bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 pandemic effects on neonatal inpatient admissions and mortality: interrupted time series analysis of facilities implementing NEST360 in Kenya, Malawi, Nigeria, and Tanzania
Authors: Malla Lucas , Ohuma Eric O. , Shabani Josephine , Ngwala Samuel , Dosunmu Olabisi , Wainaina John , Aluvaala Jalemba , Kassim Irabi , Cross James H. , Salim Nahya , Zimba Evelyn , Ezeaka Chinyere , Penzias Rebecca E. , Gathara David , Tillya Robert , Chiume Msandeni , Odedere Opeyemi , Lufesi Norman , Kawaza Kondwani , Irimu Grace , Tongo Olukemi , Murless-Collins Sarah , Bohne Christine , Richards-Kortum Rebecca , Oden Maria , Lawn Joy E.
Published: July 2024

Background

The emergence of COVID-19 precipitated containment policies (e.g., lockdowns, school closures, etc.). These policies disrupted healthcare, potentially eroding gains for Sustainable Development Goals including for neonatal mortality. Our analysis aimed to evaluate indirect effects of COVID-19 containment policies on neonatal admissions and mortality in 67 neonatal units across Kenya, Malawi, Nigeria, and Tanzania between January 2019 and December 2021.

Methods

The Oxford Stringency Index was applied to quantify COVID-19 policy stringency over time for Kenya, Malawi, Nigeria, and Tanzania. Stringency increased markedly between March and April 2020 for these four countries (although less so in Tanzania), therefore defining the point of interruption. We used March as the primary interruption month, with April for sensitivity analysis. Additional sensitivity analysis excluded data for March and April 2020, modelled the index as a continuous exposure, and examined models for each country. To evaluate changes in neonatal admissions and mortality based on this interruption period, a mixed effects segmented regression was applied. The unit of analysis was the neonatal unit (n = 67), with a total of 266,741 neonatal admissions (January 2019 to December 2021).

Results

Admission to neonatal units decreased by 15% overall from February to March 2020, with half of the 67 neonatal units showing a decline in admissions. Of the 34 neonatal units with a decline in admissions, 19 (28%) had a significant decrease of ≥ 20%. The month-to-month decrease in admissions was approximately 2% on average from March 2020 to December 2021. Despite the decline in admissions, we found no significant changes in overall inpatient neonatal mortality. The three sensitivity analyses provided consistent findings.

Conclusion

COVID-19 containment measures had an impact on neonatal admissions, but no significant change in overall inpatient neonatal mortality was detected. Additional qualitative research in these facilities has explored possible reasons. Strengthening healthcare systems to endure unexpected events, such as pandemics, is critical in continuing progress towards achieving Sustainable Development Goals, including reducing neonatal deaths to less than 12 per 1000 live births by 2030.
Outcomes of biological therapy in patients with severe asthma with chronic rhinosinusitis in Saudi Arabia: patients with nasal polyps versus those without nasal polyps
Authors: Abuelhassan Usama E. , Elnamaky Medhat , Alfifi Abdulaziz , Kadasah Sultan K. , Alshehri Mohammed A. , Alasiri Haneen A. , Al-Mani Salihah Y. , Kadasah Ali S. , Musleh Abdullah , Alshafa Fawwaz A. , Qureshi Muhammad S. S. , Assiri Abdulmohsen Y. , Falqi Abdulrahman I. , Asiri Bader I. , Ahmed Haider M. O. , Alshehri Saleem , Rahman Fasih U. , Qureshi Muhammad Amir , Abdelwahab Omar , Mohamed Sherif , Ali Ahmed R. I. , Alqahtani Saad M. A. , Abdalla Abdelrahman M.
Published: July 2024

Background

This study’s purposes were to evaluate the impact of biological therapies on outcomes in patients with severe asthma (SA) and chronic rhinosinusitis (CRS) and to compare these effects among those with NP (CRSwNP) versus those without NP (CRSsNP) in the “real-world” setting in Saudi Arabian patients.

Methods

From March to September 2022, a retrospective observational cohort study was undertaken at the severe asthma clinics of the Armed Forces Hospital—Southern Region (AFHSR) and King Khalid University Hospital, Abha, Saudi Arabia, to delineate the effects of dupilumab therapy. Outcomes were assessed, including clinical outcomes, FEV1, and laboratory findings before and one year after dupilumab. Post-therapy effects were compared between CRSwNP and CRSsNP.

Results

Fifty subjects were enrolled, with a mean age of 46.56. There were 27 (54%) females and 23(46%) males. Significant improvements in clinical parameters (frequency of asthma exacerbations and hospitalizations, the use of OCs, anosmia, SNOTT-22, and the ACT), FEV1, and laboratory ones (serum IgE and eosinophilic count) were observed 6 and 12 months after using dupilumab (p < 0.001), respectively. However, after 12 months of dupilumab therapy, there were no significant differences between those with and without NP with regards to clinical (anosmia, ACT, and OCs use), laboratory (eosinophilic count, serum IgE level) parameters, and FEV1%.

Conclusions

Patients with CRS experienced significant improvements in clinical, FEV1, and laboratory outcomes after dupilumab therapy. However, these improvements were not maintained when comparing CRSwNP with CRSsNP. There were no significant differences between those with and without NP regarding ACT and OCs use or laboratory (eosinophilic count, serum IgE level) parameters. Further prospective multicenter studies are warranted.
Pituitary-adrenal axis dysfunction induced by tislelizumab immunotherapy for non-small cell lung cancer: a case series and literature review
Authors: Wang Jiayi , Lan Huanrong , Mao Xiaowei , Chen Yefeng
Published: July 2024

Background

Adverse events of secondary adrenal insufficiency caused by anti-PD-1 immune agents are relatively rare in clinical practice, so in this article, we retrospectively analyzed three patients who suffered secondary adrenal cortex dysfunction caused by tislelizumab immunotherapy for Non-Small Cell Lung Cancer (NSCLC)and reviewed the literature. This rare immune-related adverse event was investigated by summarizing the clinical features of the patients.

Case presentation

We reported three NSCLC patients who suffered secondary adrenal cortex dysfunction induced by tislelizumab immunotherapy at our hospital from July 2021 to October 2023. We analyzed and summarized the clinical characteristic, laboratory examination, pathological staging, etc. We also reviewed related literature of pituitary inflammation and adrenal cortex dysfunction caused by immunotherapy.

Results

The median age of the three patients was 56 years. All the patients had a history of smoking. After receiving tislelizumab treatment (median cycle: 7), laboratory examination showed a decrease in morning cortisol and adrenocorticotropic hormone (ACTH), both were diagnosed with secondary adrenal insufficiency. Only one patient had symptoms of fatigue, vomiting, and weight loss. One of these patients also had simultaneous subclinical hypothyroidism. All three patients discontinued immunotherapy and received replacement therapy with glucocorticoids. At the last follow-up, none of the three patients restarted immunotherapy, because cortisol did not return to normal. This is similar to that of previous reports.

Conclusion

Based on previous reports and our three cases, when laboratory tests of NSCLC patients receiving immunotherapy showed a decrease in morning cortisol and ACTH levels, especially when clinical symptoms were obvious, the possibility of immunotherapy-related pituitary inflammation causing secondary adrenal cortex dysfunction should be considered. Prompt monitoring and hormone replacement therapy should be provided to prevent adrenal crises.
Evidence-based clinical practice guidelines for the management of acute ankle injuries according to: a PRISMA systematic review and quality appraisal with AGREE II
Authors: Bsoul Najeeb , Ning Liang , Cai Leyi , Mazmanyan Davit , Porter Daniel
Published: July 2024

Background

Acute ankle injuries are commonly seen in emergency rooms, with significant social impact and potentially devastating consequences. While several clinical practice guidelines (CPGs) related to ankle injuries have been developed by various organizations, there is a lack of critical appraisal of them. The purpose of this systematic review is to identify and critically appraise evidence-based clinical practice guidelines (EB-CPGs) related to acute ankle injuries in adults.

Method

We conducted searches in the Cochrane Library, MEDLINE, EMBASE databases, WHO, and reviewed 98 worldwide orthopedic association websites up until early 2023. Two authors independently applied the inclusion and exclusion criteria, and each evidence-based clinical practice guideline (EB-CPG) underwent independent critical appraisal of its content by all four authors using the Appraisal of Guidelines for REsearch and Evaluation (AGREE II) instrument. AGREE II scores for each domain were then calculated.

Results

This review included five evidence-based clinical practice guidelines. The mean scores for all six domains were as follows: Scope and Purpose (87.8%), Stakeholder Involvement (69.2%), Rigour of Development (72.5%), Clarity of Presentation (86.9%), Applicability (45.6%), and Editorial Independence (53.3%).

Conclusion

The number of EB-CPGs related to ankle injuries are limited and the overall quality of the existing evidence-based clinical practice guidelines (EB-CPGs) for ankle injuries is not strong, with three of them being outdated. However, valuable guidance related to Ottawa rules, manual therapy, cryotherapy, functional supports, early ambulation, and rehabilitation has been highlighted. Challenges remain in areas such as monitoring and/or auditing criteria, consideration of the target population’s views and preferences, and ensuring editorial independence. Future guidelines should prioritize improvements in these domains to enhance the quality and relevance of ankle injury management.

Systematic review

Systematic review.
Uncommon adrenal rest tumors and massive adrenal enlargement in adult with congenital adrenal hyperplasia mimicking metastasis from pleomorphic sarcoma
Authors: Mazzeo Pierluigi , Tizianel Irene , Galuppini Francesca , Sbaraglia Marta , Barbot Mattia
Published: July 2024

Background

Congenital adrenal hyperplasia (CAH) encompassed a bunch of autosomal recessive disorders characterized by impaired cortisol levels due to an enzymatic deficiency in steroid synthesis. In adult male patients with CAH, a frequent complication related to poor disease control is the development of ectopic adrenocortical tissue in the testes, named testicular adrenal rest tumors (TART). Conversely, ovarian adrenal rest tumors (OART) in females are extremely rare and adrenal rests in sites other than gonads are so uncommon to have been described only few times in literature.

Case presentation

We report a case of a male patient with untreated CAH and oncologic history of pleomorphic sarcoma who presented with massive bilateral adrenal enlargement and adrenal rest tumors in peri-lumbar and peri-cecal sites, which mimicked metastasis from sarcoma.

Conclusions

The development of massive adrenal enlargement and ectopic adrenal rest tumors in sites other than gonads, even if very uncommon, should be suspected in patients with CAH and prolonged periods of undertreatment.
Investigating fear, depressive symptoms and coping mechanisms among Egyptian nursing students amidst the covid-19 pandemic: a cross-sectional study
Authors: El-Sayed Mona Metwally , Ghazi Ghada Ahmed , Kamal Manar Ahmed , Khedr Mahmoud Abdelwahab
Published: July 2024

Background

Amidst the ongoing COVID-19 pandemic, nursing students' contribution to combating this global health crisis is becoming more significant. However, we need a more comprehensive understanding of the psychological impact of this crisis on these students. Therefore, this study holds immense importance as it offers valuable insights into the connection between COVID-19 pandemic fear, coping strategies, and depressive symptoms among nursing students.

Methods

A cross-sectional survey was conducted to collect and analyze data from 319 undergraduate nursing students. They participated in the study by responding to an online questionnaire. The questionnaire consisted of the Fear of the Coronavirus Questionnaire, Brief Coping Orientation to Problems Experienced, and the Beck Depression Inventory-II.

Results

The study revealed that 45.5% of the participants had a severe fear of COVID-19, 21.9% showed severe depressive symptoms, and 64.6% used moderate coping mechanisms. A positive correlation (r = 0.160, p = 0.01) was found between the fear of COVID-19 and depressive symptoms. Interestingly, this correlation turned negative (r = -0.074, p = 0.01) when adaptive coping strategies such as religion, acceptance, planning, positive reframing, instrumental support, emotional support, active coping, and humor were used. However, when participants resorted to maladaptive coping strategies like venting, self-distraction, self-blame, behavioral disengagement, denial, and substance abuse, the correlation between high fear levels and depressive symptoms became positive (r = 0.352, p = 0.01).

Conclusion

The study demonstrated that the fear of COVID-19 and depressive symptoms among nursing students are significantly correlated. However, the nature of this correlation is influenced by the type of coping strategies employed. Adaptive coping mechanisms can mitigate the impact of fear on depressive symptoms. In contrast, maladaptive coping can exacerbate the relationship between fear and depressive symptoms. Therefore, promoting adaptive coping strategies could be a crucial approach to managing the psychological impact of the COVID-19 pandemic.
Associations of early changes in lung ultrasound aeration scores and mortality in invasively ventilated patients: a post hoc analysis
Authors: Sinnige Jante S. , Filippini Daan F. L. , Hagens Laura A. , Heijnen Nanon F. L. , Schnabel Ronny M. , Schultz Marcus J. , Bergmans Dennis C. J. J. , Bos Lieuwe D. J. , Smit Marry R.
Published: July 2024

Background

Lung ultrasound (LUS) in an emerging technique used in the intensive care unit (ICU). The derivative LUS aeration score has been shown to have associations with mortality in invasively ventilated patients. This study assessed the predictive value of baseline and early changes in LUS aeration scores in critically ill invasively ventilated patients with and without ARDS (Acute Respiratory Distress Syndrome) on 30- and 90-day mortality.

Methods

This is a post hoc analysis of a multicenter prospective observational cohort study, which included patients admitted to the ICU with an expected duration of ventilation for at least 24 h. We restricted participation to patients who underwent a 12-region LUS exam at baseline and had the primary endpoint (30-day mortality) available. Logistic regression was used to analyze the primary and secondary endpoints. The analysis was performed for the complete patient cohort and for predefined subgroups (ARDS and no ARDS).

Results

A total of 442 patients were included, of whom 245 had a second LUS exam. The baseline LUS aeration score was not associated with mortality (1.02 (95% CI: 0.99 – 1.06), p = 0.143). This finding was not different in patients with and in patients without ARDS. Early deterioration of the LUS score was associated with mortality (2.09 (95% CI: 1.01 – 4.3), p = 0.046) in patients without ARDS, but not in patients with ARDS or in the complete patient cohort.

Conclusion

In this cohort of critically ill invasively ventilated patients, the baseline LUS aeration score was not associated with 30- and 90-day mortality. An early change in the LUS aeration score was associated with mortality, but only in patients without ARDS.

Trial registration

ClinicalTrials.gov, ID NCT04482621.
Genome-scale metabolic network of human carotid plaque reveals the pivotal role of glutamine/glutamate metabolism in macrophage modulating plaque inflammation and vulnerability
Authors: Jin Han , Zhang Cheng , Nagenborg Jan , Juhasz Peter , Ruder Adele V. , Sikkink Cornelis J. J. M. , Mees Barend M. E. , Waring Olivia , Sluimer Judith C. , Neumann Dietbert , Goossens Pieter , Donners Marjo M. P. C. , Mardinoglu Adil , Biessen Erik A. L.
Published: July 2024

Background

Metabolism is increasingly recognized as a key regulator of the function and phenotype of the primary cellular constituents of the atherosclerotic vascular wall, including endothelial cells, smooth muscle cells, and inflammatory cells. However, a comprehensive analysis of metabolic changes associated with the transition of plaque from a stable to a hemorrhaged phenotype is lacking.

Methods

In this study, we integrated two large mRNA expression and protein abundance datasets (BIKE, n = 126; MaasHPS, n = 43) from human atherosclerotic carotid artery plaque to reconstruct a genome-scale metabolic network (GEM). Next, the GEM findings were linked to metabolomics data from MaasHPS, providing a comprehensive overview of metabolic changes in human plaque.

Results

Our study identified significant changes in lipid, cholesterol, and inositol metabolism, along with altered lysosomal lytic activity and increased inflammatory activity, in unstable plaques with intraplaque hemorrhage (IPH+) compared to non-hemorrhaged (IPH−) plaques. Moreover, topological analysis of this network model revealed that the conversion of glutamine to glutamate and their flux between the cytoplasm and mitochondria were notably compromised in hemorrhaged plaques, with a significant reduction in overall glutamate levels in IPH+ plaques. Additionally, reduced glutamate availability was associated with an increased presence of macrophages and a pro-inflammatory phenotype in IPH+ plaques, suggesting an inflammation-prone microenvironment.

Conclusions

This study is the first to establish a robust and comprehensive GEM for atherosclerotic plaque, providing a valuable resource for understanding plaque metabolism. The utility of this GEM was illustrated by its ability to reliably predict dysregulation in the cholesterol hydroxylation, inositol metabolism, and the glutamine/glutamate pathway in rupture-prone hemorrhaged plaques, a finding that may pave the way to new diagnostic or therapeutic measures.
ProtecT-2-D trial protocol: cardiovascular protection in patients with type 2 diabetes and established heart and/or vascular disease at a cardio-metabolic clinic—a randomized controlled trial
Authors: Overgaard Katrine Schultz , Mohamed Roda Abdulkadir , Andersen Thomas Rueskov , Lambrechtsen Jess , Egstrup Kenneth , Auscher Søren
Published: July 2024

Background

Cardiovascular disease remains the primary cause of morbidity and mortality despite advancements in the treatment of patients with type 2 diabetes. Effective diabetes management extends beyond blood glucose control and includes cardiovascular prevention and treatment. However, the conventional healthcare model often emphasizes single-disease-specific management, leading to fragmented care. We aim to establish an affordable Cardio-Metabolic Clinic (CMC) that can provide comprehensive assessment and specialized care with a focus on cardiovascular protection.

Methods

The ProtecT-2-D study is a prospective, randomized control trial at the Cardiovascular Research Unit, Odense University Hospital Svendborg, Denmark. In this study, 1500 participants with type 2 diabetes and cardiovascular disease will be randomly assigned in a 2:1 ratio to receive either the intervention: treatment in the CMC, or the control: standard of care. The Cardio-Metabolic Clinic applies a decision-making algorithm coded with the latest guidelines to evaluate lifestyle factors and manage medical treatment. Health examinations are conducted at baseline and after three years, and clinical events will be assessed through registry and journal audits after five and ten years. The primary outcome is the time to the first occurrence of a composite of cardiovascular deaths, non-fatal acute myocardial infarctions, non-fatal stroke, or hospitalization due to heart failure at a time frame of five years.

Discussion

The Cardio-Metabolic Clinic represents a pioneering approach to diabetes management that aims to improve patient outcomes by reducing the cardiovascular disease burden. This study could transform diabetes care and offer a multidisciplinary, cost-effective, and specialized treatment. We need to establish the efficacy and feasibility of a CMC to integrate comparable clinics into broader healthcare systems, and potentially enhance cardiovascular health in patients with type 2 diabetes.

Trial registration number

ClinicalTrials.gov NCT06203860.

Graphical Abstract
Measures of overnight oxygen saturation to characterize sleep apnea severity and predict postoperative respiratory depression
Authors: Assadi Atousa , Chung Frances , Yadollahi Azadeh
Published: July 2024

Background

Sleep apnea syndrome, characterized by recurrent cessation (apnea) or reduction (hypopnea) of breathing during sleep, is a major risk factor for postoperative respiratory depression. Challenges in sleep apnea assessment have led to the proposal of alternative metrics derived from oxyhemoglobin saturation (SpO2), such as oxygen desaturation index (ODI) and percentage of cumulative sleep time spent with SpO2 below 90% (CT90), as predictors of postoperative respiratory depression. However, their performance has been limited with area under the curve of 0.60 for ODI and 0.59 for CT90. Our objective was to propose novel features from preoperative overnight SpO2 which are correlated with sleep apnea severity and predictive of postoperative respiratory depression.

Methods

Preoperative SpO2 signals from 235 surgical patients were retrospectively analyzed to derive seven features to characterize the sleep apnea severity. The features included entropy and standard deviation of SpO2 signal; below average burden characterizing the area under the average SpO2; average, standard deviation, and entropy of desaturation burdens; and overall nocturnal desaturation burden. The association between the extracted features and sleep apnea severity was assessed using Pearson correlation analysis. Logistic regression was employed to evaluate the predictive performance of the features in identifying postoperative respiratory depression.

Results

Our findings indicated a similar performance of the proposed features to the conventional apnea–hypopnea index (AHI) for assessing sleep apnea severity, with average area under the curve ranging from 0.77 to 0.81. Notably, entropy and standard deviation of overnight SpO2 signal and below average burden showed comparable predictive capability to AHI but with minimal computational requirements and individuals’ burden, making them promising for screening purposes. Our sex-based analysis revealed that compared to entropy and standard deviation, below average burden exhibited higher sensitivity in detecting respiratory depression in women than men.

Conclusion

This study underscores the potential of preoperative SpO2 features as alternative metrics to AHI in predicting postoperative respiratory.
Reactive oxygen species/glutathione dual sensitive nanoparticles with encapsulation of miR155 and curcumin for synergized cancer immunotherapy
Authors: Li Kangkang , Wang Juan , Xie Yi , Lu Ziyao , Sun Wen , Wang Kaixuan , Liang Jinxin , Chen Xuehong
Published: July 2024

Considerable attention has been directed towards exploring the potential efficacy of miR-155 in the realm of cancer immunotherapy. Elevated levels of miR-155 in dendritic cells (DCs) have been shown to enhance their maturation, migration, cytokine secretion, and their ability to promote T cell activation. In addition, overexpression of mir155 in M2 macrophages boost the polarization towards the M1 phenotype. Conversely, miR-155 has the propensity to induce the accumulation of immunosuppressive cells like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor tissue. To account for this discrepancy, it is imperative to get help from a drug that could deal with immunosuppressive effect. Curcumin (CUR) exhibits the capacity to prompt Tregs converse into T helper 1 cells, fostering the polarization of M2 tumor-associated macrophage towards the M1 phenotype, and impeding the recruitment and aggregation of MDSCs within the tumor microenvironment. Nonetheless, CUR is known to exert an immunosuppressive impact on DCs by hindering the expression of maturation markers, cytokines, and chemokines, thereby prevent DCs response to immunostimulatory agents. Hence, a reactive oxygen species/glutathione dual responsive drug conveyance platform (CUR/miR155@DssD-Hb NPs) was devised to co-deliver CUR and miR155, with the aim of exploring their synergistic potential in bolstering a sustained and robust anti-tumor immune response. In vitro and in vivo results have suggested that CUR/miR155@DssD-Hb NPs can effectively inhibit the viability of 4T1 and B16F10 tumor cells, trigger the release of damage associated molecular patterns, stimulate DCs maturation, subsequent activation of CD8+ T cells, diminish immunosuppressive cell populations (MDSCs, Tregs, M2 TAMs and exhausted T cells), promote the formation of long-term immunity and lessen the formation of metastatic nodules in the lungs. In summary, the co-delivery system integrating CUR and miR155 (CUR/miR155@DssD-Hb NPs) demonstrates promise as a promising strategy for the immunotherapy of melanoma and triple negative breast cancer.

Graphical abstract
The role of playgrounds in promoting children’s health – a scoping review
Authors: Schipperijn Jasper , Madsen Cathrine Damsbo , Toftager Mette , Johansen Danielle Nørager , Lousen Ida , Amholt Thea Toft , Pawlowski Charlotte Skau
Published: July 2024

Background

Active outdoor play is important for children’s health and development, and playgrounds provide good places for play. However, the importance of playground use for health and well-being is unclear. Our scoping review aims to create an overview of all research on playground use and health benefits for children.

Methods

Scopus, Web of Science, SportDiscus, and PsycInfo were searched using two search blocks, focusing on 'playground' and 'children' respectively, for publications from 2000 to November 2023. The primary inclusion criterion was examining the relationship between playground use and positive physical, mental, or social health outcomes. Only papers published in English were reviewed. For each publication, we synthesized and condensed the results, categorizing them by playground setting, reported health outcome, participant age group, study design, methodologies, publication's country, year, and ‘stage of evidence’.

Results

Data from 247 studies were extracted and nearly 80% of these publications were descriptive or exploratory studies. Fifty-two were intervention studies. Adding playground markings to schoolyards led to increased physical activity. Greening schoolyards had mainly positive effects on social and mental health. In Early Childhood Education and Care, renewing play structures had a positive effect on physical activity in three publications. All Public Open Space interventions we found were different, with mixed effects on health outcomes.

Conclusions

The existing evidence provides good arguments for policy makers, city planners and school-leaders to invest in adding playground markings in schoolyards as this will likely result in more physical activity. The evidence for the health benefits of investing in new play structures indicated that tailoring the playground to local needs is important as ‘one size does not fit all’ and playgrounds need to be designed as engaging and interesting places for children’s play if they are to generate health benefits. Investing in ‘greening’ playgrounds is likely to result in social and mental health benefits for children, but does not always result in more physical activity.

The research field needs more efficacy and effectiveness studies, and in particular replication and scale-up studies to demonstrate which type of playground interventions are successful.

Protocol

The review protocol was registered at Open Science Framework (https://doi.org/10.17605/OSF.IO/UYN2V).
Combined expert-in-the-loop—random forest multiclass segmentation U-net based artificial intelligence model: evaluation of non-small cell lung cancer in fibrotic and non-fibrotic microenvironments
Authors: Saqi Anjali , Liu Yucheng , Politis Michelle Garlin , Salvatore Mary , Jambawalikar Sachin
Published: July 2024

Background

The tumor microenvironment (TME) plays a key role in lung cancer initiation, proliferation, invasion, and metastasis. Artificial intelligence (AI) methods could potentially accelerate TME analysis. The aims of this study were to (1) assess the feasibility of using hematoxylin and eosin (H&E)-stained whole slide images (WSI) to develop an AI model for evaluating the TME and (2) to characterize the TME of adenocarcinoma (ADCA) and squamous cell carcinoma (SCCA) in fibrotic and non-fibrotic lung.

Methods

The cohort was derived from chest CT scans of patients presenting with lung neoplasms, with and without background fibrosis. WSI images were generated from slides of all 76 available pathology cases with ADCA (n = 53) or SCCA (n = 23) in fibrotic (n = 47) or non-fibrotic (n = 29) lung. Detailed ground-truth annotations, including of stroma (i.e., fibrosis, vessels, inflammation), necrosis and background, were performed on WSI and optimized via an expert-in-the-loop (EITL) iterative procedure using a lightweight [random forest (RF)] classifier. A convolution neural network (CNN)-based model was used to achieve tissue-level multiclass segmentation. The model was trained on 25 annotated WSI from 13 cases of ADCA and SCCA within and without fibrosis and then applied to the 76-case cohort. The TME analysis included tumor stroma ratio (TSR), tumor fibrosis ratio (TFR), tumor inflammation ratio (TIR), tumor vessel ratio (TVR), tumor necrosis ratio (TNR), and tumor background ratio (TBR).

Results

The model’s overall classification for precision, sensitivity, and F1-score were 94%, 90%, and 91%, respectively. Statistically significant differences were noted in TSR (p = 0.041) and TFR (p = 0.001) between fibrotic and non-fibrotic ADCA. Within fibrotic lung, statistically significant differences were present in TFR (p = 0.039), TIR (p = 0.003), TVR (p = 0.041), TNR (p = 0.0003), and TBR (p = 0.020) between ADCA and SCCA.

Conclusion

The combined EITL—RF CNN model using only H&E WSI can facilitate multiclass evaluation and quantification of the TME. There are significant differences in the TME of ADCA and SCCA present within or without background fibrosis. Future studies are needed to determine the significance of TME on prognosis and treatment.
Application prospects of the 2BS cell-adapted China fixed rabies virus vaccine strain 2aG4-B40
Authors: Xu Ying , Weng Lin , Wang Xuan , Li Ming , Guo Wanping , Liu Yiqing , Li Xiang , Wang Zhenping , Liu Xinyu , Xu Shengnan , He Feide , Hou Qianqian , Li Tengzhou , Du Wenke , Zhang Yabo , Chang Shumin , Zhang Liwen , Zhang Yuntao
Published: July 2024

Background

Rabies is a fatal zoonotic disease whose pathogenesis has not been fully elucidated, and vaccination is the only effective method for protecting against rabies virus infection. Most inactivated vaccines are produced using Vero cells, which are African green monkey kidney cells, to achieve large-scale production. However, there is a potential carcinogenic risk due to nonhuman DNA contamination. Thus, replacing Vero cells with human diploid cells may be a safer strategy. In this study, we developed a novel 2BS cell-adapted rabies virus strain and analysed its sequence, virulence and immunogenicity to determine its application potential as a human diploid cell inactivated vaccine.

Methods and results

The 2BS cell-adapted rabies virus strain 2aG4-B40 was established by passage for 40 generations and selection of plaques in 2BS cells. RNA sequence analysis revealed that mutations in 2BS cell-adapted strains were not located at key sites that regulate the production of neutralizing antibodies or virulence in the aG strain (GQ412744.1). The gradual increase in virulence (remaining above 7.0 logLD50/ml from the 40th to 55th generation) and antigen further indicated that these mutations may increase the affinity of the adapted strains for human diploid cells. Identification tests revealed that the 2BS cell-adapted virus strain was neutralized by anti-rabies serum, with a neutralization index of 19,952. PrEP and PEP vaccination and the NIH test further indicated that the vaccine prepared with the 2aG4-B40 strain had high neutralizing antibody levels (2.24 to 46.67 IU/ml), immunogenicity (protection index 270) and potency (average 11.6 IU/ml).

Conclusions

In this study, a 2BS cell-adapted strain of the 2aG4 rabies virus was obtained by passage for 40 generations. The results of sequencing analysis and titre determination of the adapted strain showed that the mutations in the adaptive process are not located at key sequence regions of the virus, and these mutations may enhance the affinity of the adapted strain for human diploid cells. Moreover, vaccines made from the adapted strain 2aG4-B40 had high potency and immunogenicity and could be an ideal candidate rabies virus strain for inactivated vaccine preparation.
Development and validation of an automated Tomotherapy planning method for cervical cancer
Authors: Han Feiru , Xue Yi , Huang Sheng , Lu Tong , Yang Yining , Cao Yuanjie , Chen Jie , Hou Hailing , Sun Yao , Wang Wei , Yuan Zhiyong , Tao Zhen , Jiang Shengpeng
Published: July 2024

Purpose

This study aimed to develop an automated Tomotherapy (TOMO) planning method for cervical cancer treatment, and to validate its feasibility and effectiveness.

Materials and methods

The study enrolled 30 cervical cancer patients treated with TOMO at our center. Utilizing scripting and Python environment within the RayStation (RaySearch Labs, Sweden) treatment planning system (TPS), we developed automated planning methods for TOMO and volumetric modulated arc therapy (VMAT) techniques. The clinical manual TOMO (M-TOMO) plans for the 30 patients were re-optimized using automated planning scripts for both TOMO and VMAT, creating automated TOMO (A-TOMO) and automated VMAT (A-VMAT) plans. We compared A-TOMO with M-TOMO and A-VMAT plans. The primary evaluated relevant dosimetric parameters and treatment plan efficiency were assessed using the two-sided Wilcoxon signed-rank test for statistical analysis, with a P-value < 0.05 indicating statistical significance.

Results

A-TOMO plans maintained similar target dose uniformity compared to M-TOMO plans, with improvements in target conformity and faster dose drop-off outside the target, and demonstrated significant statistical differences (P+ < 0.01). A-TOMO plans also significantly outperformed M-TOMO plans in reducing V50Gy, V40Gy and Dmean for the bladder and rectum, as well as Dmean for the bowel bag, femoral heads, and kidneys (all P+ < 0.05). Additionally, A-TOMO plans demonstrated better consistency in plan quality. Furthermore, the quality of A-TOMO plans was comparable to or superior than A-VMAT plans. In terms of efficiency, A-TOMO significantly reduced the time required for treatment planning to approximately 20 min.

Conclusion

We have successfully developed an A-TOMO planning method for cervical cancer. Compared to M-TOMO plans, A-TOMO plans improved target conformity and reduced radiation dose to OARs. Additionally, the quality of A-TOMO plans was on par with or surpasses that of A-VMAT plans. The A-TOMO planning method significantly improved the efficiency of treatment planning.
The association between heparin sensitivity index and postoperative blood loss in Chinese patients undergoing elective off-pump coronary artery bypass grafting: a single center retrospective study
Authors: Jia Bin , Ding Chenying , Deng Jinhe , Qi Wenhui , Yao Yuntai ,   The Evidence in Cardiovascular Anesthesia Group
Published: July 2024

Background

The heparin sensitivity index (HSI) is closely associated with perioperative ischemic events and increased blood loss in cardiac surgery. Previous studies have produced conflicting results. Therefore, this study aimed to investigate the relationship between HSI and postoperative blood loss specifically in Chinese patients undergoing elective off-pump coronary artery bypass grafting (OPCAB).

Methods

Patients underwent OPCAB between March 2021 and July 2022 were retrospectively included. Enrolled patients were classified into Low-HSI (HSILOW; HSI < 1.3) and Normal-HSI (HSINORM; HSI ≥ 1.3) groups. HSI = [(activated clotting time (ACT) after heparin) – (baseline ACT)] / [loading dose of heparin (IU/kg)]. Primary outcome included postoperative blood loss at 24 h. Secondary outcomes were total postoperative blood loss, transfusion requirement of red blood cell (RBC), fresh frozen plasma (FFP), platelet concentrates (PC), and other complications.

Results

We retrospectively analyzed 303 Chinese OPCAB patients. HSILOW group had higher preoperative platelet (PLT) count (221 × 109/L vs. 202 × 109/L; P = 0.041) and platelet crit (PCT) value (0.23% vs. 0.22%; P = 0.040) compared to HSINORM group. Two groups showed no significant differences in postoperative blood loss at 24 h (460 mL vs. 470 mL; P = 0.252), total blood loss (920 mL vs. 980 mL; P = 0.063), RBC transfusion requirement (3.4% vs. 3.1%; P = 1.000), FFP transfusion requirement (3.4% vs. 6.2%; P = 0.380), and other complications. Preoperative high PLT count was associated with low intraoperative HSI value (odds ratio: 1.006; 95% confidence interval: 1.002, 1.011; P = 0.008).

Conclusions

Intraoperative HSI value was not associated with postoperative blood loss in Chinese patients undergoing OPCAB. Preoperative high PLT count was an independent predictor of low intraoperative HSI value.
Panpipes: a pipeline for multiomic single-cell and spatial transcriptomic data analysis
Authors: Curion Fabiola , Rich-Griffin Charlotte , Agarwal Devika , Ouologuem Sarah , Rue-Albrecht Kevin , May Lilly , Garcia Giulia E. L. , Heumos Lukas , Thomas Tom , Lason Wojciech , Sims David , Theis Fabian J. , Dendrou Calliope A.
Published: July 2024

Single-cell multiomic analysis of the epigenome, transcriptome, and proteome allows for comprehensive characterization of the molecular circuitry that underpins cell identity and state. However, the holistic interpretation of such datasets presents a challenge given a paucity of approaches for systematic, joint evaluation of different modalities. Here, we present Panpipes, a set of computational workflows designed to automate multimodal single-cell and spatial transcriptomic analyses by incorporating widely-used Python-based tools to perform quality control, preprocessing, integration, clustering, and reference mapping at scale. Panpipes allows reliable and customizable analysis and evaluation of individual and integrated modalities, thereby empowering decision-making before downstream investigations.
Community health promotion and medical provision and impact on neonates (CHAMPION2) and support to rural India’s public education system and impact on numeracy and literacy scores (STRIPES2): an update to the study protocol (v 11) for a cluster randomised trial in Madhya Pradesh, India
Authors: Shivalli Siddharudha , Fazzio Ila , Frost Chris , Elbourne Diana , Magill Nicholas , Sharma Dropti , Shekhawat Sajjan Singh , Banerji Rukmini , Karnati Sridevi , Reddy Harshavardhan , Reddy Padmanabh , Nair Rakhi , Gopal Madan , Boone Peter
Published: July 2024

Background

This update outlines amendments to the CHAMPION2/STRIPES2 cluster randomised trial protocol primarily made due to the COVID-19 pandemic and nationwide lockdown in India in 2020. These amendments were in line with national guidelines for health research during the COVID-19 pandemic.

Methods

We did not change the original trial design, eligibility, and outcomes. Amendments were introduced to minimise the risk of COVID-19 transmission and ensure safety and wellbeing of trial staff, participants, and other villagers. CHAMPION2 intervention: participatory learning and action (PLA) and fixed day service (FDS) meeting were revised to incorporate social distancing and hygiene precautions. During the COVID-19 pandemic, PLA participation was limited to pregnant women and birthing partners. STRIPES2 intervention: before/after-school classes were halted for a period and then modified temporarily (reducing class sizes, and/or changing meeting places) with hygiene and safe distancing practices introduced. Data collection: The research team gathered as much information as possible from participants by telephone. If the participant had no telephone or could not be contacted by telephone, data were collected in person. COVID-19 precautions: trial teams were trained on COVID-19 precautions and used personal protective equipment whilst in the villages for trial-related activities.

After restarting the trial between June and September 2020 in a phased manner, some trial activities were suspended again in all the trial villages from April to June 2021 due to the second wave of COVID-19 cases and lockdown imposed in Satna, Madhya Pradesh. Trial timelines were also revised, with outcomes measured later than originally planned.

Trial registration

Clinical Trial Registry of India CTRI/2019/05/019296. Registered 23 May 2019.

https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MzExOTg=&Enc=&userName=champion2.
Application of signal processing techniques for the spectroscopic analysis of dolutegravir and lamivudine: a comparative assessment and greenness appraisal
Authors: Alnemari Reem M. , Abdelazim Ahmed H. , Almalki Atiah H. , Alqahtani Arwa S. , Alaqel Saleh I. , Alsulami Fahad T. , Serag Ahmed
Published: July 2024

HIV treatment has greatly improved over the years, with the introduction of antiretroviral drugs that target the virus and suppress its replication. Dolutegravir and lamivudine are two such antiretroviral drugs that are commonly used in HIV treatment regimens. Herein, three spectrophotometric methods manipulating ratio spectra were developed for the simultaneous analysis of dolutegravir and lamivudine in their binary mixtures. These methods include mathematical processing stages like ratio difference method or signal processing approaches such as the first derivative of the ratio spectra, and continuous wavelet transform. The developed spectrophotometric methods exploit the characteristic spectral differences between dolutegravir and lamivudine in order to quantify them simultaneously. These methods have shown promising results in terms of sensitivity and selectivity as validated per the ICH guidelines. Moreover, these methods offer a straightforward and economical alternative to more intricate analytical methodologies like high-performance liquid chromatography. By incorporating the analytical eco-scale and AGREE for greenness evaluation of the proposed methods, we can further ensure that these techniques are effective and environmentally friendly, aligning with the principles of green chemistry. This evaluation will provide a comprehensive understanding of the environmental friendliness of these spectrophotometric methods in pharmaceutical analysis.
Cytotoxic T-lymphocyte-associated 4 protein expression is associated with a high international prognostic score in advanced-stage classical Hodgkin lymphoma
Authors: Pangaribuan Flora Dameria , Ham Maria Francisca , Mutmainnah Mutiah , Harahap Agnes Stephanie
Published: July 2024

Objective

Twenty percent of all classical Hodgkin lymphoma (CHL) cases relapse and recur, especially in advanced stages with a high International Prognostic Score (IPS). Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a regulatory molecule that can inhibit the immune response and is related to tumor aggressiveness. This study aimed to determine the relationship between CTLA-4 expression in advanced-stage CHL and IPS, identifying it as a potential therapy target.

Results

In advanced-stage CHL, the group with a high IPS exhibited significantly higher mean CTLA-4 expression compared to the group with a low IPS (p = 0.003).The group with Hb level < 10.5 g/dl, leukocyte count > 15,000/µL, lymphocyte count < 8%, albumin level < 4 g/dl, and stage 4 exhibited higher CTLA-4 expression than the other group, although only leukocyte count and stage showed statistical significance (p = 0.004 and p = 0.020). Mean CTLA-4 expression was 239.84 ± 76.36 for nodular sclerosis, 293.95 ± 147.94 for mixed cellularity, 271.4 ± 23.56 for lymphocyte depleted, and 225.2 for lymphocyte-rich subtypes. The results suggest that CTLA-4 expression is associated with adverse prognostic factors in the IPS for advanced-stage CHL, supporting the notion that immune checkpoints play a role in cancer progression.
The roles of neural stem cells in myelin regeneration and repair therapy after spinal cord injury
Authors: Li Chun , Luo Yuping , Li Siguang
Published: July 2024

Spinal cord injury (SCI) is a complex tissue injury that results in a wide range of physical deficits, including permanent or progressive disabilities of sensory, motor and autonomic functions. To date, limitations in current clinical treatment options can leave SCI patients with lifelong disabilities. There is an urgent need to develop new therapies for reconstructing the damaged spinal cord neuron-glia network and restoring connectivity with the supraspinal pathways. Neural stem cells (NSCs) possess the ability to self-renew and differentiate into neurons and neuroglia, including oligodendrocytes, which are cells responsible for the formation and maintenance of the myelin sheath and the regeneration of demyelinated axons. For these properties, NSCs are considered to be a promising cell source for rebuilding damaged neural circuits and promoting myelin regeneration. Over the past decade, transplantation of NSCs has been extensively tested in a variety of preclinical models of SCI. This review aims to highlight the pathophysiology of SCI and promote the understanding of the role of NSCs in SCI repair therapy and the current advances in pathological mechanism, pre-clinical studies, as well as clinical trials of SCI via NSC transplantation therapeutic strategy. Understanding and mastering these frontier updates will pave the way for establishing novel therapeutic strategies to improve the quality of recovery from SCI.
Existence of positive periodic solutions for Liénard equation with a singularity of repulsive type
Authors: Zhu Yu
Published: July 2024

In this paper, the existence of positive periodic solutions is studied for Liénard equation with a singularity of repulsive type, $$ x''(t)+f(x(t))x'(t)+\varphi (t)x^{\mu}(t)-\frac{1}{x^{\gamma}(t)}=e(t), $$

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where $f:(0,+\infty )\rightarrow R$
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is continuous, which may have a singularity at the origin, the sign of $\varphi (t)$
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, $e(t)$
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is allowed to change, and μ, γ are positive constants. By using a continuation theorem, as well as the techniques of a priori estimates, we show that this equation has a positive T-periodic solution when $\mu \in [0,+\infty )$
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.