bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of atypical data in multicenter clinical trials using unsupervised statistical monitoring
Authors: Trotta Laura , Kabeya Yuusuke , Buyse Marc , Doffagne Erik , Venet David , Desmet Lieven , Burzykowski Tomasz , Tsuburaya Akira , Yoshida Kazuhiro , Miyashita Yumi , Morita Satoshi , Sakamoto Junichi , Praveen Paurush , Oba Koji 
Published: July 2019

Background/Aims A risk-based approach to clinical research may include a central statistical assessment of data quality. We investigated the operating characteristics of unsupervised statistical monitoring aimed at detecting atypical data in multicenter experiments. The approach is premised on the assumption that, save for random fluctuations and natural variations, data coming from all centers should be comparable and statistically consistent. Unsupervised statistical monitoring consists of performing as many statistical tests as possible on all trial data, in order to detect centers whose data are inconsistent with data from other centers. Methods We conducted simulations using data from a large multicenter trial conducted in Japan for patients with advanced gastric cancer. The actual trial data were contaminated in computer simulations for varying percentages of centers, percentages of patients modified within each center and numbers and types of modified variables. The unsupervised statistical monitoring software was run by a blinded team on the contaminated data sets, with the purpose of detecting the centers with contaminated data. The operating characteristics (sensitivity, specificity and Youden’s J-index) were calculated for three detection methods: one using the p-values of individual statistical tests after adjustment for multiplicity, one using a summary of all p-values for a given center, called the Data Inconsistency Score, and one using both of these methods. Results The operating characteristics of the three methods were satisfactory in situations of data contamination likely to occur in practice, specifically when a single or a few centers were contaminated. As expected, the sensitivity increased for increasing proportions of patients and increasing numbers of variables contaminated. The three methods showed a specificity better than 93% in all scenarios of contamination. The method based on the Data Inconsistency Score and individual p-values adjusted for multiplicity generally had slightly higher sensitivity at the expense of a slightly lower specificity. Conclusions The use of brute force (a computer-intensive approach that generates large numbers of statistical tests) is an effective way to check data quality in multicenter clinical trials. It can provide a cost-effective complement to other data-management and monitoring techniques.
Acute Kidney Injury in Pregnant Patient With Pancreas-Kidney Transplant Caused by Abdominal Compartment Syndrome: A Case Presentation, Review of Literature, and Proposal of Diagnostic Approach
Authors: Michalska Magdalena , Wen Kevin , Pauly Robert P. 
Published: July 2019

Rationale: With increasing number of complex medical patients with renal transplant who get pregnant, clinicians need to be aware of abdominal compartment syndrome which may masquerade as acute renal allograft injury in pregnancy. Presenting concerns of the patient: A 34-year-old nulliparous Caucasian female with end-stage renal disease (ESRD) due to type 1 diabetes mellitus who received a simultaneous pancreas-kidney transplant (SPK) in 2006 and then after rejection of renal allograft another, kidney-only allograft from a donation after circulatory death became pregnant in May 2013 with dichorionic, diamniotic twins without reproductive technology, and during pregnancy, she developed two episodes of acute injury to the renal allograft. Diagnoses: End-stage renal disease secondary to type I diabetes, acute renal allograft injury, tacrolimus toxicity, abdominal pain. Interventions (including prevention and lifestyle): She received intravenous hydration, medications contributing to renal failure were held, and pain and nauseas were controlled appropriately. Abdominal compartment syndrome was managed by maintaining intravascular pressure and optimizing regional and systemic vascular perfusion by appropriate fluid balance, evacuating intraluminal contents by decompressing gastrointestinal system, and improving abdominal wall compliance by using appropriate analgesics, sedation, and patient positioning. Outcomes: With advancing pregnancy, the patient developed progressive abdominal pain, nausea, leg edema, and rising creatinine that were not responsive to ongoing therapies and required delivery via Cesarean section at 31 weeks of gestational age. Lessons learned: In the era of increasing number of pregnant renal transplant patients with multiple medical issues, we need organized approach to diagnosis of acute renal allograft injury in pregnancy and we need to consider abdominal compartment syndrome as one of the causes.
Assessment of risks of feline mismatched transfusion and neonatal isoerythrolysis in the Lyon (France) area
Authors: Nectoux Alexandra , Guidetti Maryline , Barthélemy Anthony , Pouzot-Nevoret Céline , Hoareau Guillaume L , Goy-Thollot Isabelle 
Published: July 2019

Objectives The aims of this study were to update the prevalence of different feline blood types in the Lyon (France) area, as well as to determine the risk of mismatched transfusion (MT) and neonatal isoerythrolysis (NI) in kittens with parents of unknown blood type. Methods Blood samples were obtained from blood donor cats and cats admitted to an intensive care unit in Lyon. AB blood typing was performed using an immunochromatographic strip. The risk of MT was estimated by adding the risk of a major transfusion reaction and the risk of a minor transfusion reaction. The risk of NI was estimated according the equation (p²)(q²) + 2pq(q²), with q being the b allele frequency and p = 1 – q. The results were analysed by absolute and relative frequency analysis and multivariate analysis. Results The cohort study population included 320 non-pedigree cats and 37 pedigree cats. The prevalence of blood types A, B and AB was 84.3%, 14.0% and 1.7%, respectively. Considering non-pedigree cats, the prevalence of types A, B and AB was 83.7%, 14.4% and 1.9%, respectively. There were no significant differences of blood type distribution by sex ( P = 0.73) or by breed ( P = 0.90). Based on these percentages, the risks of MT and NI in non-pedigree cats were 24.3% and 12.3%, respectively. Conclusions and relevance The prevalence of type B cats is high in the Lyon area and associated with high risks of MT and NI. These results confirm the importance of performing blood typing prior to any blood transfusion or mating.
The Microbiology Characteristics of Infected Branchial Cleft Anomalies
Authors: Hirshoren Nir , Fried Neta , Weinberger Jeffrey M. , Eliashar Ron , Korem Maya 
Published: July 2019

ObjectivesTo investigate the microbiology profile of infected branchial cleft anomalies compared to deep neck infection and explore the influence of age on culture findings.Study DesignA retrospective case control study.SettingA single tertiary medical center.Subjects and MethodsPatients treated for branchial cleft anomalies between 2006 and 2016 were included. Demographic data, disease and treatment parameters, and microbiology profile, including bacteria classification, antibiotics resistance patterns, and number of pathogens, were analyzed.ResultsOf 278 cases treated for branchial cleft anomalies, we have analyzed 69 cases with infection and pathogen identification. The proportion of monobacterial infections was higher (70.6% vs 44.3%; P =. 003; odds ratio [OR], 3.02) and the proportion of Streptococcus species infection was lower (48.9% vs 77.2%; P =. 001; OR, 0.282) among the infected branchial cleft cases compared to deep neck infections. Anaerobic bacteria infection did not differ between groups (17.8% and 16.5%, respectively). There was a nonsignificant tendency toward more resistant bacterial strains among the infected branchial clefts (15.6% vs 6.3%; P =. 118; OR, 2.726). There was no difference between the bacterial profile of patients younger or older than 16 years.ConclusionsThe microbiology profile of infected branchial cleft anomalies is not age related and is different from that of deep neck infections. We demonstrate a relatively high frequency of monobacterial infections, relatively lower streptococcal infection rates, and a substantial contribution by resistant species and anaerobes. Empiric antibiotic treatment should cover Streptococcus species, including penicillin‐resistant species, as well as clindamycin‐resistant anaerobes.
Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma
Authors: Stephens Deborah M. , Li Hongli , Schöder Heiko , Straus David J. , Moskowitz Craig H. , LeBlanc Michael , Rimsza Lisa M. , Bartlett Nancy L. , Evens Andrew M. , LaCasce Ann S. , Barr Paul M. , Knopp Michael V. , Hsi Eric D. , Leonard John P. , Kahl Brad S. , Smith Sonali M. , Friedberg Jonathan W. 
Published: July 2019

AbstractThe investigators present results on the long-term value and limitations of early interim positron emission tomography (PET) scanning in advanced Hodgkin lymphoma.
Challenges and approaches to implementing master/basket trials in oncology
Authors: Burd Amy , Schilsky Richard L. , Byrd John C. , Levine Ross L. , Papadimitrakopoulou Vassiliki A. , Herbst Roy S. , Redman Mary W. , Druker Brian J. , Gandara David R. 
Published: July 2019

AbstractThe appetite for cutting-edge cancer research, across medical institutions, scientific researchers, and health care providers, is increasing based on the promise of true breakthroughs and cures with new therapeutics available for investigation. At the same time, the barriers for advancing clinical research are impacting how quickly drug development efforts are conducted. For example, we know now that under a microscope, patients with the same type of cancer and histology might look the same; however, the reality is that most cancers are driven by genomic, transcriptional, and epigenetic changes that make each patient unique. Additionally, the immunologic reaction to different tumor types is distinct among patients. The challenge for researchers developing new therapies today is vastly different than it was in the era of cytotoxics. Today, we must identify a sufficient number of patients harboring a rare mutation or other characteristic and match this to the right therapeutic option. This summary provides a guide to help inform the scientific cancer community about the benefits and challenges of conducting umbrella or basket trials (master trials), and to create a roadmap to help make this new and evolving form of clinical trial design as effective as possible.
An Exploratory Analysis of Real-World End Points for Assessing Outcomes Among Immunotherapy-Treated Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Stewart Mark , Norden Andrew D. , Dreyer Nancy , Henk Henry Joe , Abernethy Amy P. , Chrischilles Elizabeth , Kushi Lawrence , Mansfield Aaron S. , Khozin Sean , Sharon Elad , Arunajadai Srikesh , Carnahan Ryan , Christian Jennifer B. , Miksad Rebecca A. , Sakoda Lori C. , Torres Aracelis Z. , Valice Emily , Allen Jeff 
Published: July 2019

PURPOSE This pilot study examined the ability to operationalize the collection of real-world data to explore the potential use of real-world end points extracted from data from diverse health care data organizations and to assess how these relate to similar end points in clinical trials for immunotherapy-treated advanced non–small-cell lung cancer. PATIENTS AND METHODS Researchers from six organizations followed a common protocol using data from administrative claims and electronic health records to assess real-world end points, including overall survival (rwOS), time to next treatment, time to treatment discontinuation (rwTTD), time to progression, and progression-free survival, among patients with advanced non–small-cell lung cancer treated with programmed death 1/programmed death-ligand 1 inhibitors in real-world settings. Data sets included from 269 to 6,924 patients who were treated between January 2011 and October 2017. Results from contributors were anonymized. RESULTS Correlations between real-world intermediate end points (rwTTD and time to next treatment) and rwOS were moderate to high (range, 0.6 to 0.9). rwTTD was the most consistent end points as treatment detail was available in all data sets. rwOS at 1 year post–programmed death-ligand 1 initiation ranged from 40% to 57%. In addition, rwOS as assessed via electronic health records and claims data fell within the range of median OS values observed in relevant clinical trials. Data sources had been used extensively for research with ongoing data curation to assure accuracy and practical completeness before the initiation of this research. CONCLUSION These findings demonstrate that real-world end points are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision making. Differences observed likely reflect true differences between real-world and protocol-driven practices.
SRXN1 Is Necessary for Resolution of GnRH-Induced Oxidative Stress and Induction of Gonadotropin Gene Expression
Authors: Kim Taeshin , Li Danmei , Terasaka Tomohiro , Nicholas Dequina A , Knight Vashti S , Yang Joyce J , Lawson Mark A 
Published: July 2019

AbstractA defining characteristic of the hypothalamus-pituitary-gonad reproductive endocrine axis is the episodic secretion of the pituitary gonadotropin hormones LH and FSH by the anterior pituitary gonadotropes. Hormone secretion is dictated by pulsatile stimulation, with GnRH released by hypothalamic neurons that bind and activate the G protein–coupled GnRH receptor expressed by gonadotropes. Hormone secretion and synthesis of gonadotropins are influenced by the amplitude and frequency of GnRH stimulation; variation in either affects the proportion of LH and FSH secreted and the differential regulation of hormone subunit gene expression. Therefore, proper decoding of GnRH signals is essential for appropriate gonadotropin synthesis and secretion. The GnRH receptor robustly activates downstream signaling cascades to facilitate exocytosis and stimulate gene expression and protein synthesis. It is necessary to rapidly quench signaling to preserve sensitivity and adaptability to changing pulse patterns. Reactive oxygen species (ROS) generated by receptor-activated oxidases fulfill the role of rapid signaling intermediates that facilitate robust and transient signaling. However, excess ROS can be detrimental and, unchecked, can confuse signal interpretation. We demonstrate that sulfiredoxin (SRXN1), an ATP-dependent reductase, is essential for normal responses to GnRH receptor signaling and plays a central role in resolution of ROS induced by GnRH stimulation. SRXN1 expression is mitogen-activated protein kinase dependent, and knockdown reduces Lhb and Fshb glycoprotein hormone subunit mRNA and promoter activity. Loss of SRXN1 leads to increased basal and GnRH-stimulated ROS levels. We conclude that SRXN1 is essential for normal responses to GnRH stimulation and plays an important role in ROS management.
Prostate-Specific Antigen Levels During Testosterone Treatment of Hypogonadal Older Men: Data from a Controlled Trial
Authors: Cunningham Glenn R , Ellenberg Susan S , Bhasin Shalender , Matsumoto Alvin M , Parsons J Kellogg , Preston Peter , Cauley Jane A , Gill Thomas M , Swerdloff Ronald S , Wang Christina , Ensrud Kristine E , Lewis Cora E , Pahor Marco , Crandall Jill P , Molitch Mark E , Cifelli Denise , Basaria Shehzad , Diem Susan J , Stephens-Shields Alisa J , Hou Xiaoling , Snyder Peter J 
Published: July 2019

Abstract

Context
Prostate-specific antigen (PSA) changes during testosterone treatment of older hypogonadal men have not been rigorously evaluated.

Design
Double-blinded, placebo-controlled trial.

Setting
Twelve US academic medical centers.

Participants
Seven hundred ninety hypogonadal men ≥65 years of age with average testosterone levels ≤275 ng/dL. Men at high risk for prostate cancer were excluded.

Interventions
Testosterone or placebo gel for 12 months.

Main Outcomes
Percentile changes in PSA during testosterone treatment of 12 months.

Results
Testosterone treatment that increased testosterone levels from 232 ± 63 ng/dL to midnormal was associated with a small but substantially greater increase (P < 0.001) in PSA levels than placebo treatment. Serum PSA levels increased from 1.14 ± 0.86 ng/mL (mean ± SD) at baseline by 0.47 ± 1.1 ng/mL at 12 months in the testosterone group and from 1.25 ± 0.86 ng/mL by 0.06 ± 0.72 ng/mL in the placebo group. Five percent of men treated with testosterone had an increase ≥1.7 ng/mL and 2.5% of men had an increase of ≥3.4 ng/mL. A confirmed absolute PSA >4.0 ng/mL at 12 months was observed in 1.9% of men in the testosterone group and 0.3% in the placebo group. Four men were diagnosed with prostate cancer; two were Gleason 8.

Conclusions
When hypogonadal older men with normal baseline PSA are treated with testosterone, 5% had an increase in PSA ≥1.7 ng/mL, and 2.5% had an increase ≥3.4 ng/mL.
Metabolomic Urine Profile: Searching for New Biomarkers of SDHx-Associated Pheochromocytomas and Paragangliomas
Authors: Martins Raquel G , Gonçalves Luís G , Cunha Nuno , Bugalho Maria João 
Published: July 2019

AbstractContextMetabolomic studies of pheochromocytoma and paraganglioma tissue showed a correlation between metabolomic profile and presence of SDHx mutations, especially a pronounced increase of succinate.ObjectiveTo compare the metabolomic profile of 24-hour urine samples of SDHx mutation carriers with tumors (affected mutation carriers), without tumors (asymptomatic mutation carriers), and patients with sporadic pheochromocytomas and paragangliomas.MethodsProton nuclear magnetic resonance spectroscopic profiling of urine samples and metabolomic analysis using pairwise comparisons were complemented by metabolite set enrichment analysis to identify meaningful patterns.ResultsThe urine of the affected SDHx carriers showed substantially lower levels of seven metabolites than the urine of asymptomatic mutation carriers (including, succinate and N-acetylaspartate). The urine of patients with SDHx-associated tumors presented substantially higher levels of three metabolites compared with the urine of patients without mutation; the metabolite set enrichment analysis identified gluconeogenesis, pyruvate, and aspartate metabolism as the pathways that most probably explained the differences found. N-acetylaspartate was the only metabolite the urinary levels of which were significantly different between the three groups.ConclusionsThe metabolomic urine profile of the SDHx mutation carriers with tumors is different from that of asymptomatic carriers and from that of patients with sporadic neoplasms. Differences are likely to reflect the altered mitochondria energy production and pseudohypoxia signature of these tumors. The urinary levels of N-acetylaspartate and succinate contrast with those reported in tumor tissue, suggesting a defective washout process of oncometabolites in association with tumorigenesis. The role of N-acetylaspartate as a tumor marker for these tumors merits further investigation.
Key Factors for High Diastereo- and Enantioselectivity of Umpolung Cyclizations of Aldehyde-Containing Allylpalladium Intermediates
Authors: Tsukamoto Hirokazu , Kawase Ayumu , Omura Hirotaka , Doi Takayuki 
Published: July 2019

Abstract
Two palladium/chiral diphosphine-catalyzed umpolung cyclizations of aldehyde-containing allylic acetates and allenes with arylboronic acid are fully investigated to establish key factors in their high stereoselectivities. Both cyclization reactions afford cis-disubstituted pyrrolidine and tetrahydrofuran. These occur in high diastereo- and enantioselectivities through a common cationic (Z)-η1-allylpalladium, toward which a ring strain generated in the cyclization step leading to trans-isomers biases the equilibrium through η3-η1-η3-complex in the former cyclization. Varied diastereoselectivities were observed in the formation of five-membered carbocycles and six-membered heterocycles. These reflect release of a ring strain generated in the cyclization step leading to trans-isomers and a different distribution of the (Z)- and the (E)-η1-allylpalladium intermediates generated by the oxidative addition of allylic acetates to Pd(0) or carbopalladation of allenes, respectively. A sterically demanding substituent at the center of the allyl moiety is necessary for high diastereo- and enantioselectivity. The enantioselectivity of the former cyclization was lowered by the presence of organometallic reductants or reagents, possibly causing the formation of neutral η1-allylpalladium species. We used a chiral allylic acetate containing (E)-deuterium-labeled alkene to demonstrate that the electrophilic attack of the aldehyde to the allyl ligand occurred on the side where the palladium existed, consistent with the Zimmerman-Traxler transition state.
Protocol for the electroencephalography guidance of anesthesia to alleviate geriatric syndromes (ENGAGES-Canada) study: A pragmatic, randomized clinical trial
Authors: Deschamps Alain , Saha Tarit , El-Gabalawy Renée , Jacobsohn Eric , Overbeek Charles , Palermo Jennifer , Robichaud Sophie , Dumont Andrea Alicia , Djaiani George , Carroll Jo , Kavosh Morvarid S. , Tanzola Rob , Schmitt Eva M. , Inouye Sharon K. , Oberhaus Jordan , Mickle Angela , Ben Abdallah Arbi , Avidan Michael S. , Clinical Trials Group Canadian Perioperative Anesthesia 
Published: July 2019

Background: There is some evidence that electroencephalography guidance of general anesthesia can decrease postoperative delirium after non-cardiac surgery. There is limited evidence in this regard for cardiac surgery. A suppressed electroencephalogram pattern, occurring with deep anesthesia, is associated with increased incidence of postoperative delirium (POD) and death. However, it is not yet clear whether this electroencephalographic pattern reflects an underlying vulnerability associated with increased incidence of delirium and mortality, or whether it is a modifiable risk factor for these adverse outcomes. Methods: The Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES-Canada) is an ongoing pragmatic 1200 patient trial at four Canadian sites. The study compares the effect of two anesthetic management approaches on the incidence of POD after cardiac surgery. One approach is based on current standard anesthetic practice and the other on electroencephalography guidance to reduce POD. In the guided arm, clinicians are encouraged to decrease anesthetic administration, primarily if there is electroencephalogram suppression and secondarily if the EEG index is lower than the manufacturers recommended value (bispectral index (BIS) or WAVcns below 40 or Patient State Index below 25). The aim in the guided group is to administer the minimum concentration of anesthetic considered safe for individual patients. The primary outcome of the study is the incidence of POD, detected using the confusion assessment method or the confusion assessment method for the intensive care unit; coupled with structured delirium chart review. Secondary outcomes include unexpected intraoperative movement, awareness, length of intensive care unit and hospital stay, delirium severity and duration, quality of life, falls, and predictors and outcomes of perioperative distress and dissociation. Discussion: The ENGAGES-Canada trial will help to clarify whether or not using the electroencephalogram to guide anesthetic administration during cardiac surgery decreases the incidence, severity, and duration of POD. Registration: ClinicalTrials.gov (NCT02692300) 26/02/2016