bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enriched enrollment randomized double-blind placebo-controlled cross-over trial with phenytoin cream in painful chronic idiopathic axonal polyneuropathy (EPHENE): a study protocol
Authors: Kopsky David J. , van Eijk Ruben P. A. , Warendorf Janna K. , Keppel Hesselink Jan M. , Notermans Nicolette C. , Vrancken Alexander F. J. E. 
Published: October 2022

Abstract
Background
Patients with chronic idiopathic axonal polyneuropathy (CIAP) can have neuropathic pain that significantly impacts quality of life. Oral neuropathic pain medication often has insufficient pain relief and side effects. Topical phenytoin cream could circumvent these limitations.
The primary objectives of this trial are to evaluate (1) efficacy in pain reduction and (2) safety of phenytoin cream in patients with painful CIAP. The main secondary objective is to explore the usefulness of a double-blind placebo-controlled response test (DOBRET) to identify responders to sustained pain relief with phenytoin cream.

Methods
This 6-week, enriched enrollment randomized double-blind, placebo-controlled triple cross-over trial compares phenytoin 20%, 10% and placebo cream in 48 participants with painful CIAP. Enriched enrollment is based on a positive DOBRET in 48 participants who experience within 30 minutes ≥2 points pain reduction on the 11-point numerical rating scale (NRS) in the phenytoin 10% cream applied area and ≥1 point difference in pain reduction on the NRS between phenytoin 10% and placebo cream applied area, in favour of the former. To explore whether DOBRET has predictive value for sustained pain relief, 24 DOBRET-negative participants will be included.
An open-label extension phase is offered with phenytoin 20% cream for up to one year, to study long-term safety.
The main inclusion criteria are a diagnosis of CIAP and symmetrical neuropathic pain with a mean weekly pain score of ≥4 and <10 on the NRS.
The primary outcome is the mean difference between phenytoin 20% versus placebo cream in 7-day average pain intensity, as measured by the NRS, over week 2 in DOBRET positive participants.
Key secondary outcomes include the mean difference in pain intensity between phenytoin 10% and phenytoin 20% cream, and between phenytoin 10% and placebo cream. Furthermore, differences between the 3 interventions will be evaluated on the Neuropathic Pain Symptom Inventory, EuroQol EQ5-5D-5L, and evaluation of adverse events.

Discussion
This study will provide evidence on the efficacy and safety of phenytoin cream in patients with painful CIAP and will give insight into the usefulness of DOBRET as a way of personalized medicine to identify responders to sustained pain relief with phenytoin cream.

Trial registration
ClinicalTrials.gov NCT04647877. Registered on 1 December 2020.
Analgesic efficacy and safety of nalbuphine versus morphine for perioperative tumor ablation: a randomized, controlled, multicenter trial
Authors: Xue Youhua , Huang Zhengli , Cheng Bingwei , Sun Jie , Zhu Haidong , Tang Yuting , Wang Xiaoyan 
Published: October 2022

Abstract
Background
The study will compare the efficacy and safety of nalbuphine hydrochloride injection and morphine hydrochloride injection for perioperative analgesia in tumor ablation and the differences between the two groups regarding duration of surgery, average daily dose, patient satisfaction with analgesia, quality of life, and other indicators. Furthermore, it will evaluate the clinical application of nalbuphine and morphine for perioperative analgesia in ablation surgery and provides important reference and guidance for clinical practice.

Methods
This is a randomized controlled study. Patients who were diagnosed by clinicians and required tumor ablation are enrolled and randomized to the experimental groups. In the test group, nalbuphine 80 mg + 0.9% normal saline (72 ml) is set in the patient-controlled analgesia pump, which is connected 15 min before ablation under electrocardiogram monitoring and surgery is performed immediately. The doses are as follows: initial,: 0.15 ml/kg,; background:, 0.5 ml/h,; compression:, 2 ml,; and lockout time:, 15 min. If the numeric rating scale is ≥ 4 points, the drug is administered by compression. The control group receives similar treatment under similar conditions as the test group except morphine (80 mg) is administered instead of nalbuphine (80 mg). The primary endpoints are the effective rate of analgesia and the incidence of adverse reactions (nausea and vomiting, dizziness, itching, constipation, hypoxemia, and urinary retention); the secondary endpoints are pain intensity, satisfaction with analgesia, duration of surgery, postoperative hospital stay, average daily dose, uninterrupted completion rate of surgery without complaints of pain, quality of life assessment, and vital signs.

Discussion
This study, to the best of our knowledge, is the first randomized controlled trial of nalbuphine patient-controlled analgesia in ablation surgery.

Trial registration
U.S. Clinical Trials Network Registration No.: NCT05073744. Registered on 11 October, 2021.
Efficacy of Emotionally Focused Therapy among Spanish-speaking couples: study protocol of a randomized clinical trial in Argentina, Costa Rica, Guatemala, Mexico, and Spain
Authors: Rodríguez-Gonzalez Martiño , Anderson Shayne , Osorio Alfonso , Lafontaine Marie-France , Greenman Paul S. , Calatrava María , Andrade Dania , Lybbert Ragan , Martínez-Diaz Pilar , Steffen Patrick , de Irala Jokin , Sandberg Jonathan 
Published: October 2022

Abstract
Background
Couple relationship distress is common and associated with poor physical, psychological, and relational outcomes for both partners. Emotionally Focused Therapy for couples (EFT) is a short-term structured approach based on attachment theory that integrates a humanistic, experiential approach to restructuring emotional experience and a systemic structural approach to restructuring interactions. This model has been shown to be an effective treatment for couple distress. The supporting research, however, has only been conducted with English-speaking couples. Despite Spanish being the second-most spoken language and meaningful cultural differences between English- and Spanish-speaking countries, the efficacy of EFT has not been examined in this cultural context. This study will examine the efficacy of EFT in this particular context and advance the understanding of potential mechanisms of change.

Methods
We will use a multicenter randomized wait-list controlled design to examine the efficacy of EFT in a Spanish-speaking sample of moderately distressed couples. One hundred forty individuals in 70 couples in Argentina, Costa Rica, Guatemala, Mexico, and Spain will be randomly assigned to receive 19–21 sessions of EFT or be placed on a waitlist. Outcomes on a range of relational and individual mental health variables will be assessed prior to random assignment, throughout treatment, and at the conclusion of treatment. Primary outcomes will include dyadic adjustment, couple satisfaction, and attachment. Secondary variables, such as loneliness, parenting, affective communication, and sexual satisfaction, will be included as potential mediators of the treatment effect. Couples in the treatment group will also be assessed at 3-, 6-, 12-, 18-, and 24-month follow-ups. Process variables such as the therapeutic alliance will also be assessed routinely in couples assigned to the treatment group. Couples in the waitlist will receive a psycho-educational program based on EFT after completing the study.

Discussion
This study will be the first RCT of Emotionally Focused Therapy in a Spanish-speaking context. The results of the study will inform researchers interested in whether treatments developed and tested in the USA and Canada can be effective in differing cultural contexts. It may also point researchers and clinicians to areas where cultural adaptation is needed to improve efficacy.

Trial registration
ClinicalTrials.gov NCT04277325. Registered on February 20, 2020
Societal drivers of human echinococcosis in China
Authors: Wang Li-Ying , Qin Min , Gavotte Laurent , Wu Wei-Ping , Cheng Xixi , Lei Jia-Xi , Yan Jun , Frutos Roger 
Published: October 2022

Abstract
Background
Echinococcosis is a parasitic zoonotic disease that threatens human health and economic development. In China, 370 counties are endemic for echinococcosis. Qinghai-Tibet Plateau has the most patients and people at risk. Therefore, analyzing the societal factors related to susceptibility to the disease is critical for efficient prevention and control of echinococcosis.

Methods
The demographic characteristics and lifestyle of echinococcosis cases were clustered using K-means cluster analysis to determine the main factors of risk of echinococcosis.

Results
Middle-aged and young people as well as those with a low education level and herdsmen are at risk of contracting echinococcosis. Nomadism, domestic and feral dogs in the surrounding environment, and drinking heavily polluted natural surface water are the main behavioral risk factors. The cystic echinococcosis (CE) and alveolar echinococcosis (AE) cluster analysis focused on female, middle-aged, and young people, winter settlement and summer nomadism, and domestic and feral dogs in the surrounding environment. There were significant differences in lifestyle between Qinghai-Tibet Plateau cases and non-Qinghai-Tibet-Plateau cases.

Conclusion
According to the distribution of cases and CE and AE, this study identified the factors of risk of echinococcosis in the Qinghai-Tibet Plateau and non-Qinghai-Tibet Plateau. Adapted control techniques appropriate for the various epidemic areas should be established to serve as a reference for echinococcosis prevention.

Graphical Abstract
Feasibility of point of care testing for prevention and management of breast cancer therapy associated comorbidities in 6 African countries: short communication
Authors: Milambo Jean Paul Muambngu , Ndirangu James , Nyasulu Peter S , Akudugu John M 
Published: October 2022

Abstract
Objective:
Obesity and mediators of inflammation have been identified as the most important risk and predictive factors in postmenopausal breast cancer (BC) survivors using aromatase inhibitors (AIs). This study was conducted to assess the impact of point of care technology (PCOT) as part of pathology supported genetic testing (PSGT) to prevent BC therapy-associated comorbidities in African settings.

Results
The study revealed that high sensitivity C-reactive protein (hs-CRP) and body mass index (BMI) are predictors of cardiovascular (CVD) related adverse events in obese postmenopausal patients subjected to AIs. There were statistically significant variations in total body fat (TBF), weight, hs-CRP, body mass index (BMI), homocysteine, ferritin, and calcium between baseline and after 24 months of follow-up. The above inflammatory markers can be incorporated in pathology supported genetic testing (PSGT) using HyBeacon® probe technology at POC for prediction and management of AI-associated adverse events among postmenopausal breast cancer survivors and associated comorbidities. The barriers for implementation of POCT application among six African countries for diagnosis of breast cancer were documented as insufficient of BC diagnosis and management capacity at different levels of health system.
Reliability and validity of the Japanese version of the weight bias internalization scale
Authors: Endo Shota , Kasuga Hideaki , Yusuke Masuishi , Hidaka Tomoo , Kakamu Takeyasu , Fukushima Tetsuhito 
Published: October 2022

Abstract
Objective
The weight bias internalization scale (WBIS) is widely used in several languages. However, there is no Japanese version of the WBIS. The purpose of this study is to develop a Japanese version of the WBIS and to verify its reliability and validity. We translated the original version of the WBIS and had approval from the scale developer. Adults who perceived themselves to be obese completed online baseline survey (N = 285) and two-week follow-up survey (N = 100). We used the Japanese WBIS and scales for obesity-related quality of life, self-esteem, self-efficacy, and depression. We calculated Cronbach’s alpha and intra-class correlation coefficient (ICC) to assess reliability of the WBIS and conducted confirmatory factor analysis (CFA) and correlation analysis to assess its validity.

Results
Cronbach’s alpha was 0.91 at baseline and 0.92 at follow-up, and the ICC was 0.87. CFA showed that a one-factor model demonstrated an acceptable fit (χ2 (44) = 158.6, CFI = 0.93, RMSEA = 0.096, SRMR = 0.051), similar to the original version. As we had hypothesized, overall, the Japanese version of the WBIS was significantly correlated with obesity-related quality of life, self-esteem, self-efficacy, and depression. These results confirmed its adequate reliability and validity.
Delayed pharyngocutaneous fistula caused by molecular targeted therapy: a case report
Authors: Matsuo Mioko , Hashimoto Kazuki , Jiromaru Rina , Nakagawa Takashi 
Published: October 2022

Abstract
Background
Molecular-targeted agents used as a treatment for cancer can cause some rare and serious adverse events such as, delayed wound healing. Depending on the anticancer drug used, temporary withdrawal may be recommended before and after surgery to avoid complications. Once a surgical incision has healed and closed completely, wounds rarely open because of the initiation of molecular targeted therapy several months to years after surgery. Here, we aimed to describe a rare complication of pharyngocutaneous fistula in two patients that was thought to be caused by molecular targeted therapy.

Case presentation
Case 1 involved a 64-year-old asian man who developed a delayed pharyngocutaneous fistula 3 months after total laryngectomy for laryngeal cancer. Ramucirumab, a vascular endothelial growth factor receptor inhibitor used for recurrent gastric cancer, was speculated to be involved. Case 2 involved a 71-year-old japanese man who developed a delayed pharyngocutaneous fistula 2 years and 1 month after total pharyngeal laryngectomy for pharyngeal cancer. It was speculated that imatinib, a platelet-derived growth factor receptor alpha inhibitor used for chronic myeloid leukemia, was involved.

Conclusions
Although the incidence of late drug-induced anastomotic leakage is very low, when it occurs, it makes oral intake impossible for an extended period and interferes with the appropriate cancer treatment. In this report, we demonstrate the details of these two patients with such a rare complication, which may help accumulate essential data on this topic.
Mesenchymal stem cell aggregation mediated by integrin α4/VCAM-1 after intrathecal transplantation in MCAO rats
Authors: Ran Ye , Dong Yankai , Li Yuejiao , Xie Jundong , Zeng Shubin , Liang Chuanlei , Dai Wei , Tang Wenjing , Wu Yaojiong , Yu Shengyuan 
Published: October 2022

Abstract
Background
Mesenchymal stem cells (MSCs) have shown immense therapeutic potential for various brain diseases. Intrathecal administration of MSCs may enhance their recruitment to lesions in the central nervous system, but any impact on cerebrospinal fluid (CSF) flow remains unclear.

Methods
Rats with or without middle cerebral artery occlusion (MCAO) received intrathecal injections of 2D cultured MSCs, 3D cultured MSCs or an equal volume of artificial cerebrospinal fluid (ACSF). Ventricle volume was assessed by MRI on Days 2 and 14 post-MCAO surgery. A beam walking test was used to assess fine motor coordination and balance. Aggregation of MSCs was evaluated in CSF and frozen brain tissue. Differential expression of cell adhesion molecules was evaluated by RNA-Seq, flow cytometry and immunofluorescence analyses. The influence of VCAM-1 blockade in mediating the aggregation of 2D MSCs was investigated in vitro by counting cells that passed through a strainer and in vivo by evaluating ventricular dilation.

Results
MSC expanded in 2D culture formed aggregates in the CSF and caused ventricular enlargement in both MCAO and normal rats. Aggregates were associated with impaired motor function. 2D MSCs expressed higher levels of integrin α4 and VCAM-1 than 3D MSCs. Blockade of VCAM-1 in 2D MSCs reduced their aggregation in vitro and reduced lateral ventricular enlargement after intrathecal infusion. 3D MSCs exhibited lower cell aggregation and reduced cerebral ventricular dilation after intrathecal transplantation

Conclusions
The aggregation of 2D MSCs, mediated by the interaction of integrin α4 and VCAM-1, is a potential risk for obstruction of CSF flow after intrathecal transplantation.
Tumour-associated macrophages enhance breast cancer malignancy via inducing ZEB1-mediated DNMT1 transcriptional activation
Authors: Li Zhongwei , Wang Pengfei , Cui Wenjie , Yong Hongmei , Wang Diandian , Zhao Tiesuo , Wang Wenwen , Shi Ming , Zheng Junnian , Bai Jin 
Published: October 2022

Abstract
Background
DNMT1 has been shown to be highly expressed in a variety of cancers, including breast cancer. However, the mechanism is not very clear. Therefore, we aim to reveal the mechanism of DNMT1 highly express in breast cancer. And we also want to explore the role of DNMT1 in tumour microenvironment promoting breast cancer progression.

Results
In this study, we demonstrate that DNMT1 is overexpressed in breast cancer and that DNMT1 promotes breast cancer tumorigenesis and metastasis. We discovered that ZEB1 activates DNMT1 expression in breast cancer cells by recruiting P300 binding to the DNMT1 promoter and increasing its acetylation. Moreover, we revealed that tumour-associated macrophages (TAMs) increase DNMT1 expression in breast cancer cells via the IL-6-pSTAT3-ZEB1-DNMT1 axis in the tumour microenvironment. DNMT1 is required for TAM-mediated breast cancer cell migration. In addition, we confirmed that there were positive correlations among CD163 (TAM marker) expression, ZEB1 expression and DNMT1 expression in breast cancer patient tissues.

Conclusions
Our study indicates that DNMT1 is necessary for TAM-mediated breast cancer metastasis. Decitabine (DAC), as a specific DNA methylation inhibitor and FDA-approved drug, is a bona fide drug for breast cancer treatment.
Fidelity varies in the symbiosis between a gutless marine worm and its microbial consortium
Authors: Sato Yui , Wippler Juliane , Wentrup Cecilia , Ansorge Rebecca , Sadowski Miriam , Gruber-Vodicka Harald , Dubilier Nicole , Kleiner Manuel 
Published: October 2022

Abstract
Background
Many animals live in intimate associations with a species-rich microbiome. A key factor in maintaining these beneficial associations is fidelity, defined as the stability of associations between hosts and their microbiota over multiple host generations. Fidelity has been well studied in terrestrial hosts, particularly insects, over longer macroevolutionary time. In contrast, little is known about fidelity in marine animals with species-rich microbiomes at short microevolutionary time scales, that is at the level of a single host population. Given that natural selection acts most directly on local populations, studies of microevolutionary partner fidelity are important for revealing the ecological and evolutionary processes that drive intimate beneficial associations within animal species.

Results
In this study on the obligate symbiosis between the gutless marine annelid Olavius algarvensis and its consortium of seven co-occurring bacterial symbionts, we show that partner fidelity varies across symbiont species from strict to absent over short microevolutionary time. Using a low-coverage sequencing approach that has not yet been applied to microbial community analyses, we analysed the metagenomes of 80 O. algarvensis individuals from the Mediterranean and compared host mitochondrial and symbiont phylogenies based on single-nucleotide polymorphisms across genomes. Fidelity was highest for the two chemoautotrophic, sulphur-oxidizing symbionts that dominated the microbial consortium of all O. algarvensis individuals. In contrast, fidelity was only intermediate to absent in the sulphate-reducing and spirochaetal symbionts with lower abundance. These differences in fidelity are likely driven by both selective and stochastic forces acting on the consistency with which symbionts are vertically transmitted.

Conclusions
We hypothesize that variable degrees of fidelity are advantageous for O. algarvensis by allowing the faithful transmission of their nutritionally most important symbionts and flexibility in the acquisition of other symbionts that promote ecological plasticity in the acquisition of environmental resources.
Biallelic mutations of TTC12 and TTC21B were identified in Chinese patients with multisystem ciliopathy syndromes
Authors: Chen Weicheng , Wang Feifei , Zeng Weijia , Zhang Xinyan , Shen Libing , Zhang Yuan , Zhou Xiangyu 
Published: October 2022

Abstract
Background
Abnormalities in cilia ultrastructure and function lead to a range of human phenotypes termed ciliopathies. Many tetratricopeptide repeat domain (TTC) family members have been reported to play critical roles in cilium organization and function.

Results
Here, we describe five unrelated family trios with multisystem ciliopathy syndromes, including situs abnormality, complex congenital heart disease, nephronophthisis or neonatal cholestasis. Through whole-exome sequencing and Sanger sequencing confirmation, we identified compound heterozygous mutations of TTC12 and TTC21B in six affected individuals of Chinese origin. These nonsynonymous mutations affected highly conserved residues and were consistently predicted to be pathogenic. Furthermore, ex vivo cDNA amplification demonstrated that homozygous c.1464 + 2 T > C of TTC12 would cause a whole exon 16 skipping. Both mRNA and protein levels of TTC12 were significantly downregulated in the cells derived from the patient carrying TTC12 mutation c.1464 + 2 T > C by real-time qPCR and immunofluorescence assays when compared with two healthy controls. Transmission electron microscopy analysis further identified ultrastructural defects of the inner dynein arms in this patient. Finally, the effect of TTC12 deficiency on cardiac LR patterning was recapitulated by employing a morpholino-mediated knockdown of ttc12 in zebrafish.

Conclusions
To the best of our knowledge, this is the first study reporting the association between TTC12 variants and ciliopathies in a Chinese population. In addition to nephronophthisis and laterality defects, our findings demonstrated that TTC21B should also be considered a candidate gene for biliary ciliopathy, such as TTC26, which further expands the phenotypic spectrum of TTC21B deficiency in humans.