bluuebunny/crossref_metadata_2025 huggingface dataset:
Xiaoyaosan ameliorates depressive-like behavior and susceptibility to glucose intolerance in rat: involvement of LepR-STAT3/PI3K pathway in hypothalamic arcuate nucleus
Authors: Qiu Wenqi , Wu Qian , Zhang Kaiwen , Da Xiaoli , Tang Kairui , Yuan Naijun , Deng Lijuan , Wu Mansi , Zhang Ying , Quan Jiangyan , Ma Qingyu , Li Xiaojuan , Chen Jiaxu
Published: April 2023

Background

Accumulating evidence has demonstrated that arcuate nucleus (ARC) of the hypothalamus is likely responsible for the close association between chronic stress, depression, and diabetes. Xiaoyaosan (XYS), a Chinese herbal formula, remarkably improves depressive-like behavior and glucose intolerance, but the mechanism remains unclear. Leptin receptor (LepR) regulates energy expenditure and depression by mediating the action of leptin on the ARC. Therefore, we hypothesized that XYS may regulate depressive-like behavior and glucose intolerance via the leptin and its cascade LepR-STAT3/PI3K pathway in the ARC.

Methods

A rat model of depressive-like behavior and susceptibility to glucose intolerance was induced by exposure to chronic unpredictable mild stress (CUMS) for six weeks. XYS (2.224 g/kg) was orally gavaged for six weeks, and fluoxetine (2.0 mg/kg) was administrated to the positive control group. Depressive-like behaviors were assessed using the open field test (OFT), sucrose preference test (SPT) and forced swim test (FST). Fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were performed to evaluate the effects of XYS on blood glucose. Peripheral leptin and blood lipids were detected using enzyme-linked immunosorbent assay and an automatic biochemical analyzer, respectively. The effects of XYS on the LepR-STAT3/PI3K pathway were detected by quantitative real-time PCR and western blotting.

Results

XYS ameliorated CUMS-induced depressive-like behaviors and elevated blood glucose. XYS improved the food intake but have no significant effects on the body weight. Peripheral leptin and its central receptor were also suppressed by XYS, accompanied by the downregulation of JAK2/STAT3 and PI3K/AKT pathway in the ARC. Additionally, XYS increased AGRP and NPY expression but inhibited POMC in the ARC.

Conclusions

XYS improves depressive-like behaviors and susceptibility to glucose intolerance induced by CUMS, which may be achieved by the downregulation of the LepR-STAT3/PI3K signaling pathway in the ARC.
Evaluating a research training programme for frontline health workers in conflict-affected and fragile settings in the middle east
Authors: Naal Hady , Daou Tracy , Brome Dayana , Mansour Rania , Sittah Ghassan Abu , Giannou Christos , Steiger Enrique , Saleh Shadi
Published: April 2023

Background

Health Research Capacity Building (HRCB) is key to improving research production among health workers in LMICs to inform related policies and reduce health disparities in conflict settings. However, few HRCB programmes are available in the MENA region, and few evaluations of HRCB globally are reported in the literature.

Methods

Through a qualitative longitudinal design, we evaluated the first implementation of the Center for Research and Education in the Ecology of War (CREEW) fellowship. Semi-structured interviews were conducted with fellows (n = 5) throughout the programme at key phases during their completion of courses and at each research phase. Additional data was collected from supervisors and peers of fellows at their organizations. Data were analysed using qualitative content analysis and presented under pre-identified themes.

Results

Despite the success of most fellows in learning on how to conduct research on AMR in conflict settings and completing the fellowship by producing research outputs, important challenges were identified. Results are categorized under predefined categories of (1) course delivery, (2) proposal development, (3) IRB application, (4) data collection, (5) data analysis, (6) manuscript write-up, (7) long-term effects, and (8) mentorship and networking.

Conclusion

The CREEW model, based on this evaluation, shows potential to be replicable and scalable to other contexts and other health-related topics. Detailed discussion and analysis are presented in the manuscript and synthesized recommendations are highlighted for future programmes to consider during the design, implementation, and evaluation of such programmes.
Shiftwork sleep disorder and associated factors among nurses working at public hospitals in Harari Regional state and Dire Dawa Administration, Eastern Ethiopia: a cross-sectional study
Authors: Abate Henok , Letta Shiferaw , Worku Teshager , Tesfaye Dejene , Amare Eldana , Mechal Ayalnesh
Published: April 2023

Background

Shiftwork sleep disorder is one of the most common health-related effects of Shiftwork, particularly among healthcare workers. It is a chronic condition that is directly related to a person’s work schedule. In Ethiopia, although a mental health strategy is in place, little attention is given to studies that focus on shiftwork sleep disorders among nurses. This study aimed to determine the magnitude of shiftwork sleep disorder and associated factors among nurses working at public hospitals in Harari Regional State and the Dire Dawa Administration.

Methods

Institutional based cross-sectional study was conducted from June 1–30, 2021 among 392 nurses selected by a simple random sampling technique. A structured interviewer-guided self-administered questionnaire was used for data collection. The International Classification of Sleep Disorders 3rd edition (ICSD-3), Bargen Insomnia Scale (BIS) and Epworth Sleepiness Scale were used to assess shift-work sleep disorder. The data were entered into EpiData and exported to SPSS for analysis. Bivariable logistic regression was used to see the association between the outcome and the explanatory variables. Bivariate and Multivariate analyses were performed, and AOR with 95% CI was used to measure the strength of the association. Those variables with a p-values of < 0.05 were considered as statistically significant.

Results

In this study, the magnitude of shiftwork sleep disorder among nurses was 30.4% (95% CI: 25.4–34.5). Being female (AOR = 2.4, 95% CI: 1.3, 4.2), working an average number of nights > 11 per month in the last 12 months (AOR = 2.5, 95% CI: 1.3, 3.8), and khat use in the last 12 months (AOR = 4.9, 95% CI: 2.9, 8.7) were significantly associated with the shiftwork sleep disorder.

Conclusions

The study revealed that about one-third of the nurses had a shiftwork sleep disorder implying a high burden of the problem among nurses in the study setting, which endangers nurses, patients, and the healthcare system. Being female, working an average number of nights > 11 per month in the last 12 months, and khat use showed statistically significantly associated with the shiftwork sleep disorder. Early detection of shiftwork sleep disorder, having a policy on khat use and considering rest/recovery while scheduling work time should be addressed to prevent shiftwork sleep disorder.
Integrated systems immunology approach identifies impaired effector T cell memory responses as a feature of progression to severe dengue fever
Authors: Ioannidis Lisa J. , Studniberg Stephanie I. , Eriksson Emily M. , Suwarto Suhendro , Denis Dionisius , Liao Yang , Shi Wei , Garnham Alexandra L. , Sasmono R. Tedjo , Hansen Diana S.
Published: April 2023

Background

Typical symptoms of uncomplicated dengue fever (DF) include headache, muscle pains, rash, cough, and vomiting. A proportion of cases progress to severe dengue hemorrhagic fever (DHF), associated with increased vascular permeability, thrombocytopenia, and hemorrhages. Progression to severe dengue is difficult to diagnose at the onset of fever, which complicates patient triage, posing a socio-economic burden on health systems.

Methods

To identify parameters associated with protection and susceptibility to DHF, we pursued a systems immunology approach integrating plasma chemokine profiling, high-dimensional mass cytometry and peripheral blood mononuclear cell (PBMC) transcriptomic analysis at the onset of fever in a prospective study conducted in Indonesia.

Results

After a secondary infection, progression to uncomplicated dengue featured transcriptional profiles associated with increased cell proliferation and metabolism, and an expansion of ICOS+CD4+ and CD8+ effector memory T cells. These responses were virtually absent in cases progressing to severe DHF, that instead mounted an innate-like response, characterised by inflammatory transcriptional profiles, high circulating levels of inflammatory chemokines and with high frequencies of CD4low non-classical monocytes predicting increased odds of severe disease.

Conclusions

Our results suggests that effector memory T cell activation might play an important role ameliorating severe disease symptoms during a secondary dengue infection, and in the absence of that response, a strong innate inflammatory response is required to control viral replication. Our research also identified discrete cell populations predicting increased odds of severe disease, with potential diagnostic value.
Predicting long-term prognosis after percutaneous coronary intervention in patients with new onset ST-elevation myocardial infarction: development and external validation of a nomogram model
Authors: Ye Zongwei , Xu Yanan , Tang Long , Wu Min , Wu Bing , Zhu Tongjian , Wang Jun
Published: April 2023

Background

The triglyceride glucose (TyG) index is a well-established biomarker for insulin resistance (IR) that shows correlation with poor outcomes in patients with coronary artery disease. We aimed to integrate the TyG index with clinical data in a prediction nomogram for the long-term prognosis of new onset ST-elevation myocardial infarction (STEMI) following primary percutaneous coronary intervention (PCI) .

Methods

This retrospective study included new-onset STEMI patients admitted at two heart centers for emergency PCI from December 2015 to March 2018 in development and independent validation cohorts. Potential risk factors were screened applying least absolute shrinkage and selection operator (LASSO) regression. Multiple Cox regression was employed to identify independent risk factors for prediction nomogram construction. Nomogram performance was assessed based on receiver operating characteristic curve analysis, calibration curves, Harrell’s C-index and decision curve analysis (DCA).

Results

In total, 404 patients were assigned to the development cohort and 169 to the independent validation cohort. The constructed nomogram included four clinical variables: age, diabetes mellitus, current smoking, and TyG index. The Harrell’s C-index values for the nomogram were 0.772 (95% confidence interval [CI]: 0.721–0.823) in the development cohort and 0.736 (95%CI: 0.656–0.816) in the independent validation cohort. Significant correlation was found between the predicted and actual outcomes in both cohorts, indicating that the nomogram is well calibrated. DCA confirmed the clinical value of the development prediction nomogram.

Conclusions

Our validated prediction nomogram based on the TyG index and electronic health records data was shown to provide accurate and reliable discrimination of new-onset STEMI patients at high- and low-risk for major adverse cardiac events at 2, 3 and 5 years following emergency PCI.
A pandemic within a pandemic? Admission to COVID-19 wards in hospitals is associated with increased prevalence of antimicrobial resistance in two African settings
Authors: Elton Linzy , Abdel Hamid Muzamil Mahdi , Tembo John , Elbadawi Hana , Maluzi Kwitaka , Abdelraheem Mohammed H. , Cullip Teresa , Kabanda Caren , Roulston Kerry , Honeyborne Isobella , Thomason Margaret J , Elhag Kamal , Mohammed Alaelddin , Adam Abdelsalam , Mulonga Kangwa , Sikakena Kapatiso , Matibula Peter , Kabaso Mwewa , Nakazwe Ruth , Fwoloshi Sombo , Zumla Alimuddin , McHugh Timothy D
Published: April 2023

Background

Patients who develop severe illness due to COVID-19 are more likely to be admitted to hospital and acquire bacterial co-infections, therefore the WHO recommends empiric treatment with antibiotics. Few reports have addressed the impact of COVID-19 management on emergence of nosocomial antimicrobial resistance (AMR) in resource constrained settings. This study aimed to ascertain whether being admitted to a COVID-19 ward (with COVID-19 infection) compared to a non-COVID-19 ward (as a COVID-19 negative patient) was associated with a change in the prevalence of bacterial hospital acquired infection (HAI) species or resistance patterns, and whether there were differences in antimicrobial stewardship (AMS) and infection prevention and control (IPC) guidelines between COVID-19 and non-COVID-19 wards. The study was conducted in Sudan and Zambia, two resource constrained settings with differing country-wide responses to COVID-19.

Methods

Patients suspected of having hospital acquired infections were recruited from COVID-19 wards and non-COVID-19 wards. Bacteria were isolated from clinical samples using culture and molecular methods and species identified. Phenotypic and genotypic resistance patterns were determined by antibiotic disc diffusion and whole genome sequencing. Infection prevention and control guidelines were analysed for COVID-19 and non-COVID-19 wards to identify potential differences.

Results

109 and 66 isolates were collected from Sudan and Zambia respectively. Phenotypic testing revealed significantly more multi-drug resistant isolates on COVID-19 wards in both countries (Sudan p = 0.0087, Zambia p = 0.0154). The total number of patients with hospital acquired infections (both susceptible and resistant) increased significantly on COVID-19 wards in Sudan, but the opposite was observed in Zambia (both p = ≤ 0.0001). Genotypic analysis showed significantly more β-lactam genes per isolate on COVID-19 wards (Sudan p = 0.0192, Zambia p = ≤ 0.0001).

Conclusions

Changes in hospital acquired infections and AMR patterns were seen in COVID-19 patients on COVID-19 wards compared to COVID-19 negative patients on non-COVID-19 wards in Sudan and Zambia. These are likely due to a potentially complex combination of causes, including patient factors, but differing emphases on infection prevention and control, and antimicrobial stewardship policies on COVID-19 wards were highlighted.
In situ forming ROS-scavenging hybrid hydrogel loaded with polydopamine-modified fullerene nanocomposites for promoting skin wound healing
Authors: Chen Xuan , Zhang Yihui , Yu Wei , Zhang Wenkai , Tang Haozheng , Yuan Wei-En
Published: April 2023

Background

Excessive oxidative stress at the wound sites always leads to a prolonged healing and even causes chronic inflammatory wounds. Therefore, antioxidative dressings with multiple features are desired to improve wound healing performance. Herein, we fabricated a ROS-scavenging hybrid hydrogel by incorporating mussel-inspired fullerene nanocomposites (C60@PDA) into gelatin methacryloyl (GelMA) hydrogel.

Results

The developed C60@PDA/GelMA hydrogel showed a sustainable free radical scavenging ability, and eliminated ROS to protect cells against external oxidative stress damage. Besides, the hydrogel presented favorable cytocompatibility, hemocompatibility, and antibacterial ability in vitro. Furthermore, in a mouse full-thickness wound defect model, the in situ forming hybrid hydrogel accelerated wound closure by 38.5% and 42.9% on day 3 and day 7 over the control. Histological results demonstrated that hybrid hydrogels effectively enhanced wound healing on re-epithelialization, collagen deposition and angiogenesis.

Conclusion

Collectively, the C60@PDA/GelMA hydrogel could be a promising dressing for promoting cutaneous wound repair.
Women who use drugs: engagement in practices of harm reduction care
Authors: Austin Tamar , Lavalley Jennifer , Parusel Sylvia , Collins Alexandra B. , Olding Michelle , Boyd Jade
Published: April 2023

Background

Harm reduction services that employ or are operated by people who use drugs are an effective means of mitigating overdose risks and other drug-related harms. However, stereotypes portraying people who use criminalized drugs as incapable caregivers persist. This is especially true for women who use drugs, and to a greater extent racialized women, who are characterized as having diverged from traditional ideals of womanhood as a result of drug-user stigma and the intersections of gender- and class-based and racist stereotypes. In an effort to identify and understand how women who use drugs practise care through harm reduction, we explored the experiences of women accessing a low-threshold supervised consumption site exclusively for women (transgender and non-binary inclusive) in Vancouver, Canada.

Methods

Data were drawn from research conducted from May 2017 to June 2018 exploring women’s experiences accessing the supervised consumption site during an overdose crisis. Data included forty-five semistructured interviews with women recruited from the site, analysed thematically to explore practices of care through harm reduction.

Findings

Participants reported engaging in both formal and informal care. Acts of care included interventions that both aligned with and deviated from conventional understandings of care practices, including overdose reversal and education, overdose supervision/care, and assisted injection.

Conclusion

The boundary between formal and informal harm reduction care is fluid. Women who use drugs engage in harm reduction across these borders with acts of care that align with or fill the gaps in current harm reduction services in order to meet the needs of drug-using communities, challenging negative stereotypes of women who use drugs. However, these caregiving practices can increase risks to care providers’ physical, mental, and emotional health and wellness. Increased financial, social, and institutional supports, including safer supply, assisted injection, and community resources, are needed to better support women as they continue to engage in harm reduction care.
Cross-platform comparison of immune signatures in immunotherapy-treated patients with advanced melanoma using a rank-based scoring approach
Authors: Mao Yizhe , Gide Tuba N. , Adegoke Nurudeen A. , Quek Camelia , Maher Nigel , Potter Alison , Patrick Ellis , Saw Robyn P. M. , Thompson John F. , Spillane Andrew J. , Shannon Kerwin F. , Carlino Matteo S. , Lo Serigne N. , Menzies Alexander M. , da Silva Inês Pires , Long Georgina V. , Scolyer Richard A. , Wilmott James S.
Published: April 2023

Background

Gene expression profiling is increasingly being utilised as a diagnostic, prognostic and predictive tool for managing cancer patients. Single-sample scoring approach has been developed to alleviate instability of signature scores due to variations from sample composition. However, it is a challenge to achieve comparable signature scores across different expressional platforms.

Methods

The pre-treatment biopsies from a total of 158 patients, who have received single-agent anti-PD-1 (n = 84) or anti-PD-1 + anti-CTLA-4 therapy (n = 74), were performed using NanoString PanCancer IO360 Panel. Multiple immune-related signature scores were measured from a single-sample rank-based scoring approach, singscore. We assessed the reproducibility and the performance in reporting immune profile of singscore based on NanoString assay in advance melanoma. To conduct cross-platform analyses, singscores between the immune profiles of NanoString assay and the previous orthogonal whole transcriptome sequencing (WTS) data were compared through linear regression and cross-platform prediction.

Results

singscore-derived signature scores reported significantly high scores in responders in multiple PD-1, MHC-1-, CD8 T-cell-, antigen presentation-, cytokine- and chemokine-related signatures. We found that singscore provided stable and reproducible signature scores among the repeats in different batches and cross-sample normalisations. The cross-platform comparisons confirmed that singscores derived via NanoString and WTS were comparable. When singscore of WTS generated by the overlapping genes to the NanoString gene set, the signatures generated highly correlated cross-platform scores (Spearman correlation interquartile range (IQR) [0.88, 0.92] and r2 IQR [0.77, 0.81]) and better prediction on cross-platform response (AUC = 86.3%). The model suggested that Tumour Inflammation Signature (TIS) and Personalised Immunotherapy Platform (PIP) PD-1 are informative signatures for predicting immunotherapy-response outcomes in advanced melanoma patients treated with anti-PD-1-based therapies.

Conclusions

Overall, the outcome of this study confirms that singscore based on NanoString data is a feasible approach to produce reliable signature scores for determining patients’ immune profiles and the potential clinical utility in biomarker implementation, as well as to conduct cross-platform comparisons, such as WTS.
Targeting inhibition of prognosis-related lipid metabolism genes including CYP19A1 enhances immunotherapeutic response in colon cancer
Authors: Liu Lilong , Mo Min , Chen Xuehan , Chao Dongchen , Zhang Yufan , Chen Xuewei , Wang Yang , Zhang Nan , He Nan , Yuan Xi , Chen Honglei , Yang Jing
Published: April 2023

Background

Lipid metabolic reprogramming in colon cancer shows a potential impact on tumor immune microenvironment and is associated with response to immunotherapy. Therefore, this study aimed to develop a lipid metabolism-related prognostic risk score (LMrisk) to provide new biomarkers and combination therapy strategies for colon cancer immunotherapy.

Methods

Differentially expressed lipid metabolism-related genes (LMGs) including cytochrome P450 (CYP) 19A1 were screened to construct LMrisk in TCGA colon cancer cohort. The LMrisk was then validated in three GEO datasets. The differences of immune cell infiltration and immunotherapy response between LMrisk subgroups were investigated via bioinformatic analysis. These results were comfirmed by in vitro coculture of colon cancer cells with peripheral blood mononuclear cells, human colon cancer tissue microarray analysis, multiplex immunofluorescence staining and mouse xenograft models of colon cancer.

Results

Six LMGs including CYP19A1, ALOXE3, FABP4, LRP2, SLCO1A2 and PPARGC1A were selected to establish the LMrisk. The LMrisk was positively correlated with the abundance of macrophages, carcinoma-associated fibroblasts (CAFs), endothelial cells and the levels of biomarkers for immunotherapeutic response including programmed cell death ligand 1 (PD-L1) expression, tumor mutation burden and microsatellite instability, but negatively correlated with CD8+ T cell infiltration levels. CYP19A1 protein expression was an independent prognostic factor, and positively correlated with PD-L1 expression in human colon cancer tissues. Multiplex immunofluorescence analyses revealed that CYP19A1 protein expression was negatively correlated with CD8+ T cell infiltration, but positively correlated with the levels of tumor-associated macrophages, CAFs and endothelial cells. Importantly, CYP19A1 inhibition downregulated PD-L1, IL-6 and TGF-β levels through GPR30-AKT signaling, thereby enhancing CD8+ T cell-mediated antitumor immune response in vitro co-culture studies. CYP19A1 inhibition by letrozole or siRNA strengthened the anti-tumor immune response of CD8+ T cells, induced normalization of tumor blood vessels, and enhanced the efficacy of anti-PD-1 therapy in orthotopic and subcutaneous mouse colon cancer models.

Conclusion

A risk model based on lipid metabolism-related genes may predict prognosis and immunotherapeutic response in colon cancer. CYP19A1-catalyzed estrogen biosynthesis promotes vascular abnormality and inhibits CD8+ T cell function through the upregulation of PD-L1, IL-6 and TGF-β via GPR30-AKT signaling. CYP19A1 inhibition combined with PD-1 blockade represents a promising therapeutic strategy for colon cancer immunotherapy.
Large-scale genome sequencing redefines the genetic footprints of high-altitude adaptation in Tibetans
Authors: Zheng Wangshan , He Yaoxi , Guo Yongbo , Yue Tian , Zhang Hui , Li Jun , Zhou Bin , Zeng Xuerui , Li Liya , Wang Bin , Cao Jingxin , Chen Li , Li Chunxia , Li Hongyan , Cui Chaoying , Bai Caijuan , Baimakangzhuo  , Qi Xuebin , Ouzhuluobu  , Su Bing
Published: April 2023

Background

Tibetans are genetically adapted to high-altitude environments. Though many studies have been conducted, the genetic basis of the adaptation remains elusive due to the poor reproducibility for detecting selective signatures in the Tibetan genomes.

Results

Here, we present whole-genome sequencing (WGS) data of 1001 indigenous Tibetans, covering the major populated areas of the Qinghai–Tibetan Plateau in China. We identify 35 million variants, and more than one-third of them are novel variants. Utilizing the large-scale WGS data, we construct a comprehensive map of allele frequency and linkage disequilibrium and provide a population-specific genome reference panel, referred to as 1KTGP. Moreover, with the use of a combined approach, we redefine the signatures of Darwinian-positive selection in the Tibetan genomes, and we characterize a high-confidence list of 4320 variants and 192 genes that have undergone selection in Tibetans. In particular, we discover four new genes,TMEM132C,ATP13A3,SANBR, andKHDRBS2, with strong signals of selection, and they may account for the adaptation of cardio-pulmonary functions in Tibetans. Functional annotation and enrichment analysis indicate that the 192 genes with selective signatures are likely involved in multiple organs and physiological systems, suggesting polygenic and pleiotropic effects.

Conclusions

Overall, the large-scale Tibetan WGS data and the identified adaptive variants/genes can serve as a valuable resource for future genetic and medical studies of high-altitude populations.
Reverse shoulder arthroplasty versus hemiarthroplasty versus non-surgical treatment for older adults with acute 3- or 4-part fractures of the proximal humerus: study protocol for a randomised controlled trial (PROFHER-2: PROximal Fracture of Humerus Evaluation by Randomisation – Trial Number 2)
Authors: Rangan Amar , Gwilym Stephen , Keding Ada , Corbacho Belen , Kottam Lucksy , Arundel Catherine , Coleman Elizabeth , DiMascio Livio , Hewitt Catherine , Jones Valerie , Kassam Jamila , McDaid Catriona , Mitchell Natasha , Mott Andrew , O’Carroll Grace , Tharmanathan Puvan , Torgerson David
Published: April 2023

Background

Proximal humerus fractures (PHF) are common and painful injuries, with the majority resulting from falls from a standing height. As with other fragility fractures, its age-specific incidence is increasing. Surgical treatment with hemiarthroplasty (HA) and reverse shoulder arthroplasty (RSA) have been increasingly used for displaced 3- and 4-part fractures despite a lack of good quality evidence as to whether one type of arthroplasty is superior to the other, and whether surgery is better than non-surgical management. The PROFHER-2 trial has been designed as a pragmatic, multicentre randomised trial to compare the clinical and cost-effectiveness of RSA vs HA vs Non-Surgical (NS) treatment in patients with 3- and 4-part PHF.

Methods

Adults over 65 years of age presenting with acute radiographically confirmed 3- or 4-part fractures, with or without associated glenohumeral joint dislocation, who consent for trial participation will be recruited from around 40 National Health Service (NHS) Hospitals in the UK. Patients with polytrauma, open fractures, presence of axillary nerve palsy, pathological (other than osteoporotic) fractures, and those who are unable to adhere to trial procedures will be excluded. We will aim to recruit 380 participants (152 RSA, 152 HA, 76 NS) using 2:2:1 (HA:RSA:NS) randomisation for 3- or 4-part fractures without joint dislocation, and 1:1 (HA:RSA) randomisation for 3- or 4-part fracture dislocations. The primary outcome is the Oxford Shoulder Score at 24 months. Secondary outcomes include quality of life (EQ-5D-5L), pain, range of shoulder motion, fracture healing and implant position on X-rays, further procedures, and complications. Independent Trial Steering Committee and Data Monitoring Committee will oversee the trial conduct, including the reporting of adverse events and harms.

Discussion

The PROFHER-2 trial is designed to provide a robust answer to guide the treatment of patients aged 65 years or over who sustain 3- and 4-part proximal humeral fractures. The pragmatic design and recruitment from around 40 UK NHS hospitals will ensure immediate applicability and generalisability of the trial findings. The full trial results will be made available in a relevant open-access peer-reviewed journal.

Trial registration

ISRCTN76296703. Prospectively registered on 5th April 2018
Impact of the COVID-19 pandemic on a clinical trial of pneumococcal vaccine scheduling (PVS) in rural Gambia
Authors: Hossain Ilias , Osei Isaac , Lobga Galega , Wutor Baleng M. , Olatunji Yekini , Adefila Williams , Adeshola Banjo , Isa Yasir , Nguyen Cattram , Sonko Kemo , Ceesay Lamin , Baldeh Bubacarr , Barrow Omar , Young Benjamin , Ceesay Saidina , Nyassi Abdoullah , Sarwar Golam , Barjo Ousman , M.Drammeh Momodou , Salaudeen Rasheed , Mackenzie Grant
Published: April 2023

The COVID-19 pandemic represents an unprecedented challenge for clinical research. The Pneumococcal Vaccine Schedules (PVS) study is a non-inferiority, interventional trial in which infants resident in 68 geographic clusters are randomised to two different schedules for pneumococcal vaccination. From September 2019 onwards, all infants resident in the study area became eligible for trial enrolment at all Expanded Programme on Immunisation (EPI) clinics in the study area. Surveillance for clinical endpoints is conducted at all 11 health facilities in the study area. PVS is conducted as a collaboration between the Medical Research Council Unit The Gambia (MRCG) at LSHTM and the Gambian Ministry of Health (MoH). The COVID-19 pandemic caused many disruptions to PVS. MRCG instructed interventional studies that participant enrolment be suspended on 26 March 2020, and a public health emergency was declared in The Gambia on 28 March 2020. Enrolment in PVS restarted on 1 July 2020 and was suspended again on 5 August 2020 after The Gambia experienced a sharp increase in COVID-19 cases in late July 2020 and restarted again on 1 September 2020. During periods of suspended enrolment of infants at EPI clinics, PVS continued safety surveillance at health facilities, albeit with disruptions. During the periods of suspended enrolment, infants who had been enrolled before 26 March 2020 continued to receive the PCV schedule to which they had been randomly allocated based on their village of residence, whereas all other infants received the standard PCV schedule. Throughout 2020 and 2021, the trial faced numerous technical and operational challenges: disruption to MoH delivery of EPI services and clinical care at health facilities; episodes of staff illness and isolation; disruption of MRCG transport, procurement, communications and human resource management; and also a range of ethical, regulatory, sponsorship, trial monitoring and financial challenges. In April 2021, a formal review concluded that the pandemic had not compromised the scientific validity of PVS and that the trial should continue as per protocol. The continuing challenges that COVID-19 poses to PVS, and other clinical trials will persist for some time.
Radiomics model to classify mammary masses using breast DCE-MRI compared to the BI-RADS classification performance
Authors: Debbi Kawtar , Habert Paul , Grob Anaïs , Loundou Anderson , Siles Pascale , Bartoli Axel , Jacquier Alexis
Published: April 2023

Background

Recent advanced in radiomics analysis could help to identify breast cancer among benign mammary masses. The aim was to create a radiomics signature using breast DCE-MRI extracted features to classify tumors and to compare the performances with the BI-RADS classification.

Material and methods

From September 2017 to December 2019 images, exams and records from consecutive patients with mammary masses on breast DCE-MRI and available histology from one center were retrospectively reviewed (79 patients, 97 masses). Exclusion criterion was malignant uncertainty. The tumors were split in a train-set (70%) and a test-set (30%). From 14 kinetics maps, 89 radiomics features were extracted, for a total of 1246 features per tumor. Feature selection was made using Boruta algorithm, to train a random forest algorithm on the train-set. BI-RADS classification was recorded from two radiologists.

Results

Seventy-seven patients were analyzed with 94 tumors, (71 malignant, 23 benign). Over 1246 features, 17 were selected from eight kinetic maps. On the test-set, the model reaches an AUC = 0.94 95 CI [0.85–1.00] and a specificity of 33% 95 CI [10–70]. There were 43/94 (46%) lesions BI-RADS4 (4a = 12/94 (13%); 4b = 9/94 (10%); and 4c = 22/94 (23%)). The BI-RADS score reached an AUC = 0.84 95 CI [0.73–0.95] and a specificity of 17% 95 CI [3–56]. There was no significant difference between the ROC curves for the model or the BI-RADS score (p = 0.19).

Conclusion

A radiomics signature from features extracted using breast DCE-MRI can reach an AUC of 0.94 on a test-set and could provide as good results as BI-RADS to classify mammary masses.
Adrenocortical tumors in children: Sri Lankan experience from a single center, and a mini review
Authors: Naotunna Naotunna Palliya Guruge Chamidri Ra , Siriwardana Harankaha Vidanalage Dinendra Nisha , Lakmini Balagamage Chamila , Gamage Dilhara Senani , Gunarathna Sandani , Samarasinghe Malik , Gunasekara Sanjeewa , Atapattu Navoda
Published: April 2023

Background

Pediatric adrenocortical tumors include both benign adenomas and highly virulent malignant tumors. However, they are very rare among children. The aim of this study is to evaluate the clinicopathological data of children presenting with adrenocortical tumors and assess their survival in a South Asian population.

Case presentation

This is a retrospective cohort study that includes patients diagnosed with adrenocortical tumors from August 2020 to August 2022 followed-up at Lady Ridgeway Hospital. Seven children were diagnosed with adrenal cortical tumors. Their ages ranged from 10 months to 6.5 years. Five of them were boys. All displayed signs of peripheral precocious puberty. One boy phenotypically had features of Beckwith–Wiedemann syndrome. The median time for diagnosis after the onset of symptoms was 4.4 months. The preoperative diagnosis was based on clinical manifestations, elevated dehydroepiandrosterone sulfate levels, and suprarenal masses on computed tomography. All five boys had right-sided suprarenal masses, while the two girls had them on the left side. All underwent surgery for tumor resection. The diagnosis was confirmed based on the histopathology of the adrenal specimens. Four children had a Wieneke score of 4 or more, suggesting the possibility of adrenocortical carcinoma; however, only two of them behaved as malignant tumors. To date, two children have developed local recurrences within a very short period.

Conclusion

Adrenocortical tumors are uncommon in children, and treatment options are limited. To identify early recurrences, routine clinical, radiological, and biochemical examinations at least once every 6–8 weeks is important.
Evaluation of safety and efficacy of autologous oral mucosa-derived epithelial cell sheet transplantation for prevention of anastomotic restenosis in congenital esophageal atresia and congenital esophageal stenosis
Authors: Fujino Akihiro , Fuchimoto Yasushi , Mori Teizaburo , Kano Motohiro , Yamada Yohei , Ohno Michinobu , Baba Yoshiyuki , Isogawa Nobutaka , Arai Katsuhiro , Yoshioka Takako , Abe Makoto , Kanai Nobuo , Takagi Ryo , Maeda Masanori , Umezawa Akihiro
Published: April 2023

Background

We performed the first autologous oral mucosa-derived epithelial cell sheet transplantation therapy in a patient with refractory postoperative anastomotic stricture in congenital esophageal atresia (CEA) and confirmed its safety. In this study, patients with CEA and congenital esophageal stenosis were newly added as subjects to further evaluate the safety and efficacy of cell sheet transplantation therapy.

Methods

Epithelial cell sheets were prepared from the oral mucosa of the subjects and transplanted into esophageal tears created by endoscopic balloon dilatation (EBD). The safety of the cell sheets was confirmed by quality control testing, and the safety of the transplantation treatment was confirmed by 48-week follow-up examinations.

Results

Subject 1 had a stenosis resected because the frequency of EBD did not decrease after the second transplantation. Histopathological examination of the resected stenosis revealed marked thickening of the submucosal layer. Subjects 2 and 3 did not require EBD for 48 weeks after transplantation, during which time they were able to maintain a normal diet by mouth.

Conclusions

Subjects 2 and 3 were free of EBD for a long period of time after transplantation, confirming that cell sheet transplantation therapy is clearly effective in some cases. In the future, it is necessary to study more cases; develop new technologies such as an objective index to evaluate the efficacy of cell sheet transplantation therapy and a device to achieve more accurate transplantation; identify cases in which the current therapy is effective; and find the optimal timing of transplantation; and clarify the mechanism by which the current therapy improves stenosis.

Trial registration: UMIN, UMIN000034566, registered 19 October 2018, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000039393.
Menstrual blood-derived endometrial stem cells alleviate neuroinflammation by modulating M1/M2 polarization in cell and rat Parkinson’s disease models
Authors: Li Han , Wei Jinghui , Zhang Zhigang , Li Junyao , Ma Yaokai , Zhang Ping , Lin Juntang
Published: April 2023

Background

Neuroinflammation is closely related to the development of Parkinson's disease (PD). Because of the extensive sources, non-invasive and periodical collection method, human menstrual blood-derived endometrial stem cells (MenSCs) have been explored as a promising tool for treatment of PD. This study aimed to investigate if MenSCs could inhibit neuroinflammation in PD rats by regulating M1/M2 polarization and to excavate the underlying mechanisms.

Methods

MenSCs were co-cultured with 6-OHDA-exposed microglia cell lines. Then the morphology of microglia cells and the level of inflammatory factors were assessed by immunofluorescence and qRT-PCR. After MenSCs were transplanted into the brain of PD rats, animal motor function, the expression of tyrosine hydroxylase, and the level of inflammatory factors in the cerebrospinal fluid (CSF) and serum were detected to evaluate the therapeutic potential of MenSCs. Meanwhile, the expression of M1/M2 phenotype related genes was detected by qRT-PCR. One protein array kit containing 1000 kinds of factors was used to detect the protein components in the conditioned medium of MenSCs. Finally, bioinformatic analysis was performed to analyze the function of factors secreted by MenSCs and the signal pathways involved in.

Results

MenSCs could suppress 6-OHDA-induced microglia cell activation and significantly decrease inflammation in vitro. After transplantation into the brain of PD rats, MenSCs improved animal motor function, which was indicated by the increased movement distance, ambulatory episodes, exercise time on the rotarod, and less contralateral rotation. Additionally, MenSCs reduced the loss of dopaminergic neurons and down-regulated the level of pro-inflammatory factors in the CSF and serum. Moreover, q-PCR and WB results showed the transplantation of MenSCs significantly down-regulated the expression of M1 phenotype cell markers and meanwhile up-regulated the expression of M2 phenotype cell markers in the brain of PD rats. 176 biological processes including inflammatory response, negative regulation of apoptotic process, and microglial cell activation were enriched by GO-BP analysis. 58 signal pathways including PI3K/Akt and MAPK were enriched by KEGG analysis.

Conclusions

In conclusion, our results provide preliminary evidence for the anti-inflammation capacity of MenSCs by regulating M1/M2 polarization. We firstly demonstrated the biological process of factors secreted by MenSCs and the signal pathways involved in using protein array and bioinformatic analysis.
Principles and requirements for nanomaterial representations to facilitate machine processing and cooperation with nanoinformatics tools
Authors: Blekos Kostas , Chairetakis Kostas , Lynch Iseult , Marcoulaki Effie
Published: April 2023

Efficient and machine-readable representations are needed to accurately identify, validate and communicate information of chemical structures. Many such representations have been developed (as, for example, the Simplified Molecular-Input Line-Entry System and the IUPAC International Chemical Identifier), each offering advantages specific to various use-cases. Representation of the multi-component structures of nanomaterials (NMs), though, remains out of scope for all the currently available standards, as the nature of NMs sets new challenges on formalizing the encoding of their structure, interactions and environmental parameters. In this work we identify a set of principles that a NM representation should adhere to in order to provide “machine-friendly” encodings of NMs, i.e. encodings that facilitate machine processing and cooperation with nanoinformatics tools. We illustrate our principles by showing how the recently introduced InChI-based NM representation, might be augmented, in principle, to also encode morphology and mixture properties, distributions of properties, and also to capture auxiliary information and allow data reuse.
Smoking is associated with elevated blood level of volatile organic compounds: a population-based analysis of NHANES 2017–2018
Authors: Wu Guangjie , Gong Shiwei , He Yan , Liu Dong
Published: April 2023

Background

The study aims to explore the association between cigarette smoking with blood exposure to volatile organic compounds using population data from the National Health and Nutrition Examination Survey (NHANES) 2017–2018.

Methods

Based on the data of NHANES 2017–2018, we identified 1117 participants aged 18 to 65 years, who had complete VOCs testing data and filled out the Smoking-Cigarette Use and Volatile Toxicant questionnaires. The participants consisted of 214 dual-smoking persons, 41 E-cigarette smokers, 293 combustible-cigarette smokers and 569 non-smokers. We used One-way ANOVA and Welch’s ANOVA to compare differences of VOCs concentration among 4 groups and multivariable regression model to confirm the factors associated with VOCs concentration.

Results

In dual-smoking and combustible-cigarette smokers, blood concentration of 2,5-Dimethylfuran, Benzene, Benzonitrile, Furan, Isobutyronitrile were higher than non-smokers. When compared with people who never smoked, E-cigarette smokers had similar blood concentrations of VOCs. Blood concentrations of Benzene, Furan, and Isobutyronitrile were significant higher in combustible-cigarette smokers than in E-cigarette smokers. In the multivariable regression model, dual-smoking and combustible-cigarette smoking were associated with elevated blood concentrations of several VOCs except 1,4-Dichlorobenzene, while E-cigarette smoking was only associated with elevated 2,5-Dimethylfuran concentration.

Conclusions

Smoking, mainly dual-smoking and combustible-cigarette smoking, is associated with elevated blood concentration of VOCs, while the effect is weak in E-cigarette smoking.
Maternal zinc alleviates tert-butyl hydroperoxide-induced mitochondrial oxidative stress on embryonic development involving the activation of Nrf2/PGC-1α pathway
Authors: Huang Liang , Gao Wei , He Xuri , Yuan Tong , Zhang Huaqi , Zhang Xiufen , Zheng Wenxuan , Wu Qilin , Liu Ju , Wang Wence , Yang Lin , Zhu Yongwen
Published: April 2023

Background

Mitochondrial dysfunction induced by excessive mitochondrial reactive oxygen species (ROS) damages embryonic development and leads to growth arrest.

Objective

The purpose of this study is to elucidate whether maternal zinc (Zn) exert protective effect on oxidative stress targeting mitochondrial function using an avian model.

Result

In ovo injected tert-butyl hydroperoxide (BHP) increases (P < 0.05) hepatic mitochondrial ROS, malondialdehyde (MDA) and 8-hydroxy-2-deoxyguanosine (8-OHdG), and decreases (P < 0.05) mitochondrial membrane potential (MMP), mitochondrial DNA (mtDNA) copy number and adenosine triphosphate (ATP) content, contributing to mitochondrial dysfunction. In vivo and in vitro studies revealed that Zn addition enhances (P < 0.05) ATP synthesis and metallothionein 4 (MT4) content and expression as well as alleviates (P < 0.05) the BHP-induced mitochondrial ROS generation, oxidative damage and dysfunction, exerting a protective effect on mitochondrial function by enhancing antioxidant capacity and upregulating the mRNA and protein expressions of Nrf2 and PGC-1α.

Conclusions

The present study provides a new way to protect offspring against oxidative damage by maternal Zn supplementation through the process of targeting mitochondria involving the activation of Nrf2/PGC-1α signaling.

Graphical Abstract
The networked micro-decision context: a new lens on transformative urban governance
Authors: Long Le Anh Nguyen , Krause Rachel M. , Arnold Gwen , Swanson Ryan , Fatemi S. Mohsen
Published: April 2023

Recent large-scale societal disruptions, from the COVID-19 pandemic to intensifying wildfires and weather events, reveal the importance of transforming governance systems so they can address complex, transboundary, and rapidly evolving crises. Yet current knowledge of the decision-making dynamics that yield transformative governance remains scant. Studies typically focus on the aggregate outputs of government decisions, while overlooking their micro-level underpinnings. This is a key oversight because drivers of policy change, such as learning or competition, are prosecuted by people rather than organizations. We respond to this knowledge gap by introducing a new analytical lens for understanding policymaking, aimed at uncovering how characteristics of decision-makers and the structure of their relationships affect their likelihood of effectuating transformative policy responses. This perspective emphasizes the need for a more dynamic and relational view on urban governance in the context of transformation.
Force-free and autonomous active Brownian ratchets
(a)
Authors: Rein Constantin , Kolář Martin , Kroy Klaus , Holubec Viktor
Published: April 2023

Autonomous active Brownian ratchets rectify active Brownian particle motion solely by means of a spatially modulated but stationary activity, without external forces. We argue that such ratcheting requires at least a two-dimensional geometry. The underlying principle is similar to the ratcheting induced by steric obstacles in microswimmer baths: suitably polarized swimmers get channeled, while the others get trapped in low-activity regions until they lose direction. The maximum current is generally reached in the limit of large propulsion speeds, in which the rectification efficiency vanishes. Maximum efficiency is attained at intermediate activities and numerically found to be on the order of a few percent, for ratchets with simple wedge-shaped low-activity regions.