bluuebunny/crossref_metadata_2025_split huggingface dataset:
The evolution of relapse of adult T cell acute lymphoblastic leukemia
Authors: Sentís Inés , Gonzalez Santiago , Genescà Eulalia , García-Hernández Violeta , Muiños Ferran , Gonzalez Celia , López-Arribillaga Erika , Gonzalez Jessica , Fernandez-Ibarrondo Lierni , Mularoni Loris , Espinosa Lluís , Bellosillo Beatriz , Ribera Josep-Maria , Bigas Anna , Gonzalez-Perez Abel , Lopez-Bigas Nuria 
Published: November 2020

Abstract
Background
Adult T cell acute lymphoblastic leukemia (T-ALL) is a rare disease that affects less than 10 individuals in one million. It has been less studied than its cognate pediatric malignancy, which is more prevalent. A higher percentage of the adult patients relapse, compared to children. It is thus essential to study the mechanisms of relapse of adult T-ALL cases.

Results
We profile whole-genome somatic mutations of 19 primary T-ALLs from adult patients and the corresponding relapse malignancies and analyze their evolution upon treatment in comparison with 238 pediatric and young adult ALL cases. We compare the mutational processes and driver mutations active in primary and relapse adult T-ALLs with those of pediatric patients. A precise estimation of clock-like mutations in leukemic cells shows that the emergence of the relapse clone occurs several months before the diagnosis of the primary T-ALL. Specifically, through the doubling time of the leukemic population, we find that in at least 14 out of the 19 patients, the population of relapse leukemia present at the moment of diagnosis comprises more than one but fewer than 108 blasts. Using simulations, we show that in all patients the relapse appears to be driven by genetic mutations.

Conclusions
The early appearance of a population of leukemic cells with genetic mechanisms of resistance across adult T-ALL cases constitutes a challenge for treatment. Improving early detection of the malignancy is thus key to prevent its relapse.
Anakinra: efficacy in the management of fever during neutropenia and mucositis in autologous stem cell transplantation (AFFECT-2)—study protocol for a multicenter randomized double-blind placebo-controlled trial
Authors: de Mooij Charlotte E. M. , van Groningen Lenneke F. J. , de Haan Anton F. J. , Biemond Bart J. , Bakker Martijn , van der Velden Walter J. F. M. , Blijlevens Nicole M. A. 
Published: November 2020

Abstract
Background
Since decades, fever and infections have been the most important complications of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) in the treatment of hematologic malignancies. Neutropenia has long been considered to be the most important risk factor for these complications. However, recent studies have shown that not neutropenia, but the development of mucositis is the most important cause of these complications. Currently, limited options for the prevention and treatment of mucositis are available, of which most are only supportive. The pro-inflammatory cytokine interleukin-1 (IL-1) plays a crucial role in the pathogenesis of mucositis. Pre-clinical studies of chemotherapy-induced mucositis have shown that recombinant human IL-1 receptor antagonist anakinra significantly ameliorated intestinal mucositis. In our pilot study AFFECT-1, we examined the safety and maximal tolerated dose of anakinra in patients with multiple myeloma, treated with high-dose melphalan (HDM) and autologous HSCT, selecting a dose of 300 mg daily for the phase IIb trial. The aim of the AFFECT-2 study is to determine the efficacy of anakinra in preventing fever during neutropenia (FN) and mucositis in this study population.

Methods/design
A multicenter, randomized, placebo-controlled, double-blind phase IIb trial will be conducted. Ninety patients with multiple myeloma scheduled for treatment with HDM and autologous HSCT will be included. Patients will be randomized between intravenous treatment with anakinra (300 mg) or placebo. Each group will be treated from day − 2 (day of HDM; day 0 is HSCT) up until day + 12. Outcome measures will be assessed at baseline, during admission, at discharge or day + 30, at day + 90, and + 1 year. The primary outcome will be reduction of FN. Secondary outcome measures include mucositis scores, bloodstream infections, citrulline levels, quality of life, and fatigue severity.

Discussion
The AFFECT-2 trial will examine the efficacy of anakinra in the management of fever during neutropenia and mucositis in patients with multiple myeloma treated with HDM and autologous HSCT. The results of this study may provide a new treatment option for these important complications. Also, this study will give us more insight in the pathophysiology of mucositis, including the role of IL-1 and the role of the microbiota in mucositis.

Trial registration
Clinicaltrials.gov NCT04099901. Registered on September 23, 2019. EudraCT: 2018-005046-10.
Oral corticosteroids for post-infectious cough in adults: study protocol for a double-blind randomized placebo-controlled trial in Swiss family practices (OSPIC trial)
Authors: Merlo Christoph , Essig Stefan , Brancati-Badarau D. Oana , Leuppi Jörg Daniel , Speich Benjamin , Erlanger Tobias E. , Hemkens Lars G. , Zeller Andreas 
Published: November 2020

Abstract
Background
Cough is a common reason for patients to visit general practices. So-called post-infectious cough is defined as lasting 3 to 8 weeks after an upper respiratory tract infection. It can be disabling in daily activities, with substantial impact on physical and psychosocial health, leading to impaired quality of life and increased health care costs. Recommendations for the management of post-infectious cough in primary care are scarce and incoherent. A systematic review and meta-analysis of randomized clinical trials (RCT) assessing patient-relevant benefits and potential harms of available treatments identified six eligible RCTs assessing different treatment regimens (i.e. inhaled fluticasone propionate, inhaled budesonide, salbutamol plus ipratropium-bromide, montelukast, nociception-opioid-1-receptor agonist, codeine, gelatine). No RCT found clear patient-relevant benefits and most had an unclear or high risk of bias.
Post-infectious cough is thought to be mediated by inflammatory processes that are also present in exacerbations of asthma or chronic obstructive pulmonary diseases for which there is strong evidence that oral corticosteroids provide patient-relevant benefit without relevant harm. We therefore plan to conduct the first RCT evaluating the effectiveness of oral corticosteroids for post-infectious cough.

Methods
We are conducting a triple-blinded randomized-controlled and multicentred superiority trial in primary health care practices in Switzerland. We will include 204 adult patients who consult their general practitioner (GP) for a cough lasting 3 to 8 weeks following an upper respiratory tract infection. Participants will be randomly allocated to either the 5-day treatment with oral corticosteroids or placebo. The primary outcome is cough-related quality of life assessed by the Leicester Cough Questionnaire score 14 days after randomization. Secondary outcomes include cough-related quality of life at several time points, overall cessation of cough and adverse events.

Discussion
This RCT will provide evidence on whether oral corticosteroids are beneficial and safe in patients with post-infectious cough. Results can have a substantial impact on the well-being and management of these patients in Switzerland and beyond. An evidence-based treatment for this condition may reduce re-consultations with GPs and spending for antitussive drugs, thus possibly having an impact on health care spending.

Trial registration
ClinicalTrials.gov NCT04232449. Prospectively registered on 18 January 2020.
Effects of Keluoxin capsule combined with losartan potassium on diabetic kidney disease: study protocol for a randomized double-blind placebo-controlled multicenter clinical trial
Authors: Wu Rui , Wei Fan , Qu Lianlian , Bai Litao , Li Jun , Li Fei , Yan Weitian , Wang Qiuhong , Wei Junping 
Published: November 2020

Abstract
Background
Diabetic kidney disease (DKD) is one of the most important microvascular complications of diabetes, and its prevalence has increased dramatically in the past few decades. DKD is responsible for considerable morbidity and mortality of patients with diabetes. Keluoxin capsule (KLX) is a Chinese patent medicine that has been used in the clinic to control DKD for years. Previous studies have shown that KLX appears to reduce proteinuria, but the study protocols as well as the primary outcome need to be improved. Thus, we aim to evaluate whether losartan potassium combined with KLX is more effective than losartan potassium in DKD treatment and to provide validated evidence for the application of KLX in the treatment of DKD.

Methods
We will conduct a randomized double-blind placebo-controlled multicenter clinical trial. A total of 252 participants diagnosed with DKD recruited from 18 institutions will be randomly allocated to either a losartan potassium plus KLX (n = 126) or a losartan potassium plus placebo group (n = 126). The participants will be administered KLX or placebo in addition to losartan potassium for 24 weeks. The primary outcome measure will be the decline in estimated glomerular filtration rate (eGFR) (ml/min/1.73 m2/year) from baseline within 24 weeks, and the secondary outcomes will be the incidence of serum creatinine doubling, the incidence of end-stage renal disease (ESRD), the proportion of subjects with a progressive decline in eGFR > 30%, the percent change in 24 h urinary total protein (UTP), the change in the urinary albumin/creatinine ratio (UACR), and the total effective rate of the traditional Chinese medicine (TCM) syndrome scale scores. Comparison of the differences in the variables between groups will be performed according to the data revealed by independent t tests, chi-squared tests, Fisher’s exact tests, or Wilcoxon’s tests. All statistical tests will be two-sided, and significance will be considered for p values < 0.05.

Discussion
This study will be the first randomized clinical trial to evaluate the efficacy and safety of KLX versus the placebo for the treatment of patients with DKD. The outcome of this trial will provide a basis for prescribing KLX to patients with DKD.

Trial registration
Chinese Clinical Trial Registry (www.chictr.org.cn) ChiCTR1900021113. Registered on January 29, 2019.
Intralipid postconditioning in patients of cardiac surgery undergoing cardiopulmonary bypass (iCPB): study protocol for a randomized controlled trial
Authors: Yuan Yuan , Xiong Hui , Zhang Yan , Yu Hong , Zhou Rong-Hua 
Published: November 2020

Abstract
Background
Intralipid is a necessary fatty acid carrier that has been safely used as an energy supplier in the clinic. It has played an important role in rescuing the cardiac arrest caused by local anesthetic toxicity. In recent years, experimental studies have shown that intralipid postconditioning (ILPC) could reduce myocardial ischemic/reperfusion (I/R) injuries. Our research group has innovatively conducted a pilot randomized controlled trial (RCT), and the results showed that ILPC could reduce the release of cTnT and CK-MB, biomarkers of myocardial I/R injury, in valve replacement surgery. However, the potential effects of ILPC on the clinical outcome of adult cardiac surgery patients are unclear. Intralipid postconditioning in patients of cardiac surgery undergoing cardiopulmonary bypass (iCPB) trial is aimed to further study whether ILPC could improve short-term and long-term clinical outcome, as well as cardiac function in adult cardiac surgery patients.

Methods
The iCPB trial is an ongoing, single-center, prospective, double-blinded, large sample RCT. In total, 1000 adults undergoing cardiac surgery will be randomly allocated to either the ILPC group or the control group. The intervention group received an intravenous infusion of 2 mL/kg of 20% intralipid (medium-chain and long-chain fat emulsion injection C6~C24, Pharmaceutical) within 10 min before aortic cross-unclamping, and the control group received an equivalent volume of normal saline. The primary endpoints are complex morbidity of major complications during hospitalization and all-cause mortality within 30 days after surgery. The secondary endpoints include (1) all-cause mortality 6 months and 1 year postoperatively; (2) the quality of life within 1 year after surgery, using the QoR-15 questionnaire; (3) the postoperative cardiac function evaluated by LVEF, LVEDS, and LVEDD, and the myocardial injury evaluated by CK-MB, cTnT, and BNP; and (4) short-term clinical outcomes during hospitalization and total cost are also detailed evaluated.

Discussion
The iCPB trial is the first to explore ILPC on the clinical outcome of adult cardiac surgery patients. The results are expected to provide potential evidences about whether ILPC could reduce the morbidity and mortality and improve the cardiac function and quality of life. Therefore, the results will provide a rationale for the evaluation of the potentially clinically relevant benefit of intralipid therapy.

Trial registration
Chictr.org.cn ChiCTR1900024387. Prospectively registered on 9 July 2019.
Parents’ understanding and motivation to take part in a randomized controlled trial in the field of adolescent mental health: a qualitative study
Authors: O’Keeffe Sally , Weitkamp Katharina , Isaacs Danny , Target Mary , Eatough Virginia , Midgley Nick 
Published: November 2020

Abstract
Background
Little is known about why parents agree to take part in randomized controlled trials for adolescent mental health. This study aimed to investigate parents’ perspectives on participating in a trial for psychological treatment of depression. The study explored parents’ motivations, understanding of the trial and perspectives on the acceptability of the trial.

Methods
Sixty-five parents took part in this qualitative study. Their adolescent children had been randomly allocated to one of three active psychological treatments for depression as part of the IMPACT trial and were interviewed about their experiences of participating in the study. Semi-structured interviews were analysed using framework analysis.

Results
For seven of the sixty-five parents, their experience of taking part in the trial was not covered in their interview so they were excluded from the analysis. The analysis was therefore based on the data from the parents of 58 adolescents taking part in the trial. The most commonly cited motivation for taking part in the study reported by parents was a desire to help others going through similar difficulties. Parents generally reported finding trial participation acceptable, although there were aspects that some reported finding less acceptable, including randomization and the burden of research assessments. Others spoke positively about the experience of trial participation and found it enjoyable or even therapeutic. Importantly, some did not appear to have a good understanding of the trial design, including randomization and treatment allocation.

Conclusions
This study indicates that trial participation can be a positive experience for parents, yet it raises concerns about how trialists can ensure that consent is fully informed, given that some parents appeared to have a poor understanding of the trial. Future studies should seek to explore how communication with trial participants can be improved, to ensure that trial participation is fully informed. Patient and public involvement will be crucial in ensuring this communication is accessible to stakeholders.

Trial registration
ISRCTN registry ISRCTN83033550. Registered on 15 October 2009
The impact of the fipronil crisis on the financial performance of Dutch laying hen farms
Authors: Sok Jaap , van Horne Peter , Meuwissen Miranda 
Published: November 2020

Abstract
Background
Illegal use of fipronil as an insecticide in 2017 has caused substantial damage to Dutch laying hen farms. We assessed how the fipronil crisis has affected the financial performance of affected farms as well as unaffected farms. While affected farms faced culling their flocks and lost revenue, unaffected farms benefitted from temporary high egg prices.

Methods
A three-step normative modelling approach is taken using financial statements and a partial budget. The estimations are for a 50,000 laying hen farm facing the fipronil crisis for 5 months. First, a baseline is created by generating an income statement of this laying hen farm representing a ‘normal year’. Second, incremental costs and revenue as a result of the fipronil crisis are estimated. Third, the baseline income statement is updated with the outcomes of the partial budget. This results in two additional income statements that report the net operating result of this farm being unaffected and affected by the fipronil crisis.

Results
While in a normal year this average-sized farm has a net operating result of around 18,000 euros, profitability was estimated to be − 369,000 euros and + 169,000 euros for the affected and unaffected farm due to the crisis respectively. For affected farms, impacts were especially high as there was no government compensation or insurance.

Conclusions
As Dutch farms typically operate as independent family farms, there was also no compensation from other chain actors. The affected farms therefore likely have faced financial distress and have had to increase debt or use their financial reserves for household consumption and restarting the business. Outcomes contribute to discussions around liability claims and cost-benefit assessments of measures to improve the chain food safety and rapid alert systems.

Graphical Abstract
Detection of Leishmania infantum DNA in Pintomyia evansi and Lutzomyia longipalpis in Honduras
Authors: Sosa-Ochoa Wilfredo , Varela Amador Javier , Lozano-Sardaneta Yokomi , Rodriguez Segura Gabriela , Zúniga Valeriano Concepcion , Araujo Gabriela Venicia , Sandoval Pacheco Carmen María , Laurenti Márcia Dalastra , Galvis-Ovallos Fredy 
Published: November 2020

Abstract
Background
The two most abundant sand fly species on the Honduran Pacific coast are Lutzomyia (Lutzomyia) longipalpis and Pintomyia (Pifanomyia) evansi. Both species are known vectors of Leishmania (Leishmania) infantum, the etiological agent of visceral leishmaniasis (VL) in the Americas. Although VL and non-ulcerative cutaneous leishmaniasis (NUCL) are endemic on the Pacific versant of the Central American Pacific, the latter is the most frequent manifestation of leishmaniasis there. We evaluated the circulation of Leishmania spp. in the sand fly species on El Tigre Island, an endemic area of NUCL.

Results
We collected 222 specimens of six sand fly species. Lu. longipalpis (180 specimens; 81%) and Pif. (Pi.) evansi (35 specimens; 16%) were the most abundant species. L. (L.) infantum DNA was detected in nine of the 96 specimens analyzed; seven of these specimens were identified as Lu. longipalpis, and the remaining two were Pi.evansi, with an infection rate of 9.4% and 2.7%, respectively.

Conclusion
We present the first record of L. (L.) infantum DNA in Pi.evansi from a NUCL endemic region of Central America. Our results suggest that Pi. evansi could be a secondary vector of L. (L.) infantum in the transmission cycle of leishmaniasis. The detection of natural infections of L. (L.) infantum in sand flies in this region contributes to an understanding of the epidemiology of leishmaniasis in Honduras.

Graphical Abstract
Cyr61 synthesis is induced by interleukin-6 and promotes migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis
Authors: Choi Changmin , Jeong Wooseong , Ghang Byeongzu , Park Yonggeun , Hyun Changlim , Cho Moonjae , Kim Jinseok 
Published: November 2020

Abstract
Background
Interleukin-6 (IL-6) is involved in fibroblast-like synoviocyte (FLS) activation and promotes pannus formation and bone and cartilage destruction in rheumatoid arthritis (RA). Cysteine-rich 61 (Cyr61) protein regulates cell proliferation, migration, and differentiation. The aim of this study was to investigate the role of Cyr61 in RA-FLS migration and invasion after IL-6 stimulation.

Methods
Western blotting, immunohistochemistry, reverse transcription-polymerase chain reaction, and real time-polymerase chain reaction were used to examine protein and mRNA levels of Cyr61, matrix metalloproteinases (MMPs), and other signalling proteins. Knockdown of gene expression was performed with siRNA, and RNA sequencing was performed for differential gene analysis. Migration and invasion were assessed by wound healing and Boyden chamber assays.

Results
Cyr61 levels were elevated in FLSs from RA patients compared to those in osteoarthritis patients. Control and IL-6-treated FLSs showed differential gene expression. IL-6 stimulated protein synthesis of Cyr61, which was attenuated by the extracellular signal-related kinase 1/2 (ERK 1/2) inhibitor, PD98059, and knockdown of early growth response 3 (EGR3), but not of JUN. IL-6-induced Cyr61 protein synthesis increased expression of MMP2. Cyr61 promoted FLS migration and invasion in an autocrine manner. Knockdown of CYR61 and a neutralising antibody attenuated Cyr61 synthesis and IL-6-induced FLS migration.

Conclusions
By modulating the ERK/EGR3 pathway, IL-6 stimulated Cyr61 production and in turn increased invasiveness of FLS. Our data suggest that Cyr61 might be a potential target to prevent the progression of joint damage in RA.
Gut microbiota and the human gut physiological changes
Authors: Bajinka Ousman , Darboe Alansana , Tan Yurong , Abdelhalim Khalid A. , Cham Lamin B. 
Published: November 2020

Abstract
Background
The human gut can be colonized by number of microorganisms. The most studied are bacteria, which changes from birth to newborn born into adult-like gut microbiota. Much is known about the effects of dietary, medications, and lifestyles on the bacterial composition. However, the host physiological changes influencing the gut microbiota, the immediate consequences, and the possible gut microbiota therapy are not studied at length. This review is based profoundly on animal model studies through experimentation and some human clinical trials for the past 20 years.

Forward
The physiological factors studied to influences gut microbiota are bacterial mucosal receptors, mucin glycosylation, mucus, epithelial microvilli, and tight junction. Host secretions and immune response such as immunity, secretory A (sIgA), inflammasome, innate immunity, immune response, glycans, bile acids, peristalsis, microRNA, and adhesion to intestinal glycans are as well found to confer variety of alterations on gut microbial flora.

Conclusion
Despite the resilience of the gut microbiota in response to changes, chain of events causes the imbalance microbiota. Increased pro-inflammatory potential with the help of cell barriers, host secretions, and immune response mediate gut recovery.