bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunogenicity evaluation of primary polio vaccination schedule with inactivated poliovirus vaccines and bivalent oral poliovirus vaccine
Authors: Xu Jiawei , Liu Yang , Qiu Wei , Li Wenwen , Hu Xiaoxiao , Li Xia , Fan Qiang , Tang Wenge , Wang Yujie , Wang Qing , Yao Ning
Published: May 2024

Background

To assess the immunogenicity of the current primary polio vaccination schedule in China and compare it with alternative schedules using Sabin or Salk-strain IPV (sIPV, wIPV).

Methods

A cross-sectional investigation was conducted at four sites in Chongqing, China, healthy infants aged 60–89 days were conveniently recruited and divided into four groups according to their received primary polio vaccination schedules (2sIPV + bOPV, 2wIPV + bOPV, 3sIPV, and 3wIPV). The sero-protection and neutralizing antibody titers against poliovirus serotypes (type 1, 2, and 3) were compared after the last dose.

Results

There were 408 infants completed the protocol. The observed seropositivity was more than 96% against poliovirus types 1, 2, and 3 in all groups. IPV-only groups induced higher antibody titers(GMT) against poliovirus type 2 (Median:192, QR: 96–384, P<0.05) than the “2IPV + bOPV” group. While the “2IPV + bOPV” group induced significantly higher antibody titers against poliovirus type 1 (Median:2048, QR: 768–2048, P<0.05)and type 3 (Median:2048, QR: 512–2048, P<0.05) than the IPV-only group.

Conclusions

Our findings have proved that the two doses of IPV with one dose of bOPV is currently the best polio routine immunization schedule in China.
Practical surgical technique using the SMISS approach for lip reduction in involuted lip infantile hemangiomas
Authors: Chen Qianyi , Chang Shih-Jen , Gao Wei , Chang Lei , Qiu Yajing , Lin Xiaoxi
Published: May 2024

Background

Lip infantile hemangiomas tend to show less volumetric regression and are more susceptible to visible sequelae in the involuted stage. Some of them still require surgical management after propranolol therapy. This study aimed to evaluate the efficacy and safety of the Stepwise, Multi-Incisional, and Single-Stage (SMISS) approach applied to lip reduction for those with involuted lip hemangiomas.

Methods

A retrospective review was performed to evaluate patients with lip hemangioma who received previous propranolol treatment and underwent the aforementioned procedure. Demographic characteristics, lesion morphology, and medical history were reviewed. The Visual Analog Scale was applied to assess the postoperative appearance. Complications within 12 months postoperatively were recorded.

Results

A total of 18 patients with lip hemangioma were eligible. All patients received oral propranolol therapy before surgery, with treatment duration ranging from 6.0 to 23.0 months. Their age at surgery ranged from 2.5 to 9.0 years. The median Visual Analog Scale scores were 8.0, ranging from 4.0 to 10.0. No severe complications were reported.

Conclusions

This modified technique based on the SMISS approach has proven reliable and effective in improving the aesthetic outcome for involuted lip infantile hemangiomas. Practical surgical techniques still play an important part in the propranolol era.
Effects of the COVID-19 pandemic on the rates of adverse birth outcomes and fetal mortality in Japan: an analysis of national data from 2010 to 2022
Authors: Okui Tasuku , Nakashima Naoki
Published: May 2024

Background

Although the coronavirus disease 2019 (COVID-19) pandemic affected trends of multiple health outcomes in Japan, there is a paucity of studies investigating the effect of the pandemic on adverse birth outcomes and fetal mortality. This study aimed to investigate the effect of the onset of the pandemic on the trends in adverse birth outcomes and fetal mortality using national data in Japan.

Methods

We used the 2010–2022 birth and fetal mortality data from the Vital Statistics in Japan. We defined the starting time of the effect of the pandemic as April 2020, and the period from January 2010 to March 2020 and that from April 2020 to December 2022 were defined as the pre- and post- pandemic period, respectively. The rates of preterm birth, term low birth weight (TLBW), small-for-gestational-age (SGA), large-for-gestational-age (LGA), spontaneous fetal mortality, and artificial fetal mortality were used as outcomes. An interrupted time series analysis was conducted using monthly time series data of the outcomes to evaluate the effects of the pandemic. In addition, a modified Poisson regression model was used to evaluate the effects of the pandemic on these outcomes using individual-level data, and the adjusted risk ratio of the effect was calculated.

Results

The adverse birth and fetal mortality outcomes showed a decreasing trend over the years, except for preterm birth and LGA birth rates, and SGA birth rates tended to reach their lowest values after the onset of the pandemic. The interrupted time series analysis revealed that the pandemic decreased preterm birth, TLBW, and SGA birth rates. In addition, the regression analysis revealed that the pandemic decreased the TLBW, SGA, and artificial fetal mortality rates.

Conclusions

Analyses performed using national data suggested that the pandemic decreased the TLBW and SGA rates in Japan.
Navigating appendicitis care during the Covid-19 pandemic: a retrospective cohort study in China
Authors: Fu Guang , Xu Zishun , Zhang Shao
Published: May 2024

Background

The emergence of the COVID-19 pandemic in December 2019 initiated a global transformation in healthcare practices, particularly with respect to hospital management. PCR testing mandates for medical treatment seekers were introduced to mitigate virus transmission.

Aims

This study examines the impact of these changes on the management of patients with appendicitis.

Methods

We conducted a retrospective analysis of medical records for 748 patients diagnosed with appendicitis who underwent surgery at a tertiary care hospital during two distinct periods, the pre-pandemic year 2019 and the post-pandemic year 2021. Patient demographics, clinical characteristics, laboratory data, surgical outcomes, and hospital stay duration were assessed.

Results

While no significant differences were observed in the general characteristics of patients between the two groups, the time from hospital visit to operation increased significantly during the pandemic. Unexpectedly, delayed surgical intervention was associated with shorter hospital stays but did not directly impact complication rates. There was no discernible variation in the type of surgery or surgical timing based on symptom onset. The pandemic also prompted an increase in appendicitis cases, potentially related to coronavirus protein expression within the appendix.

Conclusions

The COVID-19 pandemic has reshaped the landscape of appendicitis management. This study underscores the complex interplay of factors, including changes in hospital protocols, patient concerns, and surgical timing. Further research is needed to explore the potential link between COVID-19 and appendicitis. These insights are valuable for informing healthcare practices during and beyond the pandemic.
Orthodontic camouflage treatment of a hyperdivergent adolescent patient with anterior open bite and TMD: a case report
Authors: Jiang Yilin , Wang Yajing , Wang Tianqi , Liu Dongqiao , Lin Chen , Wang Jing , Zhi Cheng , Qiu Ziqian , Hou Yuanfu , Zhang Chunxiang
Published: May 2024

Background

In orthodontics, anterior open bite is a common malocclusion that recurs frequently. Because the causes of anterior open bite are so varied, medical professionals must create customized treatment programs for each patient based on their unique etiology. Through the lowering of the posterior teeth, closure of the anterior teeth gap, and cooperation with intermaxillary traction, the treatment plan outlined in this case study sought to achieve a stable occlusion.

Case presentation

This case report aims to describe an orthodontic camouflage treatment of a 15-year-old female patient with anterior open bite, arch width discrepancy and a history of temporomandibular joint disorder. The patient was treated with intermaxillary vertical elastics and the multiple edgewise arch wire (MEAW) approach. A satisfactory occlusion with a neutral molar relationship was attained after 29 months of orthodontic therapy. The condylography recording showed that this patient’s occlusion tended to be more stable both before and after our treatment. The purpose of this case study is to provide an overview of an orthodontic camouflage treatment for a female patient, who had a history of temporomandibular joint disease, anterior open bite, and arch width disparity.

Conclusions

Our results demonstrated that more attention should be paid to levelling the occlusal plane, intrusion of the molars, decompression of temporomandibular joints and the etiology factors of malocclusion during the orthodontic period for those patients with anterior open bite.
Ease and practicability of the 2017 classification of periodontal diseases and conditions: a study of dental electronic health records
Authors: Raza Muhammad , Abud Daniela Gurpegui , Wang Joseph , Shariff Jaffer Ahmed
Published: May 2024

Background

A new classification for Periodontal and Peri-implant Diseases and Conditions was introduced in the 2017 World Workshop. In the past the 1999 Armitage Classification was commonly used in practice. This study aimed to assess the ease and practicability of retroactively diagnosing a subset of patients formerly diagnosed using the 1999 AAP/CDC classification with the 2017 AAP/EFP disease classification.

Methods

A random subset of 10% of all patients referred over a 7-year period (2011–2018) to the Post-Doctoral Periodontics Clinic at Columbia University College of Dental Medicine were reviewed by accessing the Electronic Health Records (EHRs) on axiUm. Patients diagnosed with periodontal disease based on the 1999 AAP/CDC classification (including chronic and aggressive Periodontitis) were reclassified using the 2017 classification (stage: I, II, III and grade: A, B, C).

Results

A sample of 336 patient records were examined. 132 were diagnosed with gingivitis, and 204 with periodontitis. Of these 204 patients, 68 (33.3%) were diagnosed with aggressive and 136 (66.7%) with chronic periodontitis. Patients diagnosed with aggressive periodontitis, 10% were reclassified as stage II, 47% as stage III, and 43% as stage IV periodontitis, and 100% were reclassified as grade C. Among patients with chronic periodontitis, 7% were reclassified as stage I, 65% as stage II, 21% as stage III, and 7% as stage IV; 11% of these were reclassified as grade A, 63% grade B, and 26% grade C.

Conclusions

The majority of those originally diagnosed with aggressive (90%) and chronic (80%) periodontitis were reclassified as either molar/incisor pattern stage III grade C or stage IV grade C periodontitis, and stage II or III periodontitis, respectively. The study demonstrated that it is practical to retroactively reassign a diagnosis according to the new 2017 classification using available information included in dental EHRs.
Distress among healthcare providers who provided end-of-life care during the COVID-19 pandemic: a longitudinal survey study (the CO-LIVE study)
Authors: Zee Masha S. , Onwuteaka-Philipsen Bregje D. , Witkamp Erica , Heessels Benthe , Goossensen Anne , Korfage Ida J. , Becqué Yvonne N. , Nierop-van Baalen Corine , van der Heide Agnes , Pasman H. Roeline
Published: May 2024

Introduction

The COVID-19 pandemic had a significant impact on care at the end-of-life due to restrictions and other circumstances such as high workload and uncertainty about the disease. The objective of this study is to describe the degree of various signs experienced by healthcare providers throughout the first 18 months of the pandemic and to assess what provider’s characteristics and care circumstances related to COVID-19 are associated with distress.

Methods

A longitudinal survey study among healthcare providers from different healthcare settings who provided end-of-life care during the pandemic’s first 18 months. Data of four time periods were analyzed using descriptive statistics, logistic regression analysis and Generalized Estimating Equation.

Results

Of the respondents (n=302) the majority had a nursing background (71.8%) and most worked in a hospital (30.3%). Although reported distress was highest in the first period, during the first wave of COVID-19 pandemic, healthcare providers reported signs of distress in all four time periods. Being more stressed than usual and being regularly exhausted were the most common signs of distress. Healthcare providers working in nursing homes and hospitals were more likely to experience signs of distress, compared to healthcare providers working in hospice facilities, during the whole period of 1.5 years. When HCPs were restricted in providing post-death care, they were more likely to feel more stressed than usual and find their work more often emotionally demanding.

Conclusion

A substantial amount of healthcare providers reported signs of distress during the first 1.5 years of the COVID-19 pandemic. A cause of distress appears to be that healthcare providers cannot provide the care they desire due the pandemic. Even though the pandemic is over, this remains an important and relevant finding, as high workload can sometimes force healthcare providers to make choices about how they provide care. Given that this can cause prolonged stress and this can lead to burnout (and HCPs leaving their current positions), it is now especially important to continue observing the long term developments of the well-being of our healthcare providers in palliative care and provide timely and adequate support where needed.
Learning semi-supervised enrichment of longitudinal imaging-genetic data for improved prediction of cognitive decline
Authors: Seo Hoon , Brand Lodewijk , Wang Hua ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: May 2024

Background

Alzheimer’s Disease (AD) is a progressive memory disorder that causes irreversible cognitive decline. Given that there is currently no cure, it is critical to detect AD in its early stage during the disease progression. Recently, many statistical learning methods have been presented to identify cognitive decline with temporal data, but few of these methods integrate heterogeneous phenotype and genetic information together to improve the accuracy of prediction. In addition, many of these models are often unable to handle incomplete temporal data; this often manifests itself in the removal of records to ensure consistency in the number of records across participants.

Results

To address these issues, in this work we propose a novel approach to integrate the genetic data and the longitudinal phenotype data to learn a fixed-length “enriched” biomarker representation derived from the temporal heterogeneous neuroimaging records. Armed with this enriched representation, as a fixed-length vector per participant, conventional machine learning models can be used to predict clinical outcomes associated with AD.

Conclusion

The proposed method shows improved prediction performance when applied to data derived from Alzheimer’s Disease Neruoimaging Initiative cohort. In addition, our approach can be easily interpreted to allow for the identification and validation of biomarkers associated with cognitive decline.
Perceived barriers and opportunities for implementing an integrated psychological intervention for depression in adolescents living with HIV in Tanzania
Authors: Njau Tasiana , Mwakawanga Dorkasi L. , Sunguya Bruno , Minja Agape , Kaaya Sylvia , Fekadu Abebaw
Published: May 2024

Background

Adolescents living with Human Immunodeficiency Virus (HIV) have an increased risk of depression, negatively affecting their adherence to antiretroviral therapy (ART) and treatment outcomes. Integrating mental health care in HIV care and treatment settings improves comprehensive care. However, integration remains challenging in Tanzania, like in other high-burden and low-resource settings. The overall objective of this work is to inform the development of a psychological intervention for depression in adolescents living with HIV (ALWHIV). We describe perceived barriers and opportunities for implementing an integrated, evidence-based psychological intervention to manage adolescent depression in HIV care and treatment centers (HIV-CTC) from the perspectives of adolescents, caregivers, and healthcare providers (HCPs) in Dar es Salaam, Tanzania.

Methods

To inform intervention development and implementation, this study utilized a qualitative design through a phenomenological approach informed by the Consolidated Framework for Implementation Research (CFIR) to explore implementation barriers and facilitators in ALWHIV, HCPs, and caregivers. Forty-five in-depth interviews were conducted in three HIV-CTCs in Kinondoni Dar es Salaam. Audio records were transcribed verbatim and analyzed deductively through NVIVO software.

Results

Barriers to implementing an integrated psychological intervention to address depression in ALWHIV included (A) poor mental health awareness among caregivers, adolescents, HCPs, and policy-makers, (B) high level of stigma against mental health care, (C) poor communication between adolescents and HCPs concerning mental health care, (D) lack of contextualized intervention of proven effectiveness and guidelines of mental health care, and (E) inadequate mental health care supportive supervision and mentorship. Facilitators for implementation included supportive infrastructure, positive pressure from HIV implementing partners, tension for change, and participant’s perception of the advantage of a psychological intervention as compared to just usual HIV care and treatment counseling.

Conclusion

Despite several modifiable barriers to implementing a psychological intervention in HIV CTC, there were encouraging facilitators and opportunities for implementing an integrated, evidence-based psychological intervention to address depression in ALWHIV in Kinondoni Dar es Salaam, Tanzania.
The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis
Authors: Bynigeri Ratnakar R. , Malireddi R. K. Subbarao , Mall Raghvendra , Connelly Jon P. , Pruett-Miller Shondra M. , Kanneganti Thirumala-Devi
Published: May 2024

Background

The innate immune system serves as the first line of host defense. Transforming growth factor-β–activated kinase 1 (TAK1) is a key regulator of innate immunity, cell survival, and cellular homeostasis. Because of its importance in immunity, several pathogens have evolved to carry TAK1 inhibitors. In response, hosts have evolved to sense TAK1 inhibition and induce robust lytic cell death, PANoptosis, mediated by the RIPK1-PANoptosome. PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. While PANoptosis can be beneficial to clear pathogens, excess activation is linked to pathology. Therefore, understanding the molecular mechanisms regulating TAK1 inhibitor (TAK1i)-induced PANoptosis is central to our understanding of RIPK1 in health and disease.

Results

In this study, by analyzing results from a cell death-based CRISPR screen, we identified protein phosphatase 6 (PP6) holoenzyme components as regulators of TAK1i-induced PANoptosis. Loss of the PP6 enzymatic component, PPP6C, significantly reduced TAK1i-induced PANoptosis. Additionally, the PP6 regulatory subunits PPP6R1, PPP6R2, and PPP6R3 had redundant roles in regulating TAK1i-induced PANoptosis, and their combined depletion was required to block TAK1i-induced cell death. Mechanistically, PPP6C and its regulatory subunits promoted the pro-death S166 auto-phosphorylation of RIPK1 and led to a reduction in the pro-survival S321 phosphorylation.

Conclusions

Overall, our findings demonstrate a key requirement for the phosphatase PP6 complex in the activation of TAK1i-induced, RIPK1-dependent PANoptosis, suggesting this complex could be therapeutically targeted in inflammatory conditions.
Development of a highly effective combination monoclonal antibody therapy against Herpes simplex virus
Authors: Seyfizadeh Narges , Kalbermatter David , Imhof Thomas , Ries Moritz , Müller Christian , Jenner Leonie , Blumenschein Elisabeth , Yendrzheyevskiy Alexandra , Grün Frank , Moog Kevin , Eckert Daniel , Engel Ronja , Diebolder Philipp , Chami Mohamed , Krauss Jürgen , Schaller Torsten , Arndt Michaela
Published: May 2024

Background

Infections with Herpes simplex virus (HSV)-1 or -2 usually present as mild chronic recurrent disease, however in rare cases can result in life-threatening conditions with a large spectrum of pathology. Monoclonal antibody therapy has great potential especially to treat infections with virus resistant to standard therapies. HDIT101, a humanized IgG targeting HSV-1/2 gB was previously investigated in phase 2 clinical trials. The aim of this study was to develop a next-generation therapy by combining different antiviral monoclonal antibodies.

Methods

A lymph-node derived phage display library (LYNDAL) was screened against recombinant gB from Herpes simplex virus (HSV) -1 and HDIT102 scFv was selected for its binding characteristics using bio-layer interferometry. HDIT102 was further developed as fully human IgG and tested alone or in combination with HDIT101, a clinically tested humanized anti-HSV IgG, in vitro and in vivo. T-cell stimulating activities by antigen-presenting cells treated with IgG-HSV immune complexes were analyzed using primary human cells. To determine the epitopes, the cryo-EM structures of HDIT101 or HDIT102 Fab bound to HSV-1F as well as HSV-2G gB protein were solved at resolutions < 3.5 Å.

Results

HDIT102 Fab showed strong binding to HSV-1F gB with Kd of 8.95 × 10–11 M and to HSV-2G gB with Kd of 3.29 × 10–11 M. Neutralization of cell-free virus and inhibition of cell-to-cell spread were comparable between HDIT101 and HDIT102. Both antibodies induced internalization of gB from the cell surface into acidic endosomes by binding distinct epitopes in domain I of gB and compete for binding. CryoEM analyses revealed the ability to form heterogenic immune complexes consisting of two HDIT102 and one HDIT101 Fab bound to one gB trimeric molecule. Both antibodies mediated antibody-dependent phagocytosis by antigen presenting cells which stimulated autologous T-cell activation. In vivo, the combination of HDIT101 and HDIT102 demonstrated synergistic effects on survival and clinical outcome in immunocompetent BALB/cOlaHsd mice.

Conclusion

This biochemical and immunological study showcases the potential of an effective combination therapy with two monoclonal anti-gB IgGs for the treatment of HSV-1/2 induced disease conditions.
Medical cannabis use in Australia seven years after legalisation: findings from the online Cannabis as Medicine Survey 2022–2023 (CAMS-22)
Authors: Mills Llewellyn , Arnold Jonathon C. , Suraev Anastasia , Abelev Sarah V. , Zhou Cilla , Arkell Thomas R. , McGregor Iain S. , Lintzeris Nicholas
Published: May 2024

Background

Cannabis was legalised for medical purposes in 2016. Uptake was initially slow, but since 2019 there has been a large increase in the number of Australians who have been prescribed cannabis for medical reasons. Yet a significant number of consumers continue to treat their medical conditions via illicitly-sourced cannabis. Little is known about how these two groups of medical cannabis consumers differ.

Methods

The anonymous Cannabis-As-Medicine Survey 2022–2023 (CAMS-22) was available for completion online from December 2022 to April 2023 to adult Australians who had used cannabis to treat a medical condition in the previous year. Recruitment occurred through social media, consumer forums, and medical practices. Questions included demographic characteristics, patterns of cannabis use, conditions treated, and self-rated effectiveness.

Results

Of the 3323 respondents included in these analyses, 2352 (73%) mainly used prescribed medical cannabis, 871 (27%) mainly used illicit. Prescribed users were significantly more likely than illicit users to have had their health condition diagnosed (OR = 1.7, 95% CI 1.3, 2.2), to consume their cannabis via oral (OR = 1.9; CI 1.5, 2.4) or vaporised (OR = 5.2; CI 4.0, 6.8) routes, and to be sure of the composition of their medical cannabis (OR = 25.0; CI 16.7, 50.0). Prescribed users were significantly less likely to have used cannabis non-medically before medical use (OR = 0.6, CI 0.5, 0.7), consume cannabis via smoked routes (OR = 0.2, CI 0.1, 0.2), and to report any side effects (OR = 0.1; CI 0.1, 0.2). The most common conditions among both prescribed and illicit users were pain (37%), mental health (36%), and sleep (15%) conditions. Prescribed users were significantly more likely to use cannabis to mainly treat a pain (OR = 1.3; CI 1.1, 1.5) or sleep condition (OR = 1.4; CI 1.1, 1.7) and less likely to treat a mental health condition (OR = 0.8; CI 0.7, 0.9). There were no between-group differences in effectiveness with 97% saying medical cannabis had improved their symptoms.

Conclusions

From a harm-reduction perspective there is much to recommend prescribed medical cannabis; it has fewer side-effects than illicit, is used more safely (oral or vaporised versus smoked routes), gives consumers greater certainty regarding the composition and quality of their medicine, and does not risk exposure to the criminal justice system. Of concern, however, is the apparent willingness of prescribers to prescribe for indications for which there is limited evidence of efficacy, such as mental health and sleep conditions.
Implementing Canada’s first national virtual phone based overdose prevention service: lessons learned from creating the National Overdose Response Service (NORS)
Authors: Rioux William , Taplay Pamela , Morris-Miller Lisa , Ghosh S. Monty
Published: May 2024

The opioid epidemic remains one of the largest public health crises in North America to date. While there have been many diverse strategies developed to reduce the harms associated with substance use, these are primarily concentrated within a few large urban centers. As a result, there have been increased calls for equitable access to harm reduction services for those who cannot or choose not to access in-person harm reduction services. In December 2020, Canada’s National Overdose Response Service (NORS) a telephone based overdose response hotline and virtual supervised consumption service, was established in collaboration with various agencies and people with lived and living experience of substance use (PWLLE) across Canada to expand access to harm reduction services using novel Opioid Response Technology. In this manuscript we explore the lessons learned from the establishment and continued operation of the service exploring topics related to the initial establishment of the service, securing a phone line, routing technology, EMS dispatch solutions, peer and volunteer recruitment, legal and ethical support, policy and procedure development, securing funding, and marketing. Furthermore, we detail how this service has grown and changed in response to the various needs of service users.
Diverse roles of SARS-CoV-2 Spike and Nucleocapsid proteins in EndMT stimulation through the TGF-β-MRTF axis inhibited by aspirin
Authors: Ciszewski Wojciech M. , Woźniak Lucyna A. , Sobierajska Katarzyna
Published: May 2024

Background

The SARS-CoV-2 virus causes severe COVID-19 in one-fifth of patients. In addition to high mortality, infection may induce respiratory failure and cardiovascular complications associated with inflammation. Acute or prolonged inflammation results in organ fibrosis, the cause of which might be endothelial disorders arising during the endothelial-mesenchymal transition (EndMT).

Methods

HUVECs and HMEC-1 cells were stimulated with SARS-CoV-2 S (Spike) and N (Nucleocapsid) proteins, and EndMT induction was evaluated by studying specific protein markers via Western blotting. Wound healing and tube formation assays were employed to assess the potential of SARS-CoV-2 to stimulate changes in cell behaviour. MRTF nuclear translocation, ROS generation, TLR4 inhibitors, TGF-β-neutralizing antibodies, and inhibitors of the TGF-β-dependent pathway were used to investigate the role of the TGF-β-MRTF signalling axis in SARS-CoV-2-dependent EndMT stimulation.

Results

Both viral proteins stimulate myofibroblast trans-differentiation. However, the N protein is more effective at EndMT induction. The TGF-β-MRTF pathway plays a critical role in this process. The N protein preferentially favours action through TGF-β2, whose secretion is induced through TLR4-ROS action. TGF-β2 stimulates MRTF-A and MRTF-B nuclear translocation and strongly regulates EndMT. In contrast, the Spike protein stimulates TGF-β1 secretion as a result of ACE2 downregulation. TGF-β1 induces only MRTF-B, which, in turn, weakly regulates EndMT. Furthermore, aspirin, a common nonsteroidal anti-inflammatory drug, might prevent and reverse SARS-CoV-2-dependent EndMT induction through TGF-β-MRTF pathway deregulation.

Conclusion

The reported study revealed that SARS-CoV-2 infection induces EndMT. Moreover, it was demonstrated for the first time at the molecular level that the intensity of the EndMT triggered by SARS-CoV-2 infection may vary and depend on the viral protein involved. The N protein acts through TLR4-ROS-TGF-β2-MRTF-A/B, whereas the S protein acts through ACE2-TGF-β1-MRTF-B. Furthermore, we identified aspirin as a potential anti-fibrotic drug for treating patients with SARS-CoV-2 infection.
Generalizable transcriptome-based tumor malignant level evaluation and molecular subtyping towards precision oncology
Authors: Hu Dingxue , Zhang Ziteng , Liu Xiaoyi , Wu Youchun , An Yunyun , Wang Wanqiu , Yang Mengqi , Pan Yuqi , Qiao Kun , Du Changzheng , Zhao Yu , Li Yan , Bao Jianqiang , Qin Tao , Pan Yue , Xia Zhaohua , Zhao Xin , Sun Kun
Published: May 2024

In cancer treatment, therapeutic strategies that integrate tumor-specific characteristics (i.e., precision oncology) are widely implemented to provide clinical benefits for cancer patients. Here, through in-depth integration of tumor transcriptome and patients’ prognoses across cancers, we investigated dysregulated and prognosis-associated genes and catalogued such important genes in a cancer type-dependent manner. Utilizing the expression matrices of these genes, we built models to quantitatively evaluate the malignant levels of tumors across cancers, which could add value to the clinical staging system for improved prediction of patients’ survival. Furthermore, we performed a transcriptome-based molecular subtyping on hepatocellular carcinoma, which revealed three subtypes with significantly diversified clinical outcomes, mutation landscapes, immune microenvironment, and dysregulated pathways. As tumor transcriptome was commonly profiled in clinical practice with low experimental complexity and cost, this work proposed easy-to-perform approaches for practical clinical promotion towards better healthcare and precision oncology of cancer patients.
Inhibition of mannan-binding lectin associated serine protease (MASP)-2 reduces the cognitive deficits in a mouse model of severe traumatic brain injury
Authors: Mercurio Domenico , Pischiutta Francesca , Seminara Serena , Tribuzio Francesca , Lisi Ilaria , Pasetto Laura , Bonetto Valentina , De Simoni Maria-Grazia , Schwaeble Wilhelm , Yaseen Sadam , Dudler Thomas , Zanier Elisa R. , Fumagalli Stefano
Published: May 2024

The lectin pathway (LP) of complement mediates inflammatory processes linked to tissue damage and loss of function following traumatic brain injury (TBI). LP activation triggers a cascade of proteolytic events initiated by LP specific enzymes called MASPs (for Mannan-binding lectin Associated Serine Proteases). Elevated serum and brain levels of MASP-2, the effector enzyme of the LP, were previously reported to be associated with the severity of tissue injury and poor outcomes in patients with TBI. To evaluate the therapeutic potential of LP inhibition in TBI, we first conducted a pilot study testing the effect of an inhibitory MASP-2 antibody (α-MASP-2), administered systemically at 4 and 24 h post-TBI in a mouse model of controlled cortical impact (CCI). Treatment with α-MASP-2 reduced sensorimotor and cognitive deficits for up to 5 weeks post-TBI. As previous studies by others postulated a critical role of MASP-1 in LP activation, we conducted an additional study that also assessed treatment with an inhibitory MASP-1 antibody (α-MASP-1). A total of 78 mice were treated intraperitoneally with either α-MASP-2, or α-MASP-1, or an isotype control antibody 4 h and 24 h after TBI or sham injury. An amelioration of the cognitive deficits assessed by Barnes Maze, prespecified as the primary study endpoint, was exclusively observed in the α-MASP-2-treated group. The behavioral data were paralleled by a reduction of the lesion size when evaluated histologically and by reduced systemic LP activity. Our data suggest that inhibition of the LP effector enzyme MASP-2 is a promising treatment strategy to limit neurological deficits and tissue loss following TBI. Our work has translational value because a MASP-2 antibody has already completed multiple late-stage clinical trials in other indications and we used a clinically relevant treatment protocol testing the therapeutic mechanism of MASP-2 inhibition in TBI.
Improving physical movement during stroke rehabilitation: investigating associations between sleep measured by wearable actigraphy technology, fatigue, and key biomarkers
Authors: Smith Madeleine J. , Pellegrini Michael , Major Brendan , Graco Marnie , Porter Stephanie , Kramer Sharon , Sewell Katherine , Salberg Sabrina , Chen Zhibin , Mychasiuk Richelle , Lannin Natasha A.
Published: May 2024

Background

Sleep disturbance and fatigue are common in individuals undergoing inpatient rehabilitation following stroke. Understanding the relationships between sleep, fatigue, motor performance, and key biomarkers of inflammation and neuroplasticity could provide valuable insight into stroke recovery, possibly leading to personalized rehabilitation strategies. This study aimed to investigate the influence of sleep quality on motor function following stroke utilizing wearable technology to obtain objective sleep measurements. Additionally, we aimed to determine if there were relationships between sleep, fatigue, and motor function. Lastly, the study aimed to determine if salivary biomarkers of stress, inflammation, and neuroplasticity were associated with motor function or fatigue post-stroke.

Methods

Eighteen individuals who experienced a stroke and were undergoing inpatient rehabilitation participated in a cross-sectional observational study. Following consent, participants completed questionnaires to assess sleep patterns, fatigue, and quality of life. Objective sleep was measured throughout one night using the wearable Philips Actiwatch. Upper limb motor performance was assessed on the following day and saliva was collected for biomarker analysis. Correlation analyses were performed to assess the relationships between variables.

Results

Participants reported poor sleep quality, frequent awakenings, and difficulties falling asleep following stroke. We identified a significant negative relationship between fatigue severity and both sleep quality (r=-0.539, p = 0.021) and participants experience of awakening from sleep (r=-0.656, p = 0.003). A significant positive relationship was found between grip strength on the non-hemiplegic limb and salivary gene expression of Brain-derived Neurotrophic Factor (r = 0.606, p = 0.028), as well as a significant negative relationship between grip strength on the hemiplegic side and salivary gene expression of C-reactive Protein (r=-0.556, p = 0.048).

Conclusion

The findings of this study emphasize the importance of considering sleep quality, fatigue, and biomarkers in stroke rehabilitation to optimize recovery and that interventions may need to be tailored to the individual. Future longitudinal studies are required to explore these relationships over time. Integrating wearable technology for sleep and biomarker analysis can enhance monitoring and prediction of outcomes following stroke, ultimately improving rehabilitation strategies and patient outcomes.
Quantifying the effects of sleep on sensor-derived variables from upper limb accelerometry in people with and without upper limb impairment
Authors: Miller Allison E. , Lang Catherine E. , Bland Marghuretta D. , Lohse Keith R.
Published: May 2024

Background

Despite the promise of wearable sensors for both rehabilitation research and clinical care, these technologies pose significant burden on data collectors and analysts. Investigations of factors that may influence the wearable sensor data processing pipeline are needed to support continued use of these technologies in rehabilitation research and integration into clinical care settings. The purpose of this study was to investigate the effect of one such factor, sleep, on sensor-derived variables from upper limb accelerometry in people with and without upper limb impairment and across a two-day wearing period.

Methods

This was a secondary analysis of data collected during a prospective, longitudinal cohort study (n = 127 individuals, 62 with upper limb impairment and 65 without). Participants wore a wearable sensor on each wrist for 48 h. Five upper limb sensor variables were calculated over the full wear period (sleep included) and with sleep time removed (sleep excluded): preferred time, non-preferred time, use ratio, non-preferred magnitude and its standard deviation. Linear mixed effects regression was used to quantify the effect of sleep on each sensor variable and determine if the effect differed between people with and without upper limb impairment and across a two-day wearing period.

Results

There were significant differences between sleep included and excluded for the variables preferred time (p < 0.001), non-preferred time (p < 0.001), and non-preferred magnitude standard deviation (p = 0.001). The effect of sleep was significantly different between people with and without upper limb impairment for one variable, non-preferred magnitude (p = 0.02). The effect of sleep was not substantially different across wearing days for any of the variables.

Conclusions

Overall, the effects of sleep on sensor-derived variables of upper limb accelerometry are small, similar between people with and without upper limb impairment and across a two-day wearing period, and can likely be ignored in most contexts. Ignoring the effect of sleep would simplify the data processing pipeline, facilitating the use of wearable sensors in both research and clinical practice.
Fistula of the mitral-aortic intervalvular fibrosa in a patient with bacterial endocarditis: a case report and systematic literature review
Authors: Figueroa-Casanova Rafael , Saavedra-Henao Juan D. , Figueroa-Laverde Juan S. , Beltrán-Gonzales Diego A. , Labrador-Rosales José G. , Eslait-Olaciregui Sara , Pérez Rivera Carlos J.
Published: May 2024

Background

A fistulous tract in the mitro-aortic intervalvular fibrosa (MAIVF) is a rare entity, which presents as a complication of endocarditis or surgical trauma. Generally, it is associated to a pseudoaneurysm of the MAIVF (p-MAIVF) or aortic abscesses. MAIVF fistulas could potentially lead to devastating complications and a high mortality rate. This condition is managed surgically, either by a percutaneous closure or an open surgical approach. Herein we report the complex case of a patient with a MAIVF fistula secondary to bacterial endocarditis. Further clinical deterioration was caused by severe aortic valve insufficiency and hemodynamic compromise, requiring surgical intervention.

Case presentation

A 74-year-old male patient was admitted to a primary care center with complaints of malaise, asthenia, adynamia, hyporexia, and lower limb edema over the past eight days. His past medical history is positive for arterial hypertension and being monorenal. A transesophageal echocardiogram (TEE) was performed, exhibiting a 56% left ventricle ejection fraction (LVEF) and complicated aortic valve endocarditis. Surgical management through an open approach included vegetation resection, valve replacement, and closure of the MAIVF fistula. After completing antibiotic therapy, the patient was discharged without complications. During postoperative follow-up, the patient remained asymptomatic, and the control echocardiogram showed no signs of MAIVF fistula.4.

Conclusions

The clinical case of a patient with a MAIVF fistula secondary to endocarditis by Streptococcus Anginous was presented. The fistulous tract was not associated to p-MAIVF or aortic abscess, findings which further deteriorate the patient’s condition and increase the likelihood of fatality. This case reinforces the importance of a prompt diagnosis through cardiac imaging and timely surgical closure of the defect.
Mortality after paediatric emergency calls for patients with or without pre-existing comorbidity: a nationwide population based cohort study
Authors: Nielsen Vibe Maria Laden , Søvsø Morten Breinholt , Skals Regitze Gyldenholm , Bender Lars , Corfield Alasdair Ross , Lossius Hans Morten , Mikkelsen Søren , Christensen Erika Frischknecht
Published: May 2024

Background

Life-threatening conditions are infrequent in children. Current literature in paediatric prehospital research is centred around trauma and paediatric out-of-hospital cardiac arrests (POHCA). The aims of this study were to (1) outline the distribution of trauma, POHCA or other medical symptoms among survivors and non-survivors after paediatric emergency calls, and (2) to investigate these clinical presentations’ association with mortality in children with and without pre-existing comorbidity, respectively.

Methods

Nationwide population-based cohort study including ground and helicopter emergency medical services in Denmark for six consecutive years (2016–2021). The study included all calls to the emergency number 1-1-2 regarding children ≤ 15 years (N = 121,230). Interhospital transfers were excluded, and 1,143 patients were lost to follow-up. Cox regressions were performed with trauma or medical symptoms as exposure and 7-day mortality as the outcome, stratified by ‘Comorbidity’, ‘Severe chronic comorbidity’ and ’None’ based on previous healthcare visits.

Results

Mortality analysis included 76,956 unique patients (median age 5 (1–12) years). Annual all-cause mortality rate was 7 per 100,000 children ≤ 15 years. For non-survivors without any pre-existing comorbidity (n = 121), reasons for emergency calls were trauma 18.2%, POHCA 46.3% or other medical symptoms 28.9%, whereas the distribution among the 134 non-survivors with any comorbidity was 7.5%, 27.6% and 55.2%, respectively. Compared to trauma patients, age- and sex-adjusted hazard ratio for patients with calls regarding medical symptoms besides POHCA was 0.8 [0.4;1.3] for patients without comorbidity, 1.1 [0.5;2.2] for patients with comorbidity and 6.1 [0.8;44.7] for patients with severe chronic comorbidity.

Conclusion

In both non-survivors with and without comorbidity, a considerable proportion of emergency calls had been made because of various medical symptoms, not because of trauma or POHCA. This outline of diagnoses and mortality following paediatric emergency calls can be used for directing paediatric in-service training in emergency medical services.
Composite outcome measures in high-impact critical care randomised controlled trials: a systematic review
Authors: Walker Humphrey G. M. , Brown Alastair J. , Vaz Ines P. , Reed Rebecca , Schofield Max A. , Shao Jeffrey , Nanjayya Vinodh B. , Udy Andrew A. , Jeffcote Toby
Published: May 2024

Background

The use of composite outcome measures (COM) in clinical trials is increasing. Whilst their use is associated with benefits, several limitations have been highlighted and there is limited literature exploring their use within critical care. The primary aim of this study was to evaluate the use of COM in high-impact critical care trials, and compare study parameters (including sample size, statistical significance, and consistency of effect estimates) in trials using composite versus non-composite outcomes.

Methods

A systematic review of 16 high-impact journals was conducted. Randomised controlled trials published between 2012 and 2022 reporting a patient important outcome and involving critical care patients, were included.

Results

8271 trials were screened, and 194 included. 39.1% of all trials used a COM and this increased over time. Of those using a COM, only 52.6% explicitly described the outcome as composite. The median number of components was 2 (IQR 2–3). Trials using a COM recruited fewer participants (409 (198.8–851.5) vs 584 (300–1566, p = 0.004), and their use was not associated with increased rates of statistical significance (19.7% vs 17.8%, p = 0.380). Predicted effect sizes were overestimated in all but 6 trials. For studies using a COM the effect estimates were consistent across all components in 43.4% of trials. 93% of COM included components that were not patient important.

Conclusions

COM are increasingly used in critical care trials; however effect estimates are frequently inconsistent across COM components confounding outcome interpretations. The use of COM was associated with smaller sample sizes, and no increased likelihood of statistically significant results. Many of the limitations inherent to the use of COM are relevant to critical care research.
Elevated expression of wildtype RhoC promotes ErbB2- and Pik3ca-induced mammary tumor formation
Authors: Raghuram Nandini , Temel E. Idil , Kawamata Toshihiro , Kozma Katelyn J. , Loch Amanda J. , Wang Wei , Adams Jessica R. , Muller William J. , Egan Sean E.
Published: May 2024

Copy number gains in genes coding for Rho activating exchange factors as well as losses affecting genes coding for RhoGAP proteins are common in breast cancer (BC), suggesting that elevated Rho signaling may play an important role. Extra copies and overexpression of RHOC also occur, although a role for RhoC overexpression in driving tumor formation has not been assessed in vivo. To this end, we report on the development of a Rosa26 (R26)-targeted Cre-conditional RhoC overexpression mouse (R26RhoC). This mouse was crossed to two models for ERBB2/NEU+ breast cancer: one based on expression of an oncogenic ErbB2/Neu cDNA downstream of the endogenous ErbB2 promoter (FloxNeoNeuNT), the other, a metastatic model that is based on high-level expression from MMTV regulatory elements (NIC). RhoC overexpression dramatically enhanced mammary tumor formation in FloxNeoNeuNT mice but showed a more subtle effect in the NIC line, which forms multiple mammary tumors after a very short latency. RhoC overexpression also enhanced mammary tumor formation in an activated Pik3ca model for breast cancer (Pik3caH1047R). The transforming effect of RhoC was associated with epithelial/mesenchymal transition (EMT) in ErbB2/NeuNT and Pik3caH1047R systems. Thus, our study reveals the importance of elevated wildtype Rho protein expression as a driver of breast tumor formation and highlights the significance of Copy Number Abberations that affect Rho signalling.