bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of fasudil on blood–brain barrier integrity
Authors: Sato Kei , Nakagawa Shinsuke , Morofuji Yoichi , Matsunaga Yuki , Fujimoto Takashi , Watanabe Daisuke , Izumo Tsuyoshi , Niwa Masami , Walter Fruzsina R. , Vigh Judit P. , Santa-Maria Ana Raquel , Deli Maria A. , Matsuo Takayuki
Published: June 2022

Background

Cerebral infarction accounts for 85% of all stroke cases. Even in an era of rapid and effective recanalization using an intravascular approach, the majority of patients have poor functional outcomes. Thus, there is an urgent need for the development of therapeutic agents to treat acute ischemic stroke. We evaluated the effect of fasudil, a Rho kinase inhibitor, on blood brain barrier (BBB) functions under normoxia or oxygen–glucose deprivation (OGD) conditions using a primary cell-based in vitro BBB model.

Methods

BBB models from rat primary cultures (brain capillary endothelial cells, astrocytes, and pericytes) were subjected to either normoxia or 6 h OGD/24 h reoxygenation. To assess the effects of fasudil on BBB functions, we evaluated real time impedance, transendothelial electrical resistance (TEER), sodium fluorescein permeability, and tight junction protein expression using western blotting. Lastly, to understand the observed protective mechanism on BBB functions by fasudil we examined the role of cyclooxygenase-2 and thromboxane A2 receptor agonist U-46619 in BBB-forming cells.

Results

We found that treatment with 0.3–30 µM of fasudil increased cellular impedance. Fasudil enhanced barrier properties in a concentration-dependent manner, as measured by an increased (TEER) and decreased permeability. Fasudil also increased the expression of tight junction protein claudin-5. Reductions in TEER and increased permeability were observed after OGD/reoxygenation exposure in mono- and co-culture models. The improvement in BBB integrity by fasudil was confirmed in both of the models, but was significantly higher in the co-culture than in the monoculture model. Treatment with U-46619 did not show significant changes in TEER in the monoculture model, whereas it showed a significant reduction in TEER in the co-culture model. Fasudil significantly improved the U-46619-induced TEER reduction in the co-culture models. Pericytes and astrocytes have opposite effects on endothelial cells and may contribute to endothelial injury in hyperacute ischemic stroke. Overall, fasudil protects the integrity of BBB both by a direct protective effect on endothelial cells and by a pathway mediated via pericytes and astrocytes.

Conclusions

Our findings suggest that fasudil is a BBB-protective agent against acute ischemic stroke.
Claudin-5a is essential for the functional formation of both zebrafish blood-brain barrier and blood-cerebrospinal fluid barrier
Authors: Li Yanyu , Wang Chunchun , Zhang Liang , Chen Bing , Mo Yuqian , Zhang Jingjing
Published: June 2022

Background

Mammalian Claudin-5 is the main endothelial tight junction component maintaining blood-brain barrier (BBB) permeability, while Claudin-1 and -3 seal the paracellular space of choroid plexus (CP) epithelial cells contributing to the blood-cerebrospinal fluid barrier (BCSFB). In zebrafish, two paralogs of claudin-5a and -5b are expressed while their roles in the formation of BBB and BCSFB are unclear.

Methods

The expression patterns of Claudin-5a and -5b in zebrafish brains were systematically analyzed by immunofluorescence (IF) assay. The developmental functions of Claudin-5a and -5b were characterized by generating of claudin-5a and -5b mutants respectively. Meanwhile, the cerebral inflammation and cell apoptosis in claudin-5a-/- were assessed by live imaging of transgenic zebrafish, RT-qPCR, IF, and TUNEL assay. The integrity of BBB and BCSFB was evaluated by in vivo angiographic and dye permeation assay. Finally, RT-qPCR, whole-mount RNA in situ hybridization (WISH), and transmission electron microscopy (TEM) analyses were performed to investigate the development of cerebral vessels and choroid plexus.

Results

We showed that Claudin-5a and -5b are both expressed in zebrafish cerebrovascular endothelial cells (ECs). In addition, Claudin-5a was strongly expressed in CP epithelial cells. Loss of Claudin-5b showed no effect on zebrafish vasculogenesis or BBB function. In contrast, the knockout of claudin-5a caused a lethal phenotype of severe whole-brain oedema, ventricular dilatation, and cerebral hernia in zebrafish larvae, although the cerebral vasculogenesis and the development of CP were not altered. In claudin-5a-/- , although ultrastructural analysis of CP and cerebral capillary showed intact integrity of epithelial and endothelial tight junctions, permeability assay indicated a disruption of both BBB and BCSFB functions. On the molecular level, it was found that ZO-1 was upregulated in the CP epithelium of claudin-5a-/-, while the notch and shh pathway responsible for CP development was not affected due to loss of Claudin-5a.

Conclusions

Our findings verified a non-functional role of zebrafish Claudin-5b in the BBB and identified Claudin-5a as the ortholog of mammalian Claudin-5, contributing to the development and the functional maintenance of both BBB and BCSFB.
The influence of minimally invasive esophagectomy versus open esophagectomy on postoperative pulmonary function in esophageal cancer patients: a meta-analysis
Authors: Su Jingwen , Li Shuang , Sui Qiyu , Wang Gongchao
Published: June 2022

Objective

To compare the influence of minimally invasive esophagectomy (MIE) and open esophagectomy (OE) on postoperative pulmonary function in patients with esophageal cancer.

Methods

Studies about the influence of MIE and OE on postoperative pulmonary function in esophageal cancer patients were searched from PubMed, EMBASE, the Cochrane Library, CNKI, Chinese Science and Technology Journal Database, CBM, and Wanfang Data from inception to March 18, 2021. Meta-analysis was performed using the RevMan 5.3.

Results

This analysis included eight studies, enrolling 264 patients who underwent MIE and 257 patients who underwent OE. The meta-analysis results showed that the MIE group had a higher outcome regarding the percent predicted vital capacity (%VC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and maximum voluntary ventilation (MVV) 1 month after surgery than the OE group. In addition, those who underwent MIE had lower ΔVC%, ΔFVC, and ΔFEV1 between pre-operation and 1 month after surgery than those who underwent OE. There is no statistical difference between the two groups in ΔMVV.

Conclusion

Compared with OE, MIE has a more protective effect on postoperative pulmonary function. However, due to the small number of included literature and all cohort studies, this finding needs to be validated with larger samples and higher quality RCT studies.
Surgical treatment of type A acute aortic dissection with cerebral malperfusion: a systematic review
Authors: Wang Changtian , Zhang Lei , Li Tao , Xi Zhilong , Wu Haiwei , Li Demin
Published: June 2022

Objectives

Type A acute aortic dissection (TAAAD) complicated with cerebral malperfusion (CM) is a life-threatening condition associated with high mortality, poor outcomes, and the optimal surgical management remains controversial. The aim of this review was to report the current results of surgical interventions of these patients.

Methods

A systematic review was performed using PubMed and MEDLINE search for cases underwent surgical repair for TAAAD with CM. Demographics, neurological symptom, the time from onset of symptoms to operation, operation data, mortality, neurological outcome, and follow-up were reviewed.

Results

A total of 363 patients with mean age of 65.7 ± 13 years underwent surgical repair for TAAAD with CM were identified in 12 retrospective studies. In-hospital mortality was 20.1%. Mean duration of follow-up was 40.1 ± 37.6 months. The involved supra-aortic branch vessels were RCCA (n = 99), LCCA (n = 25), B-CCA (n = 52), CCA (n = 131), IA (n = 19), and LSA (n = 8). Time from onset of neurological symptoms to surgery was 13.3 h. Antegrade and/or retrograde cerebral perfusion were applied. Postoperatively, improved, unchanged and worsened neurological status was occurred in 54.3%, 27.1%, and 8.5%, respectively in 199 patients.

Conclusion

The outcomes of surgical treatment of TAAAD complicated with CM indicate acceptable early mortality and morbidity. It is reasonable to perform lifesaving surgery on these patients. Early central surgical repair and reperfusion of brain may improve the outcomes.
Impact of sleep debt, social jetlag, and insomnia symptoms on presenteeism and psychological distress of workers in Japan: a cross-sectional study
Authors: Takano Yuta , Ibata Rui , Nakano Norihito , Sakano Yuji
Published: June 2022

Background

Presenteeism is an indicator of productivity loss and the risk of absence from work due to mental health problems. The purpose of this study was to determine the impact of sleep debt, social jetlag, and insomnia symptoms on presenteeism and psychological distress.

Methods

The participants were 351 Japanese workers (271 males, 79 females, and one of other gender, with a mean age of 49 ± 9.49 years). The eligibility criteria for this study were full-time employment, working eight hours per day, five days per week, and no night shifts. The participants answered questionnaires measuring sleep debt, social jetlag, insomnia symptoms, presenteeism, and psychological distress.

Results

Insomnia symptoms had the greatest impact on presenteeism and psychological distress when compared with sleep debt and social jetlag (adjusted odds ratio (OR) = 5.61, 95% confidence interval (CI) = 2.88–10.91; adjusted OR = 7.29, 95%CI = 3.06–17.35). Sleep debt had a greater impact on presenteeism and psychological distress than did social jetlag (adjusted OR = 1.61, 95%CI = 1.14–2.27; adjusted OR = 1.68, 95%CI = 1.11–2.54), which had no impact on these variables (adjusted OR = 1.04, 95%CI = 0.91–1.20; adjusted OR = 0.96, 95%CI = 0.76–1.22).

Conclusions

The findings of this study indicated that insomnia symptoms had a more significant impact on presenteeism and psychological distress than social jetlag and sleep debt. Although sleep debt might have an independent impact on presenteeism and psychological distress, social jetlag did not.
Assessing innovative approaches for global health capacity building in fragile settings in the MENA region: development of the evaluation of capacity building (eCAP) program
Authors: Saleh Shadi , Mansour Rania , Daou Tracy , Brome Dayana , Naal Hady
Published: June 2022

Background

Given the magnitude and frequency of conflicts in the MENA region along with their devastating impact on health responses and outcomes, there exists a strong need to invest in contextualized, innovative, and accessible capacity building approaches to enhance leadership and skills in global health. The MENA region suffers from limited (1) continued educational and career progression opportunities, (2) gender balance, and (3) skill-mix among its health workforce, which require significant attention.

Main text

The Global Health Institute at the American University of Beirut incepted the Academy division to develop and implement various global health capacity building (GHCB) initiatives to address those challenges in fragile settings across low-and middle-income countries in the MENA region. These initiatives play a strategic role in this context, especially given their focus on being accessible through employing innovative learning modalities. However, there exists a dearth of evidence-based knowledge on best practices and recommendations to optimize the design, implementation, and evaluation of GHCB in fragile settings in the MENA region. The present paper describes the development of the evaluation of capacity building program (eCAP), implemented under the Academy division, to assess the effectiveness of its initiatives. eCAP is composed of 3 phases: (1) a situational assessment, followed by (2) production of multiple case studies, and finally (3) a meta-assessment leading to model development. The goal of eCAP is not only to inform the Academy’s operations, but also to synthesize produced knowledge into the formation of an evidence-based, scalable, and replicable model for GHCB in fragile settings.

Conclusion

eCAP is an important initiative for researchers, educators, and practitioners interested in GHCB in fragile settings. Several lessons can be learned from the outcomes it has yielded so far in its first two phases of implementation, ranging from the situational assessment to the production of evaluation case studies, which are expanded on in the manuscript along with pertinent challenges.
A mixed methods study to assess the impact of COVID-19 on maternal, newborn, child health and nutrition in fragile and conflict-affected settings
Authors: Rodo Mariana , Singh Lucy , Russell Neal , Singh Neha S.
Published: June 2022

Background

The impacts of COVID-19 are unprecedented globally. The pandemic is reversing decades of progress in maternal, newborn, child health and nutrition (MNCHN), especially fragile and conflict-affected settings (FCAS) whose populations were already facing challenges in accessing basic health and nutrition services. This study aimed to investigate the collateral impact of COVID-19 on funding, services and MNCHN outcomes in FCAS, as well as adaptations used in the field to continue activities.

Methods

A scoping review of peer-reviewed and grey literature published between 1st March 2020–31st January 2021 was conducted. We analysed 103 publications using a narrative synthesis approach. 39 remote semi-structured key informant interviews with humanitarian actors and donor staff within 12 FCAS were conducted between October 2020 and February 2021. Thematic analysis was undertaken independently by two researchers on interview transcripts and supporting documents provided by key informants, and triangulated with literature review findings.

Results

Funding for MNCHN has been reduced or suspended with increase in cost of continuing the same activities, and diversion of MNCHN funding to COVID-19 activities. Disruption in supply and demand of interventions was reported across different settings which, despite data evidence still being missing, points towards likely increased maternal and child morbidity and mortality. Some positive adaptations including use of technology and decentralisation of services have been reported, however overall adaptation strategies have been insufficient to equitably meet additional challenges posed by the pandemic, and have not been evaluated for their effectiveness.

Conclusions

COVID-19 is further exacerbating negative women’s and children’s health outcomes in FCAS. Increased funding is urgently required to re-establish MNCHN activities which have been deprioritised or halted. Improved planning to sustain routine health services and enable surge planning for emergencies with focus on the community/service users throughout adaptations is vital for improved MNCHN outcomes in FCAS.
Bodily expression of psychological distress in adolescents: a qualitative study
Authors: Ludot-Grégoire Maude , Harf Aurélie , Ibrahim Nour , Merlo Médérick , Hassler Christine , Rietsch Joanne , de Bucy Charlotte , Lefèvre Hervé , Sibeoni Jordan , Moro Marie Rose
Published: June 2022

Introduction

The bodily expression of psychological disorders is one of the leading motives for consultations in adolescent medicine. The diagnostic entity corresponding to DSM-5 "Somatic symptom and related disorders" is sparsely used in the English-language literature, especially for adolescents. Qualitative studies on this topic mostly concern the experiences of healthcare professionals. This study seeks to explore the experience of adolescents expressing psychological distress through their body.

Methods

This exploratory research took place in a Paris hospital department of adolescent medicine. Our sampling method was purposive. For inclusion, patients had to be aged 11–24 years, with a "somatic symptom disorder" meeting the DSM-5 criteria. Semi-directive interviews were proposed with visual narration inspired by photoelicitation. Thematic analysis allowed us to explore the data with an inductive approach.

Results

Thirty adolescents were interviewed; they were 14–22 years old and mostly had somatic symptom or functional neurological disorders. Three principal themes emerged from our analysis of the interview contents: the personal, including bodily, experience of the disorder, the experience of relationships, and the question of what is visible through the body.

Conclusion

This research allowed us to discuss the reversal of generations, the function of the DSM-5 diagnosis, illuminated by sociology, and finally, cultural pathways. It shows the importance of recognizing the reality of the adolescents' bodily feelings, reassuring them by ruling out serious causes, and supporting their search for meaning. It is important to think about a specific framework of family therapy that can make effective use of this experience of the reversal of generations.
Prenatal diagnosis and genetic counseling of a 10p11.23q11.21 duplication associated with normal phenotype
Authors: Song Jieping , Jiang Wei , Zhang Chengcheng , Wang Bo
Published: June 2022

Background

Copy number variants (CNVs) are an important source of normal and pathogenic genome variations. Unbalanced chromosome abnormalities (UBCA) are either gains or losses or large genomic regions, but the affected person is not or only minimally clinically affected. CNVs and UBCA identified in prenatal cases need careful considerations and correct interpretation if those are harmless or harmful variants from the norm.

Case presentation

A 24-year-old, gravida 1, para 0, woman underwent amniocentesis at 17 weeks of gestation because the noninvasive prenatal testing (NIPT) results revealed a 12.4 Mb duplication from 10p11.2 to 10q11.2. GTG-banding karyotype analysis was performed on cultured amniocytes. Chromosomal microarray analysis (CMA) on uncultured amniocytes was performed.

Results

Chromosomal GTG-banding of the cultured amniocytes revealed a karyotype of 46,XX,dup(10)(p11.2q11.2). CMA detected a 12.5-Mb chromosomal duplication in the region of 10p11.23q11.21 (arr[GRCh37] 10p11.23q11.21(30,345,109_42,826,062) × 3).

Conclusion

The present report enlarges the known UBCA region 10p11.22-10q11.22 to 10p11.23-10q11.22. Also it highlights that an integration of prenatal ultrasound, NIPT, karyotype analysis, CMA and genetic counseling is helpful for the prenatal diagnosis of chromosomal deletions/duplications.
Clinical experiences with venetoclax and other pro-apoptotic agents in lymphoid malignancies: lessons from monotherapy and chemotherapy combination
Authors: Lew Thomas E. , Seymour John F.
Published: June 2022

BH3-mimetics are a novel drug class of small molecule inhibitors of BCL2 family proteins which restore apoptosis in malignant cells. The only currently approved BH3-mimetic, the selective BCL2 inhibitor venetoclax, is highly efficacious in chronic lymphocytic leukemia and has rapidly advanced to an approved standard of care in frontline and relapsed disease in combination with anti-CD20 monoclonal antibodies. In this context, tumour lysis syndrome and myelosuppression are the most commonly encountered toxicities and are readily manageable with established protocols. Venetoclax is active in other lymphoid malignancies including several B cell non-Hodgkin lymphomas, acute lymphoblastic leukemia and multiple myeloma, with the highest intrinsic sensitivity observed in mantle cell lymphoma and Waldenstrom macroglobulinemia. Venetoclax combination with standard regimens in follicular lymphoma, multiple myeloma and aggressive B cell neoplasms has shown some promise, but further studies are required to optimize dose and scheduling to mitigate increased myelosuppression and infection risk, and to find validated biomarkers of venetoclax sensitivity. Future research will focus on overcoming venetoclax resistance, targeting other BCL2 family members and the rational design of synergistic combinations.
Mammary adipocytes protect triple-negative breast cancer cells from ferroptosis
Authors: Xie Yizhao , Wang Biyun , Zhao Yannan , Tao Zhonghua , Wang Ye , Chen Guangliang , Hu Xichun
Published: June 2022

Ferroptosis, a novel non-apoptotic form of cell death, can induce tumor cell death and treatment resistance. Lipid metabolism is closely related to ferroptosis; however, the effect of mammary adipocytes on breast cancer ferroptosis remains to be elucidated. Here, we established the co-culture system of adipocyte-breast cancer cells and revealed the protection of triple-negative breast cancer from ferroptosis by adipocytes. Then, we performed the lipidomics analysis comparing lipid metabolites of co-cultured and normal-cultured cells. Mechanistically, oleic acid secreted from adipocytes inhibited lipid peroxidation and ferroptosis of triple-negative breast cancer cells in the presence of ACSL3. Taken together, mammary adipocytes can protect breast cancer cells from ferroptosis through oleic acid in the presence of ACSL3. These findings could provide new ideas and targets for tumor treatment.
The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease
Authors: Cigliano Antonio , Zhang Shanshan , Ribback Silvia , Steinmann Sara , Sini Marcella , Ament Cindy E. , Utpatel Kirsten , Song Xinhua , Wang Jingxiao , Pilo Maria G. , Berger Fabian , Wang Haichuan , Tao Junyan , Li Xiaolei , Pes Giovanni M. , Mancarella Serena , Giannelli Gianluigi , Dombrowski Frank , Evert Matthias , Calvisi Diego F. , Chen Xin , Evert Katja
Published: June 2022

Background

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver tumor with increasing incidence worldwide, dismal prognosis, and few therapeutic options. Mounting evidence underlines the role of the Hippo pathway in this disease; however, the molecular mechanisms whereby the Hippo cascade contributes to cholangiocarcinogenesis remain poorly defined.

Methods

We established novel iCCA mouse models via hydrodynamic transfection of an activated form of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, either alone or combined with the myristoylated AKT (myr-AKT) protooncogene, in the mouse liver. Hematoxylin and eosin staining, immunohistochemistry, electron microscopy, and quantitative real-time RT-PCR were applied to characterize the models. In addition, in vitro cell line studies were conducted to address the growth-promoting roles of TAZ and its paralog YAP.

Results

Overexpression of TAZ in the mouse liver triggered iCCA development with very low incidence and long latency. In contrast, co-expression of TAZ and myr-AKT dramatically increased tumor frequency and accelerated cancer formation in mice, with 100% iCCA incidence and high tumor burden by 10 weeks post hydrodynamic injection. AKT/TAZ tumors faithfully recapitulated many of the histomolecular features of human iCCA. At the molecular level, the development of the cholangiocellular lesions depended on the binding of TAZ to TEAD transcription factors. In addition, inhibition of the Notch pathway did not hamper carcinogenesis but suppressed the cholangiocellular phenotype of AKT/TAZ tumors. Also, knockdown of YAP, the TAZ paralog, delayed cholangiocarcinogenesis in AKT/TAZ mice without affecting the tumor phenotype. Furthermore, human preinvasive and invasive iCCAs and mixed hepatocellular carcinoma/iCCA displayed widespread TAZ activation and downregulation of the mechanisms protecting TAZ from proteolysis.

Conclusions

Overall, the present data underscore the crucial role of TAZ in cholangiocarcinogenesis
Footwear, foot orthoses and strengthening exercises for the non‐surgical management of hallux valgus: protocol for a randomised pilot and feasibility trial
Authors: Menz Hylton B. , Lim Polly Q. , Hurn Sheree E. , Mickle Karen J. , Buldt Andrew K. , Cotchett Matthew P. , Roddy Edward , Wluka Anita E. , Erbas Bircan , Munteanu Shannon E.
Published: June 2022

Background

Hallux valgus is a common and disabling condition. This randomised pilot and feasibility trial aims to determine the feasibility of conducting a fully‐powered parallel group randomised trial to evaluate the effectiveness of a multifaceted non‐surgical intervention for reducing pain associated with hallux valgus.

Methods

Twenty‐eight community‐dwelling women with painful hallux valgus will be randomised to receive either a multifaceted, non‐surgical intervention (footwear, foot orthoses, foot exercises, advice, and self‐management) or advice and self‐management alone. Outcome measures will be obtained at baseline, 4, 8 and 12 weeks. The primary outcome is feasibility, which will be evaluated according to demand, acceptability, adherence, adverse events, and retention rate. Limited efficacy testing will be conducted on secondary outcome measures including foot pain (the Manchester‐Oxford Foot Questionnaire), foot muscle strength (hand‐held dynamometry), general health‐related quality of life (the Short Form‐12), use of cointerventions, and participants' perception of overall treatment effect. Biomechanical testing will be conducted at baseline to evaluate the immediate effects of the footwear/orthotic intervention on pressure beneath the foot and on the medial aspect of the first metatarsophalangeal joint and hallux.

Discussion

This study will determine the feasibility of conducting a fully‐powered randomised trial of footwear, foot orthoses, foot exercises, advice and self‐management for relieving pain associated with hallux valgus and provide insights into potential mechanisms of effectiveness.

Trial registration

Australian and New Zealand Clinical Trial Registry (ACTRN12621000645853).
Diagnostic controversies in recurrent painful ophthalmoplegic neuropathy: single case report with a systematic review
Authors: Falsaperla Raffaele , Presti Santiago , Lo Bianco Manuela , Catanzaro Stefano , Marino Silvia , Ruggieri Martino
Published: June 2022

Background

Ophthalmoplegic migraine, renamed "Recurrent Painful Ophthalmoplegic Neuropathy" (RPON) in 2013 by the International Headache Society is a rare neurologic disorder characterized by recurrent attacks of ophthalmoplegia associated to ipsilateral headache. The etiology is still unknown. Typical magnetic resonance imaging findings show a focal nerve thickening and contrast enhancement. In the majority of cases, there is a full recovery within days or weeks. There is no evidence supporting a specific treatment. The review defines the characteristics of the recurrent painful ophthalmoplegic neuropathy in patients within 2 years of age underlying the importance of the role of magnetic resonance imaging even in presence of the first attack. Thus, an emblematic case report is presented.

Case presentation

The authors present a case of third cranial nerve paresis in a 17-month-old male child, presenting a neuroradiological pattern highly suggestive of schwannoma, aneurism or recurrent painful ophthalmoplegic neuropathy. Thus, a review of the literature with the pediatric casuistry of recurrent painful ophthalmoplegic neuropathy occurred within 2 years of age focusing on diagnostic considerations is presented. The authors highlight the importance to consider recurrent painful ophthalmoplegic neuropathy in presence of magnetic resonance imaging findings and clinical symptoms referable to aneurysm or schwannoma. Thus, the review defines the characteristics and the neuroradiological findings at the first RPON attack occurred under 2 years of age.

Conclusion

Although two attacks are necessary, the review strongly suggests to consider recurrent painful ophthalmoplegic neuropathy even at the first attack, in presence of described characteristics and the aforementioned magnetic resonance imaging findings.
Hereditary neuropathy with liability to pressure palsies (HNPP): Intrafamilial phenotypic variability and early childhood refusal to walk as the presenting symptom
Authors: Karklinsky Shani , Kugler Shir , Bar-Yosef Omer , Nissenkorn Andreea , Grossman-Jonish Anat , Tirosh Irit , Vivante Asaf , Pode-Shakked Ben
Published: June 2022

Background

Limping and/or refusal to walk is a common complaint in the setting of the pediatric department, with a widely diverse differential diagnosis. An unusual etiology, is that of a hereditary neuropathy.

Hereditary neuropathy with liability to pressure palsies (HNPP) is a recurrent, episodic demyelinating neuropathy, most commonly caused by a 17p11.2 chromosomal deletion encompassing the PMP22 gene.

Methods

We pursued chromosomal microarray analysis (CMA) in multiple affected individuals of a single extended family, manifesting a range of phenotypic features consistent with HNPP.

Results

A 4.5 years-old boy presented for in-patient evaluation due to refusal to walk. Initial investigations including spine MRI and bone scan failed to yield a conclusive diagnosis. Following family history, which implied an autosomal dominant mode of inheritance, CMA was pursued and confirmed a 17p11.2 deletion in the proband consistent with HNPP. Importantly, following this diagnosis, four additional affected family members were demonstrated to harbor the deletion. Their variable phenotypic features, ranging from a prenatal diagnosis of a 6 months-old sibling, to recurrent paresthesias manifesting in the fourth decade of life, are discussed.

Conclusions

Our experience with the family reported herein demonstrates how a thorough anamnesis can lead to a rare genetic etiology with a favorable prognosis and prevent unnecessary investigations, and underscores HNPP as an uncommon diagnostic possibility in the limping child.
Long COVID-19 in children: an Italian cohort study
Authors: Trapani Gianfranco , Verlato Giuseppe , Bertino Enrico , Maiocco Giulia , Vesentini Roberta , Spadavecchia Alessia , Dessì Angelica , Fanos Vassilios
Published: June 2022

Background

Long COVID-19 syndrome is a complex of symptoms that occurs after the acute SARS-CoV-2 infection, in the absence of other possible diagnoses. Studies on Long COVID-19 in pediatric population are scanty and heterogeneous in design, inclusion criteria, outcomes, and follow-up time. The objective of the present study is to assess the prevalence of Long COVID-19 syndrome in a cohort of Italian pediatric primary care patients, observed for a period of time of 8 to 36 weeks from healing. Prevalence was also assessed in a cohort of pediatric patients hospitalized during acute infection.

Methods

Data concerning 629 primary care patients with previous acute SARS-CoV-2 infection were collected by a questionnaire filled in by Primary Care Pediatrician (PCP). The questionnaire was administrated to patients by 18 PCPs based in 8 different Italian regions from June to August 2021. Data concerning 60 hospitalized patients were also collected by consultation of clinical documents.

Results

Cumulative incidence of Long COVID-19 resulted to be 24.3% in primary care patients and 58% in hospitalized patients. The most frequently reported symptoms were abnormal fatigue (7%), neurological (6.8%), and respiratory disorders (6%) for the primary care cohort. Hospitalized patients displayed more frequently psychological symptoms (36.7%), cardiac involvement (23.3%), and respiratory disorders (18.3%). No difference was observed in cumulative incidence in males and females in both cohorts. Previous diseases did not influence the probability to develop Long COVID-19. The prevalence of Long COVID-19 was 46.5% in children who were symptomatic during acute infection and 11.5% in asymptomatic ones. Children aged 0 to 5 years had a greater risk to develop respiratory symptoms, while adolescents (aged 11–16 years) had a greater risk to develop neurological and psychological Long COVID-19 symptoms.

Conclusions

Our study demonstrates that Long COVID-19 is a reality in pediatric age and could involve even patients with mild or no acute symptoms. The results stress the importance of monitoring primary care pediatric patients after acute COVID-19 infection and the relevance of vaccination programs in pediatric population, also in order to avoid the consequences of Long COVID-19 syndrome.
Orosomucoid: a promising biomarker for the assessment of exercise-induced fatigue triggered by basic combat training
Authors: Ruan Yi , Xiang Ke-fa , Zhang Hui-min , Qin Zhen , Sun Yang , Wan Jing-jing , Gu Wei , Liu Xia
Published: June 2022

Background

Orosomucoid (ORM) is a positive acute phase protein verified to be upregulated in various forms of exercise-induced fatigued (EIF) rodents. However, its association with EIF among human beings remained unknown. This study aimed to explore the association between serum ORM and EIF triggered by military basic combat training (BCT).

Methods

The degree of EIF were measured by Borg’s Rating of Perceived Exertion Scale (Borg-RPE-Scale®) as RPE score after BCT. Fifty-three male recruits were classified into three groups according to the RPE score: (1) group 1 (slight fatigue group): RPE score after BCT < 13; (2) group 2 (moderate fatigue group): RPE score after BCT = 13 or 14; (3) group 3 (severe fatigue group): RPE score after BCT > 14. The levels of blood ORM, lactate (LAC), cortisol and C-reactive protein (CRP) were determined before and after BCT. The diagnostic value of ORM was evaluated by receiver operating characteristic (ROC) curve analysis and logistic regression.

Results

After BCT, the level of LAC, CRP, and cortisol increased among all groups, but the changes had no significant between-group difference (all p > 0.05). The level of ORM had a specific significant increase in group 3 (p = 0.039), and the changes of ORM (ΔORM) had significant difference among groups (p = 0.033). ROC curve analysis showed that the estimated area under ROC curve for ΔORM was 0.724 (p = 0.009) with the recommended optimal cut-off value as 0.2565 mg/mL. Logistic analysis showed that recruits with ΔORM ≥ 0.2565 mg/mL had higher odds for suffering from severe EIF, 5.625 times (95% CI 1.542–20.523, p = 0.009) as large as those with ΔORM < 0.2565 mg/mL.

Conclusion

ORM might be a promising biomarker of severe EIF triggered by BCT among male recruits. Its potential optimal cut-off value regarding ΔORM was recommended to be 0.2565 mg/mL.
Effects of HIS-based intervention on patient education process and patient satisfaction with nurses' education
Authors: Toulabi Tahereh , Mohammadipour Fatemeh
Published: June 2022

Objective

This quasi-experimental study (before and after intervention) was designed to determine the impact of hospital information system-based intervention on the patient education process and patient satisfaction in cardiac and cardiac intensive care units.

Results

Each nurse was observed at the time of patient education on average on eight shifts (total of 256 shifts), and at last 1350 computerized reports before and after the intervention were analyzed and 150 patient satisfaction with nurses' education questionnaires were completed before and after the intervention.

After the intervention, the patient education scores were significantly improved (p < 0.001). In addition, the results of a survey of patients about the level of satisfaction with the quality of patient education showed a significant increase compared to before the intervention (p < 0.001).

The ability to easily, completely, and quickly edit and record the provided education, eased the process of patient education and documentation.
A method to correct for the influence of bovine serum albumin-associated vitamin D metabolites in protein extracts from neonatal dried blood spots
Authors: Boelt Sanne Grundvad , Plana-Ripoll Oleguer , Albiñana Clara , Vilhjálmsson Bjarni , McGrath John J. , Cohen Arieh S.
Published: June 2022

Objective

We developed an assay to measure the concentration of 25 hydroxyvitamin D2 and D3 in protein extracts derived from stored neonatal dried blood spots. During this study, we postulated that these samples had been contaminated with exogenous vitamin D metabolites because of the addition of bovine serum albumin (BSA) as part of an extraction step undertaken 7 years earlier. The aim of the current study was to develop methods in order to adjust for this contamination.

Results

We identified between-plate variations in 25 hydroxyvitamin D2 and D3 concentrations which suggested the presence of three different BSA batches. Based on repeat extraction (without the addition of BSA) and testing of 395 samples, we developed models to correct for the exogenous 25 hydroxyvitamin D2 and D3. The regression models were Diff25OHD3 = − 8.2 + 1.8* Diff25OHD2 for low contamination, Diff25OHD3 = 23.8 + 1.7* Diff25OHD2 for middle contamination, and Diff25OHD3 = 14.3 + 3.0* Diff25OHD2 for high contamination. After these corrections, the three subsamples had comparable distributions within the expected range for both 25 hydroxyvitamin D2 and D3.
Horizontal transfer of a plasmid possessing mcr-1 marked with a single nucleotide mutation between Escherichia coli isolates from community residents
Authors: Yamamoto Yoshimasa , Higashi Ayano , Ikawa Kanoko , Hoang Hoa Thi Thanh , Yamaguchi Takahiro , Kawahara Ryuji , Noguchi Hideki , Nguyen Thang Nam , Khong Diep Thi , Tran Hoa Thi
Published: June 2022

Objectives

The widespread dissemination of phenotypic colistin-resistant (COR) bacteria in the community threatens public health. The horizontal gene transfer of the mobile colistin resistance gene via plasmids is thought to be one of the main mechanisms for dissemination. However, genotypic evidence to prove this in community settings is limited. This study used genome analysis to demonstrate the direct horizontal colistin resistance gene transfer via plasmids in isolates from the community.

Results

A total of 19 isolates of COR Escherichia coli from stool specimens of 23 residents from seven households in the Vietnamese community were assessed in this study. The whole-genome sequence data of isolates were acquired using a combination of DNBSEQ short-reads and Nanopore long-read sequencing. Analysis of genomic data was performed using online tools such as Geneious. Analysis of the genomic information of COR E. coli isolates revealed that the isolates from two residents of different households had a similar IncP1 plasmid possessing mcr-1.1, marked with a single nucleotide mutation at the same position. The study provided direct evidence to prove that mcr was horizontally transmitted among bacteria in community residents.
Preventing sexism and sexual harassment in medical schools by using Theater of the Oppressed as an interactive and reflexive tool
Authors: Lüthi Emmanuelle , Pichonnaz Lauriane , Schwarz Joëlle , Morier-Genoud Pascal , Dayer Caroline , Rrustemi Ilire , Schilter Léa , Berney Alexandre , John Caroline , Dubois Julie , Rodondi Pierre-Yves , Clair Carole
Published: June 2022

Objectives

Among the measures taken to combat sexism and sexual harassment, prevention courses for medical students are one possibility. We aimed to describe the process of implementing a training course on the prevention of sexism and sexual harassment for medical students in two Swiss medical schools by using the Theater of the Oppressed as an interactive and reflexive tool within the course. The purpose of this theater was to give the students the opportunity to express themselves and to collectively look for and discuss ways to combat and escape from oppressive situations.

Results

This collaborative, innovative, and interactive implementation showed that different forms of a training course can be implemented with similar objectives in an adaptable and transferable manner. The interactive and reflexive Theater of the Oppressed was an appropriate option to reach the objectives. Courses were based on identifying and acting on concrete problematic situations by focusing on individual, collective, and institutional resources. Students reported a high level of satisfaction.
dsSurvival: Privacy preserving survival models for federated individual patient meta-analysis in DataSHIELD
Authors: Banerjee Soumya , Sofack Ghislain N. , Papakonstantinou Thodoris , Avraam Demetris , Burton Paul , Zöller Daniela , Bishop Tom R. P.
Published: June 2022

Objective

Achieving sufficient statistical power in a survival analysis usually requires large amounts of data from different sites. Sensitivity of individual-level data, ethical and practical considerations regarding data sharing across institutions could be a potential challenge for achieving this added power. Hence we implemented a federated meta-analysis approach of survival models in DataSHIELD, where only anonymous aggregated data are shared across institutions, while simultaneously allowing for exploratory, interactive modelling. In this case, meta-analysis techniques to combine analysis results from each site are a solution, but an analytic workflow involving local analysis undertaken at individual studies hinders exploration. Thus, the aim is to provide a framework for performing meta-analysis of Cox regression models across institutions without manual analysis steps for the data providers.

Results

We introduce a package (dsSurvival) which allows privacy preserving meta-analysis of survival models, including the calculation of hazard ratios. Our tool can be of great use in biomedical research where there is a need for building survival models and there are privacy concerns about sharing data.
Acute ischemic stroke: a rare complication of hump-nosed pit viper (Hypnale spp.) bite: a case report
Authors: Namal Rathnayaka R. M. M. K. , Nishanthi Ranathunga P. E. A. , Kularatne S. A. M. , Jayasinghe Sanath
Published: June 2022

Background

Hump-nosed pit viper is a medically important deadly venomous snake in Sri Lanka and is the commonest cause of venomous snakebites in the country. It frequently causes local effects and systemic manifestations such as acute kidney injury and coagulopathy that occur in less than 10% of all bites. This also includes some atypical presentations such as thrombotic microangiopathy and myocardial infarction. Currently, no antivenom is available for hump-nosed pit viper bites in Sri Lanka, and patients are managed with supportive treatment. This case illustrates an acute ischemic stroke following a hump-nosed viper bite, which is the second case in the literature.

Case presentation

A 71-year-old a Sinhalese male patient presented with left-sided hemiparesis with mouth deviation on day 2 of hump-nosed viper (Hypnale spp.) bite on the right foot. Non-contrast computed tomography of brain showed right ischemic stroke in internal capsule. He was given antiplatelets and statins and continued supportive treatment including limb physiotherapy and speech therapy. He recovered completely and was discharged on day 4 with clinic follow-up.

Conclusions

Physicians should be aware that ischemic cerebral infarcts may occur following hump-nosed pit viper bites.
A reduced level of the long non-coding RNA SNHG8 activates the NF-kappaB pathway by releasing functional HIF-1alpha in a hypoxic inflammatory microenvironment
Authors: Wang Chenxin , Yang Qiaolin , Han Yineng , Liu Hao , Wang Yue , Huang Yiping , Zheng Yunfei , Li Weiran
Published: June 2022

Background

A series of biochemical responses, including hypoxia and aseptic inflammation, occur in periodontal ligament cells (PDLCs) during periodontal tissue remodeling of orthodontic tooth movement (OTM). However, the role of long non-coding RNA (lncRNA) in these responses is still largely unknown. We investigated the role of the lncRNA SNHG8 in hypoxic and inflammatory responses during OTM and explored the underlying mechanisms.

Methods

The expression pattern of SNHG8, and hypoxic and inflammatory responses under compressive force were analyzed by qRT-PCR, immunohistochemistry, and western blotting, in vivo and in vitro. The effect of overexpression or knockdown of SNHG8 on the nuclear factor-kappaB (NF-κB) pathway was evaluated. RNA sequencing was performed for mechanistic analysis. The interaction between SNHG8 and hypoxia-inducible factor (HIF)-1α was studied using catRAPID, RNA immunoprecipitation, and RNA pulldown assays. The effect of the SNHG8–HIF-1α interaction on the NF-κB pathway was determined by western blotting.

Results

The NF-κB pathway was activated, and HIF-1α release was stabilized, in PDLCs under compressive force as well as in OTM model rats. The SNHG8 level markedly decreased both in vivo and in vitro. Overexpression of SNHG8 decreased the expression levels of inflammatory cytokines, the phosphorylation of p65, and the degradation of IκBα in PDLCs, whereas knockdown of SNHG8 reversed these effects. Mechanically, RNA sequencing showed that differentially expressed genes were enriched in cellular response to hypoxia after SNHG8 overexpression. SNHG8 binds to HIF-1α, thus preventing HIF-1 from activating downstream genes, including those related to the NF-κB pathway.

Conclusion

SNHG8 binds to HIF-1α. During OTM, the expression of SNHG8 dramatically decreased, releasing free functional HIF-1α and activating the downstream NF-κB pathway. These data suggest a novel lncRNA-regulated mechanism during periodontal tissue remodeling in OTM.
Modeling hypertrophic cardiomyopathy with human cardiomyocytes derived from induced pluripotent stem cells
Authors: Li Jiangtao , Feng Xin , Wei Xiang
Published: June 2022

One of the obstacles in studying the pathogenesis of hypertrophic cardiomyopathy (HCM) is the poor availability of myocardial tissue samples at the early stages of disease development. This has been addressed by the advent of induced pluripotent stem cells (iPSCs), which allow us to differentiate patient-derived iPSCs into cardiomyocytes (iPSC-CMs) in vitro. In this review, we summarize different approaches to establishing iPSC models and the application of genome editing techniques in iPSC. Because iPSC-CMs cultured at the present stage are immature in structure and function, researchers have attempted several methods to mature iPSC-CMs, such as prolonged culture duration, and mechanical and electrical stimulation. Currently, many researchers have established iPSC-CM models of HCM and employed diverse methods for performing measurements of cellular morphology, contractility, electrophysiological property, calcium handling, mitochondrial function, and metabolism. Here, we review published results in humans to date within the growing field of iPSC-CM models of HCM. Although there is no unified consensus, preliminary results suggest that this approach to modeling disease would provide important insights into our understanding of HCM pathogenesis and facilitate drug development and safety testing.