bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I pharmacokinetic study of single agent trametinib in patients with advanced cancer and hepatic dysfunction
Authors: Voon Pei Jye , Chen Eric X. , Chen Helen X. , Lockhart Albert C. , Sahebjam Solmaz , Kelly Karen , Vaishampayan Ulka N. , Subbiah Vivek , Razak Albiruni R. , Renouf Daniel J. , Hotte Sebastien J. , Singh Arti , Bedard Philippe L. , Hansen Aaron R. , Ivy S. Percy , Wang Lisa , Stayner Lee-Anne , Siu Lillian L. , Spreafico Anna 
Published: February 2022

AbstractBackgroundTrametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD).MethodsAdvanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on “3 + 3” design within each HD group. PK samples were collected at cycle 1 days 15-16.ResultsForty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26).ConclusionsRP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients – 1.5 mg QD in Mod group, and 1 mg QD in Sev group.Trial registrationThis study was registered in the ClinicalTrials.gov website (NCT 02070549) on February 25, 2014. .
Statistical analysis plan for the OPTIMUM study: optimising immunisation using mixed schedules, an adaptive randomised controlled trial of a mixed whole-cell/acellular pertussis vaccine schedule
Authors: Totterdell James A. , Chacon Gladymar Perez , Estcourt Marie J. , Jones Mark , Richmond Peter , Snelling Thomas L. , Marsh Julie A. 
Published: February 2022

AbstractObjectiveThe purpose of this double-blind, randomised, controlled trial is to compare allergic outcomes in children following vaccination with acellular pertussis (aP) antigen (standard of care in Australia) given at 2 months of age versus whole cell pertussis (wP) in the infant vaccine schedule.ParticipantsUp to 3000 Australian infants 6 to <12 weeks of age born ≥32 weeks gestation.InterventionsThe intervention is a wP containing vaccine as the first scheduled pertussis vaccine dose instead of an aP containing vaccine.OutcomesThe primary outcome is a binary indicator of history of IgE-mediated food allergy at the age of 12 months confirmed, where necessary, with an oral food challenge before 18 months of age. Secondary outcomes include (1) history of parent-reported clinician-diagnosed new onset of atopic dermatitis by 6 or 12 months of age with a positive skin prick test to any allergen before 12 months of age, (2) geometric mean concentration in pertussis toxin-specific IgG before and 21 to 35 days after a booster dose of aP at 18 months of age, and (3) sensitisation to at least one allergen by 12 months of age.ResultsOperating characteristics of trial decision rules were evaluated by trial simulation. The selected rules for success and futility approximately maintain type I error of 0.05 and achieved power 0.85 for a reduction in the primary outcome from 10% in the control group to 7% in the intervention group.DiscussionA detailed, prospective statistical analysis plan (SAP) is presented for this Bayesian adaptive design. The plan was written by the trial statistician and details the study design, pre-specified adaptive elements, decision thresholds, statistical methods, and the simulations used to evaluate the operating characteristics of the trial. Application of this SAP will minimise bias and supports transparent and reproducible research.Trial registrationAustralia & New Zealand Clinical Trials Registry,ACTRN12617000065392. Registered on 12 January 2017Study protocol10.1136/bmjopen-2020-042838
The Best Services Trial (BeST?): a cluster randomised controlled trial comparing the clinical and cost-effectiveness of New Orleans Intervention Model with services as usual (SAU) for infants and young children entering care
Authors: Crawford Karen , Fitzpatick Bridie , McMahon Lynn , Forde Matt , Miller Susanne , McConnachie Alex , Messow Martina , Henderson Marion , McIntosh Emma , Boyd Kathleen , Ougrin Dennis , Wilson Phil , Watson Nicholas , Minnis Helen 
Published: February 2022

Abstract
Background
Abused and neglected children are at increased risk of health problems throughout life, but negative effects may be ameliorated by nurturing family care. It is not known whether it is better to place these children permanently with substitute (foster or adoptive) families or to attempt to reform their birth families.
Previously, we conducted a feasibility randomised controlled trial (RCT) of the New Orleans Intervention Model (NIM) for children aged 0–60 months coming into foster care in Glasgow. NIM is delivered by a multidisciplinary health and social care team and offers families, whose child has been taken into foster care, a structured assessment of family relationships followed by a trial of treatment aiming to improve family functioning. A recommendation is then made for the child to return home or for adoption.
In the feasibility RCT, families were willing to be randomised to NIM or optimised social work services as usual and equipoise was maintained. Here we present the protocol of a substantive RCT of NIM including a new London site.

Methods
The study is a multi-site, pragmatic, single-blind, parallel group, cluster randomised controlled superiority trial with an allocation ratio of 1:1. We plan to recruit approximately 390 families across the sites, including those recruited in our feasibility RCT. They will be randomly allocated to NIM or optimised services as usual and followed up to 2.5 years post-randomisation. The principal outcome measure will be child mental health, and secondary outcomes will be child quality of life, the time taken for the child to be placed in permanent care (rehabilitation home or adoption) and the quality of the relationship with the primary caregiver.

Discussion
The study is novel in that infant mental health professionals rarely have a role in judicial decisions about children’s care placements, and RCTs are rare in the judicial context. The trial will allow us to determine whether NIM is clinically and cost-effective in the UK and findings may have important implications for the use of mental health assessment and treatment as part of the decision-making about children in the care system.
Bifunctional optogenetic switch for improving shikimic acid production in E. coli
Authors: Komera Irene , Gao Cong , Guo Liang , Hu Guipeng , Chen Xiulai , Liu Liming 
Published: February 2022

Abstract
Background
Biomass formation and product synthesis decoupling have been proven to be promising to increase the titer of desired value add products. Optogenetics provides a potential strategy to develop light-induced circuits that conditionally control metabolic flux redistribution for enhanced microbial production. However, the limited number of light-sensitive proteins available to date hinders the progress of light-controlled tools.

Results
To address these issues, two optogenetic systems (TPRS and TPAS) were constructed by reprogramming the widely used repressor TetR and protease TEVp to expand the current optogenetic toolkit. By merging the two systems, a bifunctional optogenetic switch was constructed to enable orthogonally regulated gene transcription and protein accumulation. Application of this bifunctional switch to decouple biomass formation and shikimic acid biosynthesis allowed 35 g/L of shikimic acid production in a minimal medium from glucose, representing the highest titer reported to date by E. coli without the addition of any chemical inducers and expensive aromatic amino acids. This titer was further boosted to 76 g/L when using rich medium fermentation.

Conclusion
The cost effective and light-controlled switch reported here provides important insights into environmentally friendly tools for metabolic pathway regulation and should be applicable to the production of other value-add chemicals.
Effects of a taped filter mask on peak power, perceived breathlessness, heart rate, blood lactate and oxygen saturation during a graded exercise test in young healthy adults: a randomized controlled trial
Authors: Ng Hoi Lam , Trefz Johannes , Schönfelder Martin , Wackerhage Henning 
Published: February 2022

Abstract
Background
Face masks are an effective, non-pharmacological strategy to reduce the transmission of Severe Acute Respiratory Syndrome Coronavirus-2 and other pathogens. However, it is a challenge to keep masks sealed during exercise, as ventilation can increase from 5 to 10 L/min at rest to up to 200 L/min so that masks may be blown away from the face. To reduce leakage e.g. during exercise, a face mask was developed that is taped onto the face. The aim of this study was to investigate during a graded exercise test the effect of a taped filter mask on the perception of breathlessness, heart rate, blood lactate concentration, and oxygen saturation when compared to a surgical mask and no mask.

Methods
Eight healthy trained participants (4 females), aged 24.5 ± 3.3 years performed graded exercise test until volitional exhaustion under three conditions: (1) No mask/control, (2) surgical mask or (3) taped filter mask. During these tests, we measured perception of breathlessness, heart rate, blood lactate concentration and peripheral oxygen saturation and analysed the resultant data with one or two-way repeated measures ANOVAs. We also used a questionnaire to evaluate mask comfort and analysed the data with paired t-tests.

Results
When compared to wearing no mask, maximal workload was significantly reduced with a taped filter face mask by 12 ± 6% (p < 0.001) and with a surgical mask by 3 ± 6% (p > 0.05). Moreover, subjects perceive the sensation of "severe breathlessness" at a 12 ± 9% lower workload (p = 0.012) with a taped face mask, and 7 ± 13% lower workload with a surgical mask (p > 0.05) when compared to wearing no mask. Oxygen saturation at 65% of the maximal workload is 1.5% lower (p = 0.018) with a taped mask than no mask. Heart rate and blood lactate concentration are not significantly different in-between no mask, surgical mask and taped mask at any workload. When compared to wearing a surgical mask, wearing a taped filter face mask has a significantly better wearing comfort (p = 0.038), feels better on the skin (p = 0.004), there is a lower sensation of moisture (p = 0.026) and wearers perceive that less heat is generated (p = 0.021). We found no sex/gender differences for any of the measured parameters.

Conclusions
A taped mask is well tolerated during light and moderate exercise intensity but reduces maximal exercise capacity.
Spontaneous regression of breast lymphoproliferative disorders after withdrawal of methotrexate in rheumatoid arthritis patients with Epstein–Barr virus infection: a case report and review of the literature
Authors: Ogawa Ayumi , Nakagawa Tsuyoshi , Kumaki Yuichi , Hosoya Tokuko , Oda Goshi , Mori Mio , Fujioka Tomoyuki , Kubota Kazunori , Onishi Iichiro , Uetake Hiroyuki 
Published: February 2022

Abstract
Background
Lymphoproliferative disorder (LPD) has been shown to occur after treatment with methotrexate (MTX). Currently, MTX-LPD has become widely recognized, but its mechanism and prognostic factors remain unclear.

Case presentation
We report the first case of Epstein–Barr virus (EBV)-associated MTX-LPD of the breast. A 63-year-old Asian woman with long-term rheumatoid arthritis presented to our facility with intermittent fever. A physical examination revealed a 3-cm lump in her left breast. She had been taking MTX for the past 15 years. Laboratory studies revealed slightly elevated levels of EBV-viral capsid antigen antibody immunoglobulin G and EBV nuclear antibody. Contrast-enhanced computer tomography revealed a mass in the left breast, a subcutaneous nodule in the abdomen, a mass in the left lung, and a nodule in the left retroperitoneum. The definitive diagnosis was consistent with MTX-LPD merging into an EBV-positive, diffuse large B-cell lymphoma. Six months following the withdrawal of MTX, the breast mass had markedly shrunk and the patient remained in good health for 1 year with no evidence of relapse of LPD.

Conclusion
MTX-LPD rarely occurs in the breast, and it is difficult to diagnose because there have only been six reported cases of breast MTX-LPD reported in the literature. EBV-positive MTX-LPD tends to regress spontaneously after MTX withdrawal, and our case also had similar results. It is important to make an appropriate diagnosis of MTX-LPD of the breast based on imaging and pathology to determine the appropriate treatment protocol for this rare disorder.
Book review of The Contested Lands of Laikipia. Histories of Claims and Conflict in a Kenyan Landscape by Marie Ladekjær Gravesen
Authors: Hughes Lotte 
Published: February 2022

Book detailsMarie Ladekjær GravesenThe Contested Lands of Laikipia. Histories of Claims and Conflict in a Kenyan LandscapeBrill: Leiden and Boston, 2021ISSN 15668-1203. ISSN 978-90-04-43519-3 (paperback). ISBN 978-90-43520-9 (e-book). 263 pages
Remediation mechanism of “double-resistant” bacteria—Sedum alfredii Hance on Pb- and Cd-contaminated soil
Authors: Mo Tongdong , Jiang Daihua , Shi Dingding , Xu Shaohui , Huang Xuejiao , Huang Zhigang 
Published: February 2022

Abstract
Background
Concentrations of heavy metals continue to increase in soil environments as a result of both anthropogenic activities and natural processes. Cadmium (Cd) and lead (Pb) is one of the most toxic heavy metals and pose health risks to both humans and the ecosystem. Therefore, effectively solving the problem of heavy metal pollution is the concern of soil workers. Among the existing remediation techniques, only the combined use of microorganisms and plants for remediation of heavy metal-contaminated soil is the greenest and most developed one. Consequently, based on this background, this study investigates the remediation mechanism of Pb and Cd heavy metals using the combined action of bacteria and Sedum alfredii Hance.

Methods
In order to enrich the research theory of combined plant and microorganism remediation of heavy metal-contaminated soil, we constructed a heavy metal composite pollution remediation system by combining Pb and Cd-tolerant bacteria with the Pb and Cd hyperaccumulator plant—Sedum alfredii Hance to investigate its combined remediation effect on Pb and Cd composite contaminated soil.

Results
The results showed that resistant bacteria were able to promote enrichment of Pb and Cd in Sedum alfredii Hance and J2 (200 ml of bacterial solution) was significantly (P < 0.05) more effective than J1 (100 ml of bacterial solution). The resistant bacteria were able to alleviate the toxic effects of Pb and Cd heavy metals on Sedum alfredii Hance and promote growth while reducing rhizosphere soil pH. The resistant bacteria were able to significantly reduce the effective state of Pb and Cd in the rhizosphere soil (P < 0.05), with the greatest reduction in the effective state of Pb in treatment A (Cd7Pb100 mg/kg), where J2 was reduced by 9.98% compared to J0, and the greatest reduction in the effective state of Cd in treatment C (Cd28Pb400 mg/kg), where J2 was 43.53% lower than J0. In addition, the resistant bacteria were able to increase the exchangeable state Cd content by 0.97 to 9.85%. The resistant bacteria had a weakly promoting effect and a highly inhibitory effect on the absorption of Pb by Sedum alfredii Hance.

Conclusions
The resistant bacteria can change the rhizosphere environment and significantly improve the remediation effect of Sedum alfredii Hance on heavy metal cadmium. The role of “double-resistant” bacteria in promoting the accumulation of Cd was greater than that of Pb.
Soil and water conservation practice effects on soil physicochemical properties and crop yield in Ethiopia: review and synthesis
Authors: Jiru Endale Bekele , Wegari Habtamu Temesgen 
Published: February 2022

Abstract
Background
Land degradation is an urgent agenda that requires great effort and resources to ameliorate. It worsens soil components through disrupting ecological functions and threatens agriculture production. To overcome it, different soil and water conservation (SWC) practices have been undertaken in numerous parts of Ethiopia. This paper aims to review the effects of SWC practices on soil physicochemical properties and crop yield. Data were collected from secondary sources via a computer library using various databases based on developed criteria. The collected data were organized, categorized, and analyzed through descriptive statistics. The mean difference of selected soil physicochemical properties obtained from treated and untreated farmland was tested using paired t-test. Factors influencing crop yield on treated farmland were determined by a multiple linear regression model.

Results
SWC practices influenced the soil physicochemical properties and crop yield either positively or negatively. The mean values of available phosphorus (10.6 ppm, 8.7 ppm), total nitrogen (0.5%, 0.4%), soil pH (6.0%, 5.8%), soil organic matter (4.4%, 3.8%), and soil organic carbon (2.2%, 1.8%) were on treated and untreated farmland under physical SWC practices, respectively. Similarly, the mean values of these variables were higher on treated farmland than untreated farmland under both biological and integrated SWC practices. The mean value of bulk density was higher on untreated farmland than treated one and statistically significant under all SWC practices. Fanya juu and stone-faced soil bund constantly increased crop yield, whereas soil bund and stone bund did not.

Conclusion
Proper implementation of SWC technologies through integrating physical and biological measures will boost the effectiveness of the practice in restoring soil physicochemical properties and improving crop yield. Meanwhile, government due attention paid for land resources management in Ethiopia, whereby the annual SWC and tree planting campaign underwent for a couple of decades, entails further scientific support for its efficacy.
Mechanisms of motor symptom improvement by long-term Tai Chi training in Parkinson’s disease patients
Authors: Li Gen , Huang Pei , Cui Shi-Shuang , Tan Yu-Yan , He Ya-Chao , Shen Xin , Jiang Qin-Ying , Huang Ping , He Gui-Ying , Li Bin-Yin , Li Yu-Xin , Xu Jin , Wang Zheng , Chen Sheng-Di 
Published: February 2022

Abstract
Background
Tai Chi has been shown to improve motor symptoms in Parkinson’s disease (PD), but its long-term effects and the related mechanisms remain to be elucidated. In this study, we investigated the effects of long-term Tai Chi training on motor symptoms in PD and the underlying mechanisms.

Methods
Ninety-five early-stage PD patients were enrolled and randomly divided into Tai Chi (n = 32), brisk walking (n = 31) and no-exercise (n = 32) groups. At baseline, 6 months and 12 months during one-year intervention, all participants underwent motor symptom evaluation by Berg balance scale (BBS), Unified PD rating-scale (UPDRS), Timed Up and Go test (TUG) and 3D gait analysis, functional magnetic resonance imaging (fMRI), plasma cytokine and metabolomics analysis, and blood Huntingtin interaction protein 2 (HIP2) mRNA level analysis. Longitudinal self-changes were calculated using repeated measures ANOVA. GEE (generalized estimating equations) was used to assess factors associated with the longitudinal data of rating scales. Switch rates were used for fMRI analysis. False discovery rate correction was used for multiple correction.

Results
Participants in the Tai Chi group had better performance in BBS, UPDRS, TUG and step width. Besides, Tai Chi was advantageous over brisk walking in improving BBS and step width. The improved BBS was correlated with enhanced visual network function and downregulation of interleukin-1β. The improvements in UPDRS were associated with enhanced default mode network function, decreased L-malic acid and 3-phosphoglyceric acid, and increased adenosine and HIP2 mRNA levels. In addition, arginine biosynthesis, urea cycle, tricarboxylic acid cycle and beta oxidation of very-long-chain fatty acids were also improved by Tai Chi training.

Conclusions
Long-term Tai Chi training improves motor function, especially gait and balance, in PD. The underlying mechanisms may include enhanced brain network function, reduced inflammation, improved amino acid metabolism, energy metabolism and neurotransmitter metabolism, and decreased vulnerability to dopaminergic degeneration.
Trial registration This study has been registered at Chinese Clinical Trial Registry (Registration number: ChiCTR2000036036; Registration date: August 22, 2020).
The crewed journey to Mars and its implications for the human microbiome
Authors: Kuehnast Torben , Abbott Carmel , Pausan Manuela R. , Pearce David A. , Moissl-Eichinger Christine , Mahnert Alexander 
Published: February 2022

AbstractA human spaceflight to Mars is scheduled for the next decade. In preparation for this unmatched endeavor, a plethora of challenges must be faced prior to the actual journey to Mars. Mission success will depend on the health of its crew and its working capacity. Hence, the journey to Mars will also depend on the microbiome and its far-reaching effects on individual crew health, the spaceship’s integrity, and food supply. As human beings rely on their microbiome, these microbes are essential and should be managed to ensure their beneficial effects outweigh potential risks. In this commentary, we focus on the current state of knowledge regarding a healthy (gut) microbiome of space travelers based on research from the International Space Station and simulation experiments on Earth. We further indicate essential knowledge gaps of microbial conditions during long-term space missions in isolated confined space habitats or outposts and give detailed recommendations for microbial monitoring during pre-flight, in-flight, and post-flight. Finally, the conclusion outlines open questions and aspects of space traveler’s health beyond the scope of this commentary.