bluuebunny/crossref_metadata_2025_split huggingface dataset:
IHC versus FISH versus NGS to detect ALK gene rearrangement in NSCLC: all questions answered?
Authors: Batra Ullas , Nathany Shrinidhi , Sharma Mansi , Pasricha Sunil , Bansal Abhishek , Jain Parveen , Mehta Anurag 
Published: March 2021

AimsAnaplastic lymphoma kinase (ALK) rearranged non-small cell lung carcinoma (NSCLC) is a distinct molecular subtype and rapid approval ofALKtyrosine kinase inhibitors (TKIs) has necessitated rapid and sensitive diagnostic modalities for the detection of this alteration. Gene rearrangements can be identified using many techniques including fluorescence in situ hybridisation (FISH), reverse transcriptase-PCR, next-generation sequencing (NGS) and immunohistochemistry (IHC) for fusion oncoprotein expression. We aimed to determine the concordance between IHC, FISH and NGS forALKbiomarker detection, and determine differences in sensitivity, and survival outcomes.MethodsWe analysed the concordance between IHC using D5F3 monoclonal antibody, FISH (break-apart) and NGS using a custom panel containing 71 differentALKvariants.ResultsAmong 71 cases included in this study, FISH was evaluable in 58 cases. The concordance of ALK IHC with FISH was 75.9% and that with NGS was 84.5%. The sensitivities of FISH and NGS were 75.6% and 87.5%, respectively. The median progression-free survival of ALK IHC-positive and FISH-negative group was 5.5 months and that of both positive was 9.97 months.ConclusionAlthough NGS offers a better throughput and visualisation, IHC still remains the quintessential screening tool in upfront diagnosis of ALK rearranged NSCLC.
Characteristics and changes over time of nicotine vaping products used by vapers in the 2016 and 2018 ITC Four Country Smoking and Vaping Surveys
Authors: Felicione Nicholas J , Fix Brian Vincent , McNeill Ann , Cummings K. Michael , Goniewicz Maciej Lukasz , Hammond David , Borland Ron , Heckman Bryan W , Bansal-Travers Maansi , Gravely Shannon , Hitchman Sara C , Levy David T , Fong Geoffrey T , O'Connor Richard 
Published: March 2021

ObjectivesRegulation of nicotine vaping products (NVPs) varies between countries, impacting the availability and use of these products. This study updated the analyses of O’Connor et al on types of NVPs used and examined changes in NVP features used over 18 months in four countries with differing regulatory environments.DesignData are from 4734 adult current vapers in Australia, Canada, England and the USA from Waves 1 (2016) and 2 (2018) of the International Tobacco Control Four Country Smoking and Vaping Survey. NVP characteristics included device description, adjustable voltage, nicotine content and tank size. Longitudinal analyses (n=1058) assessed movement towards or away from more complex/modifiable NVPs. A logistic regression was used to examine factors associated with changes in device description from 2016 to 2018.ResultsLike 2016, box-tanks were the most popular NVP (37.3%) in all four countries in 2018. Over 80% of vapers continued using the same NVP and nicotine content between waves, though movement tended towards more complex/modifiable devices (14.4% of vapers). Box-tank users, exclusive daily vapers and older vapers were most likely to continue using the same device description. Certain NVPs and features differed by country, such as higher nicotine contents in the USA (11.5% use 21+ mg/mL) and greater device stability over time in Australia (90.8% stability).ConclusionsMost vapers continued using the same vaping device and features over 18 months. Differences in NVP types and features were observed between countries, suggesting that differing NVP regulations affect consumer choices regarding the type of vaping device to use.
Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma
Authors: Najjar Yana G. , McCurry Dustin , Lin Huang , Lin Yan , Zang Yan , Davar Diwakar , Karunamurthy Arivarasan , Drabick Joseph J. , Neves Rogerio I. , Butterfield Lisa H. , Ernstoff Marc S. , Puzanov Igor , Skitzki Joseph J. , Bordeaux Jennifer , Summit IlaSri B. , Bender Jehovana O. , Kim Ju Young , Chen Beiru , Sarikonda Ghanashyam , Pahuja Anil , Tsau Jennifer , Alfonso Zeni , Laing Christian , Pingpank James F. , Holtzman Matthew P. , Sander Cindy , Rose Amy , Zarour Hassane M. , Kirkwood John M. , Tarhini Ahmad A. 
Published: March 2021

AbstractPurpose:Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.Patients and Methods:Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.Results:A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively).Conclusions:Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133
Adjuvant Sirolimus Does Not Improve Outcome in Pet Dogs Receiving Standard-of-Care Therapy for Appendicular Osteosarcoma: A Prospective, Randomized Trial of 324 Dogs
Authors: LeBlanc Amy K. , Mazcko Christina N. , Cherukuri Aswini , Berger Erika P. , Kisseberth William C. , Brown Megan E. , Lana Susan E. , Weishaar Kristen , Flesner Brian K. , Bryan Jeffrey N. , Vail David M. , Burton Jenna H. , Willcox Jennifer L. , Mutsaers Anthony J. , Woods J. Paul , Northrup Nicole C. , Saba Corey , Curran Kaitlin M. , Leeper Haley , Wilson-Robles Heather , Wustefeld-Janssens Brandan G. , Lindley Stephanie , Smith Annette N. , Dervisis Nikolaos , Klahn Shawna , Higginbotham Mary Lynn , Wouda Raelene M. , Krick Erika , Mahoney Jennifer A. , London Cheryl A. , Barber Lisa G. , Balkman Cheryl E. , McCleary-Wheeler Angela L. , Suter Steven E. , Martin Olya , Borgatti Antonella , Burgess Kristine , Childress Michael O. , Fidel Janean L. , Allstadt Sara D. , Gustafson Daniel L. , Selmic Laura E. , Khanna Chand , Fan Timothy M. 
Published: March 2021

Abstract

Purpose:
The mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression.

Patients and Methods:
A total of 324 pet dogs diagnosed with treatment-naïve appendicular osteosarcoma were randomized into a two-arm, multicenter, parallel superiority trial whereby dogs received amputation of the affected limb, followed by adjuvant carboplatin chemotherapy ± oral sirolimus therapy. The primary outcome measure was disease-free interval (DFI), as assessed by serial physical and radiologic detection of emergent macroscopic metastases; secondary outcomes included overall 1- and 2-year survival rates, and sirolimus pharmacokinetic variables and their correlative relationship to adverse events and clinical outcomes.

Results:
There was no significant difference in the median DFI or overall survival between the two arms of this trial; the median DFI and survival for standard-of-care (SOC; defined as amputation and carboplatin therapy) dogs was 180 days [95% confidence interval (CI), 144–237] and 282 days (95% CI, 224–383) and for SOC + sirolimus dogs, it was 204 days (95% CI, 157–217) and 280 days (95% CI, 252–332), respectively.

Conclusions:
In a population of pet dogs nongenomically segmented for predicted mTOR inhibition response, sequentially administered adjuvant sirolimus, although well tolerated when added to a backbone of therapy, did not extend DFI or survival in dogs with appendicular osteosarcoma.
Gastronomic Algorithms: Artistic and Sensory Exploration of Alain Passard’s Michelin Plates in the Manner of Giuseppe Arcimboldo with GANs
Authors: Spratt Emily L. 
Published: March 2021

Abstract
Although recent advances in artificial intelligence to generate images with deep learning techniques, especially generative adversarial networks (GANs), have offered radically new opportunities for its creative applications, there has been little investigation into its use as a tool to explore the senses beyond vision alone. In an artistic collaboration that brought together Chef Alain Passard, art historian and data scientist Emily Spratt and computer programmer Thomas Fan, the collaborators used photographs of the three-star Michelin plates from the Parisian restaurant Arpège as a springboard to explore the art of culinary presentation in the manner of the Renaissance painter Giuseppe Arcimboldo.
Fast floating temperature sensor measures SST, not wet bulb temperature
Authors: de Szoeke Simon P. 
Published: March 2021

AbstractA small integrated oceanographic thermometer with a nominal response time of 1 s was affixed to a floating hose “sea snake” towed near the bow of a research vessel. The sensor measured the near-surface ocean temperature accurately and in agreement with other platforms. The effect of conduction and evaporation is modeled for a sensor impulsively alternated between water and air. Large thermal mass makes most sea snake thermometers insensitive to temperature impulses. The smaller 1-s thermometer cooled by evaporation, but the sensor never reached the wet bulb temperature. The cooling was less than 6% of the (~2.7 °C) difference between the ocean temperature and the wet bulb temperature in 99% of 2 s–1 samples. Filtering outliers, such as with a median, effectively removes the evaporative cooling effect from 1- or 10-minute average temperatures.
Delegating diplomacy: rhetoric across agents in the United Nations General Assembly
Authors: Gray Julia , Baturo Alex 
Published: March 2021

When political principals send agents to international organizations, those agents are often assumed to speak in a single voice. Yet, various types of country representatives appear on the international stage, including permanent representatives as well as more overtly “political” government officials. We argue that permanent delegates at the United Nations face career incentives that align them with the bureaucracy, setting them apart from political delegates. To that end, they tend to speak more homogeneously than do other types of speakers, while also using relatively more technical, diplomatic rhetoric. In addition, career incentives will make them more reluctant to criticize the United Nations. In other words, permanent representatives speak more like bureaucratic agents than like political principals. We apply text analytics to study differences across agents’ rhetoric at the United Nations General Assembly. We demonstrate marked distinctions between the speech of different types of agents, contradictory to conventional assumptions, with implications for our understandings of the interplay between public administration and agency at international organizations. Points for practitioners Delegations to international organizations do not “speak with one voice.” This article illustrates that permanent representatives to the United Nations display more characteristics of bureaucratic culture than do other delegates from the same country. For practitioners, it is important to realize that the manner in which certain classes of international actors “conduct business” can differ markedly. These differences in tone—even among delegates from the same principal—can impact the process of negotiation and debate.
Compression treatment in acute symptomatic proximal deep venous thrombosis – Results of a worldwide survey
Authors: Rabe Daniel , Partsch Hugo , Heidl Gerhard , Hirschl Mirko , Kundi Michael , Rabe Eberhard , Pannier Felizitas 
Published: March 2021

Objectives The aim of this study was to illustrate how compression is performed worldwide in proximal DVT and if compression management has changed recently. Methods A global online survey, consisting of 36 questions, was used. The survey was solicited from membership lists of Union Internationale de Phlébologie (UIP) membership societies. For differences between the continents in comparison to Western Europe odds ratios and 95% Confidence Intervals (95%CI) where calculated. Results We received 626 answers from 41 countries. Compression is routinely used in proximal DVT in all regions (82.8%). 81.4% start compression immediately after diagnosis. In the acute phase of DVT reduction of pain and swelling (91.7%) and PTS prevention (66.2%) are the main reasons for compression. 33.2% recently changed their compression management with 43.5% starting compression earlier and 7.0% later. Conclusions Compression is still used routinely in proximal DVT in addition to anticoagulation. The changes in international guidelines towards the non-routine use of compression in proximal DVT have not caused significant changes in DVT management.
Effects of a home-based rehabilitation program in community-dwelling older people after discharge from hospital: A subgroup analysis of a randomized controlled trial
Authors: Katri Maria Turunen , Laura Aaltonen-Määttä , Erja Portegijs , Timo Rantalainen , Sirkka Keikkala , Marja-Liisa Kinnunen , Sarianna Sipilä , Riku Nikander 
Published: March 2021

Objective: To examine whether pre-admission community mobility explains the effects of a rehabilitation program on physical performance and activity in older adults recently discharged from hospital. Design: A secondary analysis of a randomized controlled trial. Setting: Home and community. Participants: Community-dwelling adults aged ⩾60 years recovering from a lower limb or back injury, surgery or other disorder who were randomized to a rehabilitation ( n = 59) or standard care control ( n = 58) group. They were further classified into subgroups that were not planned a priori: (1) mild, (2) moderate, or (3) severe pre-admission restrictions in community mobility. Interventions: The 6-month intervention consisted of a motivational interview, goal attainment process, guidance for safe walking, a progressive home exercise program, physical activity counselling, and standard care. Measurements: Physical performance was measured with the Short Physical Performance Battery and physical activity with accelerometers and self-reports. Data were analysed by generalized estimating equation models with the interactions of intervention, time, and subgroup. Results: Rehabilitation improved physical performance more in the intervention ( n = 30) than in the control group ( n = 28) among participants with moderate mobility restriction: score of the Short Physical Performance Battery was 4.4 ± 2.3 and 4.2 ± 2.2 at baseline, and 7.3 ± 2.6 and 5.8 ± 2.9 at 6 months in the intervention and control group, respectively (mean difference 1.6 points, 95% Confidence Interval 0.2 to 3.1). Rehabilitation did not increase accelerometer-based physical activity in the aforementioned subgroup and did not benefit those with either mild or severe mobility restrictions. Conclusions: Pre-admission mobility may determine the response to the largely counselling-based rehabilitation program.
Protective effect of Coenzyme Q10 on oxidative ovarian and uterine damage induced by methotrexate in rats
Authors: Kiremitli T , Kiremitli S , Akselim B , Yilmaz B , Mammadov R , Tor IH , Yazici GN , Gulaboglu M 
Published: March 2021

Methotrexate (MTX) has toxic effects on the uterus and ovaries via oxidative stress. Coenzyme Q10 (CoQ10) is an important component in electron transport in the mitochondria and an antioxidant in cellular metabolism through the inhibition of lipid peroxidation. The aim of this study was to investigate the preventive effects of CoQ10 on MTX-induced utero-ovarian damage and oxidative stress in rats. In this experimental study, 30 albino Wistar female rats were divided randomly into three groups. Once a day for a month, 10 mg/kg of CoQ10 was orally administered to the rats in the MTX+CoQ10 group, while the same volume of olive oil was administered orally to the other two groups. One hour thereafter, 20 mg/kg of MTX was injected intraperitoneally into the rats in the MTX and MTX+CoQ10 groups; the remaining group was the control. At the end of the month, biochemical and histopathologic examinations were performed on the extracted uteri and ovaries. In the uterine ovarian tissues of the animals in the MTX group, there was an increase in oxidative stress mediators and a decrease in antioxidant and anti-inflammatory mediators, but these trends were reversed in the MTX+CoQ10 group, demonstrating the antioxidant effects of CoQ10. MTX leads to oxidative stress-related ovarian and uterine injury, and CoQ10 may be useful for protecting ovarian and uterine tissue from such injury.
Influence of RFC1 c.80A>G Polymorphism on Methotrexate-Mediated Toxicity and Therapeutic Efficacy in Rheumatoid Arthritis: A Meta-analysis
Authors: Naushad Shaik Mohammad , Alrokayan Salman A. , Almajhdi Fahad N. , Hussain Tajamul 
Published: March 2021

Background: Methotrexate (MTX) is an antirheumatic drug, transported by reduced folate carrier-1 (RFC1). The most common RFC1 gene variant, c.80 A>G (rs1051266) is ambiguously linked to adverse effects of MTX therapy in some rheumatoid arthritis (RA) patients. Objective: The purpose of meta-analysis was to summarize all major published studies on c.80 A>G SNP to clarify this ambiguity in MTX therapy. Methods: A total of 18 studies representing 3592 RA patients comprising 699 men and 2893 women were included. Both fixed and random effect models were applied to study the data. Results: The RFC1 80A-allele showed null association with MTX-mediated toxicity in both fixed (odds ratio [OR] = 0.91; 95% CI = 0.80-1.03) and random effects (OR = 0.89; 95% CI: 0.71-1.11) models. Because heterogeneity was observed in this association ( P = 0.0006), data were segregated based on use of folate therapy. In 7 studies (n = 1191) where folate was used along with MTX, RFC1 AA patients showed reduced risk for MTX-mediated toxicity (OR = 0.67; 95% CI: 0.50-0.89; P = 0.0006). The RFC1 80A-allele was found to increase the efficacy of MTX therapy by 1.53-fold (95% CI: 1.24-1.88), whereas the 80AA-genotype increased the efficacy by 1.85-fold (95% CI: 1.41-2.42). No publication bias was observed in these associations. Conclusion and Relevance: RFC1 c.80 A>G is an important pharmacogenetic determinant of MTX therapy in RA. The RFC1 80A-allele robustly increased therapeutic efficacy and safety when folate was used along with MTX. Findings are relevant to decision-making in the clinical use of MTX as a treatment for RA patients harboring the RFC1 gene variant.
Evaluation of an evidence-based practice mentorship programme in a paediatric quaternary care setting
Authors: Schuler Ethan , Mott Sandra , Forbes Peter W , Schmid Alexis , Atkinson Carole , DeGrazia Michele 
Published: March 2021

Background Evidence-based practice (EBP) is essential for clinical decision-making, improving care, reducing costs and achieving optimal patient outcomes. The Evidence-based Practice Mentorship Program (EBPMP) is a flexible, self-directed programme whereby participants carry out EBP projects guided by expert mentors. Aims To evaluate EBPMP effectiveness and participant experience. Methods To evaluate effectiveness, as measured by changes in EBP value, knowledge and implementation, participants completed pre- and post-EBPMP Quick-EBP-Value, Implementation and Knowledge (VIK) surveys. To understand participants’ experiences individual and group interviews were conducted at the end of the programme and analysed using qualitative content analysis. Results Most participants were over 50 years old, Caucasian, inpatient staff nurses, baccalaureate prepared, with over 11 years’ experience. Statistically significant improvements were observed in the post Quick-EBP-VIK knowledge and implementation domains. Individual and group participant interviews revealed four categories of importance to the experience: 1. perceived benefits of EBP, 2. time as a barrier to EBP, 3. desire for more cohort interaction and 4. positive mentee–mentor experience. Conclusions EBPMP can improve participants’ knowledge and implementation of EBP in an environment that values EBP; however, opportunities exist to implement programme modifications that address barriers identified by participants including project time and increased participant interactions.
Comparative efficacy and safety of Janus kinase inhibitors and biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and network meta-analysis
Authors: Weng Chenghua , Xue Leixi , Wang Qing , Lu Wentian , Xu Jiajun , Liu Zhichun 
Published: March 2021

Objective: To evaluate the comparative efficacy and safety of Janus kinase (JAK) inhibitors and biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) and an inadequate response to at least one disease-modifying antirheumatic drug (DMARD). Methods: PubMed, Embase, Cochrane library and ClinicalTrials.gov were searched for relevant randomized controlled trials (RCTs) from inception to April 2020. The active drugs included three JAK inhibitors and eight bDMARDs while the control drugs included placebo or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Outcomes include American College of Rheumatology 20% response (ACR20), Disease Activity Score in 28 joints (DAS28), Health Assessment Questionnaire–Disability Index (HAQ-DI) and discontinuations for adverse events (AEs). We estimated summary odds ratios (ORs) and weighted mean differences (WMDs) using network meta-analysis with random effects. Results: Eighty-eight RCTs with 31,566 patients were included. All JAK inhibitors and bDMARDs were more effective than placebo in ACR20 (ORs ranging between 3.05 and 5.61), DAS28 (WMDs ranging between −1.91 and −0.80) and HAQ-DI (WMDs ranging between −0.34 and −0.21). Tocilizumab, certolizumab pegol and upadacitinib showed relatively good efficacy in these three outcomes according to their relative ranking. Notably, tocilizumab was more effective than other active drugs in DAS28 (WMDs ranging between −1.11 and −0.49). Compared with the lower recommended doses, increasing the doses of JAK inhibitors (baricitinib 4 mg versus 2 mg, tofacitinib 10 mg versus 5 mg and upadacitinib 30 mg versus 15 mg) cannot provide significant additional benefits. In terms of discontinuations for AEs, all active drugs showed no significant difference compared with placebo except certolizumab pegol [OR 1.65, 95% credible interval (CrI) 1.06–2.61] and rituximab (3.17, 1.11–10.80). Conclusions: Tocilizumab, certolizumab pegol and upadacitinib may have relatively good efficacy in patients with RA after treatment failure with csDMARDs. RA patients taking a JAK inhibitor may have a preference for a lower recommended dose.