bluuebunny/crossref_metadata_2025 huggingface dataset:
High dietary and lifestyle inflammatory scores are associated with increased risk of chronic kidney disease in Iranian adults
Authors: Farhadnejad Hossein , Teymoori Farshad , Jahromi Mitra Kazemi , Mokhtari Ebrahim , Asghari Golaleh , Mirmiran Parvin , Azizi Fereidoun
Published: January 2023

Background

Systemic inflammation can be the initiator in developing chronic diseases that may be affected by the lifestyle and diet of individuals. In the current study, we aimed to assess the association of the inflammatory potential of diet and lifestyle, determined by the food-based index of dietary inflammatory potential (FBDI), dietary inflammation score (DIS), and lifestyle inflammation score (LIS), with risk of chronic kidney disease(CKD) in Iranian adults.

Methods

A total of 6044 CKD-free individuals aged ≥ 18 years, were recruited from among participants of the Tehran Lipid and Glucose Study(surveys 3 and 4) and followed a mean of 6.03 years(follow-up rate:94.95%). Data on dietary intakes were determined using a food frequency questionnaire. The inflammatory potential of diet and lifestyle were determined based on three indices, including FBDI, DIS, and LIS. Using the National Kidney Foundation guidelines, we defined CKD as eGFR < 60 mL/min/1.73 m2.

Results

Mean ± SD age of the study population(54.3% women) was 37.8 ± 12.8 years. We identified 1216(20.1%) new cases of CKD during the 6.03 years of follow-up (46,889.8 person-years). In the multivariable-adjusted model, the risk of CKD incident is increased across quartiles of FBDI (HR = 1.21;95%CI:1.03–1.42, Ptrend:0.014) and LIS (HR = 1.28;95%CI:1.07–1.55,Ptrend:0.006). However, no significant relationship was observed between the higher DIS score and CKD risk.

Conclusion

Our findings showed that a higher inflammatory potential of diet and lifestyle, characterized by a higher score of FBDI and LIS, was related to increased incidence of CKD, while no significant relationship was reported between the DIS score and CKD incident.
Oppression and internalized oppression as an emerging theme in accessing healthcare: findings from a qualitative study assessing first-language related barriers among the Kurds in Turkey
Authors: Bayram Tevfik , Sakarya Sibel
Published: January 2023

Background

Language has been well documented to be a key determinant of accessing healthcare. Most of the literature about language barrier in accessing healthcare is in the context of miscommunication. However, it is critical to consider the historical and political contexts and power dynamics underlying actions. The literature in this matter is short. In this paper we aimed to find out how first-language affects access to healthcare for people who do not speak the official language, with a particular focus on language oppression.

Methods

We conducted this qualitative study based on patient-reported experiences of the Kurds in Turkey, which is a century-long oppressed population. We conducted 12 in-depth interviews (all ethnically Kurdish, non-Turkish speaking) in Şırnak, Turkey, in 2018–2019 using maximum variation strategy. We used Levesque’s ‘Patient-Centred Access to Healthcare’ framework which addresses individual and structural dimensions to access.

Results

We found that Kurds who do not speak the official language face multiple first-language related barriers in accessing healthcare. Poor access to health information, poor patient-provider relationship, delay in seeking health care, dependence on others in accessing healthcare, low adherence to treatments, dissatisfaction with services, and inability to follow health rights were main issues. As an unusual outcome, we discovered that the barrier processes in accessing healthcare are particularly complicated in the context of oppression and its internalization. Internalized oppression, as we found in our study, impairs access to healthcare with creating a sense of reluctance to seek healthcare, and impairs their individual and collective agency to struggle for change.

Conclusions

A human-rights-based top-down policy shift, and a bottom-up community empowerment approach is needed. At the system level, official recognition of oppressed populations, acknowledgement of the determinants of their health; and incorporating their language in official capacities (particularly education and healthcare) is crucial. Interventions should include raising awareness among relevant professions and stakeholders that internalized oppression is an issue in accessing healthcare to be considered. Given that internalized oppression can be in other forms than language or ethnicity, future research aimed at examining other aspects of access to healthcare should pay a special attention to internalized oppression.
Gene signature and prognostic value of ubiquitination-related genes in endometrial cancer
Authors: Wang Ziwei , Cheng Shuangshuang , Liu Yan , Zhao Rong , Zhang Jun , Zhou Xing , Shu Wan , Feng Dilu , Wang Hongbo
Published: January 2023

Protein ubiquitination is closely related to tumor occurrence and development. The specific role of ubiquitination in endometrial cancer remains largely unclear. Therefore, we constructed a novel endometrial cancer prognostic model based on ubiquitination-related genes. We extracted the expression matrices of ubiquitination-related genes from the Cancer Genome Atlas database, upon which we performed univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses to obtain 22 ubiquitination-related genes for the construction of the prognostic model. Survival, regression, clinical correlation, and principal component analyses were performed to assess the performance of the model. Drug sensitivity analysis was performed based on these ubiquitination-related genes. Finally, a prognostic nomogram was constructed based on the prognostic model to quantify patient outcomes. Survival, regression, clinical correlation, and principal component analyses revealed that the performance of the prognostic model was satisfactory. Drug sensitivity analysis provided a potential direction for the treatment of endometrial cancer. The prognostic nomogram could be used to effectively estimate the survival rate of patients with endometrial cancer. In summary, we constructed a new endometrial cancer prognostic model and identified 5 differentially expressed, prognosis-associated, ubiquitination-related genes. These 5 genes are potential diagnostic and treatment targets for endometrial cancer.
Splicing factor-mediated regulation patterns reveals biological characteristics and aid in predicting prognosis in acute myeloid leukemia
Authors: Zhong Fang-Min , Yao Fang-Yi , Liu Jing , Li Mei-Yong , Jiang Jun-Yao , Cheng Ying , Xu Shuai , Li Shu-Qi , Zhang Nan , Huang Bo , Wang Xiao-Zhong
Published: January 2023

Background

Alternative splicing (AS) of RNA is a fundamental biological process that shapes protein diversity. Many non-characteristic AS events are involved in the onset and development of acute myeloid leukemia (AML). Abnormal alterations in splicing factors (SFs), which regulate the onset of AS events, affect the process of splicing regulation. Hence, it is important to explore the relationship between SFs and the clinical features and biological processes of patients with AML.

Methods

This study focused on SFs of the classical heterogeneous nuclear ribonucleoprotein (hnRNP) family and arginine and serine/arginine-rich (SR) splicing factor family. We explored the relationship between the regulation patterns associated with the expression of SFs and clinicopathological factors and biological behaviors of AML based on a multi-omics approach. The biological functions of SRSF10 in AML were further analyzed using clinical samples and in vitro experiments.

Results

Most SFs were upregulated in AML samples and were associated with poor prognosis. The four splicing regulation patterns were characterized by differences in immune function, tumor mutation, signaling pathway activity, prognosis, and predicted response to chemotherapy and immunotherapy. A risk score model was constructed and validated as an independent prognostic factor for AML. Overall survival was significantly shorter in the high-risk score group. In addition, we confirmed that SRSF10 expression was significantly up-regulated in clinical samples of AML, and knockdown of SRSF10 inhibited the proliferation of AML cells and promoted apoptosis and G1 phase arrest during the cell cycle.

Conclusion

The analysis of splicing regulation patterns can help us better understand the differences in the tumor microenvironment of patients with AML and guide clinical decision-making and prognosis prediction. SRSF10 can be a potential therapeutic target and biomarker for AML.
Teriflunomide as a therapeutic means for myelin repair
Authors: Göttle Peter , Groh Janos , Reiche Laura , Gruchot Joel , Rychlik Nicole , Werner Luisa , Samper Agrelo Iria , Akkermann Rainer , Zink Annika , Prigione Alessandro , Hartung Hans-Peter , Martini Rudolf , Küry Patrick
Published: January 2023

Background

Promotion of myelin repair in the context of demyelinating diseases such as multiple sclerosis (MS) still represents a clinical unmet need, given that this disease is not only characterized by autoimmune activities but also by impaired regeneration processes. Hence, this relates to replacement of lost oligodendrocytes and myelin sheaths—the primary targets of autoimmune attacks. Endogenous remyelination is mainly mediated via activation and differentiation of resident oligodendroglial precursor cells (OPCs), whereas its efficiency remains limited and declines with disease progression and aging. Teriflunomide has been approved as a first-line treatment for relapsing remitting MS. Beyond its role in acting via inhibition of de novo pyrimidine synthesis leading to a cytostatic effect on proliferating lymphocyte subsets, this study aims to uncover its potential to foster myelin repair.

Methods

Within the cuprizone mediated de-/remyelination model teriflunomide dependent effects on oligodendroglial homeostasis and maturation, related to cellular processes important for myelin repair were analyzed in vivo. Teriflunomide administration was performed either as pulse or continuously and markers specific for oligodendroglial maturation and mitochondrial integrity were examined by means of gene expression and immunohistochemical analyses. In addition, axon myelination was determined using electron microscopy.

Results

Both pulse and constant teriflunomide treatment efficiently boosted myelin repair activities in this model, leading to accelerated generation of oligodendrocytes and restoration of myelin sheaths. Moreover, teriflunomide restored mitochondrial integrity within oligodendroglial cells.

Conclusions

The link between de novo pyrimidine synthesis inhibition, oligodendroglial rescue, and maintenance of mitochondrial homeostasis appears as a key for successful myelin repair and hence for protection of axons from degeneration.
Elamipretide alleviates pyroptosis in traumatically injured spinal cord by inhibiting cPLA2-induced lysosomal membrane permeabilization
Authors: Zhang Haojie , Chen Yituo , Li Feida , Wu Chenyu , Cai Wanta , Ye Hantao , Su Haohan , He Mingjun , Yang Liangliang , Wang Xiangyang , Zhou Kailiang , Ni Wenfei
Published: January 2023

Spinal cord injury (SCI) is a devastating injury that may result in permanent motor impairment. The active ingredients of medications are unable to reach the affected area due to the blood‒brain barrier. Elamipretide (SS-31) is a new and innovative aromatic cationic peptide. Because of its alternating aromatic and cationic groups, it freely crosses the blood‒brain barrier. It is also believed to decrease inflammation and protect against a variety of neurological illnesses. This study explored the therapeutic value of SS-31 in functional recovery after SCI and its possible underlying mechanism. A spinal cord contusion injury model as well as the Basso Mouse Scale, footprint assessment, and inclined plane test were employed to assess how well individuals could function following SCI. The area of glial scarring, the number of dendrites, and the number of synapses after SCI were confirmed by HE, Masson, MAP2, and Syn staining. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays were employed to examine the expression levels of pyroptosis-, autophagy-, lysosomal membrane permeabilization (LMP)- and MAPK signalling-related proteins. The outcomes showed that SS-31 inhibited pyroptosis, enhanced autophagy and attenuated LMP in SCI. Mechanistically, we applied AAV vectors to upregulatePla2g4Ain vivo and found that SS-31 enhanced autophagy and attenuated pyroptosis and LMP by inhibiting phosphorylation of cPLA2. Ultimately, we applied asiatic acid (a p38-MAPK agonist) to test whether SS-31 regulated cPLA2 partially through the MAPK-P38 signalling pathway. Our group is the first to suggest that SS-31 promotes functional recovery partially by inhibiting cPLA2-mediated autophagy impairment and preventing LMP and pyroptosis after SCI, which may have potential clinical application value.
Trajectory of confirmed cases and deaths: fourth wave of COVID-19 epidemic in Myanmar
Authors: Htun Ye Minn , Aung Thinzar , Kyi Myo Su , Shan Nyan Htet , Winn Zin Thu , Thu Kaung Si , Maung Nyan Lin , Win Tun Tun , Tun Kyaw Myo
Published: January 2023

The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 has affected day-to-day life worldwide and presents an unprecedented challenge to public health. Many countries performed mitigation measures to contain the disease spread and break the exponential curve. Omicron had already become a dominant variant in Myanmar and then, the fourth wave of the COVID-19 epidemic started on 28th January 2022. Myanmar performed the main community mitigation measures such as strict quarantine for the people who came back from foreign countries, expansion of testing capacity, enforcement of non-pharmaceutical interventions, and improvement of COVID-19 vaccination coverage. Although decreasing the number of COVID-19 cases and deaths, Myanmar is facing the challenges such as human resource shortages in the health sector, community trust for vaccine safety, and inequitable vaccine demand. This communication intends to give insights on what should be considered as the proper mitigation measures to contain the disease spread through the community and as the challenges that occur in implementing public health and social measures.
Reactive oxygen species enhance rAAV transduction by promoting its escape from late endosomes
Authors: Huang Xiaoping , Wang Xiao , Ren Yanxuan , Gao Pingzhang , Xu Wentao , Xie Xiaolan , Diao Yong
Published: January 2023

Background

Recent seminal studies have revealed that endosomal reactive oxygen species (ROS) promote rather than inhibit viral infection. Some ROS generators, including shikonin and H2O2, have the potential to enhance recombinant adeno-associated virus (rAAV) transduction. However, the impact of ROS on rAAV intracellular trafficking remains unclear.

Methods

To understand the effects of ROS on the transduction of rAAV vectors, especially the rAAV subcellular distribution profiles, this study systematically explored the effect of ROS on each step of rAAV intracellular trafficking pathway using fluorescently-labeled rAAV and qPCR quantification determination.

Results

The results showed promoted in-vivo and in-vitro rAAV transduction by ROS exposure, regardless of vector serotype or cell type. ROS treatment directed rAAV intracellular trafficking towards a more productive pathway by upregulating the expression of cathepsins B and L, accelerating the rAAV transit in late endosomes, and increasing the rAAV nucleus entry.

Conclusions

These data support that ROS generative drugs, such as shikonin, have the potential to promote rAAV vector transduction by promoting rAAV’s escape from late endosomes, and enhancing its productive trafficking to the nucleus.
Effects of vitamin D deficiency on blood lipids and bone metabolism: a large cross-sectional study
Authors: Gu Peng , Pu Bin , Chen BaiHang , Zheng XiaoHui , Zeng ZhanPeng , Luo WeiDong
Published: January 2023

To investigate the relationship between serum high-density lipoprotein (HDL-C) and spinal bone mineral density (BMD) under different serum 25-hydroxyvitamin D (25 (OH) D) levels in adults over 40 years old and to explore its mechanism. We include participants over the age of 40 with data on HDL-C, 25 (OH) D, spinal BMD, and other variables in the National Health and Nutrition Examination Survey 2007–2010 in the analysis. A weighted multiple linear regression model was used to evaluate the association between serum HDL-C and spinal BMD in different gender, ages, and serum 25 (OH) D levels. A total of 3599 subjects aged ≥ 40 years old were included in this study. Univariate analysis of the complete correction model showed a negative correlation between serum HDL-C and spinal BMD. In the two subgroups of serum 25 (OH) D, we found that the higher the serum HDL-C in the female with serum 25 (OH) D < 75 nmol/L aged 40–59 years old, the lower the total spinal BMD, and a similar relationship was found in the lumbar spine. However, no similar relationship was found in all populations with serum 25 (OH) D ≥ 75 nmol/L and males with serum 25 (OH) D < 75 nmol/L. These results suggest that among Americans over the age of 40, the increase in serum HDL-C is related to decreased BMD of spine only in women aged 40–59 years with vitamin D insufficiency or deficiency.
Surgeon-modified fenestrated endograft for urgent an aortic arch aneurysm: case report
Authors: Gallicchio Vito , Barbarisi Danilo , Condò Flavia , Sciarrillo Rosaria , Flora Loris
Published: January 2023

We report the case of an endovascular repair of an aortic arch aneurysm by a surgeon-modified fenestrated endograft with a single fenestration in a high-risk patient unfit for open surgery. A patient of 84 years, chronic ischemic cardiopathic, suffering from prostate adenocarcinoma in chemotherapy treatment, came to our hospital for post-traumatic fracture of the right femur. During the hospitalization, the patient exhibited dysphonia and respiratory disorders for several days, therefore, the patient performed Computed Tomography Angiography (CTA) that found the presence of voluminous aneurysm of the aortic arch with a maximum diameter of about 74 mm. The patient was treated with a hybrid-staged procedure; in the first instance, with a carotid-carotid-succlavium bypass to preserve the cerebral and upper limb vascularization and then, the procedure was completed by implanting the surgeon-modified fenestrated endograft with stent delivery to the patient with a fenestration on the anonymous trunk. This surgeon-modified fenestrated endograft was created by modifying a standard endograft by a single fenestration following the three-dimensional reconstructions of the CTA images. The procedure was successfully completed and postoperative course was uneventful. Computed Tomography Angiography demonstrated the exclusion of the aneurysm, patency of the implanted endograft modules, and absence of signs of endoleaks and / or cerebral or medullary ischemic complications.
Case of left ventricular thrombus managed with thrombectomy with left ventricular reconstruction in a patient who had coronavirus disease 2019 infection
Authors: Suzuki Kenji , Sakamoto Shun-Ichiro , Hiromoto Atsushi , Motoji Yusuke , Amitani Ryosuke , Yamaguchi Takako , Ishii Yosuke
Published: January 2023

Background

Intracardiac thrombus is relatively rare in patients with coronavirus disease 2019 (COVID-19). However, if it occurs, thrombotic complications are likely to develop. In this case, we performed a successful thrombectomy on a patient who developed left ventricular thrombus after COVID-19 infection without complications.

Case presentation

A 52-year-old man sought medical care due to fever, dyspnea, and abnormalities in the taste and smell that persisted for 2 weeks. The patient was diagnosed with COVID-19 and was treated with remdesivir, baricitinib, and heparin. Three weeks after hospitalization, electrocardiogram revealed angina pectoris, and cardiac catherization showed left anterior descending coronary artery stenosis. In addition, global hypokinesis and a thrombus at the left ventricular apex were observed on echocardiography. Left ventricular reconstruction concomitant with coronary artery bypass grafting was performed. A thrombus in the left ventricle was resected via left apical ventriculotomy, and the bovine pericardium was covered and sutured on the infarction site to exclude it. The patient was extubated a day after surgery and was transferred to another hospital for recuperation after 20 days. He did not present with complications.

Conclusions

Thrombotic events could be prevented via thrombectomy with left ventricular reconstruction using an intraventricular patch to exclude the residual thrombus.
Recurrent aortic-arch pseudoaneurysm eroding into the left main bronchus following descending thoracic aortic stent repair
Authors: Duan Lijun , Lu Xiaoqian , Pan Ruonan , Cao Dianbo
Published: January 2023

Background

Behcet's disease is a form of systematic vasculitis that affects vessels of various sizes anywhere in the body. Aortic pseudoaneurysm is the most hazardous lesion in Behcet's disease and is associated with high mortality rate once rupture.

Case presentation

In this report, we presented a patient with a known history of Behcet's disease, whose recurrent aortic-arch pseudoaneurysm eroding into the left main bronchus was identified after a 4-year duration of thoracic endovascular aortic repair for thoracic descending aortic pseudoaneurysm ruptured into the left lung. Repeated thoracic endovascular aortic repair combined with the chimney stent effectively controlled massive hemoptysis under the life-threatening circumstance, and the patient was in good condition at the 7-year follow-up.

Conclusions

Thoracic endovascular aortic repair can be used as an effective and problem-solving treatment approach for thoracic aortic aneurysms eroded into the lung, even recurrent pseudoaneurysm after thoracic endovascular aortic repair in BD patients. Among the imaging methods assessing the technical success, outcome and complications, computed tomography angiography offers a fast, accessible and sensitive imaging modality.
Low preoperative serum fibrinogen level is associated with postoperative acute kidney injury in patients with in acute aortic dissection
Authors: Guan Xin-Liang , Li Lei , Jiang Wen-Jian , Gong Ming , Li Hai-Yang , Liu Yu-Yong , Wang Xiao-Long , Zhang Hong-Jia
Published: January 2023

Objective

Acute kidney injury (AKI) after cardiac surgery is associated with serious complication and high risk of mortality. The relationship between hemostatic system and the prognosis of patients with acute type A aortic dissection (ATAAD) has not been evaluated. The purpose of this study was to investigate the association between preoperative serum fibrinogen level and risk of postoperative AKI in patients with ATAAD.

Methods

A total of 172 consecutive patients undergoing urgent aortic arch surgery for ATAAD between April 2020 and December 2021 were identified from Beijing Anzhen Hospital aortic surgery database. The primary outcome was postoperative AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria. The univariate and multivariate logistic regression analysis were done to assess the independent predictors of risk for postoperative AKI. Receiver operating characteristic (ROC) curve was generated to evaluate the predictive probabilities of risk factors for AKI.

Results

In our study, 51.2% (88/172) patients developed postoperative AKI. Multivariate logistic regression analysis identified low preoperative serum fibrinogen level (OR, 1.492; 95% CI, 1.023 to 2.476; p = 0.021) and increased body mass index (BMI) (OR, 1.153; 95% CI, 1.003 to 1.327; p = 0.046) as independent predictors of postoperative AKI in patients with ATAAD. A mixed effect analysis of variance modeling revealed that obese patients with low preoperative serum fibrinogen level had higher incidence of postoperative AKI (p = 0.04). The ROC curve indicated that low preoperative serum fibrinogen level was a significant predictor of AKI [area under the curve (AUC), 0.771; p < 0.001].

Conclusions

Low preoperative serum fibrinogen level and obesity were associated with the risk of postoperative AKI in patients with ATAAD. These data suggested that low preoperative serum fibrinogen level was preferred marker for predicting the postoperative AKI, especially in obese patients with ATAAD.
The association between preoperative anemia, blood transfusion need, and postoperative complications in adult cardiac surgery, a single center contemporary experience
Authors: Mufti Hani , Alsharm Faisal , Bahawi Mohanad , Almazmumi Mohammed , Alshaikh Yazeed , Abushouk Amir , Algarni Abdullah , Jamalallail Sahal , Almohammadi Mohammed
Published: January 2023

Background

The impact of preoperative anemia on postcardiac surgery outcomes is an area of great debate. Although several large-scale studies have been conducted, they have demonstrated conflicting results. A limited number of studies have been conducted in the Middle East. The primary aim of this study was to investigate the association between preoperative anemia and the need for blood transfusions, as well as major postoperative complications.

Methods

Adult patients who underwent cardiac surgery at King Faisal Cardiac Center in Jeddah between June 2016 and January 2020 were included in this retrospective cohort study. The study excluded patients with hereditary preoperative anemia. Among the variables studied were variables related to demographics, comorbidities, laboratory data, operation-related data, in-hospital complications, and mortality.

Results

The mean preoperative hemoglobin (Hb) level was 13.2 g/dL (SD ± 1.8). The overall mortality rate was 4.6%. A lower preoperative Hb level (pvalue = 0.016), postoperative day 1 WBC count (p-value = 0.003), and prolonged cross clamp time (pvalue < 0.001) were significantly associated with mortality. A lower Hb level during the preoperative period or within the first three days of surgery was associated with a higher blood transfusion requirement. However, there was no significant association between blood transfusion and postoperative complications. A multivariate stepwise logistic regression model was developed and several pre and intra operative factors were predictive of the need PRBCs transfusion after cardiac surgery (which included: older age, female gender, lower pre-operative hemoglobin and longer cardio-pulmonary bypass time), with had a predictive accuracy of around ~ 86%.

Conclusion

Based on our single center study, patients with preoperative lower Hb levels are at higher risk of mortality. However, blood transfusion does not seem to increase the risk of postoperative complications. Optimal utilization of blood products is an important quality metric and identification of patients at higher risk of requiring PRBCs transfusion prior to cardiac surgery can help in implementing pre or intra operative strategies to minimize the need for transfusion.
Understanding patient and parent/caregiver perceptions on gene therapy in Gaucher disease: an international survey
Authors: Collin-Histed Tanya , Rosenberg Aviva , Hopman Noortje , Pacey Jessica
Published: January 2023

Background

Gaucher disease is a rare, autosomal recessive genetic disorder. It is caused by a lack of sufficient activity of the lysosomal enzyme known as glucocerebrosidase, which leads to an accumulation of glucocerebroside, a fatty substance, in the spleen, liver, bone marrow, and rarely, the lungs or central nervous system. While there are several treatments available for people with Type 1 Gaucher disease and the visceral aspects of Type 3 Gaucher disease, no cure is present for any type of Gaucher disease. Clinical trials are currently underway to investigate the safety and efficacy of gene therapy in Gaucher disease, which has the potential to become a new type of (curative) treatment in the future. Gene therapy is a relatively new therapeutic approach, and with the desire to keep the community informed about new treatment developments, the International Gaucher Alliance (IGA) set-up a Gaucher disease specific survey to gauge current perceptions. The survey aimed to benchmark understanding of, and the educational needs surrounding, gene therapy among the Gaucher disease community.

Body

An international, online survey was developed, comprising twelve questions ranging from multiple choice, Likert scale, single tick-box, ranking and open questions. The survey was developed following three patient and caregiver focus groups and underwent review from members of the IGA for readability and accuracy before going live to respondents. The survey was available for two months and shared to audiences via specific Gaucher community channels.

Conclusion

Over 100 patients and parents/caregivers from the Gaucher disease community completed the survey, including people living with Type 1 Gaucher disease (52.88%), people living with Type 3 Gaucher disease (3.85%), parents/caregivers of people living with Type 1, 2 or 3 Gaucher disease (39.42%), and other (3.85%) who were defined as parents of multiple people with Gaucher disease. The survey uncovered various commonalities in perception of gene therapy among all groups, with large knowledge gaps identified on the mode of action, the usefulness of gene therapy and overall understanding of the therapeutic area. This survey provides an overview of the type of information that could be valuable to the Gaucher disease community when developing educational materials.
The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer
Authors: Xu Youqin , Song Mu , Hong Ziyang , Chen Wancheng , Zhang Qianbing , Zhou Jianlong , Yang Chao , He Zilong , Yu Juanjuan , Peng Xiaolin , Zhu Qiuhong , Li Shaotian , Ji Kaiyuan , Liu Minfeng , Zuo Qiang
Published: January 2023

Background

Posttranscriptional modification of tumor-associated factors plays a pivotal role in breast cancer progression. However, the underlying mechanism remains unknown. M6A modifications in cancer cells are dynamic and reversible and have been found to impact tumor initiation and progression through various mechanisms. In this study, we explored the regulatory mechanism of breast cancer cell proliferation and metabolism through m6A methylation in the Hippo pathway. 

Methods

A combination of MeRIP-seq, RNA-seq and metabolomics-seq was utilized to reveal a map of m6A modifications in breast cancer tissues and cells. We conducted RNA pull-down assays, RIP-qPCR, MeRIP-qPCR, and RNA stability analysis to identify the relationship between m6A proteins and LATS1 in m6A regulation in breast cancer cells. The expression and biological functions of m6A proteins were confirmed in breast cancer cells in vitro and in vivo. Furthermore, we investigated the phosphorylation levels and localization of YAP/TAZ to reveal that the activity of the Hippo pathway was affected by m6A regulation of LATS1 in breast cancer cells. 

Results

We demonstrated that m6A regulation plays an important role in proliferation and glycolytic metabolism in breast cancer through the Hippo pathway factor, LATS1. METTL3 was identified as the m6A writer, with YTHDF2 as the reader protein of LATS1 mRNA, which plays a positive role in promoting both tumorigenesis and glycolysis in breast cancer. High levels of m6A modification were induced by METTL3 in LATS1 mRNA. YTHDF2 identified m6A sites in LATS1 mRNA and reduced its stability. Knockout of the protein expression of METTL3 or YTHDF2 increased the expression of LATS1 mRNA and suppressed breast cancer tumorigenesis by activating YAP/TAZ in the Hippo pathway.

Conclusions

In summary, we discovered that the METTL3-LATS1-YTHDF2 pathway plays an important role in the progression of breast cancer by activating YAP/TAZ in the Hippo pathway.
A signature based on glycosyltransferase genes provides a promising tool for the prediction of prognosis and immunotherapy responsiveness in ovarian cancer
Authors: Xu Xuyao , Wu Yue , Jia Genmei , Zhu Qiaoying , Li Dake , Xie Kaipeng
Published: January 2023

Background

Ovarian cancer (OC) is the most fatal gynaecological malignancy and has a poor prognosis. Glycosylation, the biosynthetic process that depends on specific glycosyltransferases (GTs), has recently attracted increasing importance due to the vital role it plays in cancer. In this study, we aimed to determine whether OC patients could be stratified by glycosyltransferase gene profiles to better predict the prognosis and efficiency of immune checkpoint blockade therapies (ICBs).

Methods

We retrieved transcriptome data across 420 OC and 88 normal tissue samples using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, respectively. An external validation dataset containing 185 OC samples was downloaded from the Gene Expression Omnibus (GEO) database. Knockdown and pathway prediction of B4GALT5 were conducted to investigate the function and mechanism of B4GALT5 in OC proliferation, migration and invasion.

Results

A total of 50 differentially expressed GT genes were identified between OC and normal ovarian tissues. Two clusters were stratified by operating consensus clustering, but no significant prognostic value was observed. By applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, a 6-gene signature was built that classified OC patients in the TCGA cohort into a low- or high-risk group. Patients with high scores had a worse prognosis than those with low scores. This risk signature was further validated in an external GEO dataset. Furthermore, the risk score was an independent risk predictor, and a nomogram was created to improve the accuracy of prognostic classification. Notably, the low-risk OC patients exhibited a higher degree of antitumor immune cell infiltration and a superior response to ICBs. B4GALT5, one of six hub genes, was identified as a regulator of proliferation, migration and invasion in OC.

Conclusion

Taken together, we established a reliable GT-gene-based signature to predict prognosis, immune status and identify OC patients who would benefit from ICBs. GT genes might be a promising biomarker for OC progression and a potential therapeutic target for OC.
Oral transmucosal fentanyl citrate analgesia in prehospital trauma care: an observational cohort study
Authors: Pietsch Urs , Fischer Henning , Rüst Christoph Alexander , Hossfeld Björn , Grünenfelder Andreas , Wenzel Volker , Albrecht Roland
Published: January 2023

Background

Pain is one of the major prehospital symptoms in trauma patients and requires prompt management. Recent studies have reported insufficient analgesia after prehospital treatment in up to 43% of trauma patients, leaving significant room for improvement. Good evidence exists for prehospital use of oral transmucosal fentanyl citrate (OTFC) in the military setting. We hypothesized that the use of OTFC for trauma patients in remote and challenging environment is feasible, efficient, safe, and might be an alternative to nasal and intravenous applications.

Methods

This observational cohort study examined 177 patients who were treated with oral transmucosal fentanyl citrate by EMS providers in three ski and bike resorts in Switzerland. All EMS providers had previously been trained in administration of the drug and handling of potential adverse events.

Results

OTFC caused a statistically significant and clinically relevant decrease in the level of pain by a median of 3 (IQR 2 to 4) in NRS units (P < 0.0001). Multiple linear regression analysis showed a significant absolute reduction in pain, with no differences in all age groups and between genders. No major adverse events were observed.

Conclusions

Prehospital administration of OTFC is safe, easy, and efficient for extrication and transport across all age groups, gender, and types of injuries in alpine environments. Side effects were few and mild. This could provide a valuable alternative in trauma patients with severe pain, without the delay of inserting an intravenous line, especially in remote areas, where fast action and easy administration are important.
Routine administration of neostigmine after recovery of spontaneous breathing versus neuromuscular monitor-guided administration of neostigmine in pediatric patients: a parallel, randomized, controlled study
Authors: Yang Lei , Hu Na , Chang Hong , Yang Di , Zuo Yunxia
Published: January 2023

Background

Neostigmine used to reverse the muscle relaxants should be guided by neuromuscular monitoring, as the degree of spontaneous pre-reversal recovery is the key to success to reverse the neuromuscular block. But neuromuscular monitoring is not always available for some patients during anesthesia and, in consequence, we need to use other clinical judgment to guide the use of neostigmine to reverse the neuromuscular block. In this trial, we aimed to evaluate the incidence of residual neuromuscular blockade (rNMB) in pediatric patients with routine use of neostigmine after recovery of spontaneous breathing compared with the patients with the use of neostigmine guided by neuromuscular monitoring.

Methods

A parallel, randomized, controlled noninferiority study was conducted. We enrolled aged 3 months to 12 years old patients who underwent inguinal hernia repair under general anesthesia. The enrolled patients were randomly divided into experimental and control groups. After surgery, children in the experimental group were given 0.02 mg/kg neostigmine after recovery of spontaneous breathing. Children in the control group were given 0.02 mg/kg neostigmine when the train-of-four (TOF) ratio was between 0.4 and 0.9. However, no neostigmine was administered if the TOF ratio was higher than 0.9. The primary outcome was the incidence of rNMB after extubation (TOF ratio < 0.9). Secondary outcomes included the incidence of neostigmine-induced muscle paralysis, end of surgery – extubation interval, end of surgery – exit OR interval, the length of stay in the PACU, the incidence of hypoxia in the PACU, the number of children who required assisted ventilation during the PACU stay, and neostigmine-related adverse events.

Results

A total of 120 children were included in this study, with 60 in the experimental group and 60 in the control group. There was no significant difference in the incidence of rNMB after extubation between the groups (45/60 vs 44/60, RR 1.02 [95% CI, 0.83 to 1.26], p = 0.84). There was no neostigmine-induced muscle paralysis in either group. Adverse events were similar occurred in both groups. However, time from end of the surgery to leaving the operating room was earlier in the experimental group than in the control group (13.6 ± 5.2 vs 15.7 ± 5.6 min, MD −2.10 min [95% CI, −3.70 to −0.50], p = 0.04). The risk ratio of the incidence of TOF ratio < 0.3 for the experimental group was 31.12 (95%CI, 1.89 to 512.61) compared with the control group (12/60 vs 0/60, p = 0.00) in exploratory analysis.

Conclusions

Recovery of spontaneous breathing could be used as a substitute of neuromuscular monitoring to guide neostigmine use in pediatric patients following minor surgeries. However, care should be taken for the residual neuromuscular block.

Trial registration

Chinese Clinical Trial Registry ChiCTR-IOR-17012890. Registered on 5 October 2017
Prevalence of Crimean-Congo haemorrhagic fever in livestock following a confirmed human case in Lyantonde district, Uganda
Authors: Atim Stella A. , Niebel Marc , Ashraf Shirin , Vudriko Patrick , Odongo Steven , Balinandi Stephen , Aber Peace , Bameka Ronald , Ademun Anna R. , Masembe Charles , Tweyongyere Robert , Thomson Emma C.
Published: January 2023

Background

Crimean-Congo haemorrhagic fever (CCHF) is a tick-borne viral infection, characterized by haemorrhagic fever in humans and transient asymptomatic infection in animals. It is an emerging human health threat causing sporadic outbreaks in Uganda. We conducted a detailed outbreak investigation in the animal population following the death from CCHF of a 42-year-old male cattle trader in Lyantonde district, Uganda. This was to ascertain the extent of CCHF virus (CCHFV) circulation among cattle and goats and to identify affected farms and ongoing increased environmental risk for future human infections.

Methods

We collected blood and tick samples from 117 cattle and 93 goats, and tested these for anti-CCHFV antibodies and antigen using an enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and target enrichment next generation sequencing.

Results

CCHFV-specific IgG antibodies were detected in 110/117 (94.0%) cattle and 83/93 (89.3%) goats. Animal seropositivity was independently associated with female animals (AOR = 9.42, P = 0.002), and animals reared under a pastoral animal production system (AOR = 6.02, P = 0.019] were more likely to be seropositive than tethered or communally grazed animals. CCHFV was detected by sequencing in Rhipicephalus appendiculatus ticks but not in domestic animals.

Conclusion

This investigation demonstrated very high seroprevalence of CCHFV antibodies in both cattle and goats in farms associated with a human case of CCHF in Lyantonde. Therefore, building surveillance programs for CCHF around farms in this area and the Ugandan cattle corridor is indicated, in order to identify opportunities for case prevention and control.

Graphical Abstract
Who’s afraid of the X? Incorporating the X and Y chromosomes into the analysis of DNA methylation array data
Authors: Inkster Amy M. , Wong Martin T. , Matthews Allison M. , Brown Carolyn J. , Robinson Wendy P.
Published: January 2023

Background

Many human disease phenotypes manifest differently by sex, making the development of methods for incorporating X and Y-chromosome data into analyses vital. Unfortunately, X and Y chromosome data are frequently excluded from large-scale analyses of the human genome and epigenome due to analytical complexity associated with sex chromosome dosage differences between XX and XY individuals, and the impact of X-chromosome inactivation (XCI) on the epigenome. As such, little attention has been given to considering the methods by which sex chromosome data may be included in analyses of DNA methylation (DNAme) array data.

Results

With Illumina Infinium HumanMethylation450 DNAme array data from 634 placental samples, we investigated the effects of probe filtering, normalization, and batch correction on DNAme data from the X and Y chromosomes. Processing steps were evaluated in both mixed-sex and sex-stratified subsets of the analysis cohort to identify whether including both sexes impacted processing results. We found that identification of probes that have a high detection p-value, or that are non-variable, should be performed in sex-stratified data subsets to avoid over- and under-estimation of the quantity of probes eligible for removal, respectively. All normalization techniques investigated returned X and Y DNAme data that were highly correlated with the raw data from the same samples. We found no difference in batch correction results after application to mixed-sex or sex-stratified cohorts. Additionally, we identify two analytical methods suitable for XY chromosome data, the choice between which should be guided by the research question of interest, and we performed a proof-of-concept analysis studying differential DNAme on the X and Y chromosome in the context of placental acute chorioamnionitis. Finally, we provide an annotation of probe types that may be desirable to filter in X and Y chromosome analyses, including probes in repetitive elements, the X-transposed region, and cancer-testis gene promoters.

Conclusion

While there may be no single “best” approach for analyzing DNAme array data from the X and Y chromosome, analysts must consider key factors during processing and analysis of sex chromosome data to accommodate the underlying biology of these chromosomes, and the technical limitations of DNA methylation arrays.
The acyl-CoA-binding protein 2 exhibited the highest affinity for palmitoyl-CoA and promoted Monascus pigment production
Authors: Cui Jingjing , Liu Mengmeng , Wu Weiwei , Long Chuannan , Zeng Bin
Published: January 2023

Purpose

The present study aimed to explore the binding ability of acyl-CoA binding protein 2 to fatty acid acyl-CoA esters and its effect on Monascus pigment production in M. ruber CICC41233.

Methods

The Mracbp2 gene from M. ruber CICC41233 was cloned with a total DNA and cDNA as the templates through the polymerase chain reaction. The cDNA of the Mracbp2 gene fragment was ligated to expression vector pGEX-6P-1 to construct pGEX-MrACBP2, which was expressed in Escherichia coli BL21 to obtain the fusion protein GST-MrACBP2 and then measure the binding ability of fatty acid acyl-CoA esters. Additionally, the DNA of the Mracbp2 gene fragment was ligated to expression vector pNeo0380 to construct pNeo0380-MrACBP2, which was homologously over-expressed in M. ruber CICC41233 to evaluate Monascus pigment production and fatty acid.

Results

The cloned Mracbp2 gene of the DNA and cDNA sequence was 1525 bp and 1329 bp in length, respectively. The microscale thermophoresis binding assay revealed that the purified GST-MrACBP2 had the highest affinity for palmitoyl-CoA (Kd =70.57 nM). Further, the Mracbp2 gene was homologously overexpressed in M. ruber CICC41233, and a positive transformant M. ruber ACBP-E was isolated. In the Monascus pigments fermentation, the expression level of the Mracbp2 gene was increased by 1.74-fold after 2 days and 2.38-fold after 6 days. The palmitic acid content and biomass in M. ruber ACBP2-E were significantly lower than that in M. ruber CICC41233 on 2 days and 6 days. However, compared with M. ruber CICC41233, the yields of total pigment, ethanol-soluble pigment, and water-soluble pigment in M. ruber ACBP2-E increased by 63.61%, 71.61%, and 29.70%, respectively.

Conclusions

The purified fusion protein GST-MrACBP2 exhibited the highest affinity for palmitoyl-CoA. The Mracbp2 gene was overexpressed in M. ruber CICC41233, which resulted in a decrease in palmitic acid and an increase in Monascus pigments. Overall, the effect of MrACBP2 on the synthesis of fatty acid and Monascus pigment was explored. This paper explored the effect of MrACBP2 on the fatty acid synthesis and the synthesis of Monascus pigment. The results indicated the regulation of fatty acid synthesis could affect Monascus pigment synthesis, providing a novel strategy for improving the yield of Monascus pigment.