bluuebunny/crossref_metadata_2025 huggingface dataset:
On-site clinical mentoring as a maternal and new-born care quality improvement method: evidence from a nurse cohort study in Nepal
Authors: Goyet Sophie , Rajbhandari Swaraj , Alvarez Valerie Broch , Bayou Aida , Khanal Sirjana , Pokhrel Tara Nath
Published: January 2020

Background

We describe an on-site clinical mentoring program aimed at improving emergency obstetrical and new-born care (EmONC) in Nepal and assess its effectiveness on nurses’ knowledge and skills. In Nepal, both the maternal mortality ratio (MMR, 239/100,000 live births) and the neonatal mortality rate (NMR, 21/1000 live births) were among the highest in the world in 2016, despite impressive progress over recent decades considering the challenging environment.

Methods

From September 2016 to April 2018, three experienced nurses conducted repeated mentoring visits in 61 comprehensive or basic EmONC centers and birthing centers located in 4 provinces of Nepal. Using updated national training manuals and teaching aids, these clinical mentors assessed and taught 12 core EmONC clinical skills to their nurse-mentees. Clinical mentors worked with management mentors whose goal was to improve the nurses’ working environment. We assessed whether the cohort of nurse-mentees performed better as a group and individually performed better at the end of the program than at baseline using relevant tests (chi-square test, Wilcoxon matched-pairs signed-rank test, and Kruskal-Wallis equality-of-population rank test).

Results

In total, 308 nurses were assessed, including 96 (31.2%), 77 (25.0%) and 135 (43.8%) who participated in all three, two or only one mentoring session, respectively. In total, 225 (73.0%) worked as auxiliary nurse-midwives (ANMs), while 69 (22.4%) worked as nurses. One hundred and ninety five (63.3%) were trained as skilled birth attendants, of which 45 (23.1%) were nurses, 141 (72.3%) were auxiliaries and 9 (4.6%) had other positions. The proportion of ANMs and nurse-mentees who obtained a knowledge assessment score ≥ 85% increased from 57.8 to 86.1% (p <  0.001). Clinical assessment scores increased significantly for each participant, and therefore for the group. SBA-trained mentees had better knowledge of maternal and new-born care and were better able to perform the 12 core clinical skills throughout the program.

Conclusions

Our study suggests that on-site clinical mentoring of nurses coupled with health facility management mentoring can improve nurses’ clinical competences in and performance of maternity and new-born care. Assessing evidence of impact on patient safety would be the next stage in evaluating this promising intervention.
Combining patient, clinical and system perspectives in assessing performance in healthcare: an integrated measurement framework
Authors: Levesque Jean-Frederic , Sutherland Kim
Published: January 2020

Background

The science of measuring and reporting on the performance of healthcare systems is rapidly evolving. In the past decade, across many jurisdictions, organisations tasked with monitoring progress towards reform targets have broadened their purview to take a more system-functioning approach. Their aim is to bring clarity to performance assessment, using relevant and robust concepts – and avoiding reductionist measures – to build a whole-of-system view of performance. Existing performance frameworks are not fully aligned with these developments.

Methods

An eight stage process to develop a conceptual framework incorporated literature review, mapping, categorisation, integration, synthesis and validation of performance constructs that have been used by organisations and researchers in order to assess, reflect and report on healthcare performance.

Results

A total of 19 performance frameworks were identified and included in the review. Existing frameworks mostly adopted either a logic model (inputs, outputs and outcomes), a functional, or a goal-achievement approach. The mapping process identified 110 performance terms and concepts. These were integrated, synthesised and resynthesised to produce a framework that features 12 derived constructs reflecting combinations of patients’ needs and expectations; healthcare resources and structures; receipt and experience of healthcare services; healthcare processes, functions and context; and healthcare outcomes. The 12 constructs gauge performance in terms of coverage, accessibility, appropriateness, effectiveness, safety, productivity, efficiency, impact, sustainability, resilience, adaptability and equity. They reflect four performance perspectives (patient, population, delivery organisation and system).

Conclusions

Internationally, healthcare systems and researchers have used a variety of terms to categorise indicators of healthcare performance, however few frameworks are based on a theoretically-based conceptual underpinning. The proposed framework incorporates a manageable number of performance domains that together provide a comprehensive assessment, as well as conceptual and operational clarity and coherence that support multifaceted measurement systems for healthcare.
Formal home care use by older adults: trajectories and determinants in the Lc65+ cohort
Authors: Dupraz Julien , Henchoz Yves , Santos-Eggimann Brigitte
Published: January 2020

Background

Given the increasing importance of formal home care services in policies dedicated to elder care, there is major interest in studying individuals’ characteristics determining their utilization. The main objective of this research was to quantify, during a 6-year timeframe, home care use trajectories followed by community-dwelling participants in a cohort study of older adults. The secondary objective was to identify factors associated with home care utilization using Andersen’s Behavioural Model of Health Services Use.

Methods

We proceeded to an analysis of data prospectively collected in the setting of the Lc65+ population-based study conducted in Lausanne (Switzerland). Self-reported utilization of professional home care in 2012 and 2018 was used to define trajectories during this timeframe (i.e. non-users, new users, former users and continuing users). Bivariable analyses were performed to compare new users to non-users regarding the three dimensions of Andersen’s model (predisposing, enabling and need factors) measured at baseline. Then, binomial logistic regression was used in a series of two hierarchical models to adjust for need factors first, before adding predisposing and enabling factors in a second model.

Results

Of 2155 participants aged between 69 and 78 in 2012, 82.8% remained non-users in 2018, whereas 11.2% started to use professional home care. There were 3.3% of continuing users and 2.7% of former users. New users exhibited a higher burden of physical and psychological complaints, chronic health conditions and functional limitations at baseline. After adjusting for these need factors, odds of home care utilization were higher only in participants reporting a difficult financial situation (OR 1.65, 95% CI 1.12–2.45).

Conclusions

In the setting of a Swiss city, incident utilization of formal home care by older adults appeared to be largely determined by need factors. Modifiable factors like personal beliefs and knowledge about home care services did not play a role. After adjusting for need, odds of becoming home care user remained higher in participants reporting a difficult financial situation, suggesting such vulnerability does not hamper access to professional home care in this specific context.
The development of a theory informed behaviour change intervention to improve adherence to dietary and physical activity treatment guidelines in individuals with familial hypercholesterolaemia (FH)
Authors: Kinnear F. J. , Wainwright E. , Bourne J. E. , Lithander F. E. , Hamilton-Shield J. , Searle A.
Published: January 2020

Background

Familial hypercholesterolaemia (FH) is a genetic condition characterised by elevated levels of low-density lipoprotein cholesterol (LDL-C) and an increased risk of cardiovascular disease (CVD). Following dietary and physical activity guidelines could help minimise this risk but adherence is low. Interventions to target these behaviours are therefore required. A comprehensive understanding of the target behaviours and behaviour change theory should drive the process of intervention development to increase intervention effectiveness and scalability. This paper describes the application of a theoretical framework to the findings of a qualitative evidence synthesis (QES) to inform the content and delivery of an intervention to improve adherence to dietary and physical activity guidelines in individuals with FH.

Methods

The Behaviour Change Wheel (BCW) was used to guide intervention development. Factors influencing dietary and physical activity behaviours were identified from an earlier QES and mapped onto factors within the BCW. A comprehensive behavioural diagnosis of these factors was conducted through application of the theoretical domains framework (TDF). Using these data, the most appropriate intervention functions and behaviour change techniques (BCTs) for inclusion in the intervention were identified. Decision making was guided by evaluation criteria recommended by BCW guidance and feedback from individuals with FH.

Results

Factors influencing dietary and physical activity behaviours mapped onto twelve of the fourteen TDF domains, with seven intervention functions deemed suitable to target the domains’ theoretical constructs. Twenty-six BCTs were identified as being appropriate for delivery within these functions and were included in the intervention. For instance, within the enablement intervention function, the BCT problem solving was incorporated by inclusion of a ‘barriers and solutions’ section. Guided by evaluation criteria and feedback from individuals with FH, the intervention will be delivered as an hour-long family-based appointment, followed up with four telephone calls.

Conclusions

The novel application of the BCW and TDF to the results of a QES has enabled the development of a theory and evidence informed behaviour change intervention. This systematic approach facilitates evaluation of the intervention as part of an ongoing feasibility trial. The transparent approach taken can be used to guide intervention development by researchers in other fields.
DNA hypermethylation associated with upregulated gene expression in prostate cancer demonstrates the diversity of epigenetic regulation
Authors: Rauluseviciute Ieva , Drabløs Finn , Rye Morten Beck
Published: January 2020

Background

Prostate cancer (PCa) has the highest incidence rates of cancers in men in western countries. Unlike several other types of cancer, PCa has few genetic drivers, which has led researchers to look for additional epigenetic and transcriptomic contributors to PCa development and progression. Especially datasets on DNA methylation, the most commonly studied epigenetic marker, have recently been measured and analysed in several PCa patient cohorts. DNA methylation is most commonly associated with downregulation of gene expression. However, positive associations of DNA methylation to gene expression have also been reported, suggesting a more diverse mechanism of epigenetic regulation. Such additional complexity could have important implications for understanding prostate cancer development but has not been studied at a genome-wide scale.

Results

In this study, we have compared three sets of genome-wide single-site DNA methylation data from 870 PCa and normal tissue samples with multi-cohort gene expression data from 1117 samples, including 532 samples where DNA methylation and gene expression have been measured on the exact same samples. Genes were classified according to their corresponding methylation and expression profiles. A large group of hypermethylated genes was robustly associated with increased gene expression (UPUP group) in all three methylation datasets. These genes demonstrated distinct patterns of correlation between DNA methylation and gene expression compared to the genes showing the canonical negative association between methylation and expression (UPDOWN group). This indicates a more diversified role of DNA methylation in regulating gene expression than previously appreciated. Moreover, UPUP and UPDOWN genes were associated with different compartments — UPUP genes were related to the structures in nucleus, while UPDOWN genes were linked to extracellular features.

Conclusion

We identified a robust association between hypermethylation and upregulation of gene expression when comparing samples from prostate cancer and normal tissue. These results challenge the classical view where DNA methylation is always associated with suppression of gene expression, which underlines the importance of considering corresponding expression data when assessing the downstream regulatory effect of DNA methylation.
SOD2 ameliorates pulmonary hypertension in a murine model of sleep apnea via suppressing expression of NLRP3 in CD11b+ cells
Authors: Fu Cuiping , Hao Shengyu , Liu Zilong , Xie Liang , Wu Xu , Wu Xiaodan , Li Shanqun
Published: January 2020

Background

High prevalence of obstructive sleep apnea (OSA) in the pulmonary hypertension (PH) population suggests that chronic intermittent hypoxia (CIH) is an important pathogenic factor of PH. However, the exact mechanism of CIH induced PH is not clear. One of the molecules that plays a key role in regulating pulmonary artery function under hypoxic conditions is superoxide dismutase 2 (SOD2).

Methods

Our study utilized heterozygous SOD2−/+ mice firstly in CIH model to explore the exact role of SOD2 in CIH causing PH. Expression of SOD2 was analyzed in CIH model. Echocardiography and pulmonary hypertension were measured in wild type (WT) and SOD2−/+ mice under normal air or CIH condition. Hematoxylin–Eosin (H&E) staining and masson staining were carried out to evaluate pulmonary vascular muscularization and remodeling. Micro-PET scanning of in vivo 99mTc-labelled- MAG3-anti-CD11b was applied to assess CD11b in quantification and localization. Level of nod-like receptor pyrin domain containing 3 (NLRP3) was analyzed by real time PCR and immunohistochemistry (IHC).

Results

Results showed that SOD2 was down-regulated in OSA/CIH model. Deficiency of SOD2 aggravated CIH induced pulmonary hypertension and pulmonary vascular hypertrophy. CD11b+ cells, especially monocytic myeloid cell line-Ly6C+Ly6G− cells, were increased in the lung, bone marrow and the blood under CIH condition, and down-regulated SOD2 activated NLRP3 in CD11b+ cells. SOD2-deficient-CD11b+ myeloid cells promoted the apoptosis resistance and over-proliferation of human pulmonary artery smooth muscle cells (PASMCs) via up-regulating NLRP3.

Conclusion

CIH induced down-regulating of SOD2 increased pulmonary hypertension and vascular muscularization. It could be one of the mechanism of CIH leading to PH.
The European MultiPartner IPF registry (EMPIRE): validating long-term prognostic factors in idiopathic pulmonary fibrosis
Authors:   for the EMPIRE registry, Tran Tanja , Šterclová Martina , Mogulkoc Nesrin , Lewandowska Katarzyna , Müller Veronika , Hájková Marta , Kramer Mordechai R. , Jovanović Dragana , Tekavec-Trkanjec Jasna , Studnicka Michael , Stoeva Natalia , Hejduk Karel , Dušek Ladislav , Suissa Samy , Vašáková Martina
Published: January 2020

Background

Several registries of idiopathic pulmonary fibrosis (IPF) have been established to better understand its natural history, though their size and duration of follow-up are limited. Here, we describe the large European MultiPartner IPF Registry (EMPIRE) and validate predictors of long-term survival in IPF.

Methods

The multinational prospective EMPIRE registry enrolled IPF patients from 48 sites in 10 Central and Eastern European countries since 2014. Survival from IPF diagnosis until death was estimated, accounting for left-truncation. The Cox proportional hazards regression model was used to estimate adjusted hazard ratios (HR) of death for prognostic factors, using restricted cubic splines to fit continuous factors.

Results

The cohort included 1620 patients (mean age at diagnosis 67.6 years, 71% male, 63% smoking history), including 75% enrolled within 6 months of diagnosis. Median survival was 4.5 years, with 45% surviving 5 years post-diagnosis. Compared with GAP stage I, mortality was higher with GAP stages II (HR 2.9; 95% CI: 2.3–3.7) and III (HR 4.0; 95% CI: 2.8–5.7) while, with redefined cut-offs, the corresponding HRs were 2.7 (95% CI: 1.8–4.0) and 5.8 (95% CI: 4.0–8.3) respectively. Mortality was higher with concurrent pulmonary hypertension (HR 2.0; 95% CI: 1.5–2.9) and lung cancer (HR 2.6; 95% CI: 1.3–4.9).

Conclusions

EMPIRE, one of the largest long-term registries of patients with IPF, provides a more accurate confirmation of prognostic factors and co-morbidities on longer term five-year mortality. It also suggests that some fine-tuning of the indices for mortality may provide a more accurate long-term prognostic profile for these patients.
Optimization of virtual and real registration technology based on augmented reality in a surgical navigation system
Authors: Chen Long , Zhang Fengfeng , Zhan Wei , Gan Minfeng , Sun Lining
Published: January 2020

Background

The traditional navigation interface was intended only for two-dimensional observation by doctors; thus, this interface does not display the total spatial information for the lesion area. Surgical navigation systems have become essential tools that enable for doctors to accurately and safely perform complex operations. The image navigation interface is separated from the operating area, and the doctor needs to switch the field of vision between the screen and the patient’s lesion area. In this paper, augmented reality (AR) technology was applied to spinal surgery to provide more intuitive information to surgeons. The accuracy of virtual and real registration was improved via research on AR technology. During the operation, the doctor could observe the AR image and the true shape of the internal spine through the skin.

Methods

To improve the accuracy of virtual and real registration, a virtual and real registration technique based on an improved identification method and robot-assisted method was proposed. The experimental method was optimized by using the improved identification method. X-ray images were used to verify the effectiveness of the puncture performed by the robot.

Results

The final experimental results show that the average accuracy of the virtual and real registration based on the general identification method was 9.73 ± 0.46 mm (range 8.90–10.23 mm). The average accuracy of the virtual and real registration based on the improved identification method was 3.54 ± 0.13 mm (range 3.36–3.73 mm). Compared with the virtual and real registration based on the general identification method, the accuracy was improved by approximately 65%. The highest accuracy of the virtual and real registration based on the robot-assisted method was 2.39 mm. The accuracy was improved by approximately 28.5% based on the improved identification method.

Conclusion

The experimental results show that the two optimized methods are highly very effective. The proposed AR navigation system has high accuracy and stability. This system may have value in future spinal surgeries.
Antidepressant activity of ω-3 polyunsaturated fatty acids in ovariectomized rats: role of neuroinflammation and microglial polarization
Authors: Wu Bin , Song Qingen , Zhang Yongkang , Wang Changshui , Yang Mengqi , Zhang Jun , Han Wenxiu , Jiang Pei
Published: January 2020

Background

Menopause predisposes individuals to affective disorders, such as depression, which is tightly related to neuroinflammation. While the neuroinflammatory condition has been demonstrated in ovariectomized (OVX) rodents, there is limited evidence concerning microglial polarization, a key process in brain immune activation, in menopause-related brain.

Methods

Therefore, the present study aims to evaluate the polarized microglia in long-term OVX rats and we further explored whether supplementation of ω-3 polyunsaturated fatty acids (PUFA), the pleiotropic bioactive nutrient, is effective in the neurobehavioral changes caused by OVX.

Results

Our data showed that OVX-induced anxiety and depression-like behaviors in rats, accompanied with increased neural apoptosis and microglial activation in the hippocampus. Additionally, OVX enhanced proinflammatory cytokines expression and suppressed the expression of anti-inflammatory cytokine, IL-10. Correspondingly, OVX reinforced NFκB signaling and shifted the microglia from immunoregulatory M2 phenotype to proinflammatory M1 phenotype. Meanwhile, daily supplementation with PUFA suppressed microglial M1 polarization and potentiated M2 polarization in OVX rats. In parallel, PUFA also exerted antidepressant and neuroprotective activities, accompanied with neuroimmune-modulating actions.

Conclusion

Collectively, the present study firstly demonstrated the disturbed microglial polarization in the OVX brain and provide novel evidence showing the association between the antidepressant actions of PUFA and the restraint neuroinflammatory progression.
Interventions to improve team effectiveness within health care: a systematic review of the past decade
Authors: Buljac-Samardzic Martina , Doekhie Kirti D. , van Wijngaarden Jeroen D. H.
Published: January 2020

Background

A high variety of team interventions aims to improve team performance outcomes. In 2008, we conducted a systematic review to provide an overview of the scientific studies focused on these interventions. However, over the past decade, the literature on team interventions has rapidly evolved. An updated overview is therefore required, and it will focus on all possible team interventions without restrictions to a type of intervention, setting, or research design.

Objectives

To review the literature from the past decade on interventions with the goal of improving team effectiveness within healthcare organizations and identify the “evidence base” levels of the research.

Methods

Seven major databases were systematically searched for relevant articles published between 2008 and July 2018. Of the original search yield of 6025 studies, 297 studies met the inclusion criteria according to three independent authors and were subsequently included for analysis. The Grading of Recommendations, Assessment, Development, and Evaluation Scale was used to assess the level of empirical evidence.

Results

Three types of interventions were distinguished: (1)Training, which is sub-divided into training that is based on predefined principles (i.e. CRM: crew resource management and TeamSTEPPS: Team Strategies and Tools to Enhance Performance and Patient Safety), on a specific method (i.e. simulation), or on general team training. (2)Toolscovers tools that structure (i.e. SBAR: Situation, Background, Assessment, and Recommendation, (de)briefing checklists, and rounds), facilitate (through communication technology), or trigger (through monitoring and feedback) teamwork. (3)Organizational (re)designis about (re)designing structures to stimulate team processes and team functioning.(4) Aprogrammeis a combination of the previous types. The majority of studies evaluated a training focused on the (acute) hospital care setting. Most of the evaluated interventions focused on improving non-technical skills and provided evidence of improvements.

Conclusion

Over the last decade, the number of studies on team interventions has increased exponentially. At the same time, research tends to focus on certain interventions, settings, and/or outcomes. Principle-based training (i.e. CRM and TeamSTEPPS) and simulation-based training seem to provide the greatest opportunities for reaching the improvement goals in team functioning.
Myoepithelioma-like tumor of the vulvar region: a case report in China and review of the literature
Authors: Xu Yan , Gao Hui , Gao Jin-Li
Published: January 2020

Background

Myoepithelioma-like tumor of the vulvar region (MELTVR) is a recently described mesenchymal neoplasm which typically arising in vulvar regions of adult women.

Case presentation

Here we report a case of a 65-year-old woman who presented with a 6-year history of subcutaneous mass in the vulvar region. The mass had recently increased in size continuously. Histologically, the tumor cells had an epithelioid to spindled shape. Epithelioid tumor cells proliferated singly or in a loosely cohesive manner with myxoid areas, while spindled tumor cells grew in diffuse sheets or storiform arrangements mainly in nonmyxoid areas. Immunohistochemically, the tumor cells were positive for vimentin, epithelial membrane antigen, calponin, and were partially mild to moderate positive for estrogen receptor, but completely negative for S100 protein, glial fibrillary acidic protein, CD34, desmin, SMA and cytokeratin. INI1/SMARCB1 expression was deficient.EWSR1andFUSgenes were intact tested by fluorescence in situ hybridization analysis. Based on these findings, we diagnose this case as MELTVR. The patient remained relapse-free after the lesion was widely excised during 8 months follow-up.

Conclusions

This disease should be included in the differential diagnostic list of vulvar tumors with epithelioid to spindled morphology. Recognition of its histopathological features and immunohistochemical reactivity will help to understand the tumor better.
Impact of genetic variant of HIPK2 on the risk of severe radiation pneumonitis in lung cancer patients treated with radiation therapy
Authors: Tang Yang , Yang Li , Qin Wan , Yi Min’ Xiao , Liu Bo , Yuan Xiang’Lin
Published: January 2020

Background

Homeodomain-interacting protein kinase 2 (HIPK2) has increasingly drawn attention as recent researches demonstrated its unique role in the regulation of multiple fundamental processes such as apoptosis, proliferation and DNA damage repair. Most importantly, HIPK2 was shown to play regulatory role in inflammation and influence the phenotype and activity of fibroblasts. In this study, we aimed to evaluate the impact of HIPK2 gene variant on risk of radiation pneumonitis for patients with pulmonary malignancies.

Methods

169 lung cancer patients with radiotherapy were included in our prospective study and genotyped by Sanger Sequence method. Multivariable Cox hazard analysis and multiple testing were applied to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of all factors possibly related to the risk of radiation pneumonitis (RP).

Results

Patients with Mean Lung Dose (MLD) ≥ 15Gy, Lung V20 ≥ 24% had higher risk of RP ≥ grade 2 compared with those counterparts (HR = 1.888, 95% CI: 1.186–3.004, P = 0.007; HR = 2.126, 95% CI: 1.338–3.378, P = 0.001, respectively). Importantly, CC genotype of HIPK2: rs2030712 were strongly related to an increased occurrence of RP ≥ grade 2 (HR = 2.146, 95% CI: 1.215–3.791, P = 0.009).

Conclusion

HIPK2: rs2030712 was found to be significantly related to RP of grade ≥ 2 in our cohort, and may thus be one of the important predictors of severe RP before radiotherapy, if further validated in larger population.

Trial registration

Our study was prospective and observational. The research was registered in ClinicalTrials.gov database as NCT02490319.
Two cases of granuloma mimicking local recurrence after pulmonary segmentectomy
Authors: Okazaki Mikio , Sano Yoshifumi , Mori Yu , Sakao Nobuhiko , Yukumi Syungo , Shigematsu Hisayuki , Izutani Hironori
Published: January 2020

Background

Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT is the most sensitive non-invasive imaging method for the detection of tumor metastasis and recurrence, but sometimes reveals false-positive results. Herein, we report two cases of false-positive results on PET/CT scans along with elevated serum carcinoembryonic antigen (CEA) levels, mimicking local recurrence after pulmonary segmentectomy.

Case presentation

Case 1; A 75-year-old woman underwent thoracoscopic left basal segmentectomy for primary lung cancer. Follow-up at 6 months after the surgery revealed serum CEA level elevation and chest CT showed a nodule measuring 25 × 22 mm in the residual left lower lobe. PET/CT revealed FDG uptake in the nodule diagnosed as local recurrence of lung cancer, and the patient underwent partial resection of the nodule. Microscopic examination of the resected specimen revealed granuloma caused by polyglycolic acid (PGA) sheet. Case 2; A 58-year-old man underwent VATS right S1 segmentectomy for lung metastasis from rectal carcinoma. Serum CEA levels gradually increased after surgery, and PET/CT revealed FDG uptake in the stump diagnosed as local recurrence of the lung metastasis. The patient underwent completion lobectomy 6 months after the segmentectomy, and the pathology of the resected specimen revealed an inflammatory granuloma caused by PGA suture.

Conclusions

Although suture and stapler granulomas have been reported, granuloma caused by PGA sheets has never been reported. Postoperative recurrence of lung cancer should be diagnosed with not only PET/CT scans and serum tumor markers but also pathological findings, to avoid unnecessary treatment such as chemotherapy, radiation, and difficult reoperation.
Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model
Authors: Rice Heather C. , Marcassa Gabriele , Chrysidou Iordana , Horré Katrien , Young-Pearse Tracy L. , Müller Ulrike C. , Saito Takashi , Saido Takaomi C. , Vassar Robert , de Wit Joris , De Strooper Bart
Published: January 2020

The amyloid-β (Aβ) peptide, the primary constituent of amyloid plaques found in Alzheimer’s disease (AD) brains, is derived from sequential proteolytic processing of the Amyloid Precursor Protein (APP). However, the contribution of different cell types to Aβ deposition has not yet been examined in an in vivo, non-overexpression system. Here, we show that endogenous APP is highly expressed in a heterogeneous subset of GABAergic interneurons throughout various laminae of the hippocampus, suggesting that these cells may have a profound contribution to AD plaque pathology. We then characterized the laminar distribution of amyloid burden in the hippocampus of an APP knock-in mouse model of AD. To examine the contribution of GABAergic interneurons to plaque pathology, we blocked Aβ production specifically in these cells using a cell type-specific knock-out of BACE1. We found that during early stages of plaque deposition, interneurons contribute to approximately 30% of the total plaque load in the hippocampus. The greatest contribution to plaque load (75%) occurs in the stratum pyramidale of CA1, where plaques in human AD cases are most prevalent and where pyramidal cell bodies and synaptic boutons from perisomatic-targeting interneurons are located. These findings reveal a crucial role of GABAergic interneurons in the pathology of AD. Our study also highlights the necessity of using APP knock-in models to correctly evaluate the cellular contribution to amyloid burden since APP overexpressing transgenic models drive expression in cell types according to the promoter and integration site and not according to physiologically relevant expression mechanisms.
Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial
Authors:   on behalf of the Canadian Critical Care Trials Group, Masse Marie-Hélène , Ménard Julie , Sprague Sheila , Battista Marie-Claude , Cook Deborah J. , Guyatt Gordon H. , Heyland Daren K. , Kanji Salmaan , Pinto Ruxandra , Day Andrew G. , Cohen Dian , Annane Djillali , McGuinness Shay , Parke Rachael , Carr Anitra , Arabi Yaseen , Vijayaraghavan Bharath Kumar Tirupakuzhi , D’Aragon Frédérick , Carbonneau Élaine , Maslove David , Hunt Miranda , Rochwerg Bram , Millen Tina , Chassé Michaël , Lebrasseur Martine , Archambault Patrick , Deblois Estel , Drouin Christine , Lellouche François , Lizotte Patricia , Watpool Irene , Porteous Rebecca , Clarke France , Marinoff Nicole , Belley-Côté Émilie , Bolduc Brigitte , Walker Scott , Iazzetta John , Adhikari Neill K. J. , Lamontagne François
Published: January 2020

Background

Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28 days in patients with sepsis.

Methods

LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n = 800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24 h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6 months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned.

Discussion

This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis.

Trial registration

clinicaltrials.gov, NCT03680274, first posted 21 September 2018.
What does soil-transmitted helminth elimination look like? Results from a targeted molecular detection survey in Japan
Authors:   the DeWorm3 Project Team, Hasegawa Mitsuko , Pilotte Nils , Kikuchi Mihoko , Means Arianna R. , Papaiakovou Marina , Gonzalez Andrew M. , Maasch Jacqueline R. M. A. , Ikuno Hiroshi , Sunahara Toshihiko , Ásbjörnsdóttir Kristjana H. , Walson Judd L. , Williams Steven A. , Hamano Shinjiro
Published: January 2020

Background

Japan is one of the few countries believed to have eliminated soil-transmitted helminths (STHs). In 1949, the national prevalence of Ascaris lumbricoides was 62.9%, which decreased to 0.6% in 1973 due to improvements in infrastructure, socioeconomic status, and the implementation of national STH control measures. The Parasitosis Prevention Law ended in 1994 and population-level screening ceased in Japan; therefore, current transmission status of STH in Japan is not well characterized. Sporadic cases of STH infections continue to be reported, raising the possibility of a larger-scale recrudescence of STH infections. Given that traditional microscopic detection methods are not sensitive to low-intensity STH infections, we conducted targeted prevalence surveys using sensitive PCR-based assays to evaluate the current STH-transmission status and to describe epidemiological characteristics of areas of Japan believed to have achieved historical elimination of STHs.

Methods

Stool samples were collected from 682 preschool- and school-aged children from six localities of Japan with previously high prevalence of STH. Caregivers of participants completed a questionnaire to ascertain access to water, sanitation and hygiene (WASH), and potential exposures to environmental contamination. For fecal testing, multi-parallel real-time PCR assays were used to detect infections of Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale and Trichuris trichiura.

Results

Among the 682 children, no positive samples were identified, and participants reported high standards of WASH.

Conclusions

To our knowledge, this is the first STH-surveillance study in Japan to use sensitive molecular techniques for STH detection. The results suggest that recrudescence of STH infections has not occurred, and that declines in prevalence have been sustained in the sampled areas. These findings suggest that reductions in prevalence below the elimination thresholds, suggestive of transmission interruption, are possible. Additionally, this study provides circumstantial evidence that multi-parallel real-time PCR methods are applicable for evaluating elimination status in areas where STH prevalence is extremely low.
Global evaluation of taxonomic relationships and admixture within the Culex pipiens complex of mosquitoes
Authors: Aardema Matthew L. , vonHoldt Bridgett M. , Fritz Megan L. , Davis Steven R.
Published: January 2020

Background

Within theCulex pipiensmosquito complex, there are six contemporarily recognized taxa:Cx.quinquefasciatus,Cx.pipiensf.pipiens,Cx.pipiensf.molestus,Cx.pipiens pallens,Cx.australicusandCx.globocoxitus. Many phylogenetic aspects within this complex have eluded resolution, such as the relationship of the two Australian endemic taxa to the other four members, as well as the evolutionary origins and taxonomic status ofCx.pipiens pallensandCx.pipiensf.molestus. Ultimately, insights into lineage relationships within the complex will facilitate a better understanding of differential disease transmission by these mosquitoes. To this end, we have combined publicly available data with our own sequencing efforts to examine these questions.

Results

We found that the two Australian endemic complex members,Cx.australicusandCx.globocoxitus, comprise a monophyletic group, are genetically distinct, and are most closely related to the cosmopolitanCx.quinquefasciatus. Our results also show thatCx.pipiens pallensis genetically distinct, but may have arisen from past hybridization. Lastly, we observed complicated patterns of genetic differentiation within and betweenCx.pipiensf.pipiensandCx.pipiensf.molestus.

Conclusions

Two Australian endemicCulextaxa,Cx.australicusandCx.globocoxitus, belong within theCx. pipienscomplex, but have a relatively older evolutionary origin. They likely diverged fromCx.quinquefasciatusafter its colonization of Australia. The taxonCx.pipiens pallensis a distinct evolutionary entity that likely arose from past hybridization betweenCx.quinquefasciatusandCx.pipiensf.pipiens/Cx. pipiensf.molestus. Our results do not suggest it derives from ongoing hybridization. Finally, genetic differentiation within theCx.pipiensf.pipiensandCx.pipiensf.molestussamples suggests that they collectively form two separate geographic clades, one in North America and one in Europe and the Mediterranean. This may indicate that theCx.pipiensf.molestusform has two distinct origins, arising fromCx.pipiensf.pipiensin each region. However, ongoing genetic exchange within and between these taxa have obscured their evolutionary histories, and could also explain the absence of monophyly among our samples. Overall, this work suggests many avenues that warrant further investigation.
Statin-induced anti-HMGCR myopathy: successful therapeutic strategies for corticosteroid-free remission in 55 patients
Authors: Meyer Alain , Troyanov Yves , Drouin Julie , Oligny-Longpré Geneviève , Landon-Cardinal Océane , Hoa Sabrina , Hervier Baptiste , Bourré-Tessier Josiane , Mansour Anne-Marie , Hussein Sara , Morin Vincent , Rich Eric , Goulet Jean-Richard , Chartrand Sandra , Hudson Marie , Nehme Jessica , Makhzoum Jean-Paul , Zarka Farah , Villeneuve Edith , Raynauld Jean-Pierre , Landry Marianne , O’Ferrall Erin K. , Ferreira Jose , Ellezam Benjamin , Karamchandani Jason , Larue Sandrine , Massie Rami , Isabelle Catherine , Deschênes Isabelle , Leclair Valérie , Couture Hélène , Targoff Ira N. , Fritzler Marvin J. , Senécal Jean-Luc
Published: January 2020

Objective

To describe successful therapeutic strategies in statin-induced anti-HMGCR myopathy.

Methods

Retrospective data from a cohort of 55 patients with statin-induced anti-HMGCR myopathy, sequentially stratified by the presence of proximal weakness, early remission, and corticosteroid and IVIG use at treatment induction, were analyzed for optimal successful induction and maintenance of remission strategies.

Results

A total of 14 patients achieved remission with a corticosteroid-free induction strategy (25%). In 41 patients treated with corticosteroids, only 4 patients (10%) failed an initial triple steroid/IVIG/steroid-sparing immunosuppressant (SSI) induction strategy. Delay in treatment initiation was independently associated with lower odds of successful maintenance with immunosuppressant monotherapy (OR 0.92, 95% CI 0.85 to 0.97, P = 0.015). While 22 patients (40%) presented with normal strength, only 9 had normal strength at initiation of treatment.

Conclusion

While corticosteroid-free treatment of anti-HMGCR myopathy is now a safe option in selected cases, initial triple steroid/IVIG/SSI was very efficacious in induction. Delays in treatment initiation and, as a corollary, delays in achieving remission decrease the odds of achieving successful maintenance with an SSI alone. Avoiding such delays, most notably in patients with normal strength, may reset the natural history of anti-HMGCR myopathy from a refractory entity to a treatable disease.
Carvacrol ameliorates acute campylobacteriosis in a clinical murine infection model
Authors: Mousavi Soraya , Schmidt Anna-Maria , Escher Ulrike , Kittler Sophie , Kehrenberg Corinna , Thunhorst Elisa , Bereswill Stefan , Heimesaat Markus M.
Published: January 2020

Background

The prevalence of human infections with the zoonotic pathogen Campylobacter jejuni is rising worldwide. Therefore, the identification of compounds with potent anti-pathogenic and anti-inflammatory properties for future therapeutic and/or preventive application to combat campylobacteriosis is of importance for global health. Results of recent studies suggested carvacrol (4-isopropyl-2-methylphenol) as potential candidate molecule for the treatment of campylobacteriosis in humans and for the prevention of Campylobacter colonization in farm animals.

Results

To address this in a clinical murine infection model of acute campylobacteriosis, secondary abiotic IL-10−/− mice were subjected to synthetic carvacrol via the drinking water starting 4 days before peroral C. jejuni challenge. Whereas at day 6 post-infection placebo treated mice suffered from acute enterocolitis, mice from the carvacrol cohort not only harbored two log orders of magnitude lower pathogen loads in their intestines, but also displayed significantly reduced disease symptoms. Alleviated campylobacteriosis following carvacrol application was accompanied by less distinct intestinal apoptosis and pro-inflammatory immune responses as well as by higher numbers of proliferating colonic epithelial cells. Remarkably, the inflammation-ameliorating effects of carvacrol treatment were not restricted to the intestinal tract, but could also be observed in extra-intestinal organs such as liver, kidneys and lungs and, strikingly, systemically as indicated by lower IFN-γ, TNF, MCP-1 and IL-6 serum concentrations in carvacrol versus placebo treated mice. Furthermore, carvacrol treatment was associated with less frequent translocation of viable C. jejuni originating from the intestines to extra-intestinal compartments.

Conclusion

The lowered C. jejuni loads and alleviated symptoms observed in the here applied clinical murine model for human campylobacteriosis highlight the application of carvacrol as a promising novel option for both, the treatment of campylobacteriosis and hence, for prevention of post-infectious sequelae in humans, and for the reduction of C. jejuni colonization in the intestines of vertebrate lifestock animals.
Characterization of Arcobacter strains isolated from human stool samples: results from the prospective German prevalence study Arcopath
Authors: Brückner Vanessa , Fiebiger Ulrike , Ignatius Ralf , Friesen Johannes , Eisenblätter Martin , Höck Marlies , Alter Thomas , Bereswill Stefan , Heimesaat Markus M. , Gölz Greta
Published: January 2020

Background

Arcobacter constitute emerging food- and waterborne pathogens causing gastroenteritis in humans, but the underlying mechanisms are only incompletely understood. We therefore characterized Arcobacter isolates derived from human stool samples that had been collected during a prospective prevalence study in Germany in vitro. Thirty-six bacterial isolates belonging to the species A. butzleri (n = 24), A. cryaerophilus (n = 10) and A. lanthieri (n = 2) were genotyped by ERIC-PCR, the presence of 10 putative virulence genes was assessed and cytotoxic effects on the human intestinal cell line HT-29/B6 were analyzed applying the WST-assay.

Results

Genotyping revealed high genetic diversity within the species A. butzleri, A. cryaerophilus and A. lanthieri. Both, A. butzleri and A. lanthieri encoded for a large number of putative virulence genes, while fewer genes were detectable in A. cryaerophilus isolates. Notably, the three cytolethal distending toxin (CDT) genes cdtA, cdtB and cdtC were abundant in both A. lanthieri isolates. Furthermore, all A. butzleri and A. lanthieri, but only one of the A. cryaerophilus isolates exerted cytotoxic effects.

Conclusions

Our study provides evidence for the abundance of putative virulence genes in Arcobacter isolates and prominent cytotoxic effects of A. butzleri and A. lanthieri in vitro. The presence of cdtA, cdtB, cdtC in A. lanthieri points towards CDT secretion as potential mechanism underlying cytotoxicity as opposed to A. butzleri. However, the association of the Arcobacter virulence factors detected and human morbidity should be addressed in future studies.
Epigenome-wide association study of seizures in childhood and adolescence
Authors: Caramaschi Doretta , Hatcher Charlie , Mulder Rosa H. , Felix Janine F. , Cecil Charlotte A. M. , Relton Caroline L. , Walton Esther
Published: January 2020

The occurrence of seizures in childhood is often associated with neurodevelopmental impairments and school underachievement. Common genetic variants associated with epilepsy have been identified and epigenetic mechanisms have also been suggested to play a role. In this study, we analyzed the association of genome-wide blood DNA methylation with the occurrence of seizures in ~ 800 children from the Avon Longitudinal Study of Parents and Children, UK, at birth (cord blood), during childhood, and adolescence (peripheral blood). We also analyzed the association between the lifetime occurrence of any seizures before age 13 with blood DNA methylation levels. We sought replication of the findings in the Generation R Study and explored causality using Mendelian randomization, i.e., using genetic variants as proxies. The results showed five CpG sites which were associated cross-sectionally with seizures either in childhood or adolescence (1–5% absolute methylation difference at pFDR< 0.05), although the evidence of replication in an independent study was weak. One of these sites was located in theBDNFgene, which is highly expressed in the brain, and showed high correspondence with brain methylation levels. The Mendelian randomization analyses suggested that seizures might be causal for changes in methylation rather than vice-versa. In conclusion, we show a suggestive link between seizures and blood DNA methylation while at the same time exploring the limitations of conducting such study.