bluuebunny/crossref_metadata_2025 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.
New insights into the anatomy at the palmodigital junction in Dupuytren’s disease: the palmodigital spiralling sheet
Authors: Malsagova Asja T. , Zwanenburg Rinze L. , Werker Paul M. N.
Published: July 2019

The anatomy in the region of the palmodigital junction has been relatively little studied, but it is very relevant for the surgical treatment of Dupuytren’s disease. To study the microanatomy of the palmodigital junction, we dissected 26 cadaveric digits from 13 human cadaveric hands using microsurgical techniques. The dynamics of the different ligaments were studied in three hands preserved by Thiel’s method. We found a structure, which we propose to name the ‘palmodigital spiralling sheet’ (PSS), which has not been described before. It has a spiralling course around the neurovascular bundle giving rise to a neurovascular tunnel distally in the palm of the hand. It is formed proximally by fibres from the pretendinous band and the intrinsic muscle fascias and distally is in continuity with Cleland’s and Grayson’s ligaments. As such it connects the palmar and digital fascias. Its spiralling course stabilizes the neurovascular bundle in the healthy hand, but can displace it in Dupuytren’s disease, which may contribute to the development of spiral cords.
Gout
Authors: Hannaway Liam , Wellman Sophie
Published: July 2019

Gout is caused by the deposition of monosodium urate crystals in joints and soft tissues. It is the most common cause of inflammatory arthritis worldwide, and a cause of substantial pain and long-term disability. It is associated with several co-morbidities and often under-treated in both primary and secondary care. This article sets out the diagnosis and treatment of gout in primary care, and aims to promote self-management by patients through education of doctors.
Update on novel pharmacological therapies for osteoarthritis
Authors: Ghouri Asim , Conaghan Philip G.
Published: July 2019

Osteoarthritis (OA) is a chronic painful arthritis with increasing global prevalence. Current management involves non-pharmacological interventions and commonly used pharmacological treatments that generally have limited analgesic efficacy and multiple side effects. New treatments are therefore required to relieve patient symptoms and disease impact. A number of existing pharmacological therapies have been recently trialled in OA. These include extended-release triamcinolone and conventional disease-modifying anti-rheumatic drugs (DMARDs) used in the management of rheumatoid arthritis; generally, DMARDs have not shown a benefit in treating OA. Novel analgesic therapies are in development, including those targeting peripheral pain pathways. Disease-modifying osteoarthritis drugs (DMOADs) target key tissues in the OA pathophysiology process and aim to prevent structural progression; a number of putative DMOADs are in phase II development. There is preliminary evidence of structural improvement with some of these therapies but without concomitant symptom improvement, raising new considerations for future DMOAD trials.
Censorship and Publication Control in Early Post-War Taiwan: Procedures and Practices
Authors: Dluhošová Táňa
Published: July 2019

This article explores how state institutions and party organs of the Kuomintang used various means of exercising power and projecting authority in order to shape the literary scene and literary production in Taiwan during the early post-war period (1945–1949). Censorship is examined from two complementary perspectives. First, integrating the Taiwanese case into a broader political and social context, the presentation focuses on the legal framework of the publishing law of Republican China and on regulations propagated in local official bulletins. Second, the article analyses censorship as a practice and set of procedures. This second part is based on the archival files of Taiwan Historica, which holds official documents from both early post-war governments. The archival material unveils some of the motivations behind censorship practices, and helps us to understand chosen strategies to legitimise sociocultural norms.
Puppets, Compatriots, and Souls in Heaven: A Critical Discourse Analysis of Chiang Kai-shek's Early Wartime Rhetoric
Authors: Lams Lutgard , Lu Wei-lun
Published: July 2019

The study adopts a critical discourse analysis approach to Chiang Kai-shek's (CKS) internal nationalist propaganda and authoritarian discourse practices, investigating his New Year and National Day speeches in the 1950s. Authoritarian characteristics are evident in strategies such as legitimation, reification, or myth-making, in the antagonist categorisation of Self versus Other, in Self-glorification and the idolisation of the dead, in the hegemonic creation of commonality and unity, and in the metaphorical conceptualisation of reality. Patterns of idolising the dead serve to impose and legitimise CKS's worldview among his citizens. Another pattern is CKS's invention of imaginary compatriots within the “enslaved China” waiting for the best time to overthrow the “bandits”' rule. Reference to these imaginary agents indirectly presents to his audience a false but better impression of the Self, and a dimmer view of the communist bandits. A third pattern is CKS's metaphorical use of language, such as references to communist China as a puppet regime of Russia.
Learning to Drink Sorghum Liquor: Taste and Consumption in Military Front-Line Jinmen, Taiwan
Authors: Chi Chang-hui
Published: July 2019

This article asks why sorghum liquor, once a drink choice representing the taste of a dominant class, became a token of Jinmen identity among the islands' dominated local population. Being a Cold War battlefield, war-stricken Jinmen became a symbol of the Kuomintang government's determination to recover mainland China. Military authoritarianism transformed Jinmen's society in countless ways, including consumer fashions. The mass production of sorghum liquor began in 1953, with the military promoting its taste and establishing consumption of the liquor as part of a masculine ethos. This inspired mimicry among local consumers. Sorghum liquor became a local “traditional drink,” and a signifier for an identity that revolved around its consumption. This development arose from local consumers seizing on their limited freedom by making this consumption choice and making it their own under military authoritarian rule. Consumption and taste thus gave new meanings to local identity and community subjectivity.
Isolation and Pharmacological Investigation of Compounds From Euphorbia matabelensis
Authors: Hammadi Reham , Kúsz Norbert , Mwangi Peter W. , Kulmány Ágnes , Zupkó István , Orvos Péter , Tálosi László , Hohmann Judit , Vasas Andrea
Published: July 2019

This work deals with the isolation and pharmacological investigations of compounds of Euphorbia matabelensis. After multiple separation process, including thin layer chromatography (TLC), vacuum liquid chromatography, preparative TLC, and high-performance liquid chromatography, 1 diterpene (ingenol) and 2 flavonoids (naringenin and eriodictyol) were obtained from the methanol extracts prepared from the stems and roots of the plant. The structures of the isolated compounds were determined by nuclear magnetic resonance (NMR) and MS measurements and comparison with literature data. All compounds were isolated for the first time from the plant. Eriodictyol was detected for the first time from a Euphorbia species. The compounds were tested for their antiproliferative (on HeLa, C33a, MCF-7, and MDA-MB-231 cell lines) and GIRK channel blocking activities. None of the compounds proved to be active in these test systems.
Triterpenoid Saponins From the Stem Bark of Pentaclethra eetveldeana
Authors: Pertuit David , Kapundu Mpuza , Mitaine-Offer Anne-Claire , Miyamoto Tomofumi , Tanaka Chiaki , Delaude Clément , Lacaille-Dubois Marie-Aleth
Published: July 2019

Two previously undescribed triterpenoid saponins together with 4 known ones were isolated from the stem bark of Pentaclethra eetveldeana De Wild. & Th. Dur. Their structures were elucidated by spectroscopic methods including 1D and 2D NMR experiments in combination with mass spectrometry as 3- O-β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→4)]-α-L-arabinopyranosyloleanolic acid and 3- O-β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→4)]-α-L-arabinopyranosylhederagenin.
Guaiane-Type Sesquiterpenoids From Dendranthema morifolium (Ramat.) S. Kitam Flowers Protect H9c2 Cardiomyocyte From LPS-Induced Injury
Authors: Zhang Beibei , Zeng Mengnan , Li Meng , Chen Wenjing , Li Benke , Kan Yuxuan , Feng Weisheng , Zheng Xiaoke
Published: July 2019

This study investigated the protective effects of guaiane-type sesquiterpenoids isolated from Dendranthema morifolium (Ramat.) S. Kitam ﬂowers on lipopolysaccharide (LPS)-induced injury in H9c2 cardiomyocyte. Cell viability was determined by thiazolyl blue tetrazolium bromide (MTT). The content of released tumor necrosis factor alpha (TNF- α) and interleukin 6 (IL-6) was evaluated by enzyme-linked immunosorbent assay. The levels of lactate dehydrogenase (LDH) and creatine phosphate kinase (CK) were measured by using commercial available kits. The protein expression levels of pelF2 α, GRP78, Bax, caspase-3, caspase-9, Bcl-2, LC3-II, and p62 were measured by in-cell Western. Flow cytometry was used to detect H9c2 cardiomyocyte apoptosis. Compounds 5, 7, 1, 8, and 2 exhibited the effects of cardioprotection and activity sequence enhancement. The levels of IL-6, TNF- α, LDH, CK, pelF2 α, GRP78, Bax, caspase-3, caspase-9, p62, and H9c2 cardiomyocyte apoptosis were increased in LPS-treated H9c2 cardiomyocyte, while those of Bcl-2 and LC3-II were decreased. These effects could be effectively reversed by compounds 5, 7, 1, 8, and 2. Results demonstrated that the guaiane-type sesquiterpenoids could prevent LPS-induced injury in cardiomyocyte by decreasing endoplasmic reticulum (ER) stress, apoptosis, and autophagy as well as downregulating the inflammatory mediators. In addition, the active groups of guaiane-type sesquiterpenoids might be the angelate at C-8 and the exocyclic double bond at C-11.
Neuritogenic and Neuroprotective Activities of the Essential Oil From Rhizomes of Curcuma alismatifolia
Authors: Kochaphum Sirote , Banyat Parinya , Tadtong Sarin , Sareedenchai Vipaporn , Athikomkulchai Sirivan
Published: July 2019

The essential oil from rhizomes of Curcuma alismatifolia Gagnep. was extracted by hydrodistillation. Chemical analysis by gas chromatography-mass spectrometry identified 12 compounds, of which the most prominent were xanthorrhizol (82.2%), ar-curcumene (6.5%), α-cedrene (1.8%), and β-bisabolol (1.1%). The essential oil at 1 ng/mL showed neuroprotective and neuritogenic activity on P19-derived neurons by significantly enhancing cell viability, length, and branching numbers of the cultured P19-derived neurons. In addition, xanthorrhizol, the major compound of the essential oil, at 10 ng/mL also exhibited the protection of P19-derived neurons. However, the mechanism of their neuroprotective activity was not correlated with their antioxidant activity.
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.
Pride in Education: A Narrative Study of Five Finnish Schoolteachers
Authors: Etherington Matthew
Published: July 2019

This narrative inquiry explores how Finnish schoolteachers perceived the emotion of pride as a feature of teaching and learning. The study consists of face-to-face interviews with Finnish schoolteachers between 30 and 62 years of age. The results reveal perceptions of teaching and learning that are shaped by a culture of social equality, modesty, group achievement, and tenacity, that is, Sisu. Although the teachers understand achievement pride as a positive feature of learning, in association with cultural norms and values, pride is not a significant emotional response to promote in the classroom. The results are important for understanding how teachers exploit larger cultural values to judge the worth of particular emotions in the classroom.
Social Trust, Pattern of Difference, and Subjective Well-Being
Authors: Bai Caiquan , Gong Yuan , Feng Chen
Published: July 2019

Based on the pattern of difference in Chinese social trust, this study classifies the social trust into trust in family members, trust in acquaintances, and trust in strangers. Then, the correlational relationship between different types of social trust and subjective well-being is examined using the micro survey data in China. It is found that different types of social trust vary greatly in the correlation with subjective well-being. The main findings are as follows: (a) Trust in family members has no significant correlation with subjective well-being; (b) Only “totally trust acquaintances” has a significant positive correlation with subjective well-being; (c) Trust in strangers has a significant positive correlation with subjective well-being—the higher the trust level, the stronger the correlation with subjective well-being will be—and (d) Urban–rural and male–female differences exist in the correlational relationship between trust in strangers and subjective well-being.
The Microbiology Characteristics of Infected Branchial Cleft Anomalies
Authors: Hirshoren Nir , Fried Neta , Weinberger Jeffrey M. , Eliashar Ron , Korem Maya
Published: July 2019

Objectives

To investigate the microbiology profile of infected branchial cleft anomalies compared to deep neck infection and explore the influence of age on culture findings.

Study Design

A retrospective case control study.

Setting

A single tertiary medical center.

Subjects and Methods

Patients 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.

Results

Of 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.

Conclusions

The 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

The 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

The 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.
Microseismicity caused by injection of water in a gas-saturated reservoir
Authors: Macias Lucas A. , Santos Juan E. , Savioli Gabriela B. , Carcione José M.
Published: July 2019

Microseismic events along preexisting zones of weakness occur in a reservoir due to pore pressure buildup and fracturing during fluid injection. We have used a multiphase fluid-flow numerical simulator to model water injection in a gas reservoir. Previous studies generally consider a single fluid, in which the relative permeabilities and capillary pressure play no role. We analyze the effects of partial saturation on the injection process. On the basis of a spatial distribution of weak stress zones and a threshold pore pressure, the simulator models fluid transport in the formation and allows us to obtain the spatiotemporal distribution of the microseismic events. We consider uniform and fractal distributions of the pore pressure at which microearthquakes are triggered. We analyze the influence of the initial water saturation and the presence of preexisting natural fractures, as well as the effect of updating the rock properties after the microseismic events occur. Moreover, we perform simulations in a low-permeability reservoir in which the borehole pressure increment generates a system of fractures that propagate into the reservoir. The importance of considering two-phase fluid flow resides in the fact that partial saturation greatly affects the trigger time evolution. This is mainly due to the difference in compressibility of the two phases.
Uncertainty quantification in Bayesian inverse problems with model and data dimension reduction
Authors: Grana Dario , Passos de Figueiredo Leandro , Azevedo Leonardo
Published: July 2019

The prediction of rock properties in the subsurface from geophysical data generally requires the solution of a mathematical inverse problem. Because of the large size of geophysical (seismic) data sets and subsurface models, it is common to reduce the dimension of the problem by applying dimension reduction methods and considering a reparameterization of the model and/or the data. Especially for high-dimensional nonlinear inverse problems, in which the analytical solution of the problem is not available in a closed form and iterative sampling or optimization methods must be applied to approximate the solution, model and/or data reduction reduce the computational cost of the inversion. However, part of the information in the data or in the model can be lost by working in the reduced model and/or data space. We have focused on the uncertainty quantification in the solution of the inverse problem with data and/or model order reduction. We operate in a Bayesian setting for the inversion and uncertainty quantification and validate the proposed approach in the linear case, in which the posterior distribution of the model variables can be analytically written and the uncertainty of the model predictions can be exactly assessed. To quantify the changes in the uncertainty in the inverse problem in the reduced space, we compare the uncertainty in the solution with and without data and/or model reduction. We then extend the approach to nonlinear inverse problems in which the solution is computed using an ensemble-based method. Examples of applications to linearized acoustic and nonlinear elastic inversion allow quantifying the impact of the application of reduction methods to model and data vectors on the uncertainty of inverse problem solutions. Examples of applications to linearized acoustic and nonlinear elastic inversion are shown.
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

A 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

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

Context

Metabolomic studies of pheochromocytoma and paraganglioma tissue showed a correlation between metabolomic profile and presence of SDHx mutations, especially a pronounced increase of succinate.

Objective

To 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.

Methods

Proton 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.

Results

The 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.

Conclusions

The 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

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.
Cross-sectional pictorial review of IgG4-related disease
Authors: Kurowecki Darya , Patlas Michael N. , Haider Ehsan A. , Alabousi Abdullah
Published: July 2019

Immunoglobulin G4-related disease (IgG4-RD) is an autoimmune disorder characterized by the infiltration of one or more organs with IgG4-positive plasma cells resulting in inflammatory lesions and fibrosis. Although the pancreas is the most commonly affected organ, involvement of extrapancreatic organs is an increasingly recognized manifestation of the disease. Patients may be asymptomatic and serum IgG4 concentrations may be elevated or normal. Treatment consists of glucocorticosteroid treatment, with excellent response. A definitive diagnosis requires histopathology with imaging playing a key role in avoiding treatment delays. This pictorial review will focus on the most current knowledge regarding IgG4-RD including its common and less common manifestations and the roles of multidetector CT, MRI and ultrasound in the diagnosis and management of suspected IgG4-RD. Knowledge of the varied imaging findings of this multi systemic disease is essential for radiologists to avoid misdiagnosis and assist with timely and effective treatment.
Environmental and biological monitoring in the workplace: A 10-year South African retrospective analysis
Authors: Matatiele Puleng , Mochaki Lerato , Southon Bianca , Dabula Boitumelo , Poongavanum Poobalan , Kgarebe Boitumelo
Published: July 2019

This report is an overview of requests for biological and environmental monitoring of hazardous chemicals, submitted to the National Institute for Occupational Health, Analytical Services Laboratory for testing from the years 2005 to 2015. The report discusses the nature of tests requested and implications for workers’ health and environment, as well as potential impact of the uncertainties associated with monitoring of hazardous chemicals. This is a retrospective, descriptive, qualitative and quantitative audit of all samples received and tests performed retrieved from records of analysis by the laboratory. The study sample consisted of 44,221 samples. The report indicates that throughout the interrogation period the demand for biological monitoring was higher than that for environmental monitoring, with more requests for toxic metals than organic pollutants. Toxic metal testing was highest for mercury, followed by manganese, lead, aluminium and arsenic. The highest number of tests for organic pollutants was conducted for pesticides followed by toluene and xylene. The study has also revealed that the scope of tests requested is rather narrow and does not reflect the broad spectrum of South Africa’s industrial diversity. Having identified possible reasons for underutilization, a number of reforms that could enhance the laboratory’s performance have been addressed.
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
Recent advances in understanding and managing phantom limb pain
Authors: Aternali Andrea , Katz Joel
Published: July 2019

Post-amputation phantom limb pain (PLP) is highly prevalent and very difficult to treat. The high-prevalence, high-pain intensity levels, and decreased quality of life associated with PLP compel us to explore novel avenues to prevent, manage, and reverse this chronic pain condition. This narrative review focuses on recent advances in the treatment of PLP and reviews evidence of mechanism-based treatments from randomized controlled trials published over the past 5 years. We review recent evidence for the efficacy of targeted muscle reinnervation, repetitive transcranial magnetic stimulation, imaginal phantom limb exercises, mirror therapy, virtual and augmented reality, and eye movement desensitization and reprocessing therapy. The results indicate that not one of the above treatments is consistently better than a control condition. The challenge remains that there is little level 1 evidence of efficacy for PLP treatments and most treatment trials are underpowered (small sample sizes). The lack of efficacy likely speaks to the multiple mechanisms that contribute to PLP both between and within individuals who have sustained an amputation. Research approaches are called for to classify patients according to shared factors and evaluate treatment efficacy within classes. Subgroup analyses examining sex effects are recommended given the clear differences between males and females in pain mechanisms and outcomes. Use of novel data analytical approaches such as growth mixture modeling for multivariate latent classes may help to identify sub-clusters of patients with common outcome trajectories over time.
Facility conditions, obstetric and neonatal care practices, and availability of emergency obstetric and neonatal care in 72 rural health facilities in the Democratic Republic of the Congo: A cross-sectional study
Authors: Carter Rebecca , Xiong Xu , Lusamba-Dikassa Paul-Samson , Kuburhanwa Elvis C. , Kimanuka Francine , Salumu Freddy , Clarysse Guy , Tutu Baudouin Kalume , Yuma Sylvain , Iyeti Alain Mboko , Hernandez Julie H. , Shaffer Jeffrey G. , Bertrand Jane T. , Villeneuve Susie , Prual Alain , Pyne-Mercier Lee , Nigussie Assaye , Buekens Pierre
Published: July 2019

Background: Current facility conditions, obstetric and neonatal care practices, and availability of emergency obstetric and neonatal care (EmONC) were assessed in the Kwango and Kwilu provinces of the Democratic Republic of the Congo (DRC).

Methods: This is an analysis of the baseline survey data from an ongoing clinical mentoring program among 72 rural health facilities in the DRC. Data collectors visited each of the facilities and collected data through a pre-programmed smartphone. Frequencies of selected indicators were calculated by province and facility type—general referral hospital (GRH) and primary health centers (HC).

Results: Facility conditions varied across province and facility type. Maternity wards and delivery rooms were available in the highest frequency of rooms assessed (>95% of all facilities). Drinking water was available in 25.0% of all facilities; electricity was available in 49.2% of labor rooms and 67.6% of delivery rooms in all facilities. Antenatal, delivery, and postnatal care services were available but varied across facilities. While the proportion of blood pressure measured during antenatal care was high (94.9%), the antenatal screening rate for proteinuria was low (14.7%). The use of uterotonics immediately after birth was observed in high numbers across both provinces (94.4% in Kwango and 75.6% in Kwilu) and facility type (91.3% in GRH and 81.4% in HC). The provision of immediate postnatal care to mothers every 15 minutes was provided in less than 50% of all facilities. GRH facilities generally had higher frequencies of available equipment and more services available than HC. GRH facilities provided an average of 6 EmONC signal functions (range: 2-9).

Conclusions: Despite poor facility conditions and a lack of supplies, GRH and HC facilities were able to provide EmONC care in rural DRC. These findings could guide the provision of essential needs to the health facilities for better delivery of maternal and neonatal care.