bluuebunny/crossref_metadata_2025 huggingface dataset:
Laminoplasty with selective fusion at unstable segment versus laminectomy with fusion for multilevel cervical myelopathy: a case‐control study
Authors: Du Lin , Gao Yanzheng , Zhao Changqing , Zhou Tangjun , Tian Haijun , Zhang Kai , Zhao Jie
Published: May 2021

Background

Segmental cervical instability is a risk factor for the progression of osteophytic bone spurs and development of myelopathy, and is treated as a relative contraindication of cervical laminoplasty. The aim of this study was to compare laminoplasty with selective fixation (LPSF) versus laminectomy with fusion (LCF) in patients with multilevel cervical myelopathy accompanied by segmental instability.

Methods

A case-control study was conducted by reviewing data from 63 patients who underwent LPSF (n = 30) or LCF (n = 33). Cervical alignment, range of motion (ROM), neurologic status and axial symptom severity pre-operation, 3-days after operation, and at the final follow-up (minimum 24 months) were measured and compared between groups.

Results

Postoperation, patients in the LPSF group lost 31.1 ± 17.3 % of cervical lordosis and 43.2 ± 10.9 % cervical ROM while patients in the LCF group lost 5.7 ± 8.2 % and 67.9 ± 15.5 %, respectively. Both LPSF and LCF groups significantly improved neurologic status and axial symptom severity at the final follow-up with similar between-group results(P > 0.05). Blood loss, operation time, hospital stay, and medical cost in the LPSF group were significantly less than in the LCF group(P < 0.05).

Conclusions

In 2 years of clinical observation, LPSF was effective in maintaining the stability of the cervical spine with less sacrifice of mobility and surgical trauma for multilevel myelopathy with segmental instability compared to LCF.
Multiple intravenous tranexamic acid doses in total knee arthroplasty in patients with rheumatoid arthritis: a randomized controlled study
Authors: Kang Bing-xin , Xu Hui , Gao Chen-xin , Zhong Sheng , Zhang Jing , Xie Jun , Sun Song-tao , Ma Ying-hui , Xu Xi-rui , Zhao Chi , Zhai Wei-tao , Xiao Lian-bo , Gao Xiao-jun
Published: May 2021

Background

We aimed to determine the efficacy and safety of multiple doses of intravenous tranexamic acid (IV-TXA) on perioperative blood loss in patients with rheumatoid arthritis (RA) who had undergone primary unilateral total knee arthroplasty (TKA).

Methods

For this single-center, single-blind randomized controlled clinical trial, 10 male and 87 female participants with RA, aged 50–75 years, who underwent unilateral primary TKA were recruited. The patients received one dose of 1 g IV-TXA 10 min before skin incision, followed by articular injection of 1.5 g tranexamic acid after cavity suture during the surgery. The patients were randomly assigned (1:1) into two groups and received an additional single dose of IV-TXA (1 g) for 3 h (group A) or three doses of IV-TXA (1 g) for 3, 6, and 12 h (group B) postoperatively. Primary outcomes were total blood loss (TBL), hidden blood loss (HBL), and maximum hemoglobin (Hb) level decrease. Secondary outcomes were transfusion rate and D-dimer levels. All parameters were measured postoperatively during inpatient hospital stay.

Results

The mean TBL, HBL, and maximum Hb level decrease in group B (506.1 ± 227.0 mL, 471.6 ± 224.0 mL, and 17.5 ± 7.7 g/L, respectively) were significantly lower than those in group A (608.8 ± 244.8 mL, P = 0.035; 574.0 ± 242.3 mL, P = 0.033; and 23.42 ± 9.2 g/L, P = 0.001, respectively). No episode of transfusion occurred. The D-dimer level was lower in group B than in group A on postoperative day 1 (P <  0.001), and the incidence of thromboembolic events was similar between the groups (P > 0.05).

Conclusion

In patients with RA, three doses of postoperative IV-TXA further facilitated HBL and Hb level decrease without increasing the incidence of adverse events in a short period after TKA.

Trial registration

The trial was registered in the Chinese Clinical Trial Registry (ChiCTR1900025013).
Electromyographic features and efficacy of orofacial myofunctional treatment for skeletal anterior open bite in adolescents: an exploratory study
Authors: Hong Hong , Zeng Yue , Chen Xiaomin , Peng Caixia , Deng Jianqing , Zhang Xueqin , Deng Lidi , Xie Yongjian , Wu Liping
Published: May 2021

Background

Due to the multifactorial aetiology and unpredictable long-term stability, skeletal anterior open bite (SAOB) is one of the most intractable conditions for orthodontists. The abnormal orofacial myofunctional status (OMS) may be a major risk factor contributing to the development and relapse of SAOB. This study is aimed at evaluating the OMS and the efficacy of orofacial myofunctional therapy (OMT) alone for SAOB subjects.

Methods

Eighteen adolescents with SAOB (4 males, 14 females; age: 12–18 years) and eighteen adolescents with normal occlusion (2 males, 16 females; age: 12–18 years) were selected. The electromyographic activity (EMGA) associated with mastication and closed mouth state was measured. Lateral cephalography was used to evaluate craniofacial morphology. Wilcoxon signed rank tests and t-tests were performed to evaluate myofunctional and morphological differences. Pearson or Spearman correlation analysis was used to investigate the correlations between EMGA and morphological characteristics. SAOB subjects were given OMT for 3 months, and the EMGA was compared between before and after OMT.

Results

During rest, anterior temporalis activity (TAA) and mentalis muscle activity (MEA) increased in SAOB subjects, but TAA and masseter muscle activity (MMA) decreased in the intercuspal position (ICP); and upper orbicularis activity (UOA) and MEA significantly increased during lip sealing and swallowing (P < 0.05). Morphological evaluation revealed increases in the FMA, GoGn-SN, ANS-Me, N-Me, L1-MP, U6-PP, and L6-MP and decreases in the angle of the axis of the upper and lower central incisors and OB in SAOB subjects (P < 0.05). TAA, MMA and anterior digastric activity (DAA) in the ICP were negatively correlated with vertical height and positively correlated to incisor protrusion. MEA was positively correlated with vertical height and negatively correlated with incisor protrusion; and the UOA showed a similar correlation in ICP, during sealing lip and swallowing. After SAOB subjects received OMT, MEA during rest and TAA, MMA and DAA in the ICP increased, while UOA and MEA decreased (P < 0.05).

Conclusion

SAOB subjects showed abnormal OMS features including aberrant swallowing patterns and weak masticatory muscles, which were interrelated with the craniofacial dysmorphology features including a greater anterior facial height and incisor protrusion. Furthermore, OMT contributes to OMS harmonization, indicating its therapeutic prospect in SAOB.
Variability of risk factors and diabetes complications
Authors: Ceriello Antonio , Prattichizzo Francesco
Published: May 2021

Several studies suggest that, together with glucose variability, the variability of other risk factors, as blood pressure, plasma lipids, heart rate, body weight, and serum uric acid, might play a role in the development of diabetes complications. Moreover, the variability of each risk factor, when contemporarily present, may have additive effects. However, the question is whether variability is causal or a marker. Evidence shows that the quality of care and the attainment of the target impact on the variability of all risk factors. On the other hand, for some of them causality may be considered. Although specific studies are still lacking, it should be useful checking the variability of a risk factor, together with its magnitude out of the normal range, in clinical practice. This can lead to an improvement of the quality of care, which, in turn, could further hesitate in an improvement of risk factors variability.
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and cardiac arrhythmias: a systematic review and meta-analysis
Authors: Li Hang-Long , Lip Gregory Y. H. , Feng Qi , Fei Yue , Tse Yi-Kei , Wu Mei-zhen , Ren Qing-wen , Tse Hung-Fat , Cheung Bernard-M. Y. , Yiu Kai-Hang
Published: May 2021

Background

Cardiac arrhythmias are associated with poorer outcomes in patients with heart failure (HF), diabetes mellitus (DM), and chronic kidney disease (CKD). Previous studies have shown inconsistent conclusions regarding the association between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the risk of developing arrhythmias. This study aims to investigate the association of SGLT2i treatment with arrhythmia outcomes in clinical trials of patients with HF, DM, or CKD.

Methods

MEDLINE, EMBASE, and ClinicalTrials.gov were searched from inception up to 27 August 2020. Randomized controlled trials that randomized patients with DM, CKD, or HF to SGLT2i or placebo were included. The outcomes of interest include atrial fibrillation (AF), embolic stroke, atrial flutter (AFL), AF/AFL, ventricular tachycardia (VT), and cardiac arrest. Relative risks (RRs) and 95% confidence intervals (CI) were pooled using a random-effects model.

Results

Out of 4,532 citations, 22 trials with altogether 52,115 patients were included (mean age 63.2 years; 33,747 [64.8%] of participants were men). SGLT2i were associated with a lower risk of AF (RR 0.82, 95% CI 0.70–0.96), embolic stroke (RR 0.32, 95% CI 0.12–0.85), AF/AFL (RR 0.82, 95% CI 0.71–0.95), and VT (RR 0.73, 95% CI 0.53–0.99), while the risk reductions in AFL (RR 0.83, 95% CI 0.58–1.17) and cardiac arrest (RR 0.83, 95% CI 0.61–1.14) did not reach statistical significance. The associations appeared to be consistent across different baseline conditions (DM vs CKD vs HF; atherosclerotic cardiovascular disease [ASCVD] vs no ASCVD) and the SGLT2i used.

Conclusions

SGLT2i reduced the risk of cardiac arrhythmias. Our study provides further evidence for recommending the use of SGLT2i in patients with DM, CKD, and HF. Further research is needed to fully elucidate the mechanism by which SGLT2i protect against arrhythmias.
Identification and validation of a hypoxia-related prognostic and immune microenvironment signature in bladder cancer
Authors: Sun Xianchao , Zhou Zhen , Zhang Ying , Wang Jinyou , Zhao Xiaofeng , Jin Liang , Zhai Tingshuai , Liu Xiang , Zhang Jiaxin , Mei Wangli , Zhang Bihui , Luo Ming , Yao Xudong , Ye Lin
Published: May 2021

Background

Bladder cancer is the leading causes of cancer-associated mortality and seriously affects population health. Hypoxia plays a key role in tumor development and immune escape, which contributes to malignant behaviors.

Methods

In this study, we analyzed the RNA-seq and clinical information of bladder cancer patients from The Cancer Genome Atlas (TCGA) database. To investigate the hypoxia-related prognostic and immune microenvironment in bladder cancer, we constructed a hypoxia-related risk model for overall survival (OS). The RNA-seq and clinical data of bladder cancer patients from the Gene Expression Omnibus (GEO) database were used as validation sets.

Results

The hypoxia-related risk signature was significantly correlated with clinical outcomes and could independently predict OS outcomes. Furthermore, the hypoxia-related risk signature could effectively reflected the levels of immune cell type fractions and the expression of critical immune checkpoint genes were higher in the high-risk group compared to the low-risk group. We also validated the expression levels of the prognostic genes in bladder cancer and paracancerous tissue samples through qRT-PCR analysis.

Conclusion

We established a 7 hypoxia-related gene (HRG) signature that can be used as an independent clinical predictor and provided a potential mechanism in bladder cancer immunotherapy.
Spatio-temporal associations of air pollutant concentrations, GP respiratory consultations and respiratory inhaler prescriptions: a 5-year study of primary care in the borough of Lambeth, South London
Authors:   on behalf of the STEAM project research group, Ashworth Mark , Analitis Antonis , Whitney David , Samoli Evangelia , Zafeiratou Sofia , Atkinson Richard , Dimakopoulou Konstantina , Beavers Sean , Schwartz Joel , Katsouyanni Klea
Published: May 2021

Background

Although the associations of outdoor air pollution exposure with mortality and hospital admissions are well established, few previous studies have reported on primary care clinical and prescribing data. We assessed the associations of short and long-term pollutant exposures with General Practitioner respiratory consultations and inhaler prescriptions.

Methods

Daily primary care data, for 2009–2013, were obtained from Lambeth DataNet (LDN), an anonymised dataset containing coded data from all patients (1.2 million) registered at general practices in Lambeth, an inner-city south London borough. Counts of respiratory consultations and inhaler prescriptions by day and Lower Super Output Area (LSOA) of residence were constructed. We developed models for predicting daily PM2.5, PM10, NO2 and O3 per LSOA. We used spatio-temporal mixed effects zero inflated negative binomial models to investigate the simultaneous short- and long-term effects of exposure to pollutants on the number of events.

Results

The mean concentrations of NO2, PM10, PM2.5 and O3 over the study period were 50.7, 21.2, 15.6, and 49.9 μg/m3 respectively, with all pollutants except NO2 having much larger temporal rather than spatial variability. Following short-term exposure increases to PM10, NO2 and PM2.5 the number of consultations and inhaler prescriptions were found to increase, especially for PM10 exposure in children which was associated with increases in daily respiratory consultations of 3.4% and inhaler prescriptions of 0.8%, per PM10 interquartile range (IQR) increase. Associations further increased after adjustment for weekly average exposures, rising to 6.1 and 1.2%, respectively, for weekly average PM10 exposure. In contrast, a short-term increase in O3 exposure was associated with decreased number of respiratory consultations. No association was found between long-term exposures to PM10, PM2.5 and NO2 and number of respiratory consultations. Long-term exposure to NO2 was associated with an increase (8%) in preventer inhaler prescriptions only.

Conclusions

We found increases in the daily number of GP respiratory consultations and inhaler prescriptions following short-term increases in exposure to NO2, PM10 and PM2.5. These associations are more pronounced in children and persist for at least a week. The association with long term exposure to NO2 and preventer inhaler prescriptions indicates likely increased chronic respiratory morbidity.
A new pathological classification of intrahepatic cholangiocarcinoma according to protein expression of SSTR2 and Bcl2
Authors: Yamashita Shoko , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Saito Yu , Takasu Chie , Yamada Shinichiro , Tokuda Kazunori , Okikawa Shohei , Miyazaki Katsuki , Oya Takeshi , Tsuneyama Koichi , Shimada Mitsuo
Published: May 2021

Background

No universal classification method for intrahepatic cholangiocarcinoma (IHCC) has been reported based on the embryological origin of biliary epithelial cells. The aim of this study was to classify IHCC according to protein expression levels of somatostatin receptor 2 (SSTR2) and b-cell leukemia/lymphoma 2 (Bcl2) and to elucidate the clinicopathological features of each group.

Methods

Fifty-two IHCC patients who underwent hepatic resection were enrolled in this study. Protein expression levels of SSTR2 and Bcl2 were examined using immunohistochemistry. Clinicopathological factors were compared between the three groups and prognostic factors were investigated.

Results

The patients were divided into three groups: SSTR2 positive and Bcl2 negative (p-Group H, n = 21), SSTR2 negative and Bcl2 positive (p-Group P, n = 14), and the indeterminate group (p-Group U, n = 17) for cases where SSTR2 and Bcl2 were both positive or both negative. All p-Group P cases displayed curability A or B. The 5-year survival rates of p-Group H and U patients were worse than those in p-Group P. p-Group H had higher T-factor, clinical stage, and incidence of periductal infiltration than p-Group P.

Conclusions

This method could be used to classify IHCC into peripheral and perihilar type by embryological expression patterns of SSTR2 and Bcl2.
Methylation as a key regulator of Tau aggregation and neuronal health in Alzheimer’s disease
Authors: Balmik Abhishek Ankur , Chinnathambi Subashchandrabose
Published: May 2021

Neurodegenerative diseases like Alzheimer’s, Parkinson’s and Huntington’s disease involves abnormal aggregation and accumulation of toxic proteins aggregates. Post-translational modifications (PTMs) of the causative proteins play an important role in the etiology of disease as they could either slow down or accelerate the disease progression. Alzheimer disease is associated with the aggregation and accumulation of two major protein aggregates—intracellular neurofibrillary tangles made up of microtubule-associated protein Tau and extracellular Amyloid-β plaques. Post-translational modifications are important for the regulation of Tau`s function but an imbalance in PTMs may lead to abnormal Tau function and aggregation. Tau methylation is one of the important PTM of Tau in its physiological state. However, the methylation signature on Tau lysine changes once it acquires pathological aggregated form. Tau methylation can compete with other PTMs such as acetylation and ubiquitination. The state of PTM at these sites determines the fate of Tau protein in terms of its function and stability. The global methylation in neurons, microglia and astrocytes are involved in multiple cellular functions involving their role in epigenetic regulation of gene expression via DNA methylation. Here, we have discussed the effect of methylation on Tau function in a site-specific manner and their cross-talk with other lysine modifications. We have also elaborated the role of methylation in epigenetic aspects and neurodegenerative conditions associated with the imbalance in methylation metabolism affecting global methylation state of cells.
Suicide mortality data from the Italian police during the COVID-19 pandemic
Authors: Garbarino Sergio , Fornaro Michele , Messina Rita , Pompili Maurizio , Ciprani Fabrizio
Published: May 2021

Suicide is a major public health issue worldwide, with about 880,000 dying annually for such a cause. The COVID-19 pandemic has led to severe social disruption both from health and economic standpoints. Law enforcement personnel have been significantly involved in helping to face the many difficulties due to the pandemic. Police officers have been subjected to further stress from managing social restrictions imposed by governments to contain the pandemic. The Italian State Police steadily approximate 100,000 people aged 25–65 years: 14 subjects (mean age 43.64 years) died by suicide in 2015, 7 (mean age 47.5 years) in 2016, 13 (mean age 45.62 years) in 2017, 10 (mean age 48.1 years) in 2018, 18 (mean age 46.78 years) in 2019, and 12 (mean age 52 years) in 2020. Our records excluded significant changes in suicide incidence rate within 2015–2020 (till December 2020). However, the COVID-19 pandemic spread faster in Italy than in other regions, meaning that the Italian State Police possibly faced prolonged, intense stress. Suicide prevention, therefore, remains a priority, especially during this difficult time.
Systematic review of experiences and perceptions of key actors and organisations at multiple levels within health systems internationally in responding to COVID-19
Authors: Turner Simon , Botero-Tovar Natalia , Herrera Maria Alejandra , Borda Kuhlmann Juan Pablo , Ortiz Francisco , Ramírez Jean Carlo , Maldonado Luisa Fernanda
Published: May 2021

Background

COVID-19 has presented challenges to healthcare systems and healthcare professionals internationally. After one year of the pandemic, the initial evidence on health system responses begins to consolidate, and there is a need to identify and synthesise experiences of responding to COVID-19 among healthcare professionals and other health system stakeholders. This systematic review of primary qualitative studies depicts the experiences and perceptions of organisations and actors at multiple levels of health systems internationally in responding to COVID-19.

Methods

Six main databases of biomedical information, public health and health administration research were searched over the period October 1, 2019, to October 21, 2020. Information extracted from included studies was analysed thematically.

Results

Thirty-four studies were eligible for data extraction. Nine of those studies, of lower methodological quality, were removed from the thematic analysis of study results. Considering the professional level experiences, predominant themes of the studies consisted of the new roles and responsibilities of healthcare workers, burnout and distress, recognition of ´unseen´ healthcare workers, and positive changes and emergent solutions amid the crisis. Organisational level findings of the studies included provision of psychological support, COVID-19 as "catalyst" for change, and exercise of more "open" leadership by managers and health authorities. Continuous training, regulation of working conditions, providing supportive resources, coordinating a diversity of actors, and reviewing and updating regulations were roles identified  at the local health system level.

Conclusions

The experiences of frontline healthcare workers have been the focus of attention of the majority of primary qualitative studies as of October 2020. However, organisational and wider system level studies indicate that some responses to COVID-19 have been characterised by increased emphasis on coordination activities by local health system actors, making service adaptations at pace, and reliance on expanded roles of front-line workers. The need for theory-informed qualitative studies was identified at the organisational level.

Trial registration

CRD42020202875
Blocking circ-CNST suppresses malignant behaviors of osteosarcoma cells and inhibits glycolysis through circ-CNST-miR-578-LDHA/PDK1 ceRNA networks
Authors: Hu Rui , Chen Shan , Yan Jianxin
Published: May 2021

Background

CircRNA CNST (circ-CNST) is a newly identified biomarker for prognosis of osteosarcoma (OS). However, its role in OS progression remains to be well documented.

Methods

Expression of circ-CNST, microRNA (miR)-578, lactate dehydrogenase A (LDHA), and pyruvate dehydrogenase kinase 1 (PDK1) was detected by quantitative real-time polymerase chain reaction and Western blotting. The physical interaction was confirmed by dual-luciferase reporter assay. Cell behaviors and glycolysis were measured by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay, colony formation assay, flow cytometry, transwell assays, xenograft experiment, and commercial kits.

Results

Circ-CNST was upregulated in human OS tissues and cells, accompanied with downregulation of miR-578 and upregulation of LDHA and PDK1. There were negative correlations between miR-578 expression and circ-CNST or LDHA/PDK1 in OS tissues. Moreover, high circ-CNST/LDHA/PDK1 or low miR-578 might predict shorter overall survival, advanced TNM stages, and lymph node metastasis. Physically, miR-578 was targeted by circ-CNST, and miR-578 could target LDHA/PDK1. Functionally, blocking circ-CNST and restoring miR-578 enhanced apoptosis rate and suppressed cell proliferation, colony formation, migration, and invasion in 143B and U2OS cells, accompanied with decreased glucose consumption, lactate production, and adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio. Furthermore, in vivo growth of U2OS cells was retarded by silencing circ-CNST. Depletion of miR-578 could counteract the suppressive role of circ-CNST deficiency in 143B and U2OS cells, and restoring LDHA or PDK1 partially reversed the role of miR-578 inhibition as well.

Conclusion

Circ-CNST knockdown could antagonize malignant behaviors and glycolysis of OS cells by regulating miR-578-LDHA/PDK1 axes.
The effect of sacrificing the posterior cruciate ligament on total knee arthroplasty with cruciate retaining highly congruent rotating platform prosthesis
Authors: Chen Long , Xu Jie , Lin Yuan , Luo Fen Qi , Yu Yu Guo
Published: May 2021

Objective

To analyze the effect of sacrificing the posterior cruciate ligament (PCL) on the early postoperative outcome of cruciate retaining (CR) highly congruent rotating platform TKA.

Methods

From May 2018 to September 2019, 105 cases of total knee arthroplasty (TKA) with CR highly congruent rotating platform prosthesis were retrospectively analyzed. According to the tension of posterior cruciate ligament, they were divided into sacrifice group (29 cases, 27.6%) and retention group (76 cases, 72.4%). Preoperative and postoperative The Hospital for Special Surgery (HSS) score, range of motion (ROM) were compared between the two groups. In addition, postoperative infection, prosthesis loosening, bearing dislocation, and other complications were also compared.

Results

All patients were followed up for 11~24 months (mean 18.14 ± 3.52) months. There was no significant difference in general data, preoperative HSS score, and ROM between the two groups (P > 0.05). At the last follow-up, HSS score and ROM of the two groups were better than those before operation (P < 0.05). However, there was no significant difference between the two groups (P > 0.05). Moreover, there were no complications such as infection, loosening of prosthesis, and bearing dislocation in all cases.

Conclusion

In CR, highly congruent rotating platform TKA with or without tension of the PCL can achieve satisfactory outcomes. Tension-free PCL do not cause joint instability.
Model organisms contribute to diagnosis and discovery in the undiagnosed diseases network: current state and a future vision
Authors:   Undiagnosed Diseases Network, Baldridge Dustin , Wangler Michael F. , Bowman Angela N. , Yamamoto Shinya , Schedl Tim , Pak Stephen C. , Postlethwait John H. , Shin Jimann , Solnica-Krezel Lilianna , Bellen Hugo J. , Westerfield Monte
Published: May 2021

Decreased sequencing costs have led to an explosion of genetic and genomic data. These data have revealed thousands of candidate human disease variants. Establishing which variants cause phenotypes and diseases, however, has remained challenging. Significant progress has been made, including advances by the National Institutes of Health (NIH)-funded Undiagnosed Diseases Network (UDN). However, 6000–13,000 additional disease genes remain to be identified. The continued discovery of rare diseases and their genetic underpinnings provides benefits to affected patients, of whom there are more than 400 million worldwide, and also advances understanding the mechanisms of more common diseases. Platforms employing model organisms enable discovery of novel gene-disease relationships, help establish variant pathogenicity, and often lead to the exploration of underlying mechanisms of pathophysiology that suggest new therapies. The Model Organism Screening Center (MOSC) of the UDN is a unique resource dedicated to utilizing informatics and functional studies in model organisms, including worm (Caenorhabditis elegans), fly (Drosophila melanogaster), and zebrafish (Danio rerio), to aid in diagnosis. The MOSC has directly contributed to the diagnosis of challenging cases, including multiple patients with complex, multi-organ phenotypes. In addition, the MOSC provides a framework for how basic scientists and clinicians can collaborate to drive diagnoses. Customized experimental plans take into account patient presentations, specific genes and variant(s), and appropriateness of each model organism for analysis. The MOSC also generates bioinformatic and experimental tools and reagents for the wider scientific community. Two elements of the MOSC that have been instrumental in its success are (1) multidisciplinary teams with expertise in variant bioinformatics and in human and model organism genetics, and (2) mechanisms for ongoing communication with clinical teams. Here we provide a position statement regarding the central role of model organisms for continued discovery of disease genes, and we advocate for the continuation and expansion of MOSC-type research entities as a Model Organisms Network (MON) to be funded through grant applications submitted to the NIH, family groups focused on specific rare diseases, other philanthropic organizations, industry partnerships, and other sources of support.
Violence against healthcare in conflict: a systematic review of the literature and agenda for future research
Authors: Haar Rohini J. , Read Róisín , Fast Larissa , Blanchet Karl , Rinaldi Stephanie , Taithe Bertrand , Wille Christina , Rubenstein Leonard S.
Published: May 2021

Background

Attacks on health care in armed conflict, including those on health workers, facilities, patients and transports, represent serious violations of human rights and international humanitarian law. Information about these incidents and their characteristics are available in myriad forms: as published research or commentary, investigative reports, and within online data collection initiatives. We review the research on attacks on health to understand what data they rely on, what subjects they cover and what gaps exist in order to develop a research agenda going forward.

Methods and findings

This study utilizes a systematic review of peer-reviewed to identify and understand relevant data about attacks on health in situations of conflict. We identified 1479 papers published before January 1, 2020 using systematic and hand-searching and chose 45 articles for review that matched our inclusion criteria. We extracted data on geographical and conflict foci, methodology, objectives and major themes. Among the included articles, 26 focused on assessment of evidence of attacks, 15 on analyzing their impacts, three on the legal and human rights principles and one on the methods of documentation. We analyzed article data to answer questions about where and when attacks occur and are investigated, what types of attacks occur, who is perpetrating them, and how and why they are studied. We synthesized cross-cutting themes on the impacts of these attacks, mitigation efforts, and gaps in existing data.

Conclusion

Recognizing limitations in the review, we find there have been comparatively few studies over the past four decades but the literature is growing. To deepen the discussions of the scope of attacks and to enable cross-context comparisons, documentation of attacks on health must be enhanced to make the data more consistent, more thorough, more accessible, include diverse perspectives, and clarify taxonomy. As the research on attacks on health expands, practical questions on how the data is utilized for advocacy, protection and accountability must be prioritized.
circPVT1 regulates medullary thyroid cancer growth and metastasis by targeting miR-455-5p to activate CXCL12/CXCR4 signaling
Authors: Zheng Xun , Rui Shu , Wang Xiao-Fei , Zou Xiu-He , Gong Yan-Ping , Li Zhi-Hui
Published: May 2021

Background

Medullary thyroid cancer (MTC) represents 13.4 % of all thyroid cancers-related deaths. The treatments for MTC are very limited especially for patients with distal metastasis. Therefore, it is critical to understand the mechanisms of MTC to pursue novel therapeutic avenues. Here, we studied the function of circPVT1/miR-455-5p in MTC.

Methods

Human MTC tissues and cell lines were used. qRT-PCR and Western blotting were employed to measure expression levels of miR-455-5p, circPVT1, CXCL12, and epithelial mesenchymal transformation (EMT)-related proteins. Colony formation assay, flow cytometry, transwell assay, and scratch wound healing assay were used to assess the abilities of cell proliferation, apoptosis, migration and invasion, respectively. Dual luciferase assay and RNA immunoprecipitation were employed to validate interactions of circPVT1/miR-455-5p and miR-455-5p/CXCL12. Nude mouse xenograft model was used to evaluate the effects of shcircPVT1 and miR-455-5p mimics on tumor growth and metastasis in vivo.

Results

miR-455-5p was reduced in MTC tissues and cells while circPVT1 was elevated. Their levels were correlated with prognosis of MTC. Overexpression of miR-455-5p or sh-circPVT1 suppressed EMT and MTC cell proliferation, migration and invasion. miR-455-5p targeted CXCL12 while circPVT1 sponged miR-455-5p. Knockdown of CXCL12 or CXCL12/CXCR4 signaling inhibitor reversed the effects of circPVT1 overexpression or miR-455-5p inhibitor on EMT and MTC cell proliferation, migration and invasion. Knockdown of circPVT1 or miR-455-5p overexpression repressed MTC tumor growth and lung metastasis in vivo.

Conclusions

miR-455-5p suppresses MTC growth and metastasis by targeting CXCL12/CXCR4 signaling pathway while circPVT1 promotes MTC by sponging miR-455-5p. Our study sheds light on the mechanisms of MTC growth and metastasis.
Monitoring of patients with microdialysis following pancreaticoduodenectomy—the MINIMUM study: study protocol for a randomized controlled trial
Authors: Lindholm Espen , Ekiz Nil , Tønnessen Tor Inge
Published: May 2021

Background

Postoperative pancreatic fistula after pancreatoduodenectomy is a much-feared complication associated with substantial mortality and morbidity. The current standard for diagnosing postoperative pancreatic fistula, besides routine clinical examination, include radiological examinations, analysis of pancreatic drain amylase activity, and routine blood samples. Another promising method is by intraperitoneal microdialysis to monitor intraperitoneal metabolites measured at the pancreaticojejunostomy, thereby detecting what occurs locally, before chemical events can be reflected as measurable changes in systemic blood levels.

Methods

The MINIMUM study is a prospective, randomized, controlled, single center enrolling 200 patients scheduled for open pancreatoduodenectomy comparing the microdialysis method to the “standard of care.” Half of the included patients will be randomized to receive an intraperitoneal microdialysis catheter implanted at the end of surgery and will be monitored by microdialysis as an additional monitoring tool. The other half of the patients will not receive a microdialysis catheter and will be monitored according to the current standard of care. The primary objective is to evaluate if the microdialysis method can reduce the total length of stay at the hospital. Secondary endpoints are the frequency of complications, length of stay at the hospital at our institution, catheter malfunction, number of infections and bleeding episodes caused by the microdialysis catheter, patient-reported quality of life and pain, and cost per patient undergoing pancreatoduodenectomy. The patients will be randomized in a 1:1 ratio.

Discussion

Intraabdominal microdialysis could potentially reduce morbidity and mortality after pancreatoduodenectomy. Furthermore, there is a great potential for shortening the in-hospital length of stay and reducing the financial aspect considerably. This study may potentially open the possibility for using microdialysis as standard monitoring in patients undergoing pancreatoduodenectomy. The hypothesis is that the microdialysis method compared to “standard care” will reduce the total length of hospital stay.

Trial registration

Clinicaltrials.gov (NCT03631173). Registered on 7 September 2018 under the name: “Monitoring of patients With Microdialysis Following Pancreaticoduodenectomy”. Based on protocol version 19-1, dated 15th January 2019.
Evaluation of two sexual-stage antigens as bivalent transmission-blocking vaccines in rodent malaria
Authors: Yang Fan , Liu Fei , Yu Xinxin , Zheng Wenqi , Wu Yudi , Qiu Yue , Jin Ying , Cui Liwang , Cao Yaming
Published: May 2021

Background

Transmission-blocking vaccine (TBV) is a promising strategy for malaria elimination. It is hypothesized that mixing or fusing two antigens targeting different stages of sexual development may provide higher transmission-blocking activity than these antigens used individually.

Methods

A chimeric protein composed of fragments of Pbg37 and PSOP25 was designed and expressed the recombinant protein in Escherichia coli Rosetta-gami B (DE3). After immunizing mice with individual recombinant proteins Pbg37 and PSOP25, mixed proteins (Pbg37+PSOP25), or the fusion protein (Pbg37-PSOP25), the antibody titers of individual sera were analyzed by ELISA. IFA and Western blot were performed to test the reactivity of the antisera with the native proteins in the parasite. The transmission-blocking activity of the different immunization schemes was assessed using in vitro and in vivo assays.

Results

When Pbg37 and PSOP25 were co-administered in a mixture or as a fusion protein, they elicited similar antibody responses in mice as single antigens without causing immunological interference with each other. Antibodies against the mixed or fused antigens recognized the target proteins in the gametocyte, gamete, zygote, and ookinete stages. The mixed proteins or the fusion protein induced antibodies with significantly stronger transmission-reducing activities in vitro and in vivo than individual antigens.

Conclusions

There was no immunological interference between Pbg37 and PSOP25. The bivalent vaccines, which expand the portion of the sexual development during which the transmission-blocking antibodies act, produced significantly stronger transmission-reducing activities than single antigens. Altogether, these data provide the theoretical basis for the development of combination TBVs targeting different sexual stages.

Graphical Abstract
Loss of EZH2-like or SU(VAR)3–9-like proteins causes simultaneous perturbations in H3K27 and H3K9 tri-methylation and associated developmental defects in the fungus Podospora anserina
Authors: Carlier F. , Li M. , Maroc L. , Debuchy R. , Souaid C. , Noordermeer D. , Grognet P. , Malagnac F.
Published: May 2021

Background

Selective gene silencing is key to development. It is generally accepted that H3K27me3-enriched heterochromatin maintains transcriptional repression established during early development and regulates cell fate. Conversely, H3K9me3-enriched heterochromatin prevents differentiation but constitutes protection against transposable elements. We exploited the fungus Podospora anserina, a valuable alternative to higher eukaryote models, to question the biological relevance and functional interplay of these two distinct heterochromatin conformations.

Results

We established genome-wide patterns of H3K27me3 and H3K9me3 modifications, and found these marks mutually exclusive within gene-rich regions but not within repeats. We generated the corresponding histone methyltransferase null mutants and showed an interdependence of H3K9me3 and H3K27me3 marks. Indeed, removal of the PaKmt6 EZH2-like enzyme resulted not only in loss of H3K27me3 but also in significant H3K9me3 reduction. Similarly, removal of PaKmt1 SU(VAR)3–9-like enzyme caused loss of H3K9me3 and substantial decrease of H3K27me3. Removal of the H3K9me binding protein PaHP1 provided further support to the notion that each type of heterochromatin requires the presence of the other. We also established that P. anserina developmental programs require H3K27me3-mediated silencing, since loss of the PaKmt6 EZH2-like enzyme caused severe defects in most aspects of the life cycle including growth, differentiation processes and sexual reproduction, whereas loss of the PaKmt1 SU(VAR)3–9-like enzyme resulted only in marginal defects, similar to loss of PaHP1.

Conclusions

Our findings support a conserved function of the PRC2 complex in fungal development. However, we uncovered an intriguing evolutionary fluidity in the repressive histone deposition machinery, which challenges canonical definitions of constitutive and facultative heterochromatin.
A 45-year-old female patient with Sheehan’s syndrome presenting with imminent adrenal crisis: a case report
Authors: Genetu Abere , Anemen Yibeltal , Abay Sinshaw , Bante Simachew Anemen , Mihrete Kebadnew Mulatu
Published: May 2021

Background

Sheehan's syndrome is hypopituitarism due to pituitary gland necrosis resulting from hemorrhagic shock during pregnancy. It is a rare complication with varied manifestations and a considerable delay in diagnosis.

Case presentation

We describe the case of a 45-year-old Ethiopian woman who presented with generalized fatigue for 18 years which progressed to anorexia, nausea, vomiting, diarrhea, and abdominal pain of 6 years' duration, for which she was treated symptomatically throughout these years. Complete clinical evaluation, endocrine studies, and pituitary magnetic resonance scan revealed hypopituitarism secondary to Sheehan’s syndrome. She had significant improvement noted following the commencement of hormone replacement therapy.

Conclusion

Previous case reports describe patients being diagnosed after one or more complications from long-term panhypopituitarism. The present case illustrates that undiagnosed Sheehan's syndrome is associated with long-term morbidity, and we want to emphasize that a high index of suspicion is crucial for the early diagnosis of the syndrome in routine clinical visits in order to prevent complications arising with delayed diagnosis. Awareness among clinicians is also essential so that such cases are not overlooked, especially in developing nations, where home delivery is still common and obstetric care is limited.
Repurposing existing medications for coronavirus disease 2019: protocol for a rapid and living systematic review
Authors: Geisler Benjamin P. , Zahabi Lara , Lang Adam Edward , Eastwood Naomi , Tennant Elaine , Lukic Ljiljana , Sharon Elad , Chuang Hai-Hua , Kang Chang-Berm , Clayton-Johnson Knakita , Aljaberi Ahmed , Yu Haining , Bui Chinh , Le Mau Tuan , Li Wen-Cheng , Teodorescu Debbie , Hinske Ludwig Christian , Sun Dennis L. , Manian Farrin A. , Dunn Adam G.
Published: May 2021

Background

Coronavirus disease 2019 (COVID-19) has no confirmed specific treatments. However, there might be in vitro and early clinical data as well as evidence from severe acute respiratory syndrome and Middle Eastern respiratory syndrome that could inform clinicians and researchers. This systematic review aims to create priorities for future research of drugs repurposed for COVID-19.

Methods

This systematic review will include in vitro, animal, and clinical studies evaluating the efficacy of a list of 34 specific compounds and 4 groups of drugs identified in a previous scoping review. Studies will be identified both from traditional literature databases and pre-print servers. Outcomes assessed will include time to clinical improvement, time to viral clearance, mortality, length of hospital stay, and proportions transferred to the intensive care unit and intubated, respectively. We will use the GRADE methodology to assess the quality of the evidence.

Discussion

The challenge posed by COVID-19 requires not just a rapid review of drugs that can be repurposed but also a sustained effort to integrate new evidence into a living systematic review.

Trial registration

PROSPERO 2020CRD42020175648
Epiphyseal enchondroma masking as osteoid osteoma: a case report
Authors: Cao Xuyang , Ren Qiang , Li Xiangnan , Tian Yiren , Wang Zhendong
Published: May 2021

Background

Enchondromas originating in the epiphyses of long bones are rare and epiphyseal osteoid osteomas are also uncommon. Diagnosis can become elusive when enchondromas or osteoid osteomas occur in atypical locations and present with nonspecific clinical and imaging characteristics.

Case presentation

We report a case of epiphyseal enchondroma of the left proximal femur in a 15-year-old girl with a 2-month history of left lower extremity pain. Preoperative CT displayed thickened cortex in the anterior surface of the left proximal femur with specks of calcification and inhomogeneity of the adjacent bone marrow cavity. She was diagnosed with osteoid osteoma. Postoperative pathological examination of surgically excised specimens revealed a diagnosis of enchondromas.

Conclusions

Our case highlights that enchondroma should be considered in lesions of the epiphysis.
Cutaneous leishmaniasis control in Alta Verapaz (northern Guatemala): evaluating current efforts through stakeholders’ experiences
Authors: Mendizábal-Cabrera Renata , Pérez Isabel , Becerril Montekio Víctor , Pérez Freddy , Durán Erick , Trueba Mei L.
Published: May 2021

Background

Cutaneous leishmaniasis (CL), endemic in Guatemala, mostly affects poor people living in the northern region. A national control program that includes surveillance, diagnose, and treatment offered free of cost by the Ministry of Health (MoH) has been in place since 2003. However, the incidence is increasing and treatment rates are not optimal, suggesting that current efforts are not being effective. This study aimed to understand barriers and facilitators of CL control in Guatemala as experienced and perceived by key stakeholders in order to comprehend what works well and does not and suggest evidence-informed interventions.

Methods

The study was conducted in the Cobán municipality, the most endemic of Guatemala, situated in the Department of Alta Verapaz. Data were collected during May and June 2019 via focus groups and semi-structured interviews with key stakeholders, including local and national health personnel and residents of four communities of the endemic region. Thematic and content analysis of the collected data was conducted using NVIVO.

Results

Three overarching issues hamper the effectiveness of current CL efforts: resource scarcity, treatment challenges, and knowledge-action gaps. Scarce economic resources from the MoH and community residents negatively impact incidence, detection of cases and treatment rates in that preventive action is insufficient and healthcare access is low. In addition, local health workers often lack specialized CL training and access to the national CL control guidelines. With regards to the population living in the study area, misunderstanding of disease causation, shame associated with CL lesions, treatment pain fear, and long (often uncertain) waiting times for diagnose and treatment negatively affect people’s willingness to seek help, treatment adherence, and their trust on the healthcare provided.

Conclusions

Culturally sensitive CL preventive action must be developed. Given the scarce economic resources available for CL control in the country, the involvement of trained community health workers and the inclusion of thermotherapy as a treatment option is also advised. Other cost-effective actions include: ensuring all health workers receive CL training and have access to national CL control guidelines, improving national procurement system to avoid treatment shortages, and provision of motorized vehicles to increase active surveillance and treatment rates.

Graphical abstract
The development of a capacity-strengthening program to promote self-care practices among people with lymphatic filariasis-related lymphedema in the Upper West Region of Ghana
Authors: Atinbire Solomon Abotiba , Marfo Benjamin , Alomatu Bright , Ahorlu Collins , Saunderson Paul , Weiland Stefanie
Published: May 2021

Background

The Upper West region of Ghana is mostly made up of rural communities and is highly endemic for lymphatic filariasis (LF), with a significant burden of disability due to lymphedema and hydrocele. The aim of this paper is to describe an enhanced, evidence-based cascading training program for integrated lymphedema management in this region, and to present some initial outcomes.

Main text

A baseline evaluation in the Upper West Region was carried out in 2019. A cascaded training program was designed and implemented, followed by a roll-out of self-care activities in all 72 sub-districts of the Upper West Region. A post implementation evaluation in 2020 showed that patients practiced self-care more frequently and with more correct techniques than before the training program; they were supported in this by health staff and family members.

Conclusions

Self-care for lymphedema is feasible and a program of short workshops in this cascaded training program led to significant improvements. Efforts to maintain momentum and sustain what has been achieved so far, will include regular training and supervision to improve coverage, the provision of adequate resources for limb care at home, and the maintenance of district registers of lymphedema cases, which must be updated regularly.