immunotherapy as a treatment modality for patients with GBM. The discussion focuses on past failures, current limitations, failure analyses, and proposed best practices moving forward.
Radiation-induced brain injury: current concepts and therapeutic strategies targeting neuroinflammation
Authors: Turnquist Casmir , Harris Brent T , Harris Curtis C
Published: May 2020

Continued improvements in cancer therapies have increased the number of long-term cancer survivors. Radiation therapy remains one of the primary treatment modalities with about 60% of newly diagnosed cancer patients receiving radiation during the course of their disease. While radiation therapy has dramatically improved patient survival in a number of cancer types, the late effects remain a significant factor affecting the quality of life particularly in pediatric patients. Radiation-induced brain injury can result in cognitive dysfunction, including hippocampal-related learning and memory dysfunction that can escalate to dementia. In this article, we review the current understanding of the mechanisms behind radiation-induced brain injury focusing on the role of neuroinflammation and reduced hippocampal neurogenesis. Approaches to prevent or ameliorate treatment-induced side effects are also discussed along with remaining challenges in the field.
Urinary Cyanoethyl Mercapturic Acid, a Biomarker of the Smoke Toxicant Acrylonitrile, Clearly Distinguishes Smokers From Nonsmokers
Authors: Luo Xianghua , Carmella Steven G , Chen Menglan , Jensen Joni A , Wilkens Lynne R , Le Marchand Loic , Hatsukami Dorothy K , Murphy Sharon E , Hecht Stephen S
Published: May 2020

Introduction

Cyanoethyl mercapturic acid (CEMA) is a urinary metabolite of acrylonitrile, a toxicant found in substantial quantities in cigarette smoke, but not in non-combusted products such as e-cigarettes or smokeless tobacco and rarely in the diet or in the general human environment. Thus, we hypothesized that CEMA is an excellent biomarker of combusted tobacco product use.

Aims and Methods

We tested this hypothesis by analyzing CEMA in the urine of 1259 cigarette smokers (urinary cotinine ≥25 ng/mL) and 1191 nonsmokers. The analyses of CEMA and cotinine were performed by validated liquid chromatography–tandem mass spectrometry methods. Logistic regression was fit for log-transformed CEMA to construct the receiver operating characteristic curve.

Results

We found that a CEMA cutpoint of 27 pmol/mL urine differentiated cigarette smokers from nonsmokers with sensitivity and specificity greater than 99%. The use of different cotinine cutpoints to define smokers (10–30 ng/mL) had little effect on the results.

Conclusions

CEMA is a highly reliable urinary biomarker to identify users of combusted tobacco products such as cigarettes as opposed to users of non-combusted products, medicinal nicotine, or nonusers of tobacco products.

Implications

CEMA can be used to distinguish users of combusted tobacco products from non-combusted products such as e-cigarettes, smokeless tobacco, and medicinal nicotine. Levels of CEMA in the urine of people who use these non-combusted products are extremely low, in contrast to cotinine.
Painless lymphadenopathy, eosinophilia and nephrotic syndrome: a diagnostic challenge in an era of increased migration
Authors: Rebelos Eleni , Bindi Massimo , Masi Lorenzo , Petruccelli Stefania , Taddei Marco , Ciancia Eugenio Mario , Rosada Javier
Published: May 2020

Kimura’s disease is a rare chronic inflammatory condition of unknown cause that most frequently affects Asian adults. It is characterized by painless lymphadenopathy in the head and neck region and eosinophilia, often associated with nephrotic syndrome. Α young Asian male presented to our Department with œdema at the lower limbs and scrotum, retroauricular masses, eosinophilia and proteinuria. Diagnosis was reached by a combination of the clinical picture, the patient’s origin and a histological examination, which revealed well-developed lymph follicles with increased numbers of eosinophils and fibrosis, a finding typical of Kimura’s disease. In case of a young Asian male who is otherwise healthy, but presents head/neck masses and/or unexplained eosinophilia associated with nephrotic syndrome, consider Kimura’s disease in the differential diagnosis.
Instantaneous Wave-Free Ratio Measurement During Intracranial Submaximal Angioplasty: Case Series and 2-Dimensional Operative Video
Authors: Vakharia Kunal , Waqas Muhammad , Fayyaz Najya , Young Amanda , Levy Elad I , Davies Jason M , Siddiqui Adnan H
Published: May 2020

BACKGROUND

Instantaneous wave-free ratios (iFRs) are functional measures of arterial stenosis that have become essential to interventional cardiology procedures. Their use for intracranial submaximal angioplasty (angioplasty with an undersized balloon) has not been studied extensively.

OBJECTIVE

To describe the feasibility and technique of iFR measurement for stenosis assessment during intracranial angioplasty.

METHODS

We present a series of consecutive patients treated between January 1, 2017 and June 30, 2018 with submaximal intracranial angioplasty in whom pre- and postprocedure iFR measurements were obtained with a Verrata-Volcano pressure wire (Philips, Amsterdam, The Netherlands). We collected patient data on age, sex, comorbid conditions, presenting complaints, modified Rankin scale (mRS) score at admission, neurological findings, procedure duration, fluoroscopy time, intraprocedural complications, length of hospital stay, and mRS score at last clinical follow-up (favorable outcome, 0-2). Angiographic stenosis severity and iFR values were recorded before and after angioplasty.

RESULTS

A total of 12 patients underwent iFR-guided angioplasty during the study period. The median patient age was 69.5 yr (range 48-81 yr). All patients had symptomatic intracranial arterial stenosis (3-basilar, 2-vertebral, 6-middle cerebral, 1-internal carotid). Preangioplasty stenosis ranged from 55% to 90%. The median postangioplasty reduction in stenosis was 17% (range 9%-30%). Preangioplasty values ranged from 0.30 to 0.40 (n = 4). Postangioplasty values ranged from 0.6 to 0.9 (n = 5). iFR values improved considerably in all patients. No procedure-related complications occurred. The median follow-up was 8.9 mo (range 3-25 mo). Follow-up outcomes were favorable in 10 patients.

CONCLUSION

iFR measurement before and after intracranial angioplasty is feasible. It may be used to assess the adequacy of intracranial angioplasty.
Public health surveillance of habitual physical activity in adolescents and adults in Namibia: a cross-sectional validation of activity questionnaires against accelerometry
Authors: Nashandi Hilde L , Reilly John J , Janssen Xanne
Published: May 2020

Background

Monitoring population-level physical activity is crucial for examining adherence to global guidelines and addressing obesity. This study validated self-reported moderate-to-vigorous physical activity (MVPA) against an accurate device-based method in Namibia.

Methods

Adolescent girls (n = 52, mean age 16.2 years [SD 1.6]) and adult women (n = 51, mean age 31.3 years [SD 4.7]) completed the PACE+/GPAQ self-report questionnaires and were asked to wear an Actigraph accelerometer for 7 days. Validity of self-reported MVPA was assessed using rank-order correlations between self-report and accelerometry, and classification ability of the questionnaires with Mann–Whitney tests, kappa’s, sensitivity and specificity.

Results

In the adolescents, Spearman’s rank coefficients between self-reported MVPA (days/week) and accelerometry measured MVPA were positive but not significant (r = 0.240; P = 0.104). In the adults, self-reported MVPA (minutes/day) was moderately and significantly correlated with accelerometer-measured MVPA (r = 0.396; P = 0.008). In both groups, there was fair agreement between accelerometry and questionnaire-defined tertiles of MVPA (adolescents κ = 0.267; P = 0.010; adults κ = 0.284; P = 0.008), and measured MVPA was significantly higher in the individuals self-reporting higher MVPA than those reporting lower MVPA.

Conclusions

The PACE+ and GPAQ questionnaires have a degree of validity in adolescent girls and adult females in Namibia, though more suitable for population than individual level measurement.
Effects of soybean meal level on growth performance of 11- to 25-kg nursery pigs12
Authors: Cemin Henrique S , Tokach Mike D , Dritz Steve S , Woodworth Jason C , DeRouchey Joel M , Goodband Robert D
Published: May 2020

Four experiments were conducted to determine the effects of increasing soybean meal (SBM) level in diets with or without 25% distillers dried grains with solubles (DDGS) on growth performance of nursery pigs raised in university or commercial facilities. Treatments were arranged in a 2 × 3 factorial with main effects of SBM (27.5%, 32.5%, or 37.5% of the diet) and DDGS (0% or 25% of the diet). A total of 296, 2,502, 4,118, and 711 pigs with initial body weight (BW) of 10.6, 11.7, 12.5, and 12.3 kg were used in Exp. 1, 2, 3, and 4, respectively. There were 10, 16, 13, and 12 replicates per treatment in Exp. 1, 2, 3, and 4, respectively. After weaning, pigs were fed common diets for approximately 21 d. Then, pens of pigs were assigned to treatments in a randomized complete block design with BW as the blocking factor and experimental diets were fed for 21 d. Pigs were weighed and feed disappearance measured to calculate average daily gain (ADG), average daily feed intake (ADFI), gain-to-feed ratio (G:F), and caloric efficiency (CE). Data were analyzed using the GLIMMIX procedure of SAS with block as a random effect and treatment as a fixed effect. Single degree-of-freedom contrasts were constructed to test the linear and quadratic effects of increasing SBM and their interactions with DDGS. Pigs used in all experiments did not undergo major health challenges during the experimental period and due to the low number of mortality and cull events, statistical analysis was not performed on these variables. The average cull rate was 0.7%, 0.5%, 0.2%, and 0%, and the mortality rate was 0.7%, 0.3%, 0.4%, and 0% in Exp. 1–4, respectively. There were interactions (P ≤ 0.039) between SBM and DDGS for G:F and CE in Exp. 2 and for ADG and ADFI in Exp. 3. These were mostly driven by increasing SBM negatively affecting performance in a greater magnitude when diets contained DDGS compared to diets without DDGS. The main effects of DDGS and SBM were more consistently observed across experiments. Pigs fed diets with 25% DDGS had decreased (P ≤ 0.001) ADG and ADFI in all experiments, as well as poorer (P ≤ 0.028) G:F and CE except for Exp. 3. Feeding increasing amounts of SBM generally did not result in any major impact in ADG but consistently improved (linear, P ≤ 0.078) G:F and CE across experiments.
Genome-Wide Investigation of 2,4-Diacetylphloroglucinol Protection Genes in Arabidopsis thaliana
Authors: Chae Dae-Han , Kim Da-Ran , Cho Gyeongjun , Moon Suhyeon , Kwak Youn-Sig
Published: May 2020

The compound 2,4-diacetylphloroglucinol (DAPG) is a well-known secondary metabolite produced by Pseudomonas spp. that are used as biocontrol agents. DAPG displays a remarkably broad spectrum of toxic activity against pathogens of plants. Yet high concentrations of DAPG may also have negative effect on plants, but the phytotoxicity of DAPG is not clearly understood. Here, we used genome-wide activation, tagging Arabidopsis plants as the model plant to investigate the plant response to DAPG. A total of 15 lines were selected as DAPG-tolerant plants from among 62,000 lines investigated. The DAPG-responsible genes were then identified via thermal asymmetric interlaced PCR and quantitative reverse transcription PCR, and the gene ontology analysis showed the distribution of these genes having different biological processes, cellular regulations, and molecular functional properties. Collectively, these findings suggest that plants may rely on several pathways to prevent DAPG phytotoxicity.
Potato Virus Y (PVY) Isolates from Solanum betaceum Represent Three Novel Recombinants Within the PVYN Strain Group and Are Unable to Systemically Spread in Potato
Authors: Green Kelsie J. , Funke Cassandra N. , Chojnacky Jeffrey , Alvarez-Quinto Robert A. , Ochoa Jose B. , Quito-Avila Diego F. , Karasev Alexander V.
Published: May 2020

Tamarillo, or tree tomato (Solanum betaceum), is a perennial small tree or shrub species cultivated in subtropical areas for fresh fruit and juice production. In Ecuador, tamarillo orchards are affected by several viruses, with one previously identified as potato virus Y (PVY); however, the specific strain composition of PVY in tamarillo was not determined. In 2015 and 2016, eight tamarillo plants exhibiting symptoms of leaf drop, mosaic, and mottled fruit were sampled near Tumbaco and Quito, Ecuador. These tamarillo PVY isolates were able to systemically infect tobacco, Nicotiana benthamiana, naranjilla, and tamarillo. Seven of the eight PVY isolates from tamarillo exhibited N-serotype, while one of the PVY isolates studied, Tam15, had no identifiable serotype. One isolate, Tam17, had N-serotype but produced asymptomatic systemic infection in tobacco. In tamarillo, four tamarillo isolates induced mosaic and slight growth retardation and were unable to systemically infect pepper or potato. Tamarillo, on the other hand, was unable to support systemic infection of PVY isolates belonging to the PVYO and PVYEu-N strains. The whole genomes of eight PVY isolates were sequenced from a series of overlapping RT-PCR fragments. Phylogenetically, tamarillo PVY isolates were found to belong to the large PVYN lineage, in a new tamarillo clade. Recombination analysis revealed that these tamarillo PVY isolates represent at least three novel recombinant types not reported before. The combination of the biological and molecular properties found in these eight PVY isolates suggested the existence of a new tamarillo strain of PVY that may have coevolved with S. betaceum.
Is Disease Intensity a Good Surrogate for Yield Loss or Toxin Contamination? A Case Study with Fusarium Head Blight of Wheat
Authors: Madden Laurence V. , Paul Pierce A.
Published: May 2020

Sometimes plant pathologists assess disease intensity when they are primarily interested in other response variables, such as yield loss or toxin concentration in harvested products. In these situations, disease intensity potentially could be considered a surrogate of yield or toxin. A surrogate is a variable which can be used instead of the variable of interest in the evaluation of experimental treatments or in making predictions. Surrogates can be measured earlier, more conveniently, or more cheaply than the variable of primary interest, but the reliability or validity of the surrogate must be shown. We demonstrate ways of quantifying two facets of surrogacy by using a protocol originally developed by Buyse and colleagues for medical research. Coefficient-of-determination type statistics can be used to conveniently assess the strength of surrogacy on a unitless scale. As a case study, we evaluated whether field severity of Fusarium head blight (i.e., FHB index) can be used as a surrogate for yield loss and deoxynivalenol (DON) toxin concentration in harvested wheat grain. Bivariate mixed models and corresponding approximations were fitted to data from 82 uniform fungicide trials conducted from 2008 to 2013. Individual-level surrogacy—for predicting the variable of interest (yield or DON) from the surrogate (index) in plots with the same treatment—was very low. Trial-level surrogacy—for predicting the effect of treatment (e.g., mean difference) for the variable of interest based on the effect of the treatment on the surrogate (index)—was moderate for yield, and only low for DON. Challenges in using disease severity as a surrogate for yield and toxin are discussed.
Patients’ delay is the major cause for late diagnosis of slipped capital femoral epiphysis
Authors: Örtegren Jakob , Österman Johan , Tiderius Carl J.
Published: May 2020

Early diagnosis of slipped capital femoral epiphysis (SCFE) is essential in order to reduce slip severity and subsequent risk of sequelae. The aims of this study were to evaluate patients’ and doctors’ delay in SCFE diagnosis and to identify possible factors leading to delay. We performed a retrospective review of medical charts and a personal interview with 54 consecutive patients admitted with a diagnosis of stable SCFE at three hospitals in Sweden between 2001 and 2009. Data on symptom duration, symptomatology, medical visits and type of medical contacts were retrieved. Slip angle (Southwick head-shaft angle) was measured. Median total delay from onset of symptoms to surgery was 26 weeks (range 1-109). Patients’ delay was significantly longer than doctors’ delay: 10 weeks (range 1-57) vs. 4 weeks (range 0-57) (P=0.002). Boys had significantly longer patients’ delay than girls (13 vs. 6 weeks, P=0.021) but not doctors’ delay. Children with dominance of knee pain had significantly longer doctors’ delay (14 vs. 4 weeks, P=0.002) but not patients’ delay. As expected, the total delay duration correlated with slip severity (R=0.59, P<0.001). Results demonstrate considerable delay in diagnosis of SCFE in Sweden, although the major cause is patients’ delay. Boys and children with dominance of knee pain are more likely to be diagnosed late. Efforts to increase the awareness of SCFE directed to both the general society and healthcare providers are necessary to improve future outcomes. Level III. Retrospective comparative study.
Botulinum Toxin A Treatment for Primary and Secondary Raynaud's Phenomenon in Teenagers
Authors: Quintana Castanedo Lucía , Feito Rodríguez Marta , Nieto Rodríguez Daniel , Maseda Pedrero Rocío , Chiloeches Fernández Clara , de Lucas Laguna Raúl
Published: May 2020

BACKGROUND

Raynaud's phenomenon (RP) is a clinical syndrome characterized by recurrent episodes of digital vasospasm triggered by exposure to physical and chemical agents or emotional stress. Although many pharmacologic treatments have been tested, there is still no cure or gold standard therapy. Botulinum toxin treatment has been proved to reduce pain and increase arterial blood flow in treated hands of adult patients with RP.

OBJECTIVE

The aim of this study is to evaluate the efficacy of botulinum toxin A on younger than 18-year-old patients with primary and secondary RP.

MATERIALS AND METHODS

A single-center prospective study was performed, including 8 patients aged 14 to 17 years who were clinically diagnosed with primary or secondary RP. BTX was injected into each hand without sedation or anesthetic blockade. The primary outcome was pain reduction after BTX injection. Pain intensity was evaluated at baseline and in the first follow-up. Secondary outcomes included variations in the number and severity of RP episodes after the BTX injection.

RESULTS

All patients stated significant pain reduction and decreased cold sensitivity, except one patient who did not feel any changes. No patients reported any loss of strength on thumb-index finger.

CONCLUSION

BTX injection is a simple, noninvasive, and cost-effective treatment alternative, offering an important nonsurgical therapeutic option for the pediatric population. It could also help optimize the dose of other treatments used in these patients. The most commonly observed positive effect is a reduction in the pain associated with RP attacks. Further studies are needed to confirm these results.
Hypertension in children
Authors: Tran Andrew H. , Urbina Elaine M.
Published: May 2020

Purpose of review

Hypertension is a common finding in children, and increases the risk for future cardiovascular events. This review focuses on recent advances in pediatric hypertension research including changes in hypertension guidelines, epidemiology, predictors of hypertension, blood pressure (BP) measurement, effects on target organs, and treatment of hypertension.

Recent findings

Changes in the 2017 hypertension guidelines by the American Academy of Pediatrics (AAP) have resulted in increased prevalence of elevated BP and hypertension in the United States, and there is no international consensus on these changes. Despite rising pediatric overweight and obesity in China, hypertension prevalence is stable, suggesting multifactorial effects on childhood BP. Maternal diabetes and exposure to particulate matter are associated with higher childhood BP, and body size in infancy and early childhood is a determinant of adult high BP. Children with elevated BP have evidence of target organ damage with altered retinal vasculature and pulse wave velocity parameters compared to normotensive patients. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be the best antihypertensive medications for the pediatric population even for African-American patients.

Research continues to illuminate contributors to pediatric hypertension and demonstrates opportunities for further study on the effects of hypertension and its management in children.
Blood pressure variability at midlife is associated with all-cause, coronary heart disease and stroke long term mortality
Authors: Goldbourt Uri , Grossman Ehud
Published: May 2020

Objective:

Elevated blood pressure (BP) is associated with cardiovascular mortality. BP variability (BPV) is also associated with cardiovascular mortality. However, most studies evaluated hypertensive patients with a relatively short follow-up. We investigated in male workers the association between BPV and long-term all-cause and specific-cause mortality.

Methods:

Among 10 059 men, aged 40–65, tenured civil servants and municipal employees in Israel, 9398 participants who were examined in 1963, 1965 and 1968 had assessment of diabetic and coronary morbidity status and SBP levels. Participants underwent clinical and biochemical evaluations and BP measured in the recumbent position on the right arm. We conducted analysis for SD-SBP across study visits. Hazard ratios were calculated for 18 years all-cause mortality, coronary heart disease (CHD) and stroke mortality associated with quintile of SD-SBP, with the lowest quintile serving as a reference.

Results:

Multivariate analysis yielded a significant association between SD-SBP and all-cause, CHD and stroke mortality. Age and SBP-adjusted hazard ratios of all-cause mortality was 1.02 [95% confidence interval (CI), 0.90–1.17], 1.06 (95% CI, 0.94–1.20), 1.20 (95% CI, 1.06–1.35) and 1.36 (95% CI, 1.21–1.53) (for quintile 2–5, respectively). The results of CHD and stroke mortality similarly and strongly indicated increasing age-adjusted mortality risk with increasing SD-SBP. Further adjustment for smoking, BMI, diabetes mellitus and coronary heart disease yielded similar results.

Conclusion:

In this cohort of tenured male workers, BPV taken over 5 years was clearly associated with 18-year all-cause, CHD and stroke mortality.
2020 International Society of Hypertension global hypertension practice guidelines
Authors: Unger Thomas , Borghi Claudio , Charchar Fadi , Khan Nadia A. , Poulter Neil R. , Prabhakaran Dorairaj , Ramirez Agustin , Schlaich Markus , Stergiou George S. , Tomaszewski Maciej , Wainford Richard D. , Williams Bryan , Schutte Aletta E.
Published: May 2020

Document reviewers:

Hind Beheiry (Sudan), Irina Chazova (Russia), Albertino Damasceno (Mozambique), Anna Dominiczak (UK), Anastase Dzudie (Cameroon), Stephen Harrap (Australia), Hiroshi Itoh (Japan), Tazeen Jafar (Singapore), Marc Jaffe (USA), Patricio Jaramillo-Lopez (Colombia), Kazuomi Kario (Japan), Giuseppe Mancia (Italy), Ana Mocumbi (Mozambique), Sanjeevi N.Narasingan (India), Elijah Ogola (Kenya), Srinath Reddy (India), Ernesto Schiffrin (Canada), Ann Soenarta (Indonesia), Rhian Touyz (UK), Yudah Turana (Indonesia), Michael Weber (USA), Paul Whelton (USA), Xin Hua Zhang, (Australia), Yuqing Zhang (China).
Assessment of Eye Lens Dose Reduction When Using Lateral Lead Shields on the Patient’s Head during Neurointerventional Fluoroscopic Procedures and Cone-beam Computed Tomography (CBCT) Scans
Authors: Xiong Zhenyu , Rudin Stephen , Bednarek Daniel R.
Published: May 2020

The purpose of this study was to evaluate the effect of placing small lead shields on the temple region of the skull to reduce radiation dose to the lens of the eye during interventional fluoroscopically-guided procedures and cone-beam computed tomography (CBCT) scans of the head. EGSnrc Monte-Carlo code was used to determine the eye lens dose reduction when using lateral lead shields for single x-ray projections, CBCT scans with different protocols, and interventional neuroradiology procedures with the Zubal computational head phantom. A clinical C-Arm system was used to take radiographic projections and CBCT scans of anthropomorphic head phantoms without and with lead patches, and the images were compared to assess the effect of the shields. For single lateral projections, a 0.1 (0.3)-mm-thick lead patch reduced the dose to the left-eye lens by 40% to 60% (55% to 80%) from 45° to 90° RAO and to the right-eye lens by around 30% (55%) from 70° to 90° RAO. For different CBCT protocols, the reduction of lens dose with a 0.3-mm-thick lead patch ranged from 20% to 53% at 110 kVp. For CBCT scans of the anthropomorphic phantom, the lead patch introduced streak artifacts that were mainly in the orbital regions but were insignificant in the brain region where most neurointerventional activity occurs. The dose to the patient’s eye lens can be reduced considerably by placing small lead shields over the temple region of the head without substantially compromising image quality in neuro-imaging procedures.
Bowman Layer Onlay Graft for Reducing Fluctuation in Visual Acuity After Previous Radial Keratotomy
Authors: Parker Jack S. , Dockery Philip W. , Parker John S. , Dapena Isabel , van Dijk Korine , Melles Gerrit R. J.
Published: May 2020

Purpose:

To describe the clinical outcome of a first patient undergoing Bowman layer (BL) transplantation with an onlay graft to reduce fluctuation in visual acuity and refractive error after previous radial keratotomy (RK) surgery.

Methods:

In 2018, a 66-year-old woman presented with complaints of long-standing diurnal fluctuation in best-spectacle corrected visual acuity (BSCVA) after RK in 1983. After the removal of host epithelium, a BL graft was positioned onto the host cornea. BSCVA, Scheimpflug-based corneal tomography, and anterior segment optical coherence tomography were evaluated up to 12 months postoperatively.

Results:

The surgery and postoperative course were uneventful. After surgery, the subjective complaints of visual fluctuation were reduced from 10 to 3 on a scale from 1 to 10. BSCVA (20/40; 0.5) did not change from preoperative to postoperative. Corneal tomography showed an overall central corneal steepening of 5.9 diopters. Biomicroscopy, Scheimpflug imaging, and anterior segment optical coherence tomography showed a completely epithelialized and well-integrated graft, with some minor epithelial remnants located in the preexisting keratotomy incisions.

Conclusions:

BL onlay grafting may have the potential to manage patients with subjective complaints of diurnal fluctuation in visual acuity after previous RK.
Difference in thrombotic microangiopathy between concurrently and previously diagnosed systemic lupus erythematosus
Authors: Chen Wen-Chun , Ko Po-Shen , Wang Hao-Yuan , Liu Yao-Chung , Hsiao Liang-Tsai , Gau Jyh-Pyng , Liu Jin-Hwang
Published: May 2020

Background:

Thrombotic microangiopathy (TMA) syndromes are potentially life-threatening complications and are defined as integrated syndromes of microangiopathic hemolytic anemia, thrombocytopenia, and organ injury. Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect various organs, including the hematopoietic system. SLE can complicate with TMA and can be categorized into two distinct groups by chronological association: TMA occurring as the initial presentation and leading to a diagnosis of SLE concurrently (TMA-cSLE) or TMA developing in patients previously diagnosed as having SLE (TMA-pSLE). We examined the differences in clinical characteristics, treatment responses, and clinical outcomes between these groups.

Methods:

We reviewed data of patients diagnosed as having TMA and SLE at Taipei Veterans General Hospital between 2002 and 2013. We included 29 patients: 8 and 21 in TMA-cSLE and TMA-pSLE groups, respectively. All underwent plasma exchange. Patients’ demographic and clinical characteristics, disease activity, and treatment modality were summarized.

Results:

Overall survival (OS) from SLE or TMA diagnosis was poor for the TMA-cSLE group. Median OS from SLE diagnosis was 2.9 months in the TMA-cSLE group and 103.5 months in the TMA-pSLE group (p < 0.001). Median OS from TMA diagnosis was 2.9 months in the TMA-cSLE group and 10.7 months in the TMA-pSLE group (p = 0.58). Time to TMA remission after treatment appeared longer in the TMA-cSLE group (38.00 vs 10.76 days). Multivariate Cox analysis revealed TMA-cSLE and anti-RNP positivity were independent risk factors for mortality in SLE patients with TMA.

Conclusion:

The occurrence of TMA with SLE is rare, and its vigorous course results in high mortality and morbidity rates. In patients without a history of autoimmune disease, early suspicion of TMA and working-up for SLE under this condition are vital. Early recognition of TMA-cSLE and prompt plasma exchange with upfront immunosuppressive therapies for TMA-cSLE patients or anti-RNP-positive patients may improve their prognosis.
Predictive molecular markers in the era of immunotherapy
Authors: Nagaria Teddy S. , Wang Hua , Wang Huamin
Published: May 2020

Recent development in anticancer therapeutics has been centered on immune checkpoint inhibitors (ICIs). Despite early success of ICIs in several cancer types, majority of cancer patients do not respond to ICI therapy. Therefore, predictive biomarkers are urgently needed to select patients who would likely benefit from ICI therapy. Currently immunohistochemical (IHC) assay for programmed cell death ligand 1 (PD-L1) and microsatellite instability (MSI) testing are the only Food and Drug Administration-approved predictive biomarkers for ICI therapies. Tumor mutation burden (TMB) and tumor infiltrating lymphocytes (TILs) are emerging markers, which may prove to be useful predictive markers for ICIs. The guidelines for MSI testing have been well established. However, rigorous quality controls and systemic standardization for PD-L1 IHC testing and analysis of TMB and TILs, such as sample selection, tissue fixation, assay/platform selection, scoring methods, and clinically meaningful cutoff values etc. are needed to improve their clinical utility as predictive biomarkers for ICI therapy. Studies have suggested that the results of PD-L1 expression in tumor cells from various PD-L1 IHC assays are concordant and may be interchangeable. However, the variations and poor interobserver concordance of PD-L1 expression in immune cells is a major issue to be addressed for the interchangeability of different PD-L1 IHC assays, especially for carcinomas of the gastrointestinal tract. Development of new predictive biomarkers and better understanding the difference in tumor immune microenvironments between ICI-sensitive and ICI-resistant tumors will help to develop more effective strategies for immunotherapy.
64Cu-labeled minibody D2101 visualizes CDH17-positive gastric cancer xenografts with short waiting time
Authors: Fujiwara Kentaro , Akiba Hiroki , Tsuji Atsushi B. , Sudo Hitomi , Sugyo Aya , Nagatsu Kotaro , Zhang Ming-Rong , Iwanari Hiroko , Kusano-Arai Osamu , Kudo Shota , Kikuchi Chika , Tsumoto Kouhei , Momose Toshimitsu , Hamakubo Takao , Higashi Tatsuya
Published: May 2020

Objective

We previously reported 111In-labeled anti-cadherin17 (CDH17) IgG visualized CDH17-positive gastric cancer xenografts. Unfortunately, a long waiting time was required to obtain high-contrast images due to long blood retention (blood half-life: 26 h). To accelerate blood clearance, we have developed anti-CDH17 minibody (D2101 minibody) and evaluated the pharmacokinetics in gastric cancer mouse models.

Methods

Two different single chain Fvs (scFvs), D2101 mutant and D2111, were developed from each parental IgG. The binding ability to CDH17 and stability in plasma were evaluated. D2101 minibody, constructed based on D2101 mutant scFv, was labeled with 64Cu (64Cu-D2101 minibody), and the in-vitro and in-vivo properties were evaluated by cell ELISA, biodistribution experiments, and PET imaging in mice bearing CDH17-positive AGS and CDH17-negative MKN74 tumors.

Results

D2101 mutant and D2111 scFvs showed similar affinities to CDH17. D2101 mutant scFv was more stable than D2111 scFv in plasma. No loss of binding affinity of the D2101 minibody by chelate conjugation and radiolabeling procedures was observed. The biodistribution of 64Cu-D2101 minibody showed high uptake in AGS tumors and low uptake in MKN74. The blood half-life of 64Cu-D2101 minibody was 6.5 h. Improved blood clearance of 64Cu-D2101 minibody provided high tumor-to-blood ratios compared with the previous results of parental IgG in AGS xenograft mice. PET studies showed consistent results with biodistribution studies.

Conclusions

64Cu-D2101 minibody exhibited higher tumor-to-blood ratios at earlier time points than those of the radiolabeled parental IgG. 64Cu-D2101 minibody has potential as an immunoimaging agent for CDH17-positive tumors.
Efficacy and safety of concomitant 177Lu-DOTATATE and low-dose capecitabine in advanced medullary thyroid carcinoma: a single-centre experience
Authors: Satapathy Swayamjeet , Mittal Bhagwant Rai , Sood Ashwani , Verma Roshan , Panda Naresh
Published: May 2020

Aims

Peptide receptor radionuclide therapy (PRRT) has been shown to be useful in inoperable/metastatic medullary thyroid carcinoma (MTC). However, the role of concomitant PRRT and low-dose capecitabine therapy has not yet been studied in these patients. This study was conducted to evaluate the efficacy and safety of this combination approach in advanced MTC.

Materials and methods

This was a retrospective, single-centre study. Data of consecutive patients of advanced inoperable/metastatic MTC treated with concomitant 177Lu-DOTATATE+capecitabine, from January 2014 to August 2018, were collected and analysed for radiological, molecular and biochemical responses and treatment-related toxicity.

Results

Eight patients with advanced MTC received a median cumulative dose of 20.9 GBq (interquartile range 8.9–27.7 GBq) 177Lu-DOTATATE over 1–4 cycles and 1250 mg/m2 capecitabine from days 0 to 14 of each PRRT cycle. Radiological response according to Response Evaluation Criteria in Solid Tumours 1.1 criteria could be assessed in seven patients. Six out of seven patients (86%) had stable disease, while disease progression was observed in 1/7 (14%) patients. However, molecular response, as per the European Organization for Research and Treatment of Cancer criteria, was observed in all the seven patients. Biochemical response with reduction in serum calcitonin levels was observed in 3/5 (60%) patients. With the exception of grade 2 anaemia in one patient, no other significant toxicity was observed in this cohort.

Conclusion

Our results indicate the efficacy and safety of concomitant 177Lu-DOTATATE and capecitabine in advanced MTC. Larger randomized controlled trials are, however, required to establish the role of capecitabine as a radiosensitizer along with PRRT in these patients.
Long-term complications of acute kidney injury in children
Authors: Lebel Asaf , Teoh Chia W. , Zappitelli Michael
Published: May 2020

Purpose of review

The current review will describe the current evidence and mechanisms of acute kidney injury (AKI) as a risk factor for long-term kidney complications, summarize the rationale for AKI follow-up and present an approach to monitoring children with AKI. Despite emerging evidence linking AKI with risk for long-term kidney and cardiovascular outcomes, many children who develop AKI are not followed for kidney disease development after hospital discharge. Better understanding of long-term complications after AKI and practical algorithms for follow-up will hopefully increase the rate and quality of post-AKI monitoring.

Recent findings

Recent evidence shows that pediatric AKI is associated with long-term renal outcomes such as chronic kidney disease (CKD) and hypertension, both known to increase cardiovascular risk. The mechanism of AKI progression to CKD involves maladaptive regeneration of tubular epithelial and endothelial cells, inflammation, fibrosis and glomerulosclerosis. Many AKI survivors are not followed, and no guidelines for pediatric AKI follow-up have been published.

Children who had AKI are at increased risk of long-term renal complications but many of them are not monitored for these complications. Recognizing long-term outcomes post-AKI and integration of follow-up programs may have a long-lasting positive impact on patient health.