bluuebunny/crossref_metadata_2025 huggingface dataset:
Federated learning algorithms for generalized mixed-effects model (GLMM) on horizontally partitioned data from distributed sources
Authors: Li Wentao , Tong Jiayi , Anjum Md. Monowar , Mohammed Noman , Chen Yong , Jiang Xiaoqian
Published: October 2022

Objectives

This paper developed federated solutions based on two approximation algorithms to achieve federated generalized linear mixed effect models (GLMM). The paper also proposed a solution for numerical errors and singularity issues. And showed the two proposed methods can perform well in revealing the significance of parameter in distributed datasets, comparing to a centralized GLMM algorithm from R package (‘lme4’) as the baseline model.

Methods

The log-likelihood function of GLMM is approximated by two numerical methods (Laplace approximation and Gaussian Hermite approximation, abbreviated as LA and GH), which supports federated decomposition of GLMM to bring computation to data. To solve the numerical errors and singularity issues, the loss-less estimation of log-sum-exponential trick and the adaptive regularization strategy was used to tackle the problems caused by federated settings.

Results

Our proposed method can handle GLMM to accommodate hierarchical data with multiple non-independent levels of observations in a federated setting. The experiment results demonstrate comparable (LA) and superior (GH) performances with simulated and real-world data.

Conclusion

We modified and compared federated GLMMs with different approximations, which can support researchers in analyzing versatile biomedical data to accommodate mixed effects and address non-independence due to hierarchical structures (i.e., institutes, region, country, etc.).
A comparison of the effects of teaching through simulation and the traditional method on nursing students' self-efficacy skills and clinical performance: a quasi-experimental study
Authors: Azizi Marzieh , Ramezani Ghobad , Karimi Elham , Hayat Ali Asghar , Faghihi Seyed Aliakbar , Keshavarzi Mohammad Hasan
Published: October 2022

Introduction

Simulators in a clinical environment provide a space where students can acquire skills and experience under the supervision of their professors without any worries or inflicting any harm on their patients. The current study aimed to compare the effects of teaching through simulation and the traditional method on nursing students' self-efficacy skills and clinical performance.

Method

The current study was quasi-experimental and adopted a pre-test & post-test design. The population consisted of 122 students of nursing, out of whom 100 students were selected as the sample. Then, they were randomly divided into an experimental and a control group. A questionnaire assessed the students' self-efficacy skills and clinical performance before and after implementing the instructional programs. The data were analyzed using descriptive and inferential statistical techniques in SPSS 23.

Findings

The mean of the participants' self-efficacy scores increased significantly after the intervention (from 87.57 to 142.13). Moreover, the mean of the participants' clinical performance increased significantly after the intervention (from 2.16 to 4.57). The findings indicated that simulation teaching significantly affects nursing students' self-efficacy and clinical performance.

Conclusion

Simulation was recommended as an effective teaching methodology, particularly in nurses' internship wards. In other words, acquiring the essential skills through applying the simulation method is recommended before entering real-world environments.
Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo
Authors: Lundgaard Riis Malene , Matilionyte Gabriele , Nielsen John E. , Melau Cecilie , Greenald David , Juul Hare Kristine , Langhoff Thuesen Lea , Dreisler Eva , Aaboe Kasper , Brenøe Pia Tutein , Andersson Anna-Maria , Albrethsen Jakob , Frederiksen Hanne , Rajpert-De Meyts Ewa , Juul Anders , Mitchell Rod T. , Jørgensen Anne
Published: October 2022

Background

Reduced androgen action during early fetal development has been suggested as the origin of reproductive disorders comprised within the testicular dysgenesis syndrome (TDS). This hypothesis has been supported by studies in rats demonstrating that normal male development and adult reproductive function depend on sufficient androgen exposure during a sensitive fetal period, called the masculinization programming window (MPW). The main aim of this study was therefore to examine the effects of manipulating androgen production during different timepoints during early human fetal testis development to identify the existence and timing of a possible window of androgen sensitivity resembling the MPW in rats.

Methods

The effects of experimentally reduced androgen exposure during different periods of human fetal testis development and function were examined using an established and validated human ex vivo tissue culture model. The androgen production was reduced by treatment with ketoconazole and validated by treatment with flutamide which blocks the androgen receptor. Testicular hormone production ex vivo was measured by liquid chromatography-tandem mass spectrometry or ELISA assays, and selected protein markers were assessed by immunohistochemistry.

Results

Ketoconazole reduced androgen production in testes from gestational weeks (GW) 7–21, which were subsequently divided into four age groups: GW 7–10, 10–12, 12–16 and 16–21. Additionally, reduced secretion of testicular hormones INSL3, AMH and Inhibin B was observed, but only in the age groups GW 7–10 and 10–12, while a decrease in the total density of germ cells and OCT4+ gonocytes was found in the GW 7–10 age group. Flutamide treatment in specimens aged GW 7–12 did not alter androgen production, but the secretion of INSL3, AMH and Inhibin B was reduced, and a reduced number of pre-spermatogonia was observed.

Conclusions

This study showed that reduced androgen action during early development affects the function and density of several cell types in the human fetal testis, with similar effects observed after ketoconazole and flutamide treatment. The effects were only observed within the GW 7–14 period—thereby indicating the presence of a window of androgen sensitivity in the human fetal testis.
Effectiveness of inactivated and Ad5-nCoV COVID-19 vaccines against SARS-CoV-2 Omicron BA. 2 variant infection, severe illness, and death
Authors: Huang Zhuoying , Xu Shuangfei , Liu Jiechen , Wu Linlin , Qiu Jing , Wang Nan , Ren Jia , Li Zhi , Guo Xiang , Tao Fangfang , Chen Jian , Lu Donglei , Sun Xiaodong , Wang Weibing
Published: October 2022

Background

Limited data are available on the effectiveness of inactivated and Ad5-nCoV COVID-19 vaccines in real-world use—especially against Omicron variants in SARS-CoV-2 infection-naïve population.

Methods

A matched case-control study was conducted among people aged ≥ 3 years between 2 December 2021 and 13 May 2022. Cases were SARS-CoV-2-infected individuals, individuals with severe/critical COVID-19, or COVID-19-related deaths. Controls were selected from consecutively test-negative individuals at the same time as cases were diagnosed and were exact-matched on year-of-age, gender, birthplace, illness onset date, and residential district in ratios of 1:1 with infected individuals and 4:1 with severe/critical COVID-19 and COVID-19-related death. Additionally, two subsets were constructed to analyze separate vaccine effectiveness (VE) of inactivated vaccines (subset 1) and Ad5-vectored vaccine (subset 2) against each of the three outcomes.

Results

Our study included 612,597 documented SARS-CoV-2 infections, among which 1485 progressed to severe or critical illness and 568 died. Administering COVID-19 vaccines provided limited protection against SARS-CoV-2 infection across all age groups (overall VE: 16.0%, 95% CI: 15.1–17.0%) but high protection against severe/critical illness (88.6%, 85.8–90.8%) and COVID-19-related death (91.6%, 86.8–94.6%). In subset 1, inactivated vaccine showed 16.3% (15.4–17.2%) effective against infection, 88.6% (85.8–90.9%) effective against severe/critical COVIID-19, and 91.7% (86.9–94.7%) against COVID-19 death. Booster vaccination with inactivated vaccines enhanced protection against severe COVID-19 (92.7%, 90.1–94.6%) and COVID-19 death (95.9%, 91.4–98.1%). Inactivated VE against infection began to wane 12 weeks after the last dose, but two and three doses sustained high protection levels (> 80%) against severe/critical illness and death, while subset 2 showed Ad5-vectored vaccine was 13.2% (10.9–15.5%) effective against infection and 77.9% (15.6–94.2%) effective against severe/critical COVIID-19.

Conclusions

Our real-world study found high and durable two- and three-dose inactivated VE against Omicron-associated severe/critical illness and death across all age groups, but lower effectiveness against Omicron infection, which reinforces the critical importance of full-series vaccination and timely booster dose administration for all eligible individuals.
Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition
Authors: Broséus Lucile , Vaiman Daniel , Tost Jörg , Martin Camino Ruano San , Jacobi Milan , Schwartz Joel D. , Béranger Rémi , Slama Rémy , Heude Barbara , Lepeule Johanna
Published: October 2022

Background

Maternal blood pressure levels reflect cardiovascular adaptation to pregnancy and proper maternal-fetal exchanges through the placenta and are very sensitive to numerous environmental stressors. Maternal hypertension during pregnancy has been associated with impaired placental functions and with an increased risk for children to suffer from cardiovascular and respiratory diseases later on. Investigating changes in placental DNA methylation levels and cell-type composition in association with maternal blood pressure could help elucidate its relationships with placental and fetal development.

Methods

Taking advantage of a large cohort of 666 participants, we investigated the association between epigenome-wide DNA methylation patterns in the placenta, measured using the Infinium HumanMethylation450 BeadChip, placental cell-type composition, estimated in silico, and repeated measurements of maternal steady and pulsatile blood pressure indicators during pregnancy.

Results

At the site-specific level, no significant association was found between maternal blood pressure and DNA methylation levels after correction for multiple testing (false discovery rate < 0.05), but 5 out of 24 previously found CpG associations were replicated (p-value < 0.05). At the regional level, our analyses highlighted 64 differentially methylated regions significantly associated with at least one blood pressure component, including 35 regions associated with mean arterial pressure levels during late pregnancy. These regions were found enriched for genes implicated in lung development and diseases. Further mediation analyses show that a significant part of the association between steady blood pressure—but not pulsatile pressure—and placental methylation can be explained by alterations in placental cell-type composition. In particular, elevated blood pressure levels are associated with a decrease in the ratio between mesenchymal stromal cells and syncytiotrophoblasts, even in the absence of preeclampsia.

Conclusions

This study provides the first evidence that the association between maternal steady blood pressure during pregnancy and placental DNA methylation is both direct and partly explained by changes in cell-type composition. These results could hint at molecular mechanisms linking maternal hypertension to lung development and early origins of childhood respiratory problems and at the importance of controlling maternal blood pressure during pregnancy.
Reprogramming of sentinel lymph node microenvironment during tumor metastasis
Authors: Li Yen-Liang , Hung Wen-Chun
Published: October 2022

Metastasis is a major cause of death in patients with cancer. The two main routes for cancer cell dissemination are the blood and lymphatic systems. The underlying mechanism of hematogenous metastasis has been well characterized in the past few decades. However, our understanding of the molecular basis of lymphatic metastasis remains at a premature stage. Conceptually, cancer cells invade into lymphatic capillary, passively move to collecting lymphatic vessels, migrate into sentinel lymph node (SLN;, the first lymph node to which cancer cells spread from the primary tumor), and enter the blood circulatory system via the subclavian vein. Before arriving, cancer cells release specific soluble factors to modulate the microenvironment in SLN to establish a beachhead for successful colonization. After colonization, cancer cells inhibit anti-tumor immunity by inducing the recruitment of regulatory T cell and myeloid-derived suppressor cells, suppressing the function of dendritic cell and CD8+ T cell, and promoting the release of immunosuppressive cytokines. The development of novel strategies to reverse cancer cell-triggered SLN remodeling may re-activate immunity to reduce beachhead buildup and distant metastasis. In addition to being a microanatomic location for metastasis, the SLN is also an important site for immune modulation. Nanotechnology-based approaches to deliver lymph node-tropic antibodies or drug-conjugated nanoparticles to kill cancer cells on site are a new direction for cancer treatment. Conversely, the induction of stronger immunity by promoting antigen presentation in lymph nodes provides an alternate way to enhance the efficacy of immune checkpoint therapy and cancer vaccine. In this review article, we summarize recent findings on the reprogramming of SLN during lymphatic invasion and discuss the possibility of inhibiting tumor metastasis and eliciting anti-tumor immunity by targeting SLN.
Diagnostic and prognostic value of ventilatory power in pulmonary hypertension
Authors: Li Xin , Zhang Yi , Jin Qi , Zhao Zhihui , Zhao Qing , Yan Lu , Duan Anqi , Huang Zhihua , Hu Meixi , Xiong Changming , Luo Qin , Liu Zhihong
Published: October 2022

Background

Ventilatory power is a novel index which could reflect both ventilation efficiency and peripheral blood flow. However, its clinical value in pulmonary hypertension (PH) is rarely discussed. In the present study, we aimed to investigate the diagnostic and prognostic value of ventilatory power as well as its association with disease severity in PH.

Methods

Consecutive patients with normal hemodynamics and patients diagnosed with PH between September, 2012 and December, 2020 in Fuwai hospital were enrolled. Receiver operating characteristic curves were constructed to determine diagnostic power of ventilatory power and tricuspid regurgitation velocity (TRV). Spearman correlation coefficients were used to evaluate bivariate correlation. Multivariable Cox analysis were used to evaluate the association between ventilatory power and clinical worsening.

Results

A total of 679 patients were included in the study, among whom 177 were patients with normal hemodynamics, and 502 were patients with PH. Among patients with PH, those experiencing clinical worsening had lower ventilatory power than those did not. The area under the curve of TRV plus ventilatory power was higher than TRV used alone when identifying overt and borderline PH. Ventilatory power was also correlated with well-validated variables that reflected severity of PH, such as NT-proBNP. Multivariable Cox analysis showed that ventilatory power could independently predict clinical worsening and could improve the predictive power of the current PH risk assessment tool.

Conclusion

Ventilatory power could improve the predictive power of TRV in identifying overt PH and borderline PH. Moreover, it could reflect disease severity and independently predict clinical worsening.
Serum high mobility group box-1 levels associated with cardiovascular events after lower extremity revascularization: a prospective study of a diabetic population
Authors: Rando Maria Margherita , Biscetti Federico , Cecchini Andrea Leonardo , Nardella Elisabetta , Nicolazzi Maria Anna , Angelini Flavia , Iezzi Roberto , Eraso Luis H. , Dimuzio Paul J. , Pitocco Dario , Gasbarrini Antonio , Massetti Massimo , Flex Andrea
Published: October 2022

Background

Peripheral arterial disease (PAD) is one of the most disabling cardiovascular complications of type 2 diabetes mellitus and is indeed associated with a high risk of cardiovascular and limb adverse events. High mobility group box-1 (HMGB-1) is a nuclear protein involved in the inflammatory response that acts as a pro-inflammatory cytokine when released into the extracellular space. HMBG-1 is associated with PAD in diabetic patients.

The aim of this study was to evaluate the association between serum HMGB-1 levels and major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after lower-extremity endovascular revascularization (LER) in a group of diabetic patients with chronic limb-threatening ischemia (CLTI).

Methods

We conducted a prospective observational study of 201 diabetic patients with PAD and CLTI requiring LER. Baseline serum HMGB-1 levels were determined before endovascular procedure. Data on cardiovascular and limb outcomes were collected in a 12-month follow-up.

Results

During the follow-up period, 81 cases of MACE and 93 cases of MALE occurred. Patients who subsequently developed MACE and MALE had higher serum HMGB-1 levels. Specifically, 7.5 ng/mL vs 4.9 ng/mL (p < 0.01) for MACE and 7.2 ng/mL vs 4.8 ng/mL (p < 0.01) for MALE. After adjusting for traditional cardiovascular risk factors, the association between serum HMGB-1 levels and cardiovascular outcomes remained significant in multivariable analysis. In our receiver operating characteristic (ROC) curve analysis, serum HMGB-1 levels were a good predictor of MACE incidence (area under the curve [AUC] = 0.78) and MALE incidence (AUC = 0.75).

Conclusions

This study demonstrates that serum HMGB-1 levels are associated with the incidence of MACE and MALE after LER in diabetic populations with PAD and CLTI.
Identification of pyroptosis-related genes and long non-coding RNAs signatures in osteosarcoma
Authors: Zhang Jian , Deng Jianjian , Ding Rui , Yuan Jinghong , Liu Jiahao , Zhao Xiaokun , Wu Tianlong , Jia Jingyu , Cheng Xigao
Published: October 2022

Osteosarcoma is a highly malignant tumor, with very high disability and fatality rates. However, the overall prognosis is not optimistic. Pyroptosis is a newly discovered cell death modality accompanied by inflammation, which is closely related to varieties of cancers. In this study, the RNA-seq data were downloaded from public databases, the differences in the expression of the pyroptosis-related genes (PRGs) were identified, and the six PRGs signature was established through the univariate and LASSO Cox analysis. The patients were grouped according to the PRGs signature, and the prognosis between the two groups was further compared. In addition, a ten pyroptosis-related lncRNAs (PRLs) prognostic signature was also constructed. Through functional analysis of the differentially expressed genes (DEGs), the immune-related pathways were found to be enriched. The Pearson correlation analysis showed a strong correlation between the pyroptosis-related biomarkers. Finally, we identified a promising biomarker, CHMP4C, which is highly expressed in osteosarcoma. Overexpression of CHMP4C promoted the proliferation, migration and invasion of the osteosarcoma cell. Our results thus provide new evidence for exploring prognostic biomarkers and therapeutic targets of osteosarcoma.
A systematic review of the distribution of take-home naloxone in low- and middle-income countries and barriers to the implementation of take-home naloxone programs
Authors: Sajwani Hawraa Sameer , Williams Anna V
Published: October 2022

Background

Opioid overdose epidemic is hitting record highs worldwide, accounting for 76% of mortality related to substance use. Take-home naloxone (THN) strategies are being implemented in many developed countries that suffer from high opioid overdose death rates. They aim to provide overdose identification and naloxone administration training, along with THN delivery to opioid users and others likely to witness an overdose incident such as family members and peers. However, little is known about such measures in low- and middle-income countries (LMIC), where opioid use and opioid-related deaths are reportedly high. This systematic literature review aims to examine the distribution of THN in LMIC, review studies identifying barriers to the implementation of THN programs worldwide, and assess their applicability to LMIC.

Methods

The literature was searched and analyzed for eligible studies with quality assessment.

Results

Two studies were found from LMIC on THN programs with promising results, and 13 studies were found on the barriers identified in implementing THN programs worldwide. The main barriers to THN strategies were the lack of training of healthcare providers, lack of privileges, time constraints, cost, legislative/policy restrictions, stigma, fear of litigation, and some misperceptions around THN.

Conclusions

The barriers outlined in this paper are probably applicable to LMIC, but more difficult to overcome considering the differences in their response to opioid overdose, their cultural attitudes and norms, the high cost, the waivers required, the legislative differences and the severe penalties for drug-related offenses in some of these countries. The solutions suggested to counter-act these obstacles can also be more difficult to achieve in LMIC. Further research is required in this area with larger sample sizes to provide a better understanding of the obstacles to the implementation, feasibility, accessibility, and utilization of THN programs in LMIC.
Gothenburg Empowerment Scale (GES): psychometric properties and measurement invariance in adults with congenital heart disease from Belgium, Norway and South Korea
Authors: Acuña Mora Mariela , Raymaekers Koen , Van Bulck Liesbet , Goossens Eva , Luyckx Koen , Kovacs Adrienne H. , Andresen Brith , Moon Ju Ryoung , Van De Bruaene Alexander , Rassart Jessica , Moons Philip
Published: October 2022

Background

Patient empowerment is associated with improvements in different patient-reported and clinical outcomes. However, despite being widely researched, high quality and theoretically substantiated disease-generic measures of patient empowerment are lacking. The few good instruments that are available have not reported important psychometric properties, including measurement invariance. The aim of this study was to assess the psychometric properties of the 15-item Gothenburg Empowerment Scale (GES), with a particular focus on measurement invariance of the GES across individuals from three countries.

Methods

Adults with congenital heart disease from Belgium, Norway and South Korea completed the GES and other patient-reported outcomes as part of an international, cross-sectional, descriptive study called APPROACH-IS II. The scale’s content (missing data) and factorial validity (confirmatory factor analyses), measurement invariance (multi-group confirmatory factor analyses), responsiveness (floor and ceiling effects) and reliability (internal consistency) were assessed.

Results

Content validity, responsiveness and reliability were confirmed. Nonetheless, metric but not scalar measurement invariance was supported when including the three countries, possibly because the scale performed differently in the sample from South Korea. A second set of analyses supported partial scalar invariance for a sample that was limited to Norway and Belgium.

Conclusion

Our study offers preliminary evidence that GES is a valid and reliable measure of patient empowerment in adults with congenital heart disease. However, cross-country comparisons must be made with caution, given the scale did not perform equivalently across the three countries.
Lung resection surgery in Jehovah’s Witness patients: a 20-year single-center experience
Authors: Lee Andy Chao Hsuan , Ferguson Mark K. , Donington Jessica Scott
Published: October 2022

Background

The paucity of literature on surgical outcomes of Jehovah’s Witness (JW) patients undergoing lung resection suggests some patients with operable lung cancers may be denied resection. The aim of this study is to better understand perioperative outcomes and long-term cancer survival of JW patients undergoing lung resection.

Methods

All pulmonary resections in JW patients at one institution from 2000 through 2020 were examined. Demographics, comorbidities, operative parameters, and perioperative outcomes were reviewed. Among operations performed for primary non-small cell lung cancer (NSCLC), details regarding staging, extent of resection, additional therapies, recurrence, and survival were abstracted.

Results

Seventeen lung resections were performed in fourteen patients. There were nine anatomic resections and eight wedge resections. Fourteen resections (82%) were approached thoracoscopically, of which 3 of 6 anatomic resections were converted to thoracotomy as compared to 1 of 8 wedge resections. There was one (6%) perioperative death. Ten resections in 8 patients were performed for primary pulmonary malignancies, and two patients underwent procedures for recurrent disease. Median survival for resected NSCLCs (N = 7) was 65 months. Three of 6 patients who survived the immediate perioperative period underwent additional procedures: 2 pulmonary wedge resections for diagnosis and one pleural biopsy.

Conclusions

This series of JW patients undergoing lung resections demonstrates that resections for cancer and inflammatory etiologies can be performed safely in the setting of both primary and re-operative procedures.
Rare lysosomal disease registries: lessons learned over three decades of real-world evidence
Authors: Mistry P. K. , Kishnani P. , Wanner C. , Dong D. , Bender J. , Batista J. L. , Foster J.
Published: October 2022

Lysosomal storage disorders (LSD) are rare diseases, caused by inherited deficiencies of lysosomal enzymes/transporters, that affect 1 in 7000 to 1 in 8000 newborns. Individuals with LSDs face long diagnostic journeys during which debilitating and life-threatening events can occur. Clinical trials and classical descriptions of LSDs typically focus on common manifestations, which are not representative of the vast phenotypic heterogeneity encountered in real-world experience. Additionally, recognizing that there was a limited understanding of the natural history, disease progression, and real-world clinical outcomes of rare LSDs, a collaborative partnership was pioneered 30 years ago to address these gaps. The Rare Disease Registries (RDR) (for Gaucher, Fabry, Mucopolysaccharidosis type I, and Pompe), represent the largest observational database for these LSDs. Over the past thirty years, data from the RDRs have helped to inform scientific understanding and the development of comprehensive monitoring and treatment guidelines by creating a framework for data collection and establishing a standard of care, with an overarching goal to improve the quality of life of affected patients. Here, we highlight the history, process, and impact of the RDRs, and discuss the lessons learned and future directions.
Replication stress generates distinctive landscapes of DNA copy number alterations and chromosome scale losses
Authors: Shaikh Nadeem , Mazzagatti Alice , De Angelis Simone , Johnson Sarah C. , Bakker Bjorn , Spierings Diana C. J. , Wardenaar René , Maniati Eleni , Wang Jun , Boemo Michael A. , Foijer Floris , McClelland Sarah E.
Published: October 2022

Background

A major driver of cancer chromosomal instability is replication stress, the slowing or stalling of DNA replication. How replication stress and genomic instability are connected is not known. Aphidicolin-induced replication stress induces breakages at common fragile sites, but the exact causes of fragility are debated, and acute genomic consequences of replication stress are not fully explored.

Results

We characterize DNA copy number alterations (CNAs) in single, diploid non-transformed cells, caused by one cell cycle in the presence of either aphidicolin or hydroxyurea. Multiple types of CNAs are generated, associated with different genomic regions and features, and observed copy number landscapes are distinct between aphidicolin and hydroxyurea-induced replication stress. Coupling cell type-specific analysis of CNAs to gene expression and single-cell replication timing analyses pinpointed the causative large genes of the most recurrent chromosome-scale CNAs in aphidicolin. These are clustered on chromosome 7 in RPE1 epithelial cells but chromosome 1 in BJ fibroblasts. Chromosome arm level CNAs also generate acentric lagging chromatin and micronuclei containing these chromosomes.

Conclusions

Chromosomal instability driven by replication stress occurs via focal CNAs and chromosome arm scale changes, with the latter confined to a very small subset of chromosome regions, potentially heavily skewing cancer genome evolution. Different inducers of replication stress lead to distinctive CNA landscapes providing the opportunity to derive copy number signatures of specific replication stress mechanisms. Single-cell CNA analysis thus reveals the impact of replication stress on the genome, providing insights into the molecular mechanisms which fuel chromosomal instability in cancer.
Efficacy of a formulation of sarolaner/moxidectin/pyrantel (Simparica Trio®) for the prevention of Thelazia callipaeda canine eyeworm infection
Authors: Bezerra-Santos Marcos Antonio , Mendoza-Roldan Jairo Alfonso , Sgroi Giovanni , Lia Riccardo Paolo , Venegoni Giulia , Solari Basano Fabrizio , Nele Roose , Mahabir Sean P. , Borowski Stasia , Geurden Thomas , Otranto Domenico
Published: October 2022

Background

For a long time known as the oriental eyeworm, Thelazia callipaeda is a zoonotic nematode that infects the eyes of a wide range of vertebrate hosts including dogs, cats, wildlife carnivores, lagomorphs, and humans. The high occurrence of this infection in Europe and the first cases in the United States have increased scientific interest in the parasite, as it also represents a risk for people living in endemic areas. Therefore, treatment and prevention of thelaziosis in canine population are advocated to reduce the risk of human infection as well. Here, we assessed the efficacy of a formulation containing sarolaner/moxidectin/pyrantel (Simparica Trio®) administered orally at monthly intervals, for the prevention of establishment of infection with T. callipaeda in naturally infected dogs. In this formulation, moxidectin is expected to have efficacy against eyeworms, whereas sarolaner and pyrantel are not.

Methods

The study was conducted in eyeworm endemic areas of Italy and France, where dogs (n = 125) were assigned into two groups consisting of a negative control group (G1; n = 62), in which animals were treated monthly with a control product (sarolaner; Simparica®), and a treatment group (G2; n = 63) in which animals were treated monthly with Simparica Trio (sarolaner/moxidectin/pyrantel) from day 0 to day 150. In total, nine animals were withdrawn from the study (two animals became positive at day 30, and seven for reasons unrelated to eyeworm infection), resulting in 116 animals (n = 58 for G1; n = 58 for G2).

Results

In G1, 16 out of 58 animals (27.6%) were observed with eyeworms during the study, and none of the animals from G2 were ever observed with eyeworms, resulting in 100% efficacy (P < 0.0001) in the prevention of establishment of T. callipaeda infection. Adult nematodes and fourth-instar (L4)-stage larvae were recovered from the eyes of positive animals, counted, and morphologically identified as T. callipaeda. In addition, specimens from Italy were molecularly confirmed as belonging to the haplotype 1 (i.e., the only one circulating in Europe so far).

Conclusions

Data presented herein demonstrated 100% efficacy of Simparica Trio for the prevention of T. callipaeda eyeworm infection in dogs from highly endemic areas of France and Italy. The use of this formulation is advantageous, as it is a licensed product in Europe with a wide efficacy spectrum against other nematodes, multiple tick species, and fleas. In addition, preventing the development of infection in dogs could also be a prophylaxis measure for zoonotic T. callipaeda infection in humans inhabiting endemic areas.

Graphical Abstract
Monoclonal antibody treatment of COVID-19 in a pregnant woman with common variable immunodeficiency
Authors: Aberumand Babak , Kamal Ramy , McKinney Brock , Betschel Stephen
Published: October 2022

Background

Since the first reported case of COVID-19, infections due to the virus have ranged from mild to severe. Patients with inborn errors of immunity are thought to be at increased risk for infections such as COVID-19 due to the nature of their disease and being immunocompromised. Similarly, pregnant women by nature of physiological changes in immunity are susceptible to infections and consequently are felt to be at greater risk of contracting COVID-19 with potential grave consequences for not only the mother but also the fetus. Early treatment with novel therapeutics against the SARS-CoV-2 virus to prevent progression and these complications is paramount.

Case Presentation

A 31-year-old woman with a 22-year history of common variable immunodeficiency on subcutaneous immunoglobulin replacement therapy and 24 weeks pregnant with her third child presented to the Emergency Department with two-day history of pharyngitis that progressed to include nasal and chest congestion, non-productive cough and shortness of breath. Her vitals indicated temperature of 35 degrees Celsius, heart rate of 109 beats per minute, blood pressure 142/92 mmHg, respiratory rate 22/min and an oxygen saturation of 99% on room air. A workup was done and she was found to be positive for SARS-CoV-2 virus confirmed by PCR. She had a close contact, her husband, who had tested positive a few days prior. She had been previously vaccinated with three doses of the Moderna COVID-19 (Spikevax ®) vaccine. As she met the criteria for monoclonal antibody treatment, she received Sotrovimab on the same day of testing positive and tolerated it well with no side-effects. Her symptoms resolved within two to three days.

Conclusion

Our case, is the first to our knowledge, of a pregnant patient with common variable immunodeficiency diagnosed with COVID-19 and symptomatic successfully receiving treatment with Sotrovimab. Her rapid resolution of symptoms makes the use of monoclonal antibodies such as Sotrovimab a safe and useful option in this unique population.
A collaborative computation and dependency-aware task offloading method for vehicular edge computing: a reinforcement learning approach
Authors: Liu Guozhi , Dai Fei , Huang Bi , Qiang Zhenping , Wang Shuai , Li Lecheng
Published: October 2022

Vehicular edge computing (VEC) is emerging as a new computing paradigm to improve the quality of vehicular services and enhance the capabilities of vehicles. It enables performing tasks with low latency by deploying computing and storage resources close to vehicles. However, the traditional task offloading schemes only focus on one-shot offloading, taking less into consideration task dependency. Furthermore, the continuous action space problem during task offloading should be considered. In this paper, an efficient dependency-aware task offloading scheme for VEC with vehicle-edge-cloud collaborative computation is proposed, where subtasks can be processed locally or can be offloaded to an edge server, or a cloud server for execution. Specifically, first, the directed acyclic graph (DAG) is utilized to model the dependency of subtasks. Second, a task offloading algorithm based on Deep Deterministic Policy Gradient (DDPG) was proposed to obtain the optimal offloading strategy in a vehicle-edge-cloud environment, which efficiently solves the continuous control problem and helps reach fast convergence. Finally, extensive simulation experiments have been conducted, and the experimental results show that the proposed scheme can improve performance by about 13.62% on average against three baselines.
Mechanical Characteristics of Hybrid-Fiber-Reinforced Concrete Shaft Wall Structure Under Uneven Load
Authors: Yao Zhishu , Xu Yongjie , Zhang Ping , Fang Yu , Wang Chen , Diao Naihao , Hu Kun
Published: October 2022

To prevent damage to shaft walls in mines due to uneven loading, the mechanical properties of a shaft wall structure made of hybrid-fiber-reinforced concrete were studied. First, through orthogonal testing, the optimal mix proportion of the hybrid-fiber-reinforced concrete was obtained. Subsequently, a numerical calculation model of the shaft wall structure under uneven loading was established. The calculation results showed that the structure exhibits a tensile stress under the action of uneven loading and that its bearing capacity can be improved using the hybrid-fiber-reinforced concrete. Based on the numerical simulation results, a calculation formula for the bearing capacity of the shaft wall was obtained by regression. Finally, a model test was conducted on the shaft lining structure. The results obtained were consistent with those obtained using the numerical simulation regression formula, confirming the reliability of the numerical simulation results. This study showed that a hybrid-fiber-reinforced concrete shaft wall structure can better withstand uneven loads and has improved brittle failure characteristics. Hybrid-fiber-reinforced concrete is an excellent material for deep shaft wall structures.
Midpalatal suture bone repair after miniscrew-assisted rapid palatal expansion in adults
Authors: Naveda Rodrigo , dos Santos Alexandre Magno , Seminario María Pía , Miranda Felicia , Janson Guilherme , Garib Daniela
Published: October 2022

Background

Midpalatal suture (MPS) repair in growing patients after RPE has been previously reported. However, differences between young and adult patients for timing and pattern of MPS repair after rapid maxillary expansion are expected. The aim of this study was to evaluate the midpalatal suture repair pattern after miniscrew-assisted rapid palatal expansion (MARPE) in adult patients.

Materials and methods

The study included 21 patients (six males, 15 females) successfully treated with MARPE with a mean initial age of 29.1 years of age (SD = 8.0; range = 20.1–45.1). MPS repair was evaluated using maxillary axial and coronal sections derived from CBCT exams taken 16 months after the expansion (SD = 5.9). Objective and subjective assessments of MPS repair were performed. Objective assessments were performed measuring MPS bone density at anterior, median and posterior region of hard palate. Pre-expansion and post-retention bone density changes were evaluated using paired t tests (p < 0.05). Midpalatal suture bone repair was scored 0 to 3 considering, respectively, the complete absence of bone repair in the MPS, the repair of less than 50% of the MPS, the repair of more than 50% of the MPS and the complete repair of the MPS. Intra- and interexaminer reliability evaluation were assessed using Kappa coefficient.

Results

The objective evaluation showed a significant higher bone density at the pre-expansion stage in all palatal regions. The reliability of the subjective method was adequate with intra- and interexaminer agreements varying from 0.807 to 0.904. Scores 1, 2 and 3 were found in 19.05%, 38.09% and 42.86% of the sample, respectively. The most common region demonstrating absence of bone repair was the middle third. The anterior third of the midpalatal suture was repaired in all patients.

Conclusions

A decreased bone density was observed after the retention period when compared to pre-expansion stage. Most adult patients demonstrated incomplete repair of the midpalatal suture 16 months after MARPE. However, adequate bone repair covering more than half of the hard palate extension was observed in 80.95% of the patients.
Attitudes and practices in the laboratory monitoring of conventional synthetic disease modifying anti-rheumatic drugs by rheumatologists and rheumatology trainees
Authors: Tsakas James J. , Liew David F. L. , Adams Cameron L. , Hill Catherine L. , Proudman Susanna , Whittle Samuel , Buchbinder Rachelle , Robinson Philip C.
Published: October 2022

Objectives

There is scant research about laboratory monitoring in people taking conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) for rheumatic disease. Our objective was to conduct a scoping study to assess the range of current attitudes and the variation in practice of laboratory monitoring of csDMARDs by rheumatologists and trainees.

Methods

Australian and overseas rheumatologists or trainees were invited through newsletter, Twitter and personal e-mail, to complete an anonymous online survey between 1 February and 22 March 2021. Questions focused on laboratory tests requested by csDMARD prescribed, frequency/pattern of monitoring, influence of additional factors and combination therapy, actions in response to abnormal tests, and attitudes to monitoring frequencies. Results were presented descriptively and analysed using linear and logistic regression.

Results

There were 221 valid responses. Most respondents were from Australia (n = 53, 35%) followed by the US (n = 39, 26%), with a slight preponderance of women (n = 84, 56%), ≥ 11 years in rheumatology practice (n = 83, 56%) and in mostly public practice (n = 79, 53%). Respondents had a wide variation in the frequency and scheduling of tests. In general, respondents reported increasing monitoring frequency if patients had numerous comorbidities or if both methotrexate and leflunomide were being taken concurrently. There was a wide variety of responses to abnormal monitoring results and 27 (40%) considered that in general, monitoring tests are performed too frequently.

Conclusions

The results demonstrated a wide variation in the frequency of testing, factors that should influence this, and what responses to abnormal test results are appropriate, indicates a likely lack of evidence and the need to define the risks, benefits and costs of different csDMARD monitoring regimens.
Blunt traumatic aortic injury to the brachiocephalic and left carotid arteries
Authors: Inaba Yu , Iida Yasunori , Oka Hidetoshi , Miki Takahisa , Hachiya Takashi , Shimizu Hideyuki
Published: October 2022

Background

Blunt traumatic aortic injury (BTAI) is a life-threatening pathology that most commonly occurs after traffic accidents or a fall from a considerable height. We report a rare case of traumatic double transection which included the brachiocephalic artery (BCA) and left carotid artery (LCA) following a motorcycle accident.

Case presentation

A 52-year-old man was brought to our emergency room for blunt trauma. Urgent computed tomography (CT) indicated BCA and LCA transection. Two weeks after the BTAI, CT indicated an increase in the size of the BCA pseudoaneurysm, a newly developed LCA pseudoaneurysm, and a spread of hematoma. An emergency partial aortic arch replacement including BCA and LCA reconstruction was performed 17 days after the BTAI. The postoperative course was good, and he was discharged 12 days later.

Conclusions

An open aortic repair appeared to be more suited in the present case because the aortic injury occurred in a branched lesion of the aortic arch. It was thought that complete stent graft coverage of the transection lesion would be difficult. Although coexisting multiple system injuries complicate aortic repair, there was a rapid enlargement of the BCA and LCA pseudoaneurysms. Therefore, strict management is needed even in the case of cervical artery injury.
Shadow enhancers modulate distinct transcriptional parameters that differentially effect downstream patterning events
Authors: Whitney Peter H. , Shrestha Bikhyat , Xiong Jiahan , Zhang Tom , Rushlow Christine A.
Published: October 2022

Transcription in the early Drosophila blastoderm is coordinated by the collective action of hundreds of enhancers. Many genes are controlled by so-called ‘shadow enhancers’, which provide resilience to environment or genetic insult, allowing the embryo to robustly generate a precise transcriptional pattern. Emerging evidence suggests that many shadow enhancer pairs do not drive identical expression patterns, but the biological significance of this remains unclear. In this study, we characterize the shadow enhancer pair controlling the gene short gastrulation (sog). We removed either the intronic proximal enhancer or the upstream distal enhancer and monitored sog transcriptional kinetics. Notably, each enhancer differs in sog spatial expression, timing of activation and RNA Polymerase II loading rates. In addition, modeling of individual enhancer activities demonstrates that these enhancers integrate activation and repression signals differently. Whereas activation is due to the sum of the two enhancer activities, repression appears to depend on synergistic effects between enhancers. Finally, we examined the downstream signaling consequences resulting from the loss of either enhancer, and found changes in tissue patterning that can be explained by the differences in transcriptional kinetics measured.
Prepectoral Versus Subpectoral Implant-Based Breast Reconstruction: A Systemic Review and Meta-analysis
Authors: Ostapenko Edvin , Nixdorf Larissa , Devyatko Yelena , Exner Ruth , Wimmer Kerstin , Fitzal Florian
Published: October 2022

Background

Implant-based breast reconstruction (IBBR) remains the standard and most popular option for women undergoing breast reconstruction after mastectomy worldwide. Recently, prepectoral IBBR has resurged in popularity, despite limited data comparing prepectoral with subpectoral IBBR.

Methods

A systematic search of PubMed and Cochrane Library from January 1, 2011 to December 31, 2021, was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) reporting guidelines, data were extracted by independent reviewers. Studies that compared prepectoral with subpectoral IBBR for breast cancer were included.

Results

Overall, 15 studies with 3,101 patients were included in this meta-analysis. Our results showed that patients receiving prepectoral IBBR experienced fewer capsular contractures (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.32–0.92; P = 0.02), animation deformity (OR, 0.02; 95% CI, 0.00–0.25; P = 0.002), and prosthesis failure (OR, 0.58; 95% CI, 0.42–0.80; P = 0.001). There was no significant difference between prepectoral and subpectoral IBBR in overall complications (OR, 0.83; 95% CI, 0.64–1.09; P = 0.19), seroma (OR, 1.21; 95% CI, 0.59-2.51; P = 0.60), hematoma (OR, 0.76; 95% CI, 0.49–1.18; P = 0.22), infection (OR, 0.87; 95% CI, 0.63–1.20; P = 0.39), skin flap necrosis (OR, 0.70; 95% CI, 0.45–1.08; P = 0.11), and recurrence (OR, 1.31; 95% CI, 0.52–3.39; P = 0.55). Similarly, no significant difference was found in Breast-Q scores between the prepectoral and subpectoral IBBR groups.

Conclusions

The results of our systematic review and meta-analysis demonstrated that prepectoral, implant-based, breast reconstruction is a safe modality and has similar outcomes with significantly lower rates of capsular contracture, prosthesis failure, and animation deformity compared with subpectoral, implant-based, breast reconstruction.