bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of the long non-coding RNAs in regulation of Gemcitabine response in tumor cells
Authors: Maharati Amirhosein , Samsami Yalda , Latifi Hanieh , Tolue Ghasaban Faezeh , Moghbeli Meysam
Published: August 2023

Chemotherapy is widely used as one of the first line therapeutic methods in cancer patients. However, chemotherapeutic resistance is one of the most common problems in cancer patients, which leads to the therapeutic failure and tumor relapse. Considering the side effects of chemotherapy drugs in normal tissues, it is required to investigate the molecular mechanisms involved in drug resistance to improve the therapeutic strategies in cancer patients. Long non-coding RNAs (lncRNAs) have pivotal roles in regulation of cellular processes associated with drug resistance. LncRNAs deregulations have been frequently reported in a wide range of chemo-resistant tumors. Gemcitabine (GEM) as a nucleoside analog has a wide therapeutic application in different cancers. However, GEM resistance is considered as a therapeutic challenge. Considering the role of lncRNAs in the occurrence of GEM resistance, in the present review we discussed the molecular mechanisms of lncRNAs in regulation of GEM response among cancer patients. It has been reported that lncRNAs have mainly an oncogenic role as the inducers of GEM resistance through direct or indirect regulation of transcription factors, autophagy, polycomb complex, and signaling pathways such as PI3K/AKT, MAPK, WNT, JAK/STAT, and TGF-β. This review paves the way to present the lncRNAs as non-invasive markers to predict GEM response in cancer patients. Therefore, lncRNAs can be introduced as the efficient markers to reduce the possible chemotherapeutic side effects in GEM resistant cancer patients and define a suitable therapeutic strategy among these patients.
Inequality of opportunity in outpatient expenditure among the elderly with multimorbidity: evidence from China
Authors: Zhang Kangkang , You Hua , Yu Linxiang , Wu Qifeng , Xu Xinpeng
Published: August 2023

Background

Inequality of opportunity (IOp) stemming from social circumstances exists in outpatient service utilization for the multimorbid elderly in China. However, little is known regarding the magnitude of the IOp and its composition. Therefore, this study aims to measure the IOp in outpatient expenditure and provide potential pathways for policy reform by assessing the contribution of each circumstance.

Methods

This study included 3527 elderly aged ≥ 65 years with multimorbidity from the Chinese Longitudinal Healthy Longevity Study conducted in 2017–2018. An ordinary least squares regression model was used to analyze the circumstance-influencing factors of outpatient expenditure. The parametric approach was performed to quantify the IOp in outpatient expenditure and the Shapley value decomposition method was employed to determine the contribution of each circumstance. By extracting heterogeneity in the residual of the circumstance-dependent equation of outpatient expenditure across circumstance groups divided based on cluster analysis, we captured the effect of unobserved circumstances.

Results

Except for pension and distance to health facilities, all the associations between circumstance and outpatient expenditure were statistically significant. The inequality caused by circumstances accounted for 25.18% of the total inequality. The decomposition results revealed that the reimbursement rate contributed 82.92% of the IOp, followed by education duration (4.55%), household registration (3.21%), household income (3.18%), pension (1.49%), medical insurance (1.26%), physical labor (0.99%), unobserved circumstances (0.86%), distance to health facilities (0.83%) and region (0.71%).

Conclusions

The priority of policy enhancement is to effectively improve the outpatient reimbursement benefit for treating chronic diseases. Additional crucial actions include enhancing the health literacy of the multimorbid elderly to promote the shift from medical needs to demands and accelerating the construction of rural capacity for providing high-quality healthcare to the elderly with multimorbidity.
The emerging roles of MAPK-AMPK in ferroptosis regulatory network
Authors: Wang Xinyue , Tan Xiao , Zhang Jinping , Wu Jiaping , Shi Hongjuan
Published: August 2023

Ferroptosis, a newform of programmed cell death, driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes and is extremely dependent on iron ions, which is differs characteristics from traditional cell death has attracted greater attention. Based on the curiosity of this new form of regulated cell death, there has a tremendous progress in the field of mechanistic understanding of ferroptosis recent years. Ferroptosis is closely associated with the development of many diseases and involved in many diseases related signaling pathways. Not only a variety of oncoproteins and tumor suppressors can regulate ferroptosis, but multiple oncogenic signaling pathways can also have a regulatory effect on ferroptosis. Ferroptosis results in the accumulation of large amounts of lipid peroxides thus involving the onset of oxidative stress and energy stress responses. The MAPK pathway plays a critical role in oxidative stress and AMPK acts as a sensor of cellular energy and is involved in the regulation of the energy stress response. Moreover, activation of AMPK can induce the occurrence of autophagy-dependent ferroptosis and p53-activated ferroptosis. In recent years, there have been new advances in the study of molecular mechanisms related to the regulation of ferroptosis by both pathways. In this review, we will summarize the molecular mechanisms by which the MAPK-AMPK signaling pathway regulates ferroptosis. Meanwhile, we sorted out the mysterious relationship between MAPK and AMPK, described the crosstalk among ferroptosis and MAPK-AMPK signaling pathways, and summarized the relevant ferroptosis inducers targeting this regulatory network. This will provide a new field for future research on ferroptosis mechanisms and provide a new vision for cancer treatment strategies.
Advances in the study of exosomes derived from mesenchymal stem cells and cardiac cells for the treatment of myocardial infarction
Authors: Liu Yuchang , Wang Minrui , Yu Yang , Li Chunhong , Zhang Chunxiang
Published: August 2023

Acute myocardial infarction has long been the leading cause of death in coronary heart disease, which is characterized by irreversible cardiomyocyte death and restricted blood supply. Conventional reperfusion therapy can further aggravate myocardial injury. Stem cell therapy, especially with mesenchymal stem cells (MSCs), has emerged as a promising approach to promote cardiac repair and improve cardiac function. MSCs may induce these effects by secreting exosomes containing therapeutically active RNA, proteins and lipids. Notably, normal cardiac function depends on intracardiac paracrine signaling via exosomes, and exosomes secreted by cardiac cells can partially reflect changes in the heart during disease, so analyzing these vesicles may provide valuable insights into the pathology of myocardial infarction as well as guide the development of new treatments. The present review examines how exosomes produced by MSCs and cardiac cells may influence injury after myocardial infarction and serve as therapies against such injury.

Graphical Abstract
TNFSF14/LIGHT promotes cardiac fibrosis and atrial fibrillation vulnerability via PI3Kγ/SGK1 pathway-dependent M2 macrophage polarisation
Authors: Wu Yirong , Zhan Siyao , Chen Lian , Sun Mingrui , Li Miaofu , Mou Xuanting , Zhang Zhen , Xu Linhao , Xu Yizhou
Published: August 2023

Background

Tumour necrosis factor superfamily protein 14 (TNFSF14), also called LIGHT, is an important regulator of immunological and fibrosis diseases. However, its specific involvement in cardiac fibrosis and atrial fibrillation (AF) has not been fully elucidated. The objective of this study is to examine the influence of LIGHT on the development of myocardial fibrosis and AF.

Methods

PCR arrays of peripheral blood mononuclear cells (PBMCs) from patients with AF and sinus rhythm was used to identify the dominant differentially expressed genes, followed by ELISA to evaluate its serum protein levels. Morphological, functional, and electrophysiological changes in the heart were detected in vivo after the tail intravenous injection of recombinant LIGHT (rLIGHT) in mice for 4 weeks. rLIGHT was used to stimulate bone marrow-derived macrophages (BMDMs) to prepare a macrophage-conditioned medium (MCM) in vitro. Then, the MCM was used to culture mouse cardiac fibroblasts (CFs). The expression of relevant proteins and genes was determined using qRT-PCR, western blotting, and immunostaining.

Results

The mRNA levels of LIGHT and TNFRSF14 were higher in the PBMCs of patients with AF than in those of the healthy controls. Additionally, the serum protein levels of LIGHT were higher in patients with AF than those in the healthy controls and were correlated with left atrial reverse remodelling. Furthermore, we demonstrated that rLIGHT injection promoted macrophage infiltration and M2 polarisation in the heart, in addition to promoting atrial fibrosis and AF inducibility in vivo, as detected with MASSON staining and atrial burst pacing respectively. RNA sequencing of heart samples revealed that the PI3Kγ/SGK1 pathway may participate in these pathological processes. Therefore, we confirmed the hypothesis that rLIGHT promotes BMDM M2 polarisation and TGB-β1 secretion, and that this process can be inhibited by PI3Kγ and SGK1 inhibitors in vitro. Meanwhile, increased collagen synthesis and myofibroblast transition were observed in LIGHT-stimulated MCM-cultured CFs and were ameliorated in the groups treated with PI3Kγ and SGK1 inhibitors.

Conclusion

LIGHT protein levels in peripheral blood can be used as a prognostic marker for AF and to evaluate its severity. LIGHT promotes cardiac fibrosis and AF inducibility by promoting macrophage M2 polarisation, wherein PI3Kγ and SGK1 activation is indispensable.
A novel PRKDC mutation caused B lymphocytes V(D)J rearrangement disorder in the SLE-DAH like symptoms patient
Authors: Li Hongwei , Zhang Yawen , Zhang Biyun , Chen Dehui
Published: August 2023

Background

Analyzed the clinical features and treatment process of the patient suffering from immunodeficiency with systemic lupus erythematosus(SLE)-like syndrome in a novel mutation of PRKDC.

Case presentation

The patient had multiple positive auto-antibodies, chest CT and bronchoscopy showed Diffuse alveolar hemorrhage(DAH), and psychiatric symptoms showed brain atrophy by magnetic resonance imaging (MRI). Whole exon sequencing showed that novel complex heterozygous mutations of PRKDC gene (C. 1777 − 710_1777-709INSA (IVS16/IC16), C.1337T > A(p.Phe446Tyr). The mature B cell (CD19 + CD27 + CD38 dimIgD IgM-) were absent. The treatment of high-dose methylprednisolone (MP) and cyclophosphamide(CTX) can quickly relieve the symptoms of the patient.

Conclusion

We described the case of an infant immunodeficiency with SLE like-syndrome, which may cause by PRKDC mutation, treated successfully with high-dose MP and CTX.
Impairments of the ipsilesional upper-extremity in the first 6-months post-stroke
Authors: Smith Donovan B. , Scott Stephen H. , Semrau Jennifer A. , Dukelow Sean P.
Published: August 2023

Background

Ipsilesional motor impairments of the arm are common after stroke. Previous studies have suggested that severity of contralesional arm impairment and/or hemisphere of lesion may predict the severity of ipsilesional arm impairments. Historically, these impairments have been assessed using clinical scales, which are less sensitive than robot-based measures of sensorimotor performance. Therefore, the objective of this study was to characterize progression of ipsilesional arm motor impairments using a robot-based assessment of motor function over the first 6-months post-stroke and quantify their relationship to (1) contralesional arm impairment severity and (2) stroke-lesioned hemisphere.

Methods

A total of 106 participants with first-time, unilateral stroke completed a unilateral assessment of arm motor impairment (visually guided reaching task) using the Kinarm Exoskeleton. Participants completed the assessment along with a battery of clinical measures with both ipsilesional and contralesional arms at 1-, 6-, 12-, and 26-weeks post-stroke.

Results

Robotic assessment of arm motor function revealed a higher incidence of ipsilesional arm impairment than clinical measures immediately post-stroke. The incidence of ipsilesional arm impairments decreased from 47 to 14% across the study period. Kolmogorov–Smirnov tests revealed that ipsilesional arm impairment severity, as measured by our task, was not related to which hemisphere was lesioned. The severity of ipsilesional arm impairments was variable but displayed moderate significant relationships to contralesional arm impairment severity with some robot-based parameters.

Conclusions

Ipsilesional arm impairments were variable. They displayed relationships of varying strength with contralesional impairments and were not well predicted by lesioned hemisphere. With standard clinical care, 86% of ipsilesional impairments recovered by 6-months post-stroke.
Role of the protease-activated receptor-2 (PAR2) in the exacerbation of house dust mite-induced murine allergic lung disease by multi-walled carbon nanotubes
Authors: Lee Ho Young , You Dorothy J. , Taylor-Just Alexia , Tisch Logan J. , Bartone Ryan D. , Atkins Hannah M. , Ralph Lauren M. , Antoniak Silvio , Bonner James C.
Published: August 2023

Background

Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) has been reported to exert strong pro-inflammatory and pro-fibrotic adjuvant effects in mouse models of allergic lung disease. However, the molecular mechanisms through which MWCNTs exacerbate allergen-induced lung disease remain to be elucidated. We hypothesized that protease-activated receptor 2 (PAR2), a G-protein coupled receptor previously implicated in the pathogenesis of various diseases including pulmonary fibrosis and asthma, may play an important role in the exacerbation of house dust mite (HDM) allergen-induced lung disease by MWCNTs.

Methods

Wildtype (WT) male C57BL6 mice and Par2 KO mice were exposed to vehicle, MWCNTs, HDM extract, or both via oropharyngeal aspiration 6 times over a period of 3 weeks and were sacrificed 3-days after the final exposure (day 22). Bronchoalveolar lavage fluid (BALF) was harvested to measure changes in inflammatory cells, total protein, and lactate dehydrogenase (LDH). Lung protein and RNA were assayed for pro-inflammatory or profibrotic mediators, and formalin-fixed lung sections were evaluated for histopathology.

Results

In both WT and Par2 KO mice, co-exposure to MWCNTs synergistically increased lung inflammation assessed by histopathology, and increased BALF cellularity, primarily eosinophils, as well as BALF total protein and LDH in the presence of relatively low doses of HDM extract that alone produced little, if any, lung inflammation. In addition, both WT and par2 KO mice displayed a similar increase in lung Cc1-11 mRNA, which encodes the eosinophil chemokine CCL-11, after co-exposure to MWCNTs and HDM extract. However, Par2 KO mice displayed significantly less airway fibrosis as determined by quantitative morphometry compared to WT mice after co-exposure to MWCNTs and HDM extract. Accordingly, at both protein and mRNA levels, the pro-fibrotic mediator arginase 1 (ARG-1), was downregulated in Par2 KO mice exposed to MWCNTs and HDM. In contrast, phosphorylation of the pro-inflammatory transcription factor NF-κB and the pro-inflammatory cytokine CXCL-1 was increased in Par2 KO mice exposed to MWCNTs and HDM.

Conclusions

Our study indicates that PAR2 mediates airway fibrosis but not eosinophilic lung inflammation induced by co-exposure to MWCNTs and HDM allergens.
Adverse childhood experiences and trauma informed care for chiropractors: a call to awareness and action
Authors: Baca Kira J. , Salsbury Stacie A.
Published: August 2023

Background

Trauma is an emotional response to distressing events where coping and subsequent recovery are absent. Adverse Childhood Experiences (ACEs) are traumas, occurring before the age of 18 years, such as child abuse or neglect, caregiver instability, and household dysfunction. Sixty-four percent of the U.S. population report experiencing at least one ACE, with over 1 billion children experiencing abuse and neglect annually worldwide. Chronic exposure to stressful circumstances or multiple traumatic events has negative physiologic impacts. Persons who experience 3 or more ACEs in childhood are at greater risk of poor mental health outcomes and may be more likely to engage in high-risk behaviors, predisposing them to long-term health impacts, such as metabolic diseases, anxiety, depression, substance use, and chronic pain. Trauma informed care (TIC) is a recommended approach to healthcare delivery across professions, especially when a trauma history is suspected. This commentary aims to increase awareness of the impact of ACEs on health outcomes and introduce TIC concepts as they may apply to chiropractic care for adults with a history of ACEs.

Discussion

This commentary reviews an introductory model (4R's: realize, recognize, respond, resist re-traumatization) as one TIC framework used by healthcare practitioners. Prior trauma can lessen trust, alter perceptions of physical touch, and hands-on examinations and chiropractic treatments may trigger stress responses. Using TIC after appropriate training, includes referrals to multidisciplinary providers to address trauma-related concerns outside the scope of chiropractic, and screening for ACEs if deemed appropriate. Creating safe spaces, communicating clearly, avoiding victimizing language, explaining procedures, asking for consent before physical contact, and giving patients choice and control in their own care may avoid triggering prior traumas.

Conclusion

Given the high worldwide prevalence of persons experiencing 3 or more ACEs, TIC principles are practical adaptations to chiropractic care for use with many patient populations. As TIC and ACEs are emerging concepts within chiropractic, students and practitioners are encouraged to undertake additional training to better understand these complex and sensitive topics. Exploratory research on the incidence, presentation, and impacts of various trauma types, including ACEs, to support adoption of TIC in chiropractic settings is essential.
Impact of a double catastrophe, war and COVID-19, on health service utilization of a tertiary care hospital in Tigray: an interrupted time-series study
Authors: Abraha Hiluf Ebuy , Tequare Mengistu Hagazi , Teka Hale , Gebremedhin Micheal Berhe , Desta Kibrom Gebreselassie , Ebrahim Mohamedawel Mohamedniguss , Yemane Awol , Gebremariam Sintayehu Misgina , Gebresilassie Kibrom Berhanu , Tekle Tesfay Hailu , Atsbaha Mussie Tesfay , Berhe Ephrem , Berhe Bereket , Berhe Derbew Fikadu , Gebregziabher Mulugeta , Wall L. Lewis
Published: August 2023

Background

In developing nations with fragile healthcare systems, the effect of war is likely to be much worse than it would be in more developed countries. The presence of COVID-19 will also likely exacerbate the war’s impact. This study set out to determine the effect of armed conflict and the COVID-19 pandemic on health service utilization at Ayder Comprehensive Specialized Hospital, in the Tigray region of Ethiopia.

Methods

An interrupted time-series study design was used to analyze patient visits over forty-eight consecutive months (from July 2017 to June 2021) at inpatient, outpatient, and emergency departments. Data were analyzed using segmented regression analysis with a defined outcome of level and trend changes in the number of patient visits. In addition, negative binomial regression analysis was also used to estimate the impact of both COVID-19 and the war on patient flow.

Results

There were 59,935 admissions, 876,533 outpatient visits, and 127,872 emergency room visits. The effect of COVID-19 was seen as soon as the Tigray regional government imposed comprehensive restrictions. Immediately after COVID-19 appeared, all the service areas exhibited a significant monthly drop in visits; [-35.6% (95% CI: -48.2%, -23.1%)] for inpatient, [-60.6% (95% CI: -71.6%, -49.5%)] for outpatient, and [-44.1% (95% CI: -59.5%, -28.7%)] for emergency department visits. The impact of the war became apparent after a lag time of one month. Controlling the effects of time and COVID-19, the war led to a significant fall in inpatient visits [-44.3% (95% CI: -67.2%, -21.5%)], outpatients [-52.1% (95% CI: -82.7%, -21.5%)], and emergency-room attendances [-45.0% (95% CI: -74.8%, -15.2%)]. An upward trend in outpatient flow was observed after the war [1,219.4 (95% CI: 326.1, 2,112.8)].

Conclusions

The present study has clearly indicated that the war and COVID-19 have led to a large reduction in admissions, outpatient attendance, and emergency department visits. The evidence from this study suggests that due to this double catastrophe, thousands of patients could not gain access to healthcare, with probable negative consequences. Governments and organizations should implement measures to buttress the healthcare system to maintain pre-war status of service.
Challenges in the care of patients with RET-altered thyroid cancer: a multicountry mixed-methods study
Authors: Murray Suzanne , Subbiah Vivek , Sherman Steven I. , Péloquin Sophie , Sireci Anthony , Grohé Christian , Bubach Patrick , Lazure Patrice
Published: August 2023

Background

The discovery of driver oncogenes for thyroid carcinomas and the identification of genomically targeted therapies to inhibit those oncogenes have altered the treatment algorithm in thyroid cancer (TC), while germline testing for RET mutations has become indicated for patients with a family history of RET gene mutations or hereditary medullary TC (MTC). In the context of an increasing number of selective RET inhibitors approved for use, this paper aims to describe challenges and barriers affecting providers’ ability to deliver optimal care for patients with RET-altered TC across the patient healthcare journey.

Methods

A mixed-method educational and behavioral needs assessment was conducted in Germany (GER), Japan (JPN), the United Kingdom (UK), and the United States (US) prior to RET-selective inhibitor approval. Participants included medical oncologists (MO), endocrinologists (EN) and clinical pathologists (CP) caring for patients affected with TC. Data collection tools were implemented in three languages (English, German, Japanese). Qualitative data were coded and thematically analyzed in NVivo. Quantitative data were analyzed via frequency and crosstabulations in SPSS. The findings presented here were part of a broader study that also investigated lung cancer challenges and included pulmonologists.

Results

A total of 44 interviews and 378 surveys were completed. Suboptimal knowledge and skills were self-identified among providers, affecting (1) assessment of genetic risk factors (56%, 159/285 of MOs and ENs), (2) selection of appropriate genetic biomarkers (59%, 53/90 of CPs), (3) treatment plan initiation (65%, 173/275 of MOs and ENs), (4) management of side effects associated with multitargeted tyrosine kinase inhibitors (78%, 116/149 of MOs and ENs), and (5) transfer of patients into palliative care services (58%, 160/274 of MOs and ENs). Interviews underscored the presence of systemic barriers affecting the use of RET molecular tests and selective inhibitors, in addition to suboptimal knowledge and skills necessary to manage the safety and efficacy of targeted therapies.

Conclusion

This study describes concrete educational needs for providers involved in the care of patients with RET-altered thyroid carcinomas. Findings can be used to inform the design of evidence-based education and performance improvement interventions in the field and support integration into practice of newly approved RET-selective inhibitors.
Circulating 27-hydroxycholesterol, lipids, and steroid hormones in breast cancer risk: a nested case–control study of the Multiethnic Cohort Study
Authors: DeRouen Mindy C. , Yang Juan , Li Yuqing , Franke Adrian A. , Tome Anne N. , White Kami K. , Hernandez Brenda Y. , Shvetsov Yurii , Setiawan Veronica , Wu Anna H. , Wilkens Lynne R. , Le Marchand Loïc , Loo Lenora W. M. , Cheng Iona
Published: August 2023

Background

Laboratory studies have indicated that a cholesterol metabolite and selective estrogen receptor modulator, 27-hydroxycholesterol (27HC), may be important in breast cancer etiology and explain associations between obesity and postmenopausal breast cancer risk. Epidemiologic evidence for 27HC in breast cancer risk is limited, particularly in multiethnic populations.

Methods

In a nested case–control study of 1470 breast cancer cases and 1470 matched controls within the Multiethnic Cohort Study, we examined associations of pre-diagnostic circulating 27HC with breast cancer risk among African American, Japanese American, Native Hawaiian, Latino, and non-Latino White postmenopausal females. We used multivariable logistic regression adjusted for age, education, parity, body mass index, and smoking status. Stratified analyses were conducted across racial and ethnic groups, hormone receptor (HR) status, and use of lipid-lowering drugs. We assessed interactions of 27HC with steroid hormones.

Results

27HC levels were inversely related to breast cancer risk (odds ratio [OR] 0.80; 95% confidence interval [CI] 0.58, 1.12), but the association was not statistically significant in the full model. Directions of associations differed by racial and ethnic group. Results suggested an inverse association with HR-negative breast cancer (OR 0.46; 95% CI 0.20, 1.06). 27HC interacted with testosterone, but not estrone, on risk of breast cancer; 27HC was only inversely associated with risk among those with the highest levels of testosterone (OR 0.46; 95% CI 0.24, 0.86).

Conclusion

This is the first US study to examine circulating 27HC and breast cancer risk and reports a weak inverse association that varies across racial and ethnic groups and testosterone level.
SCR-6852, an oral and highly brain-penetrating estrogen receptor degrader (SERD), effectively shrinks tumors both in intracranial and subcutaneous ER + breast cancer models
Authors: Zhou Feng , Yang Guimei , Xue Liting , Liu Yajing , Guo Yao , Zhu Ji , Yuan Linlin , Gu Peng , Tang Feng , Shan Jinwen , Tang Renhong
Published: August 2023

Background

Targeted estrogen receptor degradation has been approved to effectively treat ER + breast cancers. Due to the poor bioavailability of fulvestrant, the first generation of SERD, many efforts were made to develop oral SERDs. With the approval of Elacestrant, oral SERDs demonstrated superior efficacy than fulvestrant. However, due to the poor ability of known SERDs to penetrate the blood–brain barrier (BBB), breast cancer patients with brain metastasis cannot benefit from clinical SERDs.

Methods

The ER inhibitory effects were evaluated on ERα protein degradation, and target genes downregulation. And anti-proliferation activities were further determined in a panel of ER + breast cancer cell lines. The subcutaneous and intracranial ER + tumor models were used to evaluate the efficacy of anti-tumor effects. Brain penetrability was determined in multiple animal species.

Results

SCR-6852 is a novel SERD and currently is under early clinical evaluation. In vitro studies demonstrated that it strongly induced both wildtype and mutant ERα degradation. It potently inhibited cell proliferation in a panel of ER + breast cancer cell lines, including the cell lines containing ESR1 mutations (Y537 and D538). Furthermore, SCR-6852 exhibited pure antagonistic activities on the ERɑ signal axis identified both in vitro and in vivo. Oral administration of SCR-6852 at 10 mg/kg resulted in tumor shrinkage which was superior to Fulvestrant at 250 mg/kg, notably, in the intracranial tumor model, SCR-6852 effectively inhibited tumor growth and significantly prolonged mice survival, which correlated well with the high exposure in brains. In addition to mice, SCR-6852 also exhibited high brain penetrability in rats and dogs.

Conclusions

SCR-6852 is a novel SERD with high potency in inducing ERα protein degradation and pure antagonistic activity on ERɑ signaling in vitro and in vivo. Due to the high brain penetrability, SCR-6852 could be used to treat breast patients with brain metastasis.
Translation and validation of urdu version short form-mcgill pain questionnaire-2
Authors: Sharif Amna , Amjad Fareeha , Arslan Syed Asadullah , Ahmad Ashfaq
Published: August 2023

Background

Low back pain is one of the most common complaints affecting many individuals. The McGill Pain Questionnaire is used in various clinical settings to assess different types of pain and one of the most extensively used outcomes measures for pain in the world. The purpose of this study was to translate and validate the original English version of the SF-MPQ-2 into Urdu (SF-MPQ-2-U).

Methods

For this study, Mapi Research Trust protocols were followed for the forward and backward translation. Test-retest reliability was used to assess the reliability. Cronbach’s alpha and Omega was used to determine internal consistency. Pearson’s correlation was used to evaluate convergent validity. Confirmatory factor analysis was also conducted.

Results

The Cronbach’s alpha for SF-MPQ-2-U was 0.73 to 0.79, indicating acceptable internal consistency. Omega score for the SF-MPQ-U were 0.918. The ICC varied from 0.799 to 0.878 for domains of SF-MPQ-2-U. The CFA of the SF-MPQ-2-U met model fit indices with GFI and NFI > 0.90. The inter-scale correlation between baseline and re-test data was from 0.63 to 0.71, indicating a positive and strong correlation. The SF-MPQ-2-U and ODI-U had a baseline correlation of 0.547. The correlation of SF-MPQ-2-U & VAS at baseline data was 0.558. Pearson’s correlation between subscales was r = 0.253 with p 0.01, which was statistically significant.

Conclusion

The SF-MPQ-2-U is considered to have good convergent validity at inter scale and between two scale levels. Reliability was checked by test-retest reliability, Internal consistency was checked using Cronbach’s alpha and Omega that showed good internal consistency for measuring different types of pain in patients with low back pain who speak Urdu. To make the questionnaire more valid and reliable, it is recommended for the researchers to do in-depth research on larger sample size.
The effects of provenance, climate, and chemical defense on the resistance of Pinus pinaster Aiton to Bursaphelenchus xylophilus (Steiner and Buhrer)
Authors: Torres-Sánchez Esteban , Menéndez-Gutiérrez María , Villar Lucía , Díaz Raquel
Published: August 2023

Key message

The resistance of Pinus pinaster Aiton to pinewood nematode Bursaphelenchus xylophilus (Steiner and Buhrer) varied among populations from the Iberian Peninsula, with survival rates for inoculated seedlings ranging from 5 to 100%. These differences in resistance were paralleled by differences in some constitutive chemical defenses. Populations from the southeastern Iberian Peninsula displayed higher resistance than northern populations.

Context

The presence of the pinewood nematode (PWN), Bursaphelenchus xylophilus (Steiner and Buhrer), in Portugal threatens Mediterranean pine species such as Pinus pinaster Aiton.

Aims

We have focused on assessing the resistance of P. pinaster populations to B. xylophilus, looking for any relationship between the PWN resistance and some constitutive chemical defenses and geoclimatic parameters.

Methods

Two-year-old seedlings from 32 provenances and two seed orchards were evaluated in an experiment of artificial inoculation following a randomized complete block design under greenhouse conditions. We measured growth-related traits, response to B. xylophilus inoculations, and constitutive chemical compounds in needles of the evaluated seedlings and compiled geoclimatic data for each population. Mixed models, nonparametric tests, correlations, and PCA were used to analyze the data.

Results

Survival, wilting symptoms, morphological traits, and nematode density varied significantly among populations. Lower concentrations of constitutive polyphenols, lipid-soluble substances, and tannins were related to higher PWN resistance. Populations from the southeast of the Iberian Peninsula showed higher survival rates than those from further north. Additionally, we observed that populations to warm, dry climates showed higher resistance to B. xylophilus than populations originating from humid, temperate climates.

Conclusion

Higher susceptibility to PWN is related to lower growth traits, to lower levels of certain constitutive chemical compounds, and to adaptations to harsher climate.
Burden of neglected tropical diseases and access to medicine and diagnostics in Ethiopia: a scoping review
Authors: Semahegn Agumasie , Manyazewal Tsegahun , Getachew Eyerusalem , Fekadu Bethelhem , Assefa Esubalew , Kassa Munir , Davey Gail , Hopkins Michael , Araya Mesele , Woldehanna Tassew , Hanlon Charlotte , Fekadu Abebaw
Published: August 2023

Background

More than 1.7 billion people are affected by neglected tropical diseases (NTDs) worldwide. Forty percent of the NTD-affected people live in Africa with the poorest, most vulnerable, and hard to reach geographical areas. The NTDs cause significant social and economic burden and deepen marginalization and stigmatization. The World Health Organization’s current roadmap for NTD aims to prevent, control, eliminate, or eradicate 20 tropical diseases. Ethiopia experiences a high burden of these diseases, but current access to diagnostics, medicine, and/or care has been little explored to inform the country’s NTD strategic plan. The overall purpose of the scoping review was to map and characterize the burden of NTDs and challenges in access to diagnostics, medicine, and/or care in Ethiopia.

Methods

A systematic search of evidence was conducted in PubMed, Cochrane Library, and Google Scholar from January 2000 until May 2022, without restrictions of language or study design. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Review was followed for screening of studies. Key findings were extracted and narrated qualitatively.

Results

The search resulted in 4532 articles, of which 105 met the inclusion criteria and were included in the scoping review under three themes: burden of NTDs, access to diagnostics, medicine and/or care, and key barriers. Although gains have been made in the prevention and control of NTDs in Ethiopia, the burden remains high, and progress in access to diagnostics, medicine/drugs, and/or care is very slow. Poverty, poor quality of life, and underfunding of NTD programs decelerate the process of NTD elimination program in the country.

Conclusions

The scoping review identified a considerable number of studies on the burden of NTDs in Ethiopia and strategies for diagnosis, treatment, and/or care; however, there is a paucity of evidence on the suitability and potential benefits of novel diagnostic technologies and medicines in the country. A regular review and analysis of such country-level evidence is important to inform the country NTDs roadmap and local implementation strategies.
Prevalence of gonococcal and chlamydial infections among men who have sex with men in sub-Saharan Africa: protocol for a systematic review and meta-analysis
Authors: Mofolorunsho Kehinde Charles , Dorsamy Vinogrin , Bagwandeen Chauntelle , Abbai Nathlee Samantha
Published: August 2023

Background

Bacterial sexually transmitted infections (STIs) includingNeisseria gonorrhoeaeandChlamydia trachomatisare common in men who have sex with men (MSM). These infections increase the risk of acquiring and transmitting human immunodeficiency virus (HIV) in this key population. Access to MSM in many countries in sub-Saharan Africa remains generally difficult due to discrimination or criminalization of their sexual orientation which could lead to depression and risky sexual practices associated with prevalence. This protocol therefore proposes to undertake a systematic review and meta-analysis of literature on the prevalence of gonococcal and chlamydial infections among MSM in Sub-Saharan Africa.

Methods

This review which aims to ascertain the pooled prevalence and risk factors of these infections in sub-Saharan Africa’s MSM population will follow the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) guidelines. The search strategy will review relevant articles from the following databases: PubMed, Scopus, ISI Web of Science and the Directory of Open Access Journals (DOAJ). Articles screening for eligibility and data extraction will be conducted by two independent reviewers. All discrepancies will be resolved by the third and fourth reviewers. Heterogeneity in studies will be evaluated using theI2statistic and where heterogeneity is high and significant, a random effect model will be used to estimate the pooled prevalence. Publication bias will be assessed using the Doi plot. Extracted data will be analysed using MetaXL add-on for Microsoft excel. Data will be presented in tables and graphically presented in forest plots.

Discussion

In this study, we anticipate being able to systematically determine the prevalence ofNeisseria gonorrhoeaeandChlamydia trachomatisamong MSM as well as explore possible risk factors associated with prevalence. The outcomes of the systematic review and meta-analyses will serve to support researchers and public health stakeholders in identifying healthcare priorities and in addressing issues pertaining to the overall wellbeing of the MSM community.

Systematic review registration

PROSPERO CRD42022327095
Economic costs for outpatient treatment of eating disorders in Japan
Authors: Kurisu Ken , Nohara Nobuhiro , Inada Shuji , Otani Makoto , Noguchi Haruko , Endo Yuka , Sato Yasuhiro , Fukudo Shin , Nakazato Michiko , Yamauchi Tsuneo , Harada Tomoko , Inoue Koki , Hata Tomokazu , Takakura Shu , Sudo Nobuyuki , Iida Naoko , Mizuhara Yuki , Wada Yoshihisa , Ando Tetsuya , Yoshiuchi Kazuhiro
Published: August 2023

Background

Few studies have examined the economic costs of outpatient care for eating disorders in Japan. This study aimed to clarify the reimbursement for outpatient treatment of eating disorders and compare the costs between the departments of Psychosomatic Medicine and Psychiatry in Japan.

Method

A multicenter, prospective, observational study of patients with an eating disorder was conducted in the Psychosomatic Medicine departments of three centers and the Psychiatry departments of another three centers in Japan. We analyzed medical reimbursement for an outpatient revisit, time of clinical interviews, and the treatment outcome measured by the Eating Disorder Examination Questionnaire (EDE-Q) global scores and body mass index (BMI) at 3 months. Multivariate linear regression models were performed to adjust for covariates.

Results

This study included 188 patients in the Psychosomatic Medicine departments and 68 in the Psychiatry departments. The average reimbursement cost for an outpatient revisit was 4670 yen. Even after controlling for covariates, the Psychosomatic Medicine departments had lower reimbursement points per minute of interviews than the Psychiatry departments (coefficient = − 23.86; 95% confidence interval = − 32.09 to − 15.63; P < 0.001). In contrast, EDE-Q global scores and BMI at 3 months were not significantly different between these departments.

Conclusions

This study clarifies the economic costs of treating outpatients with eating disorders in Japan. The medical reimbursement points per interview minute were lower in Psychosomatic Medicine departments than in Psychiatry departments, while there were no apparent differences in the treatment outcomes. Addressing this issue is necessary to provide an adequate healthcare system for patients with eating disorders in Japan.
Cathepsin B abundance, activity and microglial localisation in Alzheimer’s disease-Down syndrome and early onset Alzheimer’s disease; the role of elevated cystatin B
Authors: Wu Yixing , Mumford Paige , Noy Suzanna , Cleverley Karen , Mrzyglod Alicja , Luo Dinghao , van Dalen Floris , Verdoes Martijn , Fisher Elizabeth M. C. , Wiseman Frances K.
Published: August 2023

Cathepsin B is a cysteine protease that is implicated in multiple aspects of Alzheimer’s disease pathogenesis. The endogenous inhibitor of this enzyme, cystatin B (CSTB) is encoded on chromosome 21. Thus, individuals who have Down syndrome, a genetic condition caused by having an additional copy of chromosome 21, have an extra copy of an endogenous inhibitor of the enzyme. Individuals who have Down syndrome are also at significantly increased risk of developing early-onset Alzheimer’s disease (EOAD). The impact of the additional copy of CSTB on Alzheimer’s disease development in people who have Down syndrome is not well understood. Here we compared the biology of cathepsin B and CSTB in individuals who had Down syndrome and Alzheimer’s disease, with disomic individuals who had Alzheimer’s disease or were ageing healthily. We find that the activity of cathepsin B enzyme is decreased in the brain of people who had Down syndrome and Alzheimer’s disease compared with disomic individuals who had Alzheimer’s disease. This change occurs independently of an alteration in the abundance of the mature enzyme or the number of cathepsin B+ cells. We find that the abundance of CSTB is significantly increased in the brains of individuals who have Down syndrome and Alzheimer’s disease compared to disomic individuals both with and without Alzheimer’s disease. In mouse and human cellular preclinical models of Down syndrome, three-copies of CSTB increases CSTB protein abundance but this is not sufficient to modulate cathepsin B activity. EOAD and Alzheimer’s disease-Down syndrome share many overlapping mechanisms but differences in disease occur in individuals who have trisomy 21. Understanding this biology will ensure that people who have Down syndrome access the most appropriate Alzheimer’s disease therapeutics and moreover will provide unique insight into disease pathogenesis more broadly.
Issues of virtual fashion influencers’ reproduced bodies: a qualitative analysis based on body discourse
Authors: Shin Yeongyo , Lee Selee
Published: August 2023

A recent development in the fashion industry, where digital transformation has accelerated, has been the birth and rise of virtual fashion influencers. With their close imitation of the human body and how active they are on social media, their influence on the fashion industry is gradually growing. The purpose of this study is to explore the trends in the activities of virtual fashion influencers and to determine the main issues in their body representation by identifying the types and current status of their reproduced bodies. One hundred and fifteen virtual fashion influencers who are active in the global fashion industry were selected as the research subjects and observed with a focus on their body reproduction. Our qualitative analysis is based on Rosi Braidotti’s theory on posthumans’ existence and body of subjectivity formation discourse. Based on the above theories, these reproduced bodies can suggest the following issues related to the risks of modern society: (1) the reproduction of standardized stereotypes, (2) the expression of the male gaze, power, and desire, and (3) colonial gender hierarchy.
Intramuscular Tendon Injuries of the Hamstring Muscles: A More Severe Variant? A Narrative Review
Authors: Kerin Fearghal , O’Flanagan Stuart , Coyle Joe , Farrell Garreth , Curley Darragh , McCarthy Persson Ulrik , De Vito Giuseppe , Delahunt Eamonn
Published: August 2023

Hamstring strain injuries (HSI) are one of the most common sport-related injuries. They have a high injury burden and a high recurrence rate. The development of novel muscle injury grading systems has provided new insights into the possible impact of injury location on the time to return to play (TTRTP) and re-injury following HSI. In particular, injuries to the intramuscular tendon (IMT) may be present in up to 41% of all HSI and have been described as a ‘serious thigh muscle strain’. Re-injury rates as high as 60% have been described in elite track and field athletes, as well as prolonged TTRTP. A systematic search was carried out using appropriate keywords to identify articles reporting on HSI involving the IMT in athletes. The primary aim was to determine whether IMT injuries warrant being classified as a distinct clinical entity with different expected outcomes to other hamstring muscle injuries. This narrative review summarises the existing evidence on: (1) the anatomy of the IMT and its response to injury; (2) the role of MRI and novel grading scales in IMT injury management (3) clinical assessment of IMT injuries, (4) TTRTP and re-injury rates across sports following IMT, (5) conservative rehabilitation and the role of specific ‘IMT-oriented’ strategies, and (6) indications for and approaches to surgery. The review found that important clinical outcomes such as re-injury rates and TTRTP vary across populations, cohorts and sports which suggest that outcomes are specific to the sporting context. Bespoke rehabilitation, tailored to IMT injury, has been shown to significantly reduce re-injuries in elite track and field athletes, without compromising TTRTP. Continued prospective studies across other sports and cohorts, are warranted to further establish relevant clinical findings, indications for surgical intervention and outcomes across other sporting cohorts.
Participatory evaluation of the process of co-producing resources for the public on data science and artificial intelligence
Authors: Teodorowski Piotr , Gleason Kelly , Gregory Jonathan J. , Martin Martha , Punjabi Reshma , Steer Suzanne , Savasir Serdar , Vema Pournamy , Murray Kabelo , Ward Helen , Chapko Dorota
Published: August 2023

Background

The growth of data science and artificial intelligence offers novel healthcare applications and research possibilities. Patients should be able to make informed choices about using healthcare. Therefore, they must be provided with lay information about new technology. A team consisting of academic researchers, health professionals, and public contributors collaboratively co-designed and co-developed the new resource offering that information. In this paper, we evaluate this novel approach to co-production.

Methods

We used participatory evaluation to understand the co-production process. This consisted of creative approaches and reflexivity over three stages. Firstly, everyone had an opportunity to participate in three online training sessions. The first one focused on the aims of evaluation, the second on photovoice (that included practical training on using photos as metaphors), and the third on being reflective (recognising one’s biases and perspectives during analysis). During the second stage, using photovoice, everyone took photos that symbolised their experiences of being involved in the project. This included a session with a professional photographer. At the last stage, we met in person and, using data collected from photovoice, built the mandala as a representation of a joint experience of the project. This stage was supported by professional artists who summarised the mandala in the illustration.

Results

The mandala is the artistic presentation of the findings from the evaluation. It is a shared journey between everyone involved. We divided it into six related layers. Starting from inside layers present the following experiences (1) public contributors had space to build confidence in a new topic, (2) relationships between individuals and within the project, (3) working remotely during the COVID-19 pandemic, (4) motivation that influenced people to become involved in this particular piece of work, (5) requirements that co-production needs to be inclusive and accessible to everyone, (6) expectations towards data science and artificial intelligence that researchers should follow to establish public support.

Conclusions

The participatory evaluation suggests that co-production around data science and artificial intelligence can be a meaningful process that is co-owned by everyone involved.