bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact and causal directions for the associations between diagnosis of ADHD, socioeconomic status, and intelligence by use of a bi-directional two-sample Mendelian randomization design
Authors: Michaëlsson Madeleine , Yuan Shuai , Melhus Håkan , Baron John A. , Byberg Liisa , Larsson Susanna C. , Michaëlsson Karl
Published: April 2022

Background

Previous studies have reported associations between attention-deficit/hyperactivity disorder (ADHD) and lower socioeconomic status and intelligence. We aimed to evaluate the causal directions and strengths for these associations by use of a bi-directional two-sample Mendelian randomization (MR) design.

Methods

We used summary-level data from the largest available genome-wide association studies (GWAS) to identify genetic instruments for ADHD, intelligence, and markers of socioeconomic status including the Townsend deprivation index, household income, and educational attainment. Effect estimates from individual genetic variants were combined using inverse-variance weighted regression.

Results

A genetically predicted one standard deviation (SD) increment in the Townsend deprivation index conferred an odds ratio (OR) of 5.29 (95% confidence interval (CI) 1.89–14.76) for an ADHD diagnosis (p<0.001). A genetically predicted one SD higher education level conferred an OR of 0.30 (95% CI 0.25–0.37) (p<0.001), and a genetically predicted one SD higher family income provided an OR of 0.35 (95% CI 0.25–0.49; p<0.001). The associations remained after adjustment for intelligence whereas the lower odds of an ADHD diagnosis with higher intelligence did not persist after adjustment for liability to greater educational attainment (adjusted OR 1.03, 95% CI 0.68–1.56; p=0.87). The MR analysis of the effect of ADHD on socioeconomic markers found that genetic liability to ADHD was statistically associated with each of them (p<0.001) but not intelligence. However, the average change in the socioeconomic markers per doubling of the prevalence of ADHD corresponded only to 0.05–0.06 SD changes.

Conclusions

Our results indicate that an ADHD diagnosis may be a direct and strong intelligence-independent consequence of socioeconomic related factors, whereas ADHD appears to lead only to modestly lowered socioeconomic status. Low intelligence seems not to be a major independent cause or consequence of ADHD.
The pharmacokinetics of buserelin after intramuscular administration in pigs and cows
Authors: Kong Jingyuan , Su Fuqin , Liu Yu , Yang Yuxin , Cao Yuying , Qiu Jicheng , Wang Yue , Zhang Lu , Wang Jianzhong , Cao Xingyuan
Published: April 2022

Background

Buserelin is a luteinizing hormone releasing hormone (LHRH) agonist used for the treatment of hormone-dependent diseases in males and females. However, the pharmacokinetics of buserelin in pigs and cows are not fully understood. This study was designed to develop a sensitive method to determine the concentration of buserelin in blood plasma and to investigate the pharmacokinetic parameters after intramuscular (i.m.) administration in pigs and cows.

Results

A sensitive and rapid stability method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed. The pharmacokinetic parameters of buserelin after i.m. administration were studied in five pigs and five cows at a single dose of 1 mg per pig and 3 mg per cow. The plasma kinetics were analyzed by WinNonlin 8.1.0 software using a non-compartmental model. The mean concentration area under the curve (AUC0-t) was 25.02 ± 6.93 h × ng/mL for pigs and 5.63 ± 1.86 h × ng/mL for cows. The maximum plasma concentration (Cmax) and time to reach the maximum concentration (tmax) were 10.99 ± 2.04 ng/mL and 0.57 ± 0.18 h for pigs and 2.68 ± 0.36 ng/mL and 1.05 ± 0.27 h for cows, respectively. The apparent volume of distribution (Vz) in pigs and cows was 80.49 ± 43.88 L and 839.88 ± 174.77 L, respectively. The elimination half-time (t1/2), and clearance (CL) were 1.29 ± 0.40 h and 41.15 ± 11.18 L/h for pigs and 1.13 ± 0.3 h and 545.04 ± 166.40 L/h for cows, respectively. No adverse effects were observed in any of the animals.

Conclusion

This study extends previous studies describing the pharmacokinetics of buserelin following i.m. administration in pigs and cows. Further studies investigating other factors were needed to establish therapeutic protocol in pigs and cows and to extrapolate these parameters to others economic animals.
Responsible companion animal guardianship is associated with canine visceral leishmaniasis: an analytical cross-sectional survey in an urban area of southeastern Brazil
Authors: Soares Paulo Henrique Araújo , da Silva Eduardo Sérgio , Penaforte Klauber Menezes , Ribeiro Renata Aparecida Nascimento , de Melo Marcella Oliveira Gama , Cardoso Diogo Tavares , Santos Ingrid Morselli , Machado Raissa Cotta , Trindade Clara Lemos Carneiro , Cunha Anna Karolyna Rodrigues , Teixeira-Neto Rafael Gonçalves , de Melo Saulo Nascimento , de Aquino Vanessa Vilela , Belo Vinícius Silva
Published: April 2022

Background

Responsible companion animal guardianship (RCAG) comprises a set of concepts involving activities, behavior and care that guardians must provide to ensure the welfare of their animals. When such principles are disregarded, the risk of animals developing zoonotic diseases, such as canine visceral leishmaniasis (CVL), increases. This disease is a public health problem in many urban settings in Brazil because dogs are the main reservoirs of Leishmania and are involved in the transmission of the parasites to humans. Our analytical cross-sectional epidemiological survey aimed to investigate the prevalence of CVL in a city in southeastern Brazil and to establish the association between the disease and a number of predictor variables including dog traits, socioeconomic status of guardians, ecological features of the domicile and RCAG.

Results

Our study showed that the global prevalence of CVL in the sample canine population was 6.7% (47/704). All variables related to better dog care were associated with lower chances of infection. Multiple regression analysis revealed that the chances of animals being seropositive for CVL were significantly (p < 0.05) higher when guardians had no formal education or possessed a university degree (vs. those with complete primary or secondary schooling) and when dogs were sheltered outside the house and had free access to the streets. An additional novel finding was that dogs that were acquired as puppies presented half of the chance of developing the disease in comparison with those acquired at the adult stage. Geographically weighted logistic regression coefficients showed that the strengths of the predictor/CVL associations varied depending on the studied geographical space. Both models demonstrated that the associations were always in the same directions.

Conclusions

Our findings indicate that regardless of age and mode of acquisition, adult dogs should be submitted to clinical evaluation and tests for CVL. RCAG can exert positive effects on the control of CVL.
FAM201A, a long noncoding RNA potentially associated with atrial fibrillation identified by ceRNA network analyses and WGCNA
Authors: Chen Xi , He Xiang-Yu , Dan Qing , Li Yang
Published: April 2022

Background

Being the most common arrhythmia in clinic, atrial fibrillation (AF) causes various comorbidities to patients such as heart failure and stroke. LncRNAs were reported involved in pathogenesis of AF, yet, little is known about AF-associated lncRNAs. The present study aims to explore lncRNAs associated with AF susceptibility based on competing endogenous RNA (ceRNA) network analysis and weighted gene co-expression network analysis (WGCNA).

Methods

GSE41177 and GSE79768 datasets were obtained from the Gene Expression Omnibus (GEO) database. Competing endogenous RNA (ceRNA) network analysis was performed using GSE41177. Differentially expressed lncRNAs (DElncRNAs), mRNAs (DEmRNAs) between AF patients and patients with sinus rhythm (SR) were identified from GSE41177 using R software. Then, the ceRNA network was constructed based on DElncRNAs, the predicted target miRNAs and DEmRNAs. Weighted gene co-expression network analysis (WGCNA) was performed using GSE79768 to validate the AF-related lncRNAs identified from GSE41177. LncRNA modules and crucial lncRNAs relevant to AF and were identified.

Results

In summary, 18 DElncRNAs and 350 DEmRNAs were found between AF patients and SR patients. A total of 5 lncRNAs, 10 miRNAs, and 21 mRNAs were contained in the final ceRNA network. Taking into consideration both the ceRNA theory and inference scores from the comparative toxicogenomics database (CTD) database, the ceRNA axis FAM201A-miR-33a-3p-RAC3 was identified as mostly relevant to AF susceptibility. FAM201A (Gene significance, GS = − 0.62; Module membership, MM = 0.75) was also proved in the blue module, which was identified most highly relevant with AF by WGCNA.

Conclusions

These results demonstrated that decreased expression of FAM201A might be associated with susceptibility of AF. Working as the ceRNA to regulate RAC3 might be one function of FAM201A in AF susceptibility, which requires further exploration in future research.
Examining lung mechanical strains as influenced by breathing volumes and rates using experimental digital image correlation
Authors: Mariano C. A. , Sattari S. , Quiros K. A. M. , Nelson T. M. , Eskandari M.
Published: April 2022

Background

Mechanical ventilation is often employed to facilitate breathing in patients suffering from respiratory illnesses and disabilities. Despite the benefits, there are risks associated with ventilator-induced lung injuries and death, driving investigations for alternative ventilation techniques to improve mechanical ventilation, such as multi-oscillatory and high-frequency ventilation; however, few studies have evaluated fundamental lung mechanical local deformations under variable loading.

Methods

Porcine whole lung samples were analyzed using a novel application of digital image correlation interfaced with an electromechanical ventilation system to associate the local behavior to the global volume and pressure loading in response to various inflation volumes and breathing rates. Strains, anisotropy, tissue compliance, and the evolutionary response of the inflating lung were analyzed.

Results

Experiments demonstrated a direct and near one-to-one linear relationship between applied lung volumes and resulting local mean strain, and a nonlinear relationship between lung pressures and strains. As the applied air delivery volume was doubled, the tissue surface mean strains approximately increased from 20 to 40%, and average maximum strains measured 70–110%. The tissue strain anisotropic ratio ranged from 0.81 to 0.86 and decreased with greater inflation volumes. Local tissue compliance during the inflation cycle, associating evolutionary strains in response to inflation pressures, was also quantified.

Conclusion

Ventilation frequencies were not found to influence the local stretch response. Strain measures significantly increased and the anisotropic ratio decreased between the smallest and greatest tidal volumes. Tissue compliance did not exhibit a unifying trend. The insights provided by the real-time continuous measures, and the kinetics to kinematics pulmonary linkage established by this study offers valuable characterizations for computational models and establishes a framework for future studies to compare healthy and diseased lung mechanics to further consider alternatives for effective ventilation strategies.
Leadership, politics, and communication: challenges of the epidemiology workforce during emergency response
Authors: Parry Amy Elizabeth , Kirk Martyn D. , Colquhoun Samantha , Durrheim David N. , Housen Tambri
Published: April 2022

Background

Improving the epidemiological response to emergencies requires an understanding of who the responders are, their role and skills, and the challenges they face during responses. In this paper, we explore the role of the epidemiologist and identify challenges they face during emergency response.

Methods

We conducted a cross-sectional survey to learn more about epidemiologists who respond to public health emergencies. The online survey included open and closed-ended questions on challenges faced while responding, the roles of epidemiology responders, self-rating of skills, and support needed and received. We used purposive sampling to identify participants and a snowballing approach thereafter. We compared data by a number of characteristics, including national or international responder on their last response prior to the survey. We analysed the data using descriptive, content, and exploratory factor analysis.

Results

We received 166 responses from individuals with experience in emergency response. The most frequently reported challenge was navigating the political dynamics of a response, which was more common for international responders than national. National responders experienced fewer challenges related to culture, language, and communication. Epidemiology responders reported a lack of response role clarity, limited knowledge sharing, and communication issues during emergency response. Sixty-seven percent of participants reported they needed support to do their job well; males who requested support were statistically more likely to receive it than females who asked.

Conclusions

Our study identified that national responders have additional strengths, such as better understanding of the local political environment, language, and culture, which may in turn support identification of local needs and priorities. Although this research was conducted prior to the COVID-19 pandemic, the results are even more relevant now. This research builds on emerging evidence on how to strengthen public health emergency response and provides a platform to begin a global conversation to address operational issues and the role of the international epidemiology responder.
Evaluation of the effects of meteorological factors on COVID-19 prevalence by the distributed lag nonlinear model
Authors: Ai Hongjing , Nie Rongfang , Wang Xiaosheng
Published: April 2022

Background

Although numerous studies have explored the impact of meteorological factors on the epidemic of COVID-19, their relationship remains controversial and needs to be clarified.

Methods

We assessed the risk effect of various meteorological factors on COVID-19 infection using the distributed lag nonlinear model, based on related data from July 1, 2020, to June 30, 2021, in eight countries, including Portugal, Greece, Egypt, South Africa, Paraguay, Uruguay, South Korea, and Japan, which are in Europe, Africa, South America, and Asia, respectively. We also explored associations between COVID-19 prevalence and individual meteorological factors by the Spearman’s rank correlation test.

Results

There were significant non-linear relationships between both temperature and relative humidity and COVID-19 prevalence. In the countries located in the Northern Hemisphere with similar latitudes, the risk of COVID-19 infection was the highest at temperature below 5 ℃. In the countries located in the Southern Hemisphere with similar latitudes, their highest infection risk occurred at around 15 ℃. Nevertheless, in most countries, high temperature showed no significant association with reduced risk of COVID-19 infection. The effect pattern of relative humidity on COVID-19 depended on the range of its variation in countries. Overall, low relative humidity was correlated with increased risk of COVID-19 infection, while the high risk of infection at extremely high relative humidity could occur in some countries. In addition, relative humidity had a longer lag effect on COVID-19 than temperature.

Conclusions

The effects of meteorological factors on COVID-19 prevalence are nonlinear and hysteretic. Although low temperature and relative humidity may lower the risk of COVID-19, high temperature or relative humidity could also be associated with a high prevalence of COVID-19 in some regions.
Mitigated suppressive function of regulatory T cells (Treg) upon Th17-inducing cytokines in oligo- and polyarticular Juvenile Idiopathic Arthritis (JIA) patients
Authors: Holzer Marie-Therese , Almanzar Giovanni , Woidich Robert , Hügle Boris , Haas Johannes-Peter , Prelog Martina
Published: April 2022

Background

The plasticity of T helper-17 (Th17) and regulatory T (Treg) cells may be a clue to pathogenesis of Juvenile Idiopathic Arthritis (JIA). It is still unclear, whether targeted suppression of Interleukin (IL)-17 is able to influence regulatory function of Treg to control pro-inflammatory effectors in JIA. This study aimed to assess the effect of a Th17-stimulating cytokine environment and of IL-17A-inhibition on phenotype plasticity and suppressive function of Treg derived from JIA patients.

Methods

Th17 and Treg characteristics of CD4+ helper T cells were investigated in blood samples of JIA patients with oligo- and polyarticular pattern and healthy controls (HC). Isolated CD4+CD25+CD127− cells defined as Treg were cultivated with Th17-inducing cytokine environment as well as with IL-17A-inhibitors and analyzed for plasticity of phenotype by flow cytometry. Furthermore, inhibitory function of Treg on autologous effectors after cultivation with these stimuli was determined by suppression assays.

Results

Our findings demonstrated significantly elevated proportions of Th17 and Th17-like Treg in JIA compared to HC. After incubation with Th17-inducing stimuli, increased FoxP3 expression in separated Treg in JIA and an impaired suppressive capacity in JIA and HC were found. Blockade of IL-17A resulted in adjustment of FoxP3-expression in JIA to proportions found in controls and in regular suppressive function.

Conclusions

Our results demonstrate an induction of FoxP3 expressing Treg by Th17-inducing cytokines with concomitant mitigated suppressive function. In contrast, specific IL-17A blockade maintains suppressive Treg function and adjusted FoxP3-expression in JIA to levels found in controls. These findings may help to provide experimental evidence for the successful clinical use of IL-17A inhibition in JIA patients.
Real-world data reveals the complexity of disease modifying anti-rheumatic drug treatment patterns in juvenile idiopathic arthritis: an observational study
Authors: Grazziotin Luiza R. , Currie Gillian , Twilt Marinka , Ijzerman Maarten J. , Kip Michelle M. A. , Koffijberg Hendrik , Benseler Susanne M. , Swart Joost F. , Vastert Sebastiaan J. , Wulffraat Nico M. , Yeung Rae S. M. , Marshall Deborah A.
Published: April 2022

Objective

Pharmacological treatment is a cornerstone of care for children with juvenile idiopathic arthritis (JIA). The objective of this study is to evaluate prescription patterns of conventional and biologic disease modifying anti-rheumatic drugs (c-DMARDs and b-DMARDs) for patients with JIA.

Methods

We conducted a retrospective cohort study of children diagnosed with JIA at a rheumatology pediatric clinic. Eligibility criteria were defined as children and youth newly diagnosed with enthesis-related arthritis, polyarticular, or oligoarticular JIA between 2011 and 2019, with at least one year of observation. Data on c-DMARDs and b-DMARDs prescriptions were obtained from electronic medical charts. We used descriptive statistics, Kaplan–Meier survival methods, and Sankey diagrams to describe treatment prescription patterns.

Results

A total of 325 patients with JIA were included, with a median observation time of 3.7 years. The most frequently prescribed c-DMARD and b-DMARD were methotrexate and etanercept, respectively. Within the first year of rheumatology care, 62% and 21% of patients had a c-DMARD and a b-DMARD prescribed, respectively. These proportions varied greatly by JIA subtype. Among the 147 (147/325, 45%) patients that had at least one b-DMARD prescribed, 24% were prescribed a second, and 7% a third-line of b-DMARD. A total of 112 unique treatment sequences were observed, with c-DMARD monotherapy followed by the addition of either a b-DMARD (56%) or another c-DMARD (30%) being the two most prevalent patterns in this cohort.

Conclusion

We observed a variety of treatment trajectories, with many patients experiencing multiple treatment lines, illustrating the complexity of the overall JIA treatment path.
Integrated pond aquaculture and regional identity: ethnobiology of the golden humped tench of Poirino highlands, Northwest Italy
Authors: Delpero Alessandro , Volpato Gabriele
Published: April 2022

Background

Social–ecological systems are based on particular species and on their direct and human-mediated interactions. The ‘golden humped tench’ ortinca gobba dorata, a variety of tench—Tinca tinca(L., 1758)—traditionally bred in artificial ponds calledpeschierein Poirino highlands, northwest Italy, is one of such species. The aim of the study is to investigate the traditional farming of the golden humped tench, the associated knowledge, practices, and gastronomy, and to discuss the changes that the tench, the ponds, and their role in the local social–ecological system are going through.

Methods

The data analyzed were collected in different locations of Poirino highlands during May–September 2021. Fieldwork included semi-structured interviews (n = 23) with current and former tench farmers about the breeding and gastronomy of the tench and the management of thepeschiere. The interviewees’ selection occurred through an exponential non-discriminative snowball sampling, and interview transcripts were qualitatively analyzed through inductive thematic content analysis.

Results

The golden humped tench has been farmed for centuries in ponds used also to water livestock and to irrigate cultivated fields, and managed by every peasant household in the area. This integrated aquaculture system is underpinned by detailed knowledge on thepeschieraecosystem and on the tench life cycle and supports a gastronomic knowledge that is part of the local heritage. The ongoing process of gastronomic valorization of the tench is sustaining the role of the fish in locals’ livelihoods and as a marker of regional identity, but it is also transforming tench farming, already threatened by livelihood change, pesticides, and invasive species, in controversial ways.

Conclusions

We argue that ponds and tenches are core elements of the local social–ecological system, defining the cultural landscape and engendering a form of regional identity around them. Studying integrated aquaculture systems and associated knowledge and practices is relevant to design sustainable systems of food production and to address possibilities of conservation of biodiversity and livelihoods in aquatic environments.
Quantitative monitoring of paramagnetic contrast agents and their allocation in plant tissues via DCE-MRI
Authors: Mayer Simon , Munz Eberhard , Hammer Sebastian , Wagner Steffen , Guendel Andre , Rolletschek Hardy , Jakob Peter M. , Borisjuk Ljudmilla , Neuberger Thomas
Published: April 2022

Background

Studying dynamic processes in living organisms with MRI is one of the most promising research areas. The use of paramagnetic compounds as contrast agents (CA), has proven key to such studies, but so far, the lack of appropriate techniques limits the application of CA-technologies in experimental plant biology. The presented proof-of-principle aims to support method and knowledge transfer from medical research to plant science.

Results

In this study, we designed and tested a new approach for plant Dynamic Contrast Enhanced Magnetic Resonance Imaging (pDCE-MRI). The new approach has been applied in situ to a cereal crop (Hordeum vulgare). The pDCE-MRI allows non-invasive investigation of CA allocation within plant tissues. In our experiments, gadolinium-DTPA, the most commonly used contrast agent in medical MRI, was employed. By acquiring dynamic T1-maps, a new approach visualizes an alteration of a tissue-specific MRI parameter T1(longitudinal relaxation time) in response to the CA. Both, the measurement of local CA concentration and the monitoring of translocation in low velocity ranges (cm/h) was possible using this CA-enhanced method.

Conclusions

A novel pDCE-MRI method is presented for non-invasive investigation of paramagnetic CA allocation in living plants. The temporal resolution of the T1-mapping has been significantly improved to enable the dynamic in vivo analysis of transport processes at low-velocity ranges, which are common in plants. The newly developed procedure allows to identify vascular regions and to estimate their involvement in CA allocation. Therefore, the presented technique opens a perspective for further development of CA-aided MRI experiments in plant biology.
The enduring consequences of conflict-related sexual violence: a qualitative study of women survivors in northern Uganda
Authors: Woldetsadik Mahlet A. , Acan Grace , Odiya Okwir Isaac
Published: April 2022

Background

One in three women in northern Uganda report having suffered from conflict-related sexual violence (CRSV), including forced marriage and rape. Research on the long-term effects of CRSV on the health and social well-being of survivors is scant, but crucial to informing policy and improving programs tailored to conflict-affected communities. Understanding women’s perceptions of and experiences with CRSV, especially related to the persistent health and social challenges they continue to face, is critical for developing effective and targeted interventions.

Methods

We worked with a local, survivor-led organization to recruit participants purposively from three post-conflict districts in northern Uganda: Gulu, Lira, and Pader. Women who had experienced CRSV and who were 18 years of age or older were eligible to participate. We asked participants open-ended questions about their experience with CRSV, including how it continues to affect their health and social well-being, any impact it had on their relationships, and if they faced barriers to accessing services. We transcribed, translated, and uploaded interview responses to the qualitative data analysis software MAXQDA and analyzed data thematically using a modified approach to grounded theory.

Results

We conducted 30 interviews between October 2016 and March 2017. All participants reported experiencing forced marriage, rape, or forced pregnancy. Over two-thirds of participants said they continued to face physical and psychological issues, including untreated sexually transmitted infections, anxiety, and depression. Almost half of the women faced challenges with maintaining links with family members, stigma related to their experiences during abduction that also extended to their children born in captivity, and difficulty with accessing and affording health care. Barriers to seeking care included fear of disclosure and being unable to find services. Women identified peer-support from other survivors as a key coping mechanism.

Conclusions

Women survivors continue to face multifaceted health and social problems in the post-conflict period. Most health-related programs that were set up at the end of the war in northern Uganda are no longer available. Increasing access to care, particularly services tailored to treating chronic reproductive health issues and mental health, is paramount for women survivors in northern Uganda and other conflict-affected regions.
Selective sorting and secretion of hY4 RNA fragments into extracellular vesicles mediated by methylated YBX1 to promote lung cancer progression
Authors: Li Chuang , Wang Wei , Sun Yuting , Ni Yifan , Qin Fang , Li Xiaolu , Wang Tao , Guo Mingxiong , Sun Guihong
Published: April 2022

Background

Extracellular vesicles (EVs) are emerging mediators of intercellular communication that have been shown to play important roles in tumor progression. YRNA fragments, a type of small non-coding RNA, are dysregulated in non-small cell lung cancer (NSCLC) cell-derived EVs, suggesting that they may be an effective biomarker for cancer diagnosis and treatment strategies.

Methods

Differentially expressed YRNA hY4 fragments (hY4F) in EVs from NSCLC cells and normal lung fibroblasts were isolated by differential ultra-centrifugation. RNA-binding proteins that interacted with hY4F were identified by screening with an RNA pulldown assay and mass spectrometry. The molecular mechanism of hY4F and the RNA-binding protein Y box binding protein 1 (YBX1) was demonstrated by qRT-PCR, western blot, RNA pulldown, and rescue experiments. Transcriptome sequencing, qRT-PCR validation, bioinformatics analysis and NF-κB pathway inhibitor assays elucidate the mechanism of YBX1 and hY4F inhibiting lung cancer. A peptide pulldown assay was performed to screen and identify a potential methyltransferase for YBX1. The roles of hY4F, YBX1, and SET domain containing 3 in biological functions, such as proliferation, migration, invasion, and apoptosis, in lung cancer cells were also examined by EdU incorporation assay, Transwell assay, flow cytometry, and other methods. Lastly, a mouse xenograft assay was used to assess the clinical relevance of YBX1 and hY4F in vivo.

Results

Our data demonstrate that hY4 RNA fragments were upregulated in lung cancer- derived EVs, hY4F inhibits tumor progression through downregulating MAPK/NF-κB signaling, and then the selective sorting and secretion of hY4F into lung cancer EVs is regulated by the RNA-binding protein YBX1. Furthermore, we identified lysine K264 within the YBX1 C-terminal domain as the necessary site for its interaction with hY4Fs. K264 is modified by methylation, which affects its binding to hY4F and subsequent selective sorting into EVs in lung cancer cells.

Conclusion

Our findings demonstrate that hY4F acts as a tumor suppressor and is selectively sorted into lung cancer cell-derived EVs by interacting with methylated YBX1, which in turn promotes lung cancer progression. hY4F is a promising circulating biomarker for non-small cell lung cancer diagnosis and prognosis and an exceptional candidate for further therapeutic exploration.
Peripheral lymphocyte populations in ovarian cancer patients and correlations with clinicopathological features
Authors: Ye Shuang , Chen Wei , Zheng Yuwei , Wu Yutuan , Xiang Libing , Li Teng , Ping Bo , Zhang Xiaoming , Yang Huijuan
Published: April 2022

Background

To investigate the alterations of peripheral lymphocyte subpopulations in ovarian cancer patients compared to benign or borderline counterparts. The possible clinicopathological implications were also evaluated.

Methods

We enrolled 112 treatment-naive ovarian cancer patients, 14 borderline tumor patients and 44 benign tumor patients between 09/2016 and 01/2019. Flow cytometry was used to measure the peripheral lymphocyte subsets consisting of T cells (CD3+, CD3+CD4+, CD3+CD8+ and CD8+CD28+), regulatory T cells (Tregs, CD4+CD25+CD127−), natural killer cells (NK cells, CD3−CD56+) and B cells (CD19+).

Results

Most ovarian cancer patients were high-grade serous carcinoma (84.8%), followed by clear cell carcinoma (8.03%). Late-stage tumor (FIGO III + IV) accounted for 82.1%. The study showed that the proportions of peripheral lymphocyte subsets underwent apparent changes in ovarian cancer patients. We observed elevated levels of Treg cells in patients with both ovarian borderline and malignant tumor compared to those with benign tumors, which achieved statistic significance. In contrast, CD3+CD8+ T and CD8+CD28+ T cells were significantly lower in ovarian cancer patients. Interestingly, low level of B cells was correlated to clear cell carcinoma (P = 0.024), advanced tumor (P = 0.028) and platinum-resistant recurrence (P = 0.014). Regarding the changes of lymphocyte subsets after surgery, CD8+CD28+ T cells had a significant decreasing tendency (P = 0.007) while B cells were the opposite (P < 0.001).

Conclusions

Ovarian cancer patients have altered circulating lymphocyte profile (elevated Treg cell, depressed CD3+CD8+ T and CD8+CD28+ T cells). Low level of B cells might be related to disease aggressiveness, and it recovered after the removal of tumor, which merits further study.
The Positive Choices trial: update to study protocol for a phase-III RCT trial of a whole-school social-marketing intervention to promote sexual health and reduce health inequalities
Authors: Ponsford Ruth , Meiksin Rebecca , Allen Elizabeth , Melendez-Torres G. J. , Morris Steve , Mercer Catherine , Campbell Rona , Young Honor , Lohan Maria , Coyle Karin , Bonell Chris
Published: April 2022

Background

Positive Choices is a whole-school social-marketing intervention to promote sexual health among secondary school students. Intervention comprises the following: school health promotion council involving staff and students coordinating delivery, student survey to inform local tailoring, teacher-delivered classroom curriculum, student-run campaigns, parent information and review of sexual/reproductive health services to inform improvements. This trial builds on an optimisation/pilot-RCT study which met progression criteria, plus findings from another pilot RCT of the Project Respect school-based intervention to prevent dating and relationship violence which concluded such work should be integrated within Positive Choices. Young people carry a disproportionate burden of adverse sexual health; most do not report competence at first sex. Relationships and sex education in schools can contribute to promoting sexual health but effects are small, inconsistent and not sustained. Such work needs to be supplemented by ‘whole-school’ (e.g. student campaigns, sexual health services) and ‘social marketing’ (harnessing commercial marketing to social ends) approaches for which there is good review-level evidence but not from the UK.

Methods

We will conduct a cluster RCT across 50 schools (minimum 6440, maximum 8500 students) allocated 1:1 to intervention/control assessing outcomes at 33 months. Our primary outcome is non-competent first sex. Secondary outcomes are non-competent last sex, age at sexual debut, non-use of contraception at first and last sex among those reporting heterosexual intercourse, number of sexual partners, dating and relationship violence, sexually transmitted infections and pregnancy and unintended pregnancy for girls and initiation of pregnancy for boys. We will recruit 50 school and undertake baseline surveys by March 2022, implement the intervention over the 2022–2024 school years and conduct the economic and process evaluations by July 2024; undertake follow-up surveys by December 2024; complete analyses, all patient and policy involvement and draft the study report by March 2025 and engage in knowledge exchange from December 2024.

Discussion

This trial is one of a growing number focused on whole-school approaches to public health in schools. The key scientific output will be evidence about the effectiveness, costs and potential scalability and transferability of Positive Choices.

Trial registration

ISRCTN No: ISRCTN16723909. Registered on 3 September 2021.
Using a modified nominal group technique to develop complex interventions for a randomised controlled trial in children with symptomatic pes planus
Authors: Backhouse Michael R. , Parker Daniel J. , Morison Stewart C. , Anderson Jenny , Cockayne Sarah , Adamson Joy A.
Published: April 2022

Background

Children with symptomatic flat feet (pes planus) frequently present for care but there remains uncertainty about how best to manage their condition. There is considerable variation in practice between and within professions. We intend to conduct a three-arm trial to evaluate three frequently used interventions for pes planus (exercise and advice, exercise and advice plus prefabricated orthoses, and exercise and advice plus custom made orthoses). Each of these interventions are complex and required developing prior to starting the trial. This paper focusses on the development process undertaken to develop the interventions.

Methods

We used a modified Nominal Group Technique combining an electronic survey with two face-to-face meetings to achieve consensus on the final logic model and menu of options for each intervention. Using the Nominal Group Technique across consecutive meetings in combination with a questionnaire is novel, and enabled us to develop complex interventions that reflect contemporary clinical practice.

Results

In total 16 healthcare professionals took part in the consensus. These consisted of 11 podiatrists, two orthotists, two physiotherapists, and one orthopaedic surgeon.

Both meetings endorsed the logic model with amendments to reflect the wider psychosocial impact of pes planus and its treatment, as well as the increasing use of shared decision making in practice. Short lists of options were agreed for prefabricated and custom made orthoses, structures to target in stretching and strengthening exercises, and elements of health education and advice.

Conclusions

Our novel modification of the nominal group technique produced a coherent logic model and shortlist of options for each of the interventions that explicitly enable adaptability. We formed a consensus on the range of what is permissible within each intervention so that their integrity is kept intact and they can be adapted and pragmatically applied. The process of combining survey data with face-to-face meetings has ensured the interventions mirror contemporary practice and may provide a template for other trials.
Dogs with leishmaniosis: how are we managing proteinuria in daily practice? A Portuguese questionnaire-based study
Authors: Monteiro Marta , Prata Sara , Cardoso Luís , Pereira da Fonseca Isabel , Leal Rodolfo Oliveira
Published: April 2022

Background

Proteinuria is a common finding in dogs with leishmaniosis. Although antileishmanial therapeutic protocols are widely implemented, little information is available on which treatments are most adequate for identifying proteinuria in patients with canine leishmaniosis (CanL), especially regarding the use of immunosuppressants. The aim of this study was to explore the current paradigm regarding the antiproteinuric approach adopted by veterinary practitioners in Portugal to treat dogs with CanL.

Methods

A questionnaire-based study was developed using Google Forms®. The questionnaire presented a number of different hypothetical scenarios of CanL, and the topics surveyed included the general features of the respondents and the protocols preferred by these respondents to manage proteinuria in the presented scenarios, including choice of therapeutic drugs, appropriate diet and use of immunosuppressants, in dogs with immune-mediated glomerulonephritis. The questionnaire was internally prevalidated and diffused online over a 2-month period through Portuguese veterinary social networking groups, and data were collected for descriptive analysis.

Results

A total of 86 veterinary practitioners responded to the survey. When exposed to theoretical scenarios of proteinuria in dogs with CanL at stages IIb, III and IV (LeishVet guidelines), 16.3%, 62.8% and 93.8% of the respondents, respectively, answered that they would treat it. The dog was started on a renal diet as therapy by 28.6%, 83.3% and 97.4% of respondents, respectively. Angiotensin-converting enzyme inhibitors (ACEI) were prescribed by 100%, 85.2% and 78.9% of respondents as first-choice drugs for CanL at stages IIb, III and IV, respectively, with ACEI used in monotherapy by 64.3%, 40.7% and 46.1%. In comparison, protocols using ACEI in combination with other compounds were chosen by 7.1%, 33.3% and 39.5% of respondents, and combination therapy which did not include ACEI was the choice of 0.0%, 12.9% and 14.5%. Regarding immunosuppressants, 44.2% of the respondents answered they would prescribe them, with 97.4% electing for prednisolone and 5.3% choosing mycophenolate mofetil.

Conclusions

Among the veterinary practitioners who responded, proteinuria treatment was considered since stage IIb CanL, although implementation of a therapeutic approach was more evident in advanced CanL stages. ACEI were the first-choice drugs, particularly for the treatment of stage IIb CanL; in advanced stages, a combination of antiproteinuric drugs was more often used. Immunosuppressant use was controversial, although when applied, prednisolone was the preferred choice. These findings reinforce the small body of evidence that supports the use of such drugs and the need to further explore their role in CanL.

Graphical Abstract
Association of tramadol with all-cause mortality, cardiovascular diseases, venous thromboembolism, and hip fractures among patients with osteoarthritis: a population-based study
Authors: Li Lingyi , Marozoff Shelby , Lu Na , Xie Hui , Kopec Jacek A. , Cibere Jolanda , Esdaile John M. , Aviña-Zubieta J. Antonio
Published: April 2022

Background

The use of tramadol among osteoarthritis (OA) patients has been increasing rapidly around the world, but population-based studies on its safety profile among OA patients are scarce. We sought to determine if tramadol use in OA patients is associated with increased risks of all-cause mortality, cardiovascular diseases (CVD), venous thromboembolism (VTE), and hip fractures compared with commonly prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) or codeine.

Methods

Using administrative health datasets from British Columbia, Canada, we conducted a sequential propensity score-matched cohort study among all OA patients between 2005 and 2013. The tramadol cohort (i.e., tramadol initiation) was matched with four comparator cohorts (i.e., initiation of naproxen, diclofenac, cyclooxygenase-2 [Cox-2] inhibitors, or codeine). Outcomes are all-cause mortality, first-ever CVD, VTE, and hip fractures within the year after the treatment initiation. Patients were followed until they either experienced an event, left the province, or the 1-year follow-up period ended, whichever occurred first. Cox proportional hazard models were used to estimate hazard ratios after adjusting for competing risk of death.

Results

Overall, 100,358 OA patients were included (mean age: 68 years, 63% females). All-cause mortality was higher for tramadol compared to NSAIDs with rate differences (RDs/1000 person-years, 95% CI) ranging from 3.3 (0.0–6.7) to 8.1 (4.9–11.4) and hazard ratios (HRs, 95% CI) ranging from 1.2 (1.0–1.4) to 1.5 (1.3–1.8). For CVD, no differences were observed between tramadol and NSAIDs. Tramadol had a higher risk of VTE compared to diclofenac, with RD/1000 person-years (95% CI) of 2.2 (0.7–3.7) and HR (95% CI) of 1.7 (1.3–2.2). Tramadol also had a higher risk of hip fractures compared to diclofenac and Cox-2 inhibitors with RDs/1000 person-years (95% CI) of 1.9 (0.4–3.4) and 1.7 (0.2–3.3), respectively, and HRs (95% CI) of 1.6 (1.2–2.0) and 1.4 (1.1–1.9), respectively. No differences were observed between tramadol and NSAIDs for all events.

Conclusions

OA patients initiating tramadol have an increased risk of mortality, VTE, and hip fractures within 1 year compared with commonly prescribed NSAIDs, but not with codeine.
Using magnetic resonance imaging to map the hidden burden of muscle involvement in systemic sclerosis
Authors: Ross Laura , Lindqvist Anniina , Costello Benedict , Hansen Dylan , Brown Zoe , Day Jessica A. , Stevens Wendy , Burns Andrew , Perera Warren , Pianta Marcus , La Gerche André , Nikpour Mandana
Published: April 2022

Background

Skeletal muscle can be directly affected by systemic sclerosis (SSc); however, a significant burden of SSc-associated myopathy is undetected because clinical parameters such as weakness and creatine kinase (CK) are unreliable biomarkers of muscle involvement. This study presents qualitative and quantitative magnetic resonance imaging (MRI) findings that quantify the prevalence of myopathy and evaluate any association between skeletal and cardiac muscle involvement in SSc.

Methods

Thirty-two patients with SSc who fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria underwent skeletal muscle MRI in addition to cardiac MRI. Skeletal muscles were independently assessed by two musculoskeletal radiologists for evidence of oedema, fatty infiltration and atrophy. Skeletal muscle T2 mapping times and percentage fat fraction were calculated. Linear regression analysis was used to evaluate the clinical and myocardial associations with skeletal muscle oedema and fatty infiltration. Cardiac MRI was performed using post gadolinium contrast imaging and parametric mapping techniques to assess focal and diffuse myocardial fibrosis.

Results

Thirteen participants (40.6%) had MRI evidence of skeletal muscle oedema. Five (15.6%) participants had fatty infiltration. There was no association between skeletal muscle oedema and muscle strength, creatine kinase, inflammatory markers or fibroinflammatory myocardial disease. Patients with skeletal muscle oedema had higher T2-mapping times; there was a significant association between subjective assessments of muscle oedema and T2-mapping time (coef 2.46, p = 0.02) and percentage fat fraction (coef 3.41, p = 0.02). Diffuse myocardial fibrosis was a near-universal finding, and one third of patients had focal myocardial fibrosis. There was no association between skeletal myopathy detected by MRI and burden of myocardial disease.

Conclusions

MRI is a sensitive measure of muscle oedema and systematic assessment of SSc patients using MRI shows that myopathy is highly prevalent, even in patients without symptoms or other signs of muscle involvement. Similarly, cardiac fibrosis is highly prevalent but occurs independently of skeletal muscle changes. These results indicate that novel quantitative MRI techniques may be useful for assessing sub-clinical skeletal muscle disease in SSc.
An association between excessive valgus hindfoot alignment and postural stability during single-leg standing in adolescent athletes
Authors: Ikuta Yasunari , Nakasa Tomoyuki , Fujishita Hironori , Obayashi Hiromune , Fukuhara Kouki , Sakamitsu Tetsuhiko , Ushio Kai , Adachi Nobuo
Published: April 2022

Background

Diminished balance is associated with the incidence of ankle and lower extremity injuries in adolescents. Although flexible flatfoot is a common foot condition in pediatric and adolescent populations, the association between balance control and foot morphology remain unclear in adolescent athletes.

Methods

Rearfoot angle in the double-limb standing position, body mass index (BMI), and isometric muscle strength related to the knee joint were retrospectively reviewed in 101 adolescent athletes (75 boys and 26 girls) with a mean age of 14.0 years (range 12–17). Postural stability during single-leg standing on static and dynamic platforms was investigated using Balance System SD in 119 feet without functional ankle instability. The participants were divided according to their rearfoot angle into control (less than 7°) and valgus (greater than or equal to 7°) groups. The measured parameters were compared between the control and valgus groups using Welch’s t-test, and P values < 0.05 were considered statistically significant. Multiple regression analysis was conducted to identify the factors that significantly influenced postural control.

Results

The average rearfoot angle was 4.6° in all participants. An excessive valgus rearfoot angle was detected in 53 feet (26.2%). No significant difference was found between the groups in terms of BMI and isometric knee muscle strength. Although no statistical differences were observed in postural stability on the static platform between the control and valgus groups, the valgus group demonstrated poorer postural stability for single-leg standing on the dynamic platform. Multiple regression analysis revealed that BMI and rearfoot angle were significantly associated with a poor postural control on the dynamic platform.

Conclusions

Our findings suggest that excessive rearfoot valgus specifically contributes to the deterioration of postural stability in adolescent athletes, and that rearfoot alignment should be evaluated for the adolescent population to prevent sports-related lower extremity injury.