bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reconstruction and analysis of a large-scale binary Ras-effector signaling network
Authors: Catozzi Simona , Ternet Camille , Gourrege Alize , Wynne Kieran , Oliviero Giorgio , Kiel Christina 
Published: March 2022

AbstractBackgroundRas is a key cellular signaling hub that controls numerous cell fates via multiple downstream effector pathways. While pathways downstream of effectors such as Raf, PI3K and RalGDS are extensively described in the literature, how other effectors signal downstream of Ras is often still enigmatic.MethodsA comprehensive and unbiased Ras-effector network was reconstructed downstream of 43 effector proteins (converging onto 12 effector classes) using public pathway and protein–protein interaction (PPI) databases. The output is an oriented graph of pairwise interactions defining a 3-layer signaling network downstream of Ras. The 2290 proteins comprising the network were studied for their implication in signaling crosstalk and feedbacks, their subcellular localizations, and their cellular functions.ResultsThe final Ras-effector network consists of 2290 proteins that are connected via 19,080 binary PPIs, increasingly distributed across the downstream layers, with 441 PPIs in layer 1, 1660 in layer 2, and 16,979 in layer 3. We identified a high level of crosstalk among proteins of the 12 effector classes. A class-specific Ras sub-network was generated in CellDesigner (.xml file) and a functional enrichment analysis thereof shows that 58% of the processes have previously been associated to a respective effector pathway, with the remaining providing insights into novel and unexplored functions of specific effector pathways.ConclusionsOur large-scale and cell general Ras-effector network is a crucial steppingstone towards defining the network boundaries. It constitutes a ‘reference interactome’ and can be contextualized for specific conditions, e.g. different cell types or biopsy material obtained from cancer patients. Further, it can serve as a basis for elucidating systems properties, such as input–output relationships, crosstalk, and pathway redundancy.Graphical abstract
Cementless modular total hip arthroplasty with subtrochanteric transverse shortening osteotomy for high hip dislocations
Authors: Sukur Erhan , Senel Ahmet , Ozdemir Ugur , Akman Yunus Emre , Azboy İbrahim , Ozturkmen Yusuf 
Published: March 2022

AbstractBackgroundPerforming a total hip arthroplasty for a high hip dislocation is technically demanding and presents several challenges, with appropriate evaluation of the bone morphology of the hip and proper implant selection being critical for successful outcomes.ObjectiveThe purpose of our study was to evaluate the clinical and radiographic outcomes of cementless modular total hip arthroplasty for the treatment of high hip dislocations with sub-trochanteric transverse shortening osteotomy.MethodsSixty-eight hips with a high hip dislocation, were treated using a sub-trochanteric transverse shortening osteotomy and cementless modular total hip arthroplasty, retrospectively reviewed. Hip function was assessed using the Harris hip score, with hip abduction strength evaluated using the Trendelenburg test. Radiographic assessment included the measurement of leg length discrepancy, identification of implant loosening, localization of the hip center, and union at the osteotomy site.ResultsThe mean follow-up period was 12.9 (range 5.2–16.8) years. The mean Harris hip score improved from a pre-operative score of 48.6 ± 3.6 to 82.4 ± 4.2 (p < 0.05). The hip was within the true acetabulum in all patients, postoperatively. Osteotomy union was achieved in 67 of the 68 hips (98.5%) in a mean latency of 12.5 ± 0.6 weeks. The mean length of femoral shortening was 66.5 ± 4.5 mm, with a mean pull-down length of the proximal part of 35.5 ± 3.5 mm.ConclusionFor the treatment of high hip dislocations with satisfactory clinical outcomes, the modular stem offers an adjustable anteversion angle to restore sufficient rotational stability and the transverse osteotomy provides sufficient compression pressure across the osteotomy site to facilitate union.Trial registrationIt was a retrospective study and approved by Istanbul Research and Training Hospital institutional Ethics Review Board (772-05/02/2016).
Properties of tests for knee joint threshold to detect passive motion following anterior cruciate ligament injury: a systematic review and meta-analysis
Authors: Strong Andrew , Arumugam Ashokan , Tengman Eva , Röijezon Ulrik , Häger Charlotte K. 
Published: March 2022

Abstract
Background
Threshold to detect passive motion (TTDPM) tests of the knee joint are commonly implemented among individuals with anterior cruciate ligament (ACL) injury to assess proprioceptive acuity. Their psychometric properties (PMPs), i.e. reliability, validity and responsiveness, are however unclear. This systematic review aimed to establish the PMPs of existing knee joint TTDPM tests among individuals with ACL injury.

Methods
The databases PubMed, AMED, CINAHL, SPORTDiscus, Web of Science, Scopus, CENTRAL and ProQuest were searched to identify studies that assessed the properties of knee joint TTDPM tests in individuals with ACL injury. The risk of bias for each included study was assessed at the outcome level for each test. Overall quality and levels of evidence for each property were rated according to established criteria. Meta-analyses with mean differences were conducted using random-effects models when adequate data were available.

Results
Fifty-one studies covering 108 TTDPM tests and 1632 individuals with unilateral ACL injury were included. A moderate-to-strong level of evidence indicated insufficient quality for all of the following: convergent validity, known-groups validity, discriminative validity, responsiveness between subgroups, and responsiveness to intervention. Subgroup meta-analyses for known-groups validity did however find that a starting angle of 15° resulted in significantly worse TTDPM for knees with ACL injury compared to those of asymptomatic persons (mean difference 0.28°; 95% CI 0.03 to 0.53; P = 0.03), albeit based on only three studies. Due to the lack of evidence, it was not possible to estimate the quality of reliability, measurement error, and criterion validity, nor responsiveness from a criterion and construct approach.

Conclusions
Among persons with ACL injury, existing tests of knee joint TTDPM lack either sufficient quality or evidence for their reliability, validity and responsiveness. Significantly worse thresholds for ACL-injured knees compared to those of asymptomatic controls from a 15° starting angle and trends towards significance for some validity measures nevertheless encourage the development of standardised tests. Further research investigating the influence of modifiable test components (e.g. starting angle and motion direction) on the PMPs of knee joint TTDPM tests following ACL injury is warranted.
One year of COVID-19: infection rates and symptoms in patients with inherited metabolic diseases followed by MetabERN
Authors: Paneghetti Laura , Bellettato Cinzia Maria , Sechi Annalisa , Stepien Karolina M. , Scarpa Maurizio 
Published: March 2022

Abstract
Background
Since the beginning of the COVID-19 pandemic, MetabERN has been monitoring the SARS-CoV-2 infection rates within its metabolic community. To gather data on the total number of cases and the severity of symptoms among IMD patients one year into the pandemic, an online survey was distributed among all MetabERN healthcare providers (HCP). Epidemiological analysis was performed by integrating the survey’s data with the MetabERN database.

Results
Survey’s respondents reported a total of 452 cases of COVID-19 among their IMD patients (213 paediatric and 239 adults). Considering the total number of patients followed by the respondents (n = 26,347), the registered prevalence of COVID-19 in the IMD population was of 1716 × 100,000. Italy emerged as the most affected country (25.4% of cases), followed by the United Kingdom (14.2% of cases). Most of the paediatric cases of COVID-19 displayed no or mild symptoms during the disease: 34% of HCP reported having asymptomatic patients in 75–100% of cases, while 37.5% reported mild symptoms in about a quarter of their patients. Similarly to paediatric cases, most adult IMD patients with COVID-19 were asymptomatic or had mild symptoms: about one third of respondents reported 75–100% asymptomatic patients and about 65% of HCP had between 0 and 50% of patients with mild symptoms. The majority of the respondents reported no deaths due to COVID-19 in adult and paediatric patients with IMDs.

Conclusions
Most of MetabERN’s IMD patients who got COVID-19 during the first year of the pandemic had mild symptoms and a positive outcome of the disease. However, fatal events were recorded in paediatric patients; this, together with the lack of information on the long-term effects of COVID-19 in IMDs, call for caution in the metabolic population.
Predicting molecular initiating events using chemical target annotations and gene expression
Authors: Bundy Joseph L. , Judson Richard , Williams Antony J. , Grulke Chris , Shah Imran , Everett Logan J. 
Published: March 2022

Abstract
Background
The advent of high-throughput transcriptomic screening technologies has resulted in a wealth of publicly available gene expression data associated with chemical treatments. From a regulatory perspective, data sets that cover a large chemical space and contain reference chemicals offer utility for the prediction of molecular initiating events associated with chemical exposure. Here, we integrate data from a large compendium of transcriptomic responses to chemical exposure with a comprehensive database of chemical-protein associations to train binary classifiers that predict mechanism(s) of action from transcriptomic responses. First, we linked reference chemicals present in the LINCS L1000 gene expression data collection to chemical identifiers in RefChemDB, a database of chemical-protein interactions. Next, we trained binary classifiers on MCF7 human breast cancer cell line derived gene expression profiles and chemical-protein labels using six classification algorithms to identify optimal analysis parameters. To validate classifier accuracy, we used holdout data sets, training-excluded reference chemicals, and empirical significance testing of null models derived from permuted chemical-protein associations. To identify classifiers that have variable predicting performance across training data derived from different cellular contexts, we trained a separate set of binary classifiers on the PC3 human prostate cancer cell line.

Results
We trained classifiers using expression data associated with chemical treatments linked to 51 molecular initiating events. This analysis identified and validated 9 high-performing classifiers with empirical p-values lower than 0.05 and internal accuracies ranging from 0.73 to 0.94 and holdout accuracies of 0.68 to 0.92. High-ranking predictions for training-excluded reference chemicals demonstrating that predictive accuracy extends beyond the set of chemicals used in classifier training. To explore differences in classifier performance as a function of training data cellular context, MCF7-trained classifier accuracies were compared to classifiers trained on the PC3 gene expression data for the same molecular initiating events.

Conclusions
This methodology can offer insight in prioritizing candidate perturbagens of interest for targeted screens. This approach can also help guide the selection of relevant cellular contexts for screening classes of candidate perturbagens using cell line specific model performance.
A phase III randomized trial of weight loss to reduce cancer-related fatigue among overweight and obese breast cancer patients: MEDEA Study design
Authors: Di Meglio Antonio , Martin Elise , Crane Tracy E. , Charles Cecile , Barbier Aude , Raynard Bruno , Mangin Anthony , Tredan Olivier , Bouleuc Carole , Cottu Paul H. , Vanlemmens Laurence , Segura-Djezzar Carine , Lesur Anne , Pistilli Barbara , Joly Florence , Ginsbourger Thomas , Coquet Bernadette , Pauporte Iris , Jacob Guillemette , Sirven Aude , Bonastre Julia , Ligibel Jennifer A. , Michiels Stefan , Vaz-Luis Ines 
Published: March 2022

Abstract
Background
Elevated body mass index (BMI) represents a risk factor for cancer-related fatigue (CRF). Weight loss interventions are feasible and safe in cancer survivors, leading to improved cardio-metabolic and quality of life (QOL) outcomes and modulating inflammatory biomarkers. Randomized data are lacking showing that a lifestyle intervention aimed at weight loss, combining improved diet, exercise, and motivational counseling, reduces CRF. Motivating to Exercise and Diet, and Educating to healthy behaviors After breast cancer (MEDEA) is a multi-center, randomized controlled trial evaluating the impact of weight loss on CRF in overweight or obese survivors of breast cancer. Herein, we described the MEDEA methodology.

Methods
Patients (N = 220) with stage I–III breast cancer and BMI ≥ 25 kg/m2, within 12 months of primary treatment, and able to walk ≥ 400 m are eligible to enroll. Participants are randomized 1:1 to health education alone vs. a personalized telephone-based weight loss intervention plus health education. Both arms receive a health education program focusing on healthy living. Patients in the intervention arm are paired with an individual lifestyle coach, who delivers the intervention through 24 semi-structured telephone calls over 1 year. Intervention goals include weight loss ≥ 10% of baseline, caloric restriction of 500–1000 Kcal/day, and increased physical activity (PA) to 150 (initial phase) and 225–300 min/week (maintenance phase). The intervention is based on the social cognitive theory and is adapted from the Breast Cancer Weight Loss trial (BWEL, A011401). The primary endpoint is the difference in self-reported CRF (EORTC QLQ-C30) between arms. Secondary endpoints include the following: QOL (EORTC QLQ-C30, -BR45, -FA12), anxiety, and depression (HADS); weight and BMI, dietary habits and quality, PA, and sleep; health care costs (hospital-admissions, all-drug consumption, sick leaves) and cost-effectiveness (cost per quality-adjusted life-year); and patient motivation and satisfaction. The primary analysis of MEDEA will compare self-reported CRF at 12 months post-randomization between arms, with 80.0% power (two-sided α = 0.05) to detect a standardized effect size of 0.40.

Discussion
MEDEA will test the impact of a weight loss intervention on CRF among overweight or obese BC survivors, potentially providing additional management strategies and contributing to establish weight loss support as a new standard of clinical care.

Trial registration
ClinicalTrials.govNCT04304924
Immediate effects of hybrid assistive limb gait training on lower limb function in a chronic myelopathy patient with postoperative late neurological deterioration
Authors: Kubota Shigeki , Kadone Hideki , Shimizu Yukiyo , Koda Masao , Takahashi Hiroshi , Miura Kousei , Eto Fumihiko , Furuya Takeo , Sankai Yoshiyuki , Yamazaki Masashi 
Published: March 2022

Abstract
Objective
The Hybrid Assistive Limb (HAL) has recently been used to treat movement disorders. Although studies have shown its effectiveness for chronic myelopathy, the immediate effects of HAL gait training on lower limb function have not been clarified. We conducted HAL gait training and examined its immediate effects on a 69-year-old man with re-deterioration of myelopathy in the chronic phase after surgery for compression myelopathy. The HAL intervention was performed every 4 weeks for 10 total sessions. Immediately before and after each session, we analyzed the patient’s walking ability using the 10-m walk test. In the 4th HAL session, the gastrocnemius muscle activity was measured bilaterally using a synchronized motion capture-electromyogram system.

Results
The training effects became steady after the 2nd session. In sessions 2–10, the step length increased from 0.56 to 0.63 m (mean: 0.031 m) immediately after HAL training. The motion capture-electromyogram analyses showed that considerable amounts of gastrocnemius muscle activity were detected during the stance and swing phases before HAL training. During and immediately after HAL training, gastrocnemius activity during the swing phase was diminished. HAL gait training has an immediate effect for inducing a normal gait pattern with less spasticity in those with chronic myelopathy.
Effect of small extracellular vesicles derived from IL-10-overexpressing mesenchymal stem cells on experimental autoimmune uveitis
Authors: Li Yongtao , Ren Xinjun , Zhang Zhihui , Duan Yanan , Li Huan , Chen Shuang , Shao Hui , Li Xiaorong , Zhang Xiaomin 
Published: March 2022

Abstract
Background
Autoimmune uveitis is a sight-threatening intraocular inflammation mainly caused by immune dysregulation. The development of safe and effective therapeutic approaches is urgently needed. Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have been demonstrated to inhibit autoimmune responses; however, the immunosuppressive effect of MSC-sEVs is too weak for clinical transfer. In the current study, we investigated the therapeutic effect of IL-10-overexpressing MSC-sEVs (sEV-IL10) on experimental autoimmune uveitis (EAU) and studied the underlying mechanism.

Methods
Mice were randomly grouped and received a single tail vein injection of different sEVs (50 μg) or PBS on day 11 post-immunization. The clinical and histological scores were graded, and the percentage of T helper cell was measured. To investigate the effect of sEVs on the proliferation of T-cells and the differentiation of Th1, Th17 and Treg cells, T-cells were cocultured with sEVs under the corresponding culture conditions. After labeled with PKH-26, sEVs were traced both in vivo and in vitro.

Results
Compared with normal or vector sEV-treated groups, mice in the sEV-IL10-treated group had lower clinical and histological scores with lower percentages of Th1 and Th17 cells in the eyes and higher percentages of Treg cells in the spleen and draining lymph nodes (LN). Furthermore, sEV-IL10 enhanced the suppressive effect of MSC-sEVs on the proliferation of T-cells and differentiation of Th1 and Th17 cells, whereas upregulated the differentiation of Treg cells. Both in vivo and in vitro experiments demonstrated that MSC-sEVs were rapidly enriched in target tissues and internalized by T-cells.

Conclusion
These results suggested that sEV-IL10 effectively ameliorates EAU by regulating the proliferation and differentiation of T-cells, indicating sEVs as a potential novel therapy for autoimmune uveitis or other autoimmune diseases.
Parked on the verge: vocational rehabilitation of long-term unemployed citizens – a mixed methods study
Authors: Andersen Lotte Nygaard , Stochkendahl Mette Jensen , Roessler Kirsten K. 
Published: March 2022

Abstract
Background
Vocational rehabilitation programs (VRP) developing and improving work ability are used in Denmark to assist long-term unemployed citizens with complex problems. The aims of this study were to (1) describe VRP-participants in relation to general health, well-being, work ability and self-efficacy at baseline and one-year follow-up, (2) obtain an understanding of VRP-participants’ personal development towards improving work ability, and (3) explore VRP-participants’ hopes and thoughts about their future.

Methods
In a mixed methods approach, data from a longitudinal survey and semi-structured interviews were collected. In the quantitative longitudinal survey, all participants completed paper questionnaires at baseline and one-year follow-up. For the qualitative semi-structured interviews, VRP participants were recruited with a maximum variation sampling strategy through VRP coordinators and personal contact. Data were analysed by descriptive statistics and systematic text condensation. Following analysis, data were merged and presented in combination according to identified themes.

Results
At baseline and one-year follow-up 146 (response rate 34%) and 74 participants (response rate 52%) respectively, responded to the questionnaire. Seven participants were interviewed. The analysis revealed four themes: 1) Individual explanations of life situation and health; 2) Finding the path; 3) Work as giving meaning to life; 4) Hope for the future. Despite self-reported scores indicating poor general health, lack of well-being, low work ability and low self-efficacy, VRP-activities seemed to have assisted participants in finding meaning in life. VRP-components that may be drivers of successful recovery processes were identified.

Conclusions
VRP-participants experienced life situations that include multifactorial burdens, and low levels of general health, well-being, work ability, and self-efficacy at baseline and 1 year later. From the outset, most did not have a clear goal of employment, but over time, new goals were set as realistic opportunities for re-developing their work ability were explored. Successful core components of VRP were individually tailored programs and support, development of new relationships, and accommodated flexible internships and jobs.

Trial registration
ClinicalTrials.gov Identifier: NCT02641704, date of registration December 29, 2015.
An investigation into the pharmaceutical advertising in Iranian medical journals
Authors: Yousefi Nazila , Sharif Zahra , Chahian Fateme , Mombeini Tayebe , Peiravian Farzad 
Published: March 2022

Abstract
Background
Pharmaceutical advertising is not only considered a key factor in the successful launch of pharmaceutical products, but is also an important source of public health information with a significant impact on consumer choice and behavior. Nowadays, advertising has become the broadest dissemination channel for various products, including medicines, which may ultimately lead to the generalization of self-treatment or mistreatment. Improper drug promotion can exacerbate unhealthy outcomes by making false or misleading claims, using inferior references, and failing to meet international standards. This study aimed to examine the requirements for pharmaceutical advertising from regulatory perspective and the compliance of Iranian pharmaceutical advertisements to related standards and guidelines. It is limited to print advertisements in Iranian national medical journals and magazines.

Method
The present study is a descriptive–analytical study using bibliometric methods. As a first step, a comprehensive review of the national and international regulations on drug advertising was conducted and a comparison of different regulations was provided. In the second step, a checklist was created to evaluate the compliance of drug advertising with the extracted regulations.

Result
The results of the present study show that the claims made in Iranian drug advertisements are 29.10% valid, 27.67% exaggerated, 23.10% controversial, 12.62% misleading, and 6.8% invalid. In general, we found that most medical advertisements in Iranian journals and magazines comply with national laws and regulations. However, many international requirements are not met in these advertisements.

Conclusions
Although we found that printed medical advertisements in Iran are roughly compliant with national regulations, there is still a long way to achieve full compliance. Monitoring processes should be improved and clearly defined penalties should be set to avoid misleading claims and their likely health consequences. It is very important in Iran to update the existing rules and regulations for medical advertisements according to international guidelines. More careful monitoring of the content of advertising and the accuracy of claims are also needed.