bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of a home blood pressure monitoring program for the management of hypertensive disorders of pregnancy, an observational study in British Columbia, Canada
Authors: Tran Karen C , Freiman Sabina , Chaworth-Musters Tessa , Purkiss Susan , Foster Colleen , Khan Nadia A , Chan Wee Shian
Published: May 2023

Background

COVID-19 pandemic has influenced health care delivery. We conducted an observational study to understand how obstetric medicine (ObM) physicians utilized home blood pressure monitoring (HBPM) to manage hypertension in pregnancy.

Methods

Pregnant participants with risk factors or diagnosis of hypertensive disorders of pregnancy (HDP) were enrolled, May 2020–December 2021, and provided with validated home blood pressure (BP) monitor. ObM physicians completed questionnaires to elicit how home BP readings were interpreted to manage HDP.

Results

We enrolled 103 people: 44 antepartum patients (33.5 ± 5 years, gestational age of 24 ± 5 weeks); 59 postpartum patients (35 ± 6 years, enrolled 6 ± 4 days post-partum). ObM physicians used range of home BP readings (70%) for management of HDP.

Conclusions

HBPM to manage HDP is acceptable and can be used to manage hypertension during pregnancy. Further studies are needed to assess the generalizability of our findings and the safety of HBPM reliance alone in management of HDP.
Countertopographies and the futures of geographical thought
Authors: Anthias Penelope
Published: May 2023

In this commentary, I extend Derickson's (2020) conception of the ‘annihilation of time by space’ to reflect on an experience of making a documentary about women-led resistance to hydrocarbon development in Southern Bolivia, where the forging of new spatial knowledges, practices, and relations – or countertopographies of extraction – played a critical role in disrupting fossil futures. I consider what geographers might learn from these women's example about the potentialities of space and materiality for unsettling liberal futurities and suggest how a focus on countertopographies might reorient the futures of geographical thought and praxis.
Narrative review based on fingolimod therapy in pediatric MS
Authors: Piri Cinar Bilge , Konuskan Bahadır , Anlar Banu , Ozakbas Serkan
Published: May 2023

The course of pediatric-onset multiple sclerosis and adult multiple sclerosis shows some clinical differences. The rate of having a second attack after the first clinical event is 80% in children and around 45% in adults but the time to the second event is similar in all age groups. The pediatric group usually has a more aggressive onset than adults. On the other hand, a higher rate of complete recovery is observed in pediatric-onset multiple sclerosis after the first clinical event compared to the adult group. Despite a highly active initial disease course, pediatric-onset multiple sclerosis patients show a slower increase in disability than patients with adult-onset disease. This is thought to be due to greater remyelination capacity and plasticity of the developing brain. The management of pediatric-onset multiple sclerosis includes safety issues as well as effective disease control. In the pediatric-onset multiple sclerosis group, similar to adult multiple sclerosis, injectable treatments have been used for many years with reasonable efficacy and safety. Since 2011, oral treatments and then infusion treatments have been approved and used effectively in adult multiple sclerosis and have gradually entered clinical use in the pediatric-onset multiple sclerosis group. However, clinical trials are fewer, smaller, and include shorter follow-up due to the much lower prevalence of pediatric-onset multiple sclerosis than adult multiple sclerosis. This is particularly important in the era of recent disease-modifying treatments. This review of the literature presents existing data on the safety and efficacy of fingolimod, pointing to a relatively favorable profile.
Unmet Social Needs and Patterns of Hair Cortisol Concentration in Mother–Child Dyads
Authors: Keeton Victoria F , Bidwell Julie T , de Mendonça Filho Euclides José , Silveira Patricia P , Hessler Danielle , Pantell Matthew S , Wing Holly , Brown Erika M , Iott Bradley , Gottlieb Laura M
Published: May 2023

Background

Mothers and their children demonstrate dyadic synchrony of hypothalamic–pituitary–adrenal (HPA) axis function, likely influenced by shared genetic or environmental factors. Although evidence has shown that chronic stress exposure has physiologic consequences for individuals—including on the HPA axis—minimal research has explored how unmet social needs such as food and housing instability may be associated with chronic stress and HPA axis synchrony in mother–child dyads.

Methods

We conducted a secondary analysis of data from 364 mother–child dyads with low-income recruited during a randomized trial conducted in an urban pediatric clinic. We used latent profile analysis (LPA) to identify subgroups based on naturally occurring patterns of within-dyad hair cortisol concentration (HCC). A logistic regression model predicted dyadic HCC profile membership as a function of summative count of survey-reported unmet social needs, controlling for demographic and health covariates.

Results

LPA of HCC data from dyads revealed a 2-profile model as the best fit. Comparisons of log HCC for mothers and children in each profile group resulted in significantly “higher dyadic HCC” versus “lower dyadic HCC” profiles (median log HCC for mothers: 4.64 vs 1.58; children: 5.92 vs 2.79, respectively; P < .001). In the fully adjusted model, each one-unit increase in number of unmet social needs predicted significantly higher odds of membership in the higher dyadic HCC profile when compared to the lower dyadic HCC profile (odds ratio  =  1.13; 95% confidence interval [1.04-1.23]; P  =  .01).

Conclusion

Mother–child dyads experience synchronous patterns of physiologic stress, and an increasing number of unmet social needs is associated with a profile of higher dyadic HCC. Interventions aimed at decreasing family-level unmet social needs or maternal stress are, therefore, likely to affect pediatric stress and related health inequities; efforts to address pediatric stress similarly may affect maternal stress and related health inequities. Future research should explore the measures and methods needed to understand the impact of unmet social needs and stress on family dyads.
Possible, yes, but useful? Why the search for possibilities is limited but can be enhanced by expertise
Authors: Ormerod Thomas C
Published: May 2023

In creative domains such as art, design and science, the generation of novel possibilities is highly desirable. However, most human activity takes place outside of domains where the generation of novel possibilities is prescriptively optimal, and indeed to do so may be undesirable. In this paper, evidence for the paucity of possibility generation will be described, even in instances where generation of multiple possibilities might be desirable. Conversely, the value of focussing on currently explored rather than novel possibilities is demonstrated with reference to a computational model of insight problem-solving. It is suggested that, in domains where generation of creative possibilities is a task requirement, strategies acquired though domain expertise are needed to push thinking into new possibility spaces. These strategies are illustrated by case studies and data from domains of insurance fraud and police investigations, educational task design and puzzle solving.
Pirtobrutinib: A New Hope for patients with BTK-inhibitor refractory lymphoproliferative disorders
Authors: Thompson Philip A , Tam Constantine
Published: May 2023

Patients with lymphoproliferative disorders such as CLL and Mantle Cell Lymphoma (MCL) who are resistant to covalent BTK inhibitors (cBTKi), especially if also venetoclax-refractory, have an unmet therapeutic need. Pirtobrutinib, a non-covalent BTK inhibitor, achieves high response rates in cBTKi refractory patients regardless of mechanism of cBTKi resistance. This led to recent accelerated FDA approval in MCL. The toxicity profile in early studies suggests suitability for use in combination approaches. We summarize existing pre-clinical and clinical data with pirtobrutinib.
TRIM37 exacerbates hepatic ischemia/reperfusion injury by facilitating IKKγ translocation
Authors: Yang Hang , Huang Zuotian , Luo Yunhai , Lei Dengliang , Yan Ping , Shen Ai , Liu Wenbin , Li Dewei , Wu Zhongjun
Published: May 2023

Background

Hepatic ischemia/reperfusion (I/R) injury is one of the major pathological processes associated with various liver surgeries. However, there is still a lack of strategies to protect against hepatic I/R injury because of the unknown underlying mechanism. The present study aimed to identify a potential strategy and provide a fundamental experimental basis for treating hepatic I/R injury.

Method

A classic 70% ischemia/reperfusion injury was established. Immunoprecipitation was used to identify direct interactions between proteins. The expression of proteins from different subcellular localizations was detected by Western blotting. Cell translocation was directly observed by immunofluorescence. HE, TUNEL and ELISA were performed for function tests.

Result

We report that tripartite motif containing 37 (TRIM37) aggravates hepatic I/R injury through the reinforcement of IKK-induced inflammation following dual patterns. Mechanistically, TRIM37 directly interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), inducing K63 ubiquitination and eventually leading to the phosphorylation of IKKβ. TRIM37 enhances the translocation of IKKγ, a regulatory subunit of the IKK complex, from the nucleus to the cytoplasm, thereby stabilizing the cytoplasmic IKK complex and prolonging the duration of inflammation. Inhibition of IKK rescued the function of TRIM37 in vivo and in vitro.

Conclusion

Collectively, the present study discloses some potential function of TRIM37 in hepatic I/R injury. Targeting TRIM37 might be potential for treatment against hepatic I/R injury.Targeting TRIM37 might be a potential treatment strategy against hepatic I/R injury.

Graphical Abstract
Access block and overcrowding at the emergency department at Tupua Tamasese Meaole Hospital in Samoa
Authors: Leong-Nowell Tamara Ah , Tamani Ledua , Kaspar Annette
Published: May 2023

Background

Access block and overcrowding are known to adversely impact on patient outcomes, service delivery, and patient experiences within emergency departments (ED) worldwide. There are no studies on access block or overcrowding from the Pacific Islands. The aim of the present study is to provide preliminary data on access block and overcrowding in the ED of the national tertiary hospital of Samoa.

Methods

Mixed methods study design. Data collection was performed in March 2020. The quantitative strand calculated (1) the point prevalence of patients impacted by access block in the ED, and (2) the ED bed occupancy rate to assess for overcrowding. The qualitative strand used thematic analysis of two focus group interviews exploring access block and overcrowding with ED medical and nursing staff members.

Results

On the day of data collection, a total of 60 patients presented through the ED triage system. Of the 20 patients who were admitted into ED, 80% were triaged as ‘see without delay’ (CAT1), ‘emergency’ (CAT2) or ‘urgent’ (CAT3). For patients requiring admission to hospital wards, 100% waited 4 + h in ED, and 100% waited 8 + h, suggesting the presence of access block. Overcrowding in the ED setting was also evident, with an ED bed occupancy rate of 0.95, and an adjusted bed occupancy rate of 1.43. The major themes emerging from the ED staff focus groups and individual in-depth interviews were (1) the adverse impacts of access block and overcrowding, i.e., violence towards ED staff members, (2) the preventable contributing factors, i.e., lack of physical beds in the ED, and (3) practical recommendations to improve patient flow through the ED, i.e., improved collaboration between ED, outpatient services, and the hospital wards.

Conclusions

Preliminary evidence suggested the presence of access block and overcrowding in the ED of the national tertiary hospital of Samoa. ED staff interviews provided insight into the ED frontline challenges and offered practical recommendations for ED health service improvement.
GKLOMLI: a link prediction model for inferring miRNA–lncRNA interactions by using Gaussian kernel-based method on network profile and linear optimization algorithm
Authors: Wong Leon , Wang Lei , You Zhu-Hong , Yuan Chang-An , Huang Yu-An , Cao Mei-Yuan
Published: May 2023

Background

The limited knowledge of miRNA–lncRNA interactions is considered as an obstruction of revealing the regulatory mechanism. Accumulating evidence on Human diseases indicates that the modulation of gene expression has a great relationship with the interactions between miRNAs and lncRNAs. However, such interaction validation via crosslinking-immunoprecipitation and high-throughput sequencing (CLIP-seq) experiments that inevitably costs too much money and time but with unsatisfactory results. Therefore, more and more computational prediction tools have been developed to offer many reliable candidates for a better design of further bio-experiments.

Methods

In this work, we proposed a novel link prediction model based on Gaussian kernel-based method and linear optimization algorithm for inferring miRNA–lncRNA interactions (GKLOMLI). Given an observed miRNA–lncRNA interaction network, the Gaussian kernel-based method was employed to output two similarity matrixes of miRNAs and lncRNAs. Based on the integrated matrix combined with similarity matrixes and the observed interaction network, a linear optimization-based link prediction model was trained for inferring miRNA–lncRNA interactions.

Results

To evaluate the performance of our proposed method, k-fold cross-validation (CV) and leave-one-out CV were implemented, in which each CV experiment was carried out 100 times on a training set generated randomly. The high area under the curves (AUCs) at 0.8623 ± 0.0027 (2-fold CV), 0.9053 ± 0.0017 (5-fold CV), 0.9151 ± 0.0013 (10-fold CV), and 0.9236 (LOO-CV), illustrated the precision and reliability of our proposed method.

Conclusion

GKLOMLI with high performance is anticipated to be used to reveal underlying interactions between miRNA and their target lncRNAs, and deciphers the potential mechanisms of the complex diseases.
Circulating mid-regional proadrenomedullin is a predictor of mortality in patients with COVID-19: a systematic review and meta-analysis
Authors: Wang Na , Liu Lushan , He Wei , Shang Na , Li Junyu , Qin Zhou , Du Xiaoxia
Published: May 2023

Background

Although there is increasing understanding of the changes in the laboratory parameters of Coronavirus disease 2019 (COVID-19), the correlation between circulating Mid-regional Proadrenomedullin (MR-proADM) and mortality of patients with COVID-19 is not fully understood. In this study, we conducted a systematic review and meta-analysis to evaluate the prognostic value of MR-proADM in patients with COVID-19.

Methods

The PubMed, Embase, Web of Science, Cochrane Library, Wanfang, SinoMed and Chinese National Knowledge Infrastructure (CNKI) databases were searched from 1 January 2020 to 20 March 2022 for relevant literature. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to assess quality bias, STATA was employed to pool the effect size by a random effects model, and potential publication bias and sensitivity analyses were performed.

Results

14 studies comprising 1822 patients with COVID-19 met the inclusion criteria, there were 1145 (62.8%) males and 677 (31.2%) females, and the mean age was 63.8 ± 16.1 years. The concentration of MR-proADM was compared between the survivors and non-survivors in 9 studies and the difference was significant (P < 0.01), I2 = 46%. The combined sensitivity was 0.86 [0.73–0.92], and the combined specificity was 0.78 [0.68–0.86]. We drew the summary receiver operating characteristic (SROC) curve and calculated the area under curve (AUC) = 0.90 [0.87–0.92]. An increase of 1 nmol/L of MR-proADM was independently associated with a more than threefold increase in mortality (odds ratio (OR) 3.03, 95% confidence interval (CI) 2.26–4.06, I2 = 0.0%, P = 0.633). The predictive value of MR-proADM for mortality was better than many other biomarkers.

Conclusion

MR-proADM had a very good predictive value for the poor prognosis of COVID-19 patients. Increased levels of MR-proADM were independently associated with mortality in COVID-19 patients and may allow a better risk stratification.
Whipple’s disease presenting as weight gain and constipation in a Chinese woman
Authors: Ye Haiyan , Hu Xiao , Tong Tommy Richard Sun-Wing , Chen Shuang , Li Tao , Xing Fanfan , Chan Jasper Fuk-Woo , Yuen Kwok-Yung , Chiu Kelvin Hei-Yeung
Published: May 2023

Background

Whipple’s disease is a chronic infection due to Tropheryma whipplei, commonly reported in the Caucasian but not in the Chinese population.

Case presentation

A 52-year-old female with good past health, was diagnosed with Whipple’s disease, presenting with constipation, unintentional weight gain, and fleeting polyarthralgia. Investigations prior to admission showed raised CA125 and computed tomography of the abdomen showed multiple retroperitoneal mesenteric lymphadenopathies. Extensive investigations performed on secondary causes of weight gain were unrevealing. Subsequent PET-CT scan revealed generalized lymphadenopathy involving the left deep cervical, supraclavicular, and retroperitoneal mesenteric area. Excisional biopsy of the left supraclavicular lymph node was performed, with histology showing infiltrations of Periodic acid-Schiff positive foamy macrophages. T. whipplei DNA was detected in her serum, saliva, stool, and lymph node by PCR targeting the 16S ribosomal RNA gene. She was started on intravenous ceftriaxone, and then stepped down to oral antibiotics for a total of 44 months. The recurrence of fever after 12 days of ceftriaxone raised the suspicion of Immune Reconstitution Inflammatory Syndrome (IRIS). Serial imaging showed a gradual reduction in the size of retroperitoneal lymphadenopathies. Literature review on Whipple’s disease in the Chinese population identified 13 reports of detectable T. whipplei DNA in clinical specimens. The majority of the cases were pneumonia, followed by culture-negative endocarditis, encephalitis, and skin and soft tissue infection. However, most patients with pneumonia were diagnosed based on next generation sequencing alone, with the resolution of pulmonary infiltrates without adequate duration of antibiotics, suggesting the possibility of colonization instead of infection. The recommendation of long-term doxycycline suppression after treatment may be supported by the slow response of retroperitoneal lymphadenopathies to antibiotics in our patient.

Conclusions

Unintentional weight gain and constipation could be atypical presentations of Whipple’s disease. It is a rare disease in the Chinese population despite the advancement of molecular techniques in the diagnosis of infections. A prolonged course of antibiotics may be required due to slow clinical response as documented by serial imaging in our case. The possibility of IRIS should be considered in patients with breakthrough fever during treatment of Whipple’s disease.
What data collection methods work best for COVID19 outbreak surveillance for people with end stage kidney disease? An observational cohort study using the UK Renal Registry
Authors: Santhakumaran Shalini , Savino Manuela , Benoy-Deeney Fran , Steenkamp Retha , Medcalf James , Nitsch Dorothea
Published: May 2023

Background

Patients on kidney replacement therapy (KRT) are vulnerable to severe illness from COVID-19. Timely, accurate surveillance is essential for planning and implementing infection control at local, regional and national levels. Our aim was to compare two methods of data collection for COVID-19 infections amongst KRT patients in England.

Methods

Adults receiving KRT in England were linked to two sources of data on positive COVID-19 tests recorded March-August 2020: (1) submissions from renal centres to the UK Renal Registry (UKRR) and (2) Public Health England (PHE) laboratory data. Patient characteristics, cumulative incidence by modality (in-centre haemodialysis (ICHD), home HD, peritoneal dialysis (PD) and transplant), and 28-day survival were compared between the two sources.

Results

2,783/54,795 patients (5.1%) had a positive test in the combined UKRR-PHE dataset. Of these 2,783, 87% had positive tests in both datasets. Capture was consistently high for PHE (> 95% across modalities) but varied for UKRR (ranging from ICHD 95% to transplant 78%, p < 0.0001). Patients captured only by PHE were more likely to be on transplant or home therapies (OR 3.5 95% CI [2.3–5.2] vs. ICHD) and to be infected in later months (OR 3.3 95%CI [2.4–4.6] for May-June, OR 6.5 95%CI [3.8–11.3] for July-August, vs. March-April), compared to patients in both datasets. Stratified by modality, patient characteristics and 28-day survival were similar between datasets.

Conclusions

For patients undergoing ICHD treatment the collection of data submitted directly by renal centres allows constant monitoring in real time. For other KRT modalities, using a national swab test dataset through frequent linkage may be the most effective method. Optimising central surveillance can improve patient care by informing interventions and assisting planning at local, regional and national levels.
Proteogenomic characterization of ferroptosis regulators reveals therapeutic potential in glioblastoma
Authors: Wang Xinzhuang , Zhang Hong , Zhang Mingchu , Zhang Xuezhi , Mao Wenbin , Gao Ming
Published: May 2023

Background

Ferroptosis is iron-dependent non-apoptotic cell death, that is characterized by the excessive accumulation of lipid peroxides. Ferroptosis-inducing therapy also shows promise in the treatment of cancers. However, ferroptosis-inducing therapy for glioblastoma multiforme (GBM) is still in the exploratory stage.

Methods

We identified the differentially expressed ferroptosis regulators using Mann–Whitney U test in the proteome data from Clinical Proteomic Tumor Analysis Consortium (CPTAC). We next analyzed the effect of mutation on protein abundance. A multivariate Cox model was constructed to identify the prognostic signature.

Results

In this study, we systemically portrayed the proteogenomic landscape of ferroptosis regulators in GBM. We observed that some mutation-specific ferroptosis regulators, such as down-regulated ACSL4 in EGFR-mutated patients and up-regulated FADS2 in IDH1-mutated patients, were linked to the inhibited ferroptosis activity in GBM. To interrogate the valuable treatment targets, we performed the survival analysis and identified five ferroptosis regulators (ACSL3, HSPB1, ELAVL1, IL33, and GPX4) as the prognostic biomarkers. We also validated their efficiency in external validation cohorts. Notably, we found overexpressed protein and phosphorylation abundances of HSPB1 were poor prognosis markers for overall survival of GBM to inhibit ferroptosis activity. Alternatively, HSPB1 showed a significant association with macrophage infiltration levels. Macrophage-secreted SPP1 could be a potential activator for HSPB1 in glioma cells. Finally, we recognized that ipatasertib, a novel pan-Akt inhibitor, could be a potential drug for suppressing HSPB1 phosphorylation, inducing ferroptosis of glioma cells.

Conclusion

In summary, our study characterized the proteogenomic landscape of ferroptosis regulators and identified that HSPB1 could be a candidate target for ferroptosis-inducing therapy strategy for GBM.
Diagnostic value of SHOX2, RASSF1A gene methylation combined with CEA level detection in malignant pleural effusion
Authors: Chen Shaosen , Huang Kunlun , Zou Lin , Chen Lu , Hu Peicun
Published: May 2023

Aim

To investigate the diagnostic value of combined detection of SHOX2 and RASSF1A gene methylation with carcinoembryonic antigen (CEA) level in diagnosing malignant pleural effusion.

Methods

Between March 2020 and December 2021, we enrolled 68 patients with pleural effusion admitted to the Department of Respiratory and critical care medicine of Foshan Second People's Hospital. The study group included 35 cases of malignant pleural effusion and 33 cases of benign pleural effusion. Methylation of the short homeobox 2 genes (SHOX2) and RAS-related region family 1A gene (RASSF1A) in pleural effusion samples were detected by real-time fluorescence quantitative PCR, and the level of carcinoembryonic antigen (CEA) in pleural effusion samples was detected by immune flow cytometry fluorescence quantitative chemiluminescence.

Results

SHOX2 or RASSF1A gene methylation was detected in 5 cases in the benign pleural effusion group and 25 patients in the malignant pleural effusion group. The positive rate of SHOX2 or RASSF1A gene methylation in the malignant pleural effusion group was significantly higher than in the benign pleural effusion group (71.4% vs. 15.2%, P < 0.01). Positive CEA (CEA > 5 ng/m) was detected in 1 case in the benign pleural effusion group and 26 patients in the malignant pleural effusion group. The CEA-positive rate in the malignant pleural effusion group was significantly higher than in the benign pleural effusion group (74.3% vs. 3%, P < 0.01). When SHOX2 and RASSF1A gene methylation was combined with CEA detection, 6 cases were positive in the benign pleural effusion group, and 31 patients were positive in the malignant pleural effusion group. The positive rate of combined detection in the malignant pleural effusion group was significantly higher than in the benign pleural effusion group (88.6% vs. 18.2%, P < 0.01). The sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and Youden’s index of SHOX2, RASSF1A gene methylation combined with CEA in diagnosing malignant pleural effusion were 88.6%, 81.8%, 85.3%, 83.8%, 87.1% and 0.7 respectively.

Conclusion

The combined detection of SHOX2 and RASSF1A gene methylation with CEA level in pleural effusion has a high diagnostic value for malignant pleural effusion.
Nursing students’ learning strategies for e-learning during the Covid-19 pandemic in Iran: a qualitative study
Authors: Cheraghbeigi Nesa , Molavynejad Shahram , Rokhafroz Dariush , Elahi Nasrin , Rezaei Eisa
Published: May 2023

Background

In response to the emergency brought about by the Covid-19 pandemic, many universities around the world had to change their teaching methods from in-person classes to e-learning. The purpose of this study was to identify the learning strategies of nursing students in e-learning during the pandemic.

Methods

This study had a qualitative design and used content analysis approach to collect and analyze the data. Sixteen semi-structured interviews were conducted with 12 Iranian undergraduate nursing students who were selected using purposive sampling method.

Results

Most nursing students in this study generally used two different strategies for e-learning, namely self-centered learning strategies and collaborative learning strategies. Some students, on the other hand, adopted a passive approach in which they did not take any effective action to contribute to their learning.

Conclusion

In e-learning during the pandemic, students adopted different learning strategies. Therefore, designing teaching strategies tailored to the students’ strategies can promote their learning and academic achievement. Also, knowledge of these strategies helps policy makers and nursing educators to take necessary measures in order to optimize and facilitate student learning in an e-learning environment.
Secondary structure of the human mitochondrial genome affects formation of deletions
Authors: Shamanskiy Victor , Mikhailova Alina A. , Tretiakov Evgenii O. , Ushakova Kristina , Mikhailova Alina G. , Oreshkov Sergei , Knorre Dmitry A. , Ree Natalia , Overdevest Jonathan B. , Lukowski Samuel W. , Gostimskaya Irina , Yurov Valerian , Liou Chia-Wei , Lin Tsu-Kung , Kunz Wolfram S. , Reymond Alexandre , Mazunin Ilya , Bazykin Georgii A. , Fellay Jacques , Tanaka Masashi , Khrapko Konstantin , Gunbin Konstantin , Popadin Konstantin
Published: May 2023

Background

Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Such deletions are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded mitochondrial DNA (mtDNA) might play a role in the formation of deletions.

Results

By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a “hot spot” where one deletion breakpoint occurred within the region of 6–9 kb and another within 13–16 kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions, can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11 kb and contacting regions between 6–9 kb and 13–16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470–8482 bp (base pair) and a second arm at 13,447–13,459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. A comparison of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging.

Conclusions

Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.
Mild photothermal/radiation therapy potentiates ferroptosis effect for ablation of breast cancer via MRI/PA imaging guided all-in-one strategy
Authors: Zhang Zhe , Lo Hsuan , Zhao Xingyang , Li Wenya , Wu Ke , Zeng Fanchu , Li Shiying , Sun Hongzan
Published: May 2023

Background

Nanotheranostics advances anticancer management by providing therapeutic and diagnostic functions, that combine programmed cell death (PCD) initiation and imaging-guided treatment, thus increasing the efficacy of tumor ablation and efficiently fighting against cancer. However, mild photothermal/radiation therapy with imaging-guided precise mediating PCD in solid tumors, involving processes related to apoptosis and ferroptosis, enhanced the effect of breast cancer inhibition is not fully understood.

Results

Herein, targeted peptide conjugated gold nano cages, iRGD-PEG/AuNCs@FePt NPs ternary metallic nanoparticles (Au@FePt NPs) were designed to achieve photoacoustic imaging (PAI)/Magnetic resonance imaging (MRI) guided synergistic therapy. Tumor-targeting Au@FePt forms reactive oxygen species (ROS), initiated by X-ray-induced dynamic therapy (XDT) in collaboration with photothermal therapy (PTT), inducing ferroptosis-augmented apoptosis to realize effective antitumor therapeutics. The relatively high photothermal conversion ability of Au@FePt increases the temperature in the tumor region and hastens Fenton-like processes to achieve enhanced synergistic therapy. Especially, RNA sequencing found Au@FePt inducting the apoptosis pathway in the transcriptome profile.

Conclusion

Au@FePt combined XDT/PTT therapy activate apoptosis and ferroptosis related proteins in tumors to achieve breast cancer ablation in vitro and in vivo. PAI/MRI images demonstrated Au@FePt has real-time guidance for monitoring synergistic anti-cancer therapy effect. Therefore, we have provided a multifunctional nanotheranostics modality for tumor inhibition and cancer management with high efficacy and limited side effects.

Graphical Abstract
Assessment of health-related quality of life and health status in patients with treatment-resistant depression treated with esketamine nasal spray plus an oral antidepressant
Authors: Jamieson Carol , Popova Vanina , Daly Ella , Cooper Kimberly , Drevets Wayne C. , Rozjabek Heather M. , Singh Jaskaran
Published: May 2023

Background

Patients with treatment-resistant depression (TRD) report significant deficits in physical and mental health, as well as severely impaired health-related quality of life (HRQoL) and functioning. Esketamine effectively enhances the daily functioning in these patients while also improving their depressive symptoms. This study assessed HRQoL and health status of patients with TRD, who were treated with esketamine nasal spray and an oral antidepressant (ESK + AD) vs. placebo nasal spray and an AD (AD + PBO).

Methods

Data from TRANSFORM-2, a phase 3, randomized, double-blind, short-term flexibly dosed study, were analyzed. Patients (aged 18–64 years) with TRD were included. The outcome assessments included the European Quality of Life Group, Five Dimension, Five Level (EQ-5D-5L), EQ-Visual Analogue Scale (EQ-VAS), and Sheehan Disability Scale (SDS). The health status index (HSI) was calculated using EQ-5D-5L scores.

Results

The full analysis set included 223 patients (ESK + AD: 114; AD + PBO: 109; mean [SD] age: 45.7 [11.89]). At Day 28, a lower percentage of patients reported impairment in the ESK + AD vs. AD + PBO group in all five EQ-5D-5L dimensions: mobility (10.6% vs. 25.0%), self-care (13.5% vs. 32.0%), usual activities (51.9% vs. 72.0%), pain/discomfort (35.6% vs. 54.0%), and anxiety/depression (69.2% vs. 78.0%). The mean (SD) change from baseline in HSI at Day 28 was 0.310 (0.219) for ESK + AD and 0.235 (0.252) for AD + PBO, with a higher score reflecting better levels of health. The mean (SD) change from baseline in EQ-VAS score at Day 28 was greater in ESK + AD (31.1 [25.67]) vs. AD + PBO (22.1 [26.43]). The mean (SD) change in the SDS total score from baseline to Day 28 also favored ESK + AD (-13.6 [8.31]) vs. AD + PBO (-9.4 [8.43]).

Conclusions

Greater improvements in HRQoL and health status were observed among patients with TRD treated with ESK + AD vs. AD + PBO.

Trial registration

ClinicalTrials.gov Identifier: NCT02418585.
Contrast-enhanced ultrasound-guided sentinel lymph node biopsy in early-stage breast cancer: a prospective cohort study
Authors: Cui Qiuxia , Dai Li , Li Jialu , Shen Yang , Tao Huijiang , Zhou Xiaofeng , Xue Jialei
Published: May 2023

Objective

This study evaluated the identification efficiency of contrast-enhanced ultrasound (CEUS) for sentinel lymph nodes (SLN) to accurately represent the axillary node status in early-stage breast cancer.

Method

In total, 109 consecutive consenting patients with clinically node-negative and T1-2 breast cancer were included in this study. All patients received CEUS to identify SLN before surgery, and a guidewire was deployed to locate SLN in those who were successfully explored by CEUS. The patients underwent sentinel lymph node biopsy (SLNB), and the blue dye was used to trace SLN during the surgery. The decision to perform axillary lymph node dissection (ALND) depended on the intraoperative pathological identification of SLN by CEUS (CE-SLN). The concordance rate of pathological status between CE-SLN and dyed SLN was calculated.

Result

The CEUS detection rate was 96.3%; CE-SLN failed in 4 patients. Among the remaining 105 successful identifications, 18 were CE-SLN positive by intraoperative frozen section, and one with CE-SLN micrometastasis was diagnosed by paraffin section. No additional lymph node metastases were found in CE-SLN-negative patients. The concordance rate of pathological status between CE-SLN and dyed SLN was 100%.

Conclusion

CEUS can accurately represent the status of axillary lymph nodes in patients with clinically node-negative and small tumor burden breast cancer.

Graphical Abstract
PcTrim prevents early infection with white spot syndrome virus by inhibiting AP1-induced endocytosis
Authors: Cao Xiao-Tong , Wu Lian-Jie , Xu Feng-Lin , Li Xin-Cang , Lan Jiang-Feng
Published: May 2023

Viruses have evolved various strategies to achieve early infection by initiating transcription of their own early genes via host transcription factors, such as NF-κb, STAT, and AP1. How the host copes with this immune escape has been a topic of interest. Tripartite motif (TRIM) family proteins with RING-type domains have E3 ubiquitin ligase activity and are known as host restriction factors. Trim has been reported to be associated with phagocytosis and is also believed to be involved in the activation of autophagy. Preventing the virus from entering the host cell may be the most economical way for the host to resist virus infection. The role of TRIM in the early stage of virus infection in host cells remains to be further interpreted. In the current study, a crayfish TRIM with a RING-type domain, designated as PcTrim, was significantly upregulated under white spot syndrome virus (WSSV) infection in the red swamp crayfish (Procambarus clarkii). Recombinant PcTrim significantly inhibited WSSV replication in crayfish. RNAi targeting PcTrim or blocking PcTrim with an antibody promoted WSSV replication in crayfish. Pulldown and co-IP assays showed that PcTrim can interact with the virus protein VP26. PcTrim restricts the expression level of dynamin, which is involved in the regulation of phagocytosis, by inhibiting AP1 entry into the nucleus. AP1-RNAi effectively reduced the expression levels of dynamin and inhibited host cell endocytosis of WSSV in vivo. Our study demonstrated that PcTrim might reduce early WSSV infection by binding to VP26 and then inhibiting AP1 activation, resulting in reduced endocytosis of WSSV in crayfish hemocytes.
Migrasomes, a new mode of intercellular communication
Authors: Jiang Yuyun , Liu Xi , Ye Jixian , Ma Yongbin , Mao Jiahui , Feng Dingqi , Wang Xuefeng
Published: May 2023

Migrasomes are newly discovered extracellular vesicles (EVs) that are formed in migrating cells and mediate intercellular communication. However, their size, biological generation, cargo packaging, transport, and effects on recipient cells by migrasomes are different from those of other EVs. In addition to mediating organ morphogenesis during zebrafish gastrulation, discarding damaged mitochondria, and lateral transport of mRNA and proteins, growing evidence has demonstrated that migrasomes mediate a variety of pathological processes. In this review, we summarize the discovery, mechanisms of formation, isolation, identification, and mediation of cellular communication in migrasomes. We discuss migrasome-mediated disease processes, such as osteoclast differentiation, proliferative vitreoretinopathy, tumor cell metastasis by PD-L1 transport, immune cell chemotaxis to the site of infection by chemokines, angiogenesis promotion via angiogenic factors by immune cells, and leukemic cells chemotaxis to the site of mesenchymal stromal cells. Moreover, as new EVs, we propose the potential of migrasomes for disease diagnosis and treatment.
Potential of CRISPR/Cas system as emerging tools in the detection of viral hepatitis infection
Authors: Bahrulolum Howra , Tarrahimofrad Hossein , Rouzbahani Fatemeh Nouri , Nooraei Saghi , Sameh Mehdi Mousavi , Hajizade Abbas , Ahmadian Gholamreza
Published: May 2023

Viral hepatitis, the most common cause of inflammatory liver disease, affects hundreds of millions of people worldwide. It is most commonly associated with one of the five nominal hepatitis viruses (hepatitis A–E viruses). HBV and HCV can cause acute infections and lifelong, persistent chronic infections, while HAV and HEV cause self-limiting acute infections. HAV and HEV are predominantly transmitted through the fecal-oral route, while diseases transmitted by the other forms are blood-borne diseases. Despite the success in the treatment of viral hepatitis and the development of HAV and HBV vaccines, there is still no accurate diagnosis at the genetic level for these diseases. Timely diagnosis of viral hepatitis is a prerequisite for efficient therapeutic intervention. Due to the specificity and sensitivity of clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated sequences (Cas) technology, it has the potential to meet critical needs in the field of diagnosis of viral diseases and can be used in versatile point-of-care (POC) diagnostic applications to detect viruses with both DNA and RNA genomes. In this review, we discuss recent advances in CRISPR–Cas diagnostics tools and assess their potential and prospects in rapid and effective strategies for the diagnosis and control of viral hepatitis infection.
An investigation of the internal morphology of asbestos ferruginous bodies: constraining their role in the onset of malignant mesothelioma
Authors: Avramescu Maya-Liliana , Potiszil Christian , Kunihiro Tak , Okabe Kazunori , Nakamura Eizo
Published: May 2023

Background

Asbestos is a fibrous mineral that was widely used in the past. However, asbestos inhalation is associated with an aggressive type of cancer known as malignant mesothelioma (MM). After inhalation, an iron-rich coat forms around the asbestos fibres, together the coat and fibre are termed an “asbestos ferruginous body” (AFB). AFBs are the main features associated with asbestos-induced MM. Whilst several studies have investigated the external morphology of AFBs, none have characterised the internal morphology. Here, cross-sections of multiple AFBs from two smokers and two non-smokers are compared to investigate the effects of smoking on the onset and growth of AFBs. Morphological and chemical observations of AFBs were undertaken by transmission electron microscopy, energy dispersive x-ray spectroscopy and selected area diffraction.

Results

The AFBs of all patients were composed of concentric layers of 2-line or 6-line ferrihydrite, with small spherical features being observed on the outside of the AFBs and within the cross-sections. The spherical components are of a similar size to Fe-rich inclusions found within macrophages from mice injected with asbestos fibres in a previous study. As such, the spherical components composing the AFBs may result from the deposition of Fe-rich inclusions during frustrated phagocytosis. The AFBs were also variable in terms of their Fe, P and Ca abundances, with some layers recording higher Fe concentrations (dense layers), whilst others lower Fe concentrations (porous layers). Furthermore, smokers were found to have smaller and overall denser AFBs than non-smokers.

Conclusions

The AFBs of smokers and non-smokers show differences in their morphology, indicating they grew in lung environments that experienced disparate conditions. Both the asbestos fibres of smokers and non-smokers were likely subjected to frustrated phagocytosis and accreted mucopolysaccharides, resulting in Fe accumulation and AFB formation. However, smokers’ AFBs experienced a more uniform Fe-supply within the lung environment compared to non-smokers, likely due to Fe complexation from cigarette smoke, yielding denser, smaller and more Fe-rich AFBs. Moreover, the lack of any non-ferrihydrite Fe phases in the AFBs may indicate that the ferritin shell was intact, and that ROS may not be the main driver for the onset of MM.
Analysis of 665 thyroid nodules using both EU-TIRADS and ACR TI-RADS classification systems
Authors: Borges Ana Paula , Antunes Célia , Caseiro-Alves Filipe , Donato Paulo
Published: May 2023

Background

Ultrasound-based classification systems allow stratification of thyroid nodules to recommend fine-needle aspiration (FNA) based on their malignancy risk. However, these have discrepancies that may have an impact in thyroid cancer detection. We aimed to compare European Thyroid Association (EU-TIRADS) and American College of Radiology (ACR TI-RADS), in terms of FNA indication and diagnostic performance.

Methods

Retrospective study of 665 thyroid nodules from 598 patients who underwent ultrasound and fine-needle aspiration at a tertiary-care institution between January 1st of 2016 and July 31st of 2019. Based on their sonographic features they were classified according to the EU-TIRADS and ACR TI-RADS classification and then their cytological results were obtained. Differences in FNA indications according to these two classifications were analysed. In patients who underwent surgical removal of the nodules, the final pathological diagnosis was obtained.

Results

A statistically significant association was found between EU-TIRADS and ACR TI-RADS classification systems (p < 0.001). ACR TI-RADS allowed greatest reduction in FNA performed (32% vs 24.5%). A different risk category was obtained in 174 (26.1%) nodules, mostly higher with EU-TIRADS. The indication to FNA changed in 54 (8.1%) nodules (49 only indicated following EU-TIRADS recommendations), of which 4 had Bethesda IV and 5 had Bethesda III cytology. The FNA indication in a higher number of nodules using EU-TIRADS was due to difference in the dimensional threshold for FNA on low-risk nodules; to the fact that hypoechogenicity in a mixed nodule ascribes it moderate risk, while using ACR TI-RADS it would only be considered of low risk, and to the use of isolated sonographic features, namely marked hypoechogenicity, microcalcifications and irregular margins, to automatically categorize a nodules as high risk in EU-TIRADS, while ACR TI-RADS requires a group of potentially suspicious features to consider a nodule of high risk. The analysis of pathology proven nodules revealed equally good sensitivity of both systems in the detection of malignancy, but weak specificity, slightly greater with ACR TI-RADS (27.1% vs 18.6%).

Conclusions

The EU-TIRADS and ACR TI-RADS are both suitable to assess thyroid nodules and through risk stratification avoid unnecessary FNA. FNA was less performed using ACR TI-RADS, which was slightly more efficiency in excluding malignancy.
Effects of airway pressure release ventilation on lung physiology assessed by electrical impedance tomography in patients with early moderate-to-severe ARDS
Authors: Li Ruiting , Wu Yongran , Zhang Hongling , Wang Azhen , Zhao Xin , Yuan Shiying , Yang Le , Zou Xiaojing , Shang You , Zhao Zhanqi
Published: May 2023

Objective

The aim of this study was to investigate the physiological impact of airway pressure release ventilation (APRV) on patients with early moderate-to-severe acute respiratory distress syndrome (ARDS) by electrical impedance tomography (EIT).

Methods

In this single-center prospective physiological study, adult patients with early moderate-to-severe ARDS mechanically ventilated with APRV were assessed by EIT shortly after APRV (T0), and 6 h (T1), 12 h (T2), and 24 h (T3) after APRV initiation. Regional ventilation and perfusion distribution, dead space (%), shunt (%), and ventilation/perfusion matching (%) based on EIT measurement at different time points were compared. Additionally, clinical variables related to respiratory and hemodynamic condition were analyzed.

Results

Twelve patients were included in the study. After APRV, lung ventilation and perfusion were significantly redistributed to dorsal region. One indicator of ventilation distribution heterogeneity is the global inhomogeneity index, which decreased gradually [0.61 (0.55–0.62) to 0.50 (0.42–0.53), p < 0.001]. The other is the center of ventilation, which gradually shifted towards the dorsal region (43.31 ± 5.07 to 46.84 ± 4.96%, p = 0.048). The dorsal ventilation/perfusion matching increased significantly from T0 to T3 (25.72 ± 9.01 to 29.80 ± 7.19%, p = 0.007). Better dorsal ventilation (%) was significantly correlated with higher PaO2/FiO2 (r = 0.624, p = 0.001) and lower PaCO2 (r = -0.408, p = 0.048).

Conclusions

APRV optimizes the distribution of ventilation and perfusion, reducing lung heterogeneity, which potentially reduces the risk of ventilator-induced lung injury.