bluuebunny/crossref_metadata_2025 huggingface dataset:
The diabetic microenvironment causes mitochondrial oxidative stress in glomerular endothelial cells and pathological crosstalk with podocytes
Authors: Casalena Gabriella A. , Yu Liping , Gil Roberto , Rodriguez Samuel , Sosa Shantel , Janssen William , Azeloglu Evren U. , Leventhal Jeremy S. , Daehn Ilse S.
Published: July 2020

Background

In the setting of diabetes mellitus, mitochondrial dysfunction and oxidative stress are important pathogenic mechanisms causing end organ damage, including diabetic kidney disease (DKD), but mechanistic understanding at a cellular level remains obscure. In mouse models of DKD, glomerular endothelial cell (GEC) dysfunction precedes albuminuria and contributes to neighboring podocyte dysfunction, implicating GECs in breakdown of the glomerular filtration barrier. In the following studies we wished to explore the cellular mechanisms by which GECs become dysfunctional in the diabetic milieu, and the impact to neighboring podocytes.

Methods

Mouse GECs were exposed to high glucose media (HG) or 2.5% v/v serum from diabetic mice or serum from non-diabetic controls, and evaluated for mitochondrial function (oxygen consumption), structure (electron microscopy), morphology (mitotracker), mitochondrial superoxide (mitoSOX), as well as accumulation of oxidized products (DNA lesion frequency (8-oxoG, endo-G), double strand breaks (γ-H2AX), endothelial function (NOS activity), autophagy (LC3) and apoptotic cell death (Annexin/PI; caspase 3). Supernatant transfer experiments from GECs to podocytes were performed to establish the effects on podocyte survival and transwell experiments were performed to determine the effects in co-culture.

Results

Diabetic serum specifically causes mitochondrial dysfunction and mitochondrial superoxide release in GECs. There is a rapid oxidation of mitochondrial DNA and loss of mitochondrial biogenesis without cell death. Many of these effects are blocked by mitoTEMPO a selective mitochondrial anti-oxidant. Secreted factors from dysfunctional GECs were sufficient to cause podocyte apoptosis in supernatant transfer experiments, or in co-culture but this did not occur when GECs had been previously treated with mitoTEMPO.

Conclusion

Dissecting the impact of the diabetic environment on individual cell-types from the kidney glomerulus indicates that GECs become dysfunctional and pathological to neighboring podocytes by increased levels of mitochondrial superoxide in GEC. These studies indicate that GEC-signaling to podocytes contributes to the loss of the glomerular filtration barrier in DKD.

Graphical abstract
The brains of aged mice are characterized by altered tissue diffusion properties and cerebral microbleeds
Authors: Taylor Erik N. , Huang Nasi , Wisco Jonathan , Wang Yandan , Morgan Kathleen G. , Hamilton James A.
Published: July 2020

Background

Brain aging is a major risk factor in the progression of cognitive diseases including Alzheimer’s disease (AD) and vascular dementia. We investigated a mouse model of brain aging up to 24 months old (mo).

Methods

A high field (11.7T) MRI protocol was developed to characterize specific features of brain aging including the presence of cerebral microbleeds (CMBs), morphology of grey and white matter, and tissue diffusion properties. Mice were selected from age categories of either young (3 mo), middle-aged (18 mo), or old (24 mo) and fed normal chow over the duration of the study. Mice were imaged in vivo with multimodal MRI, including conventional T2-weighted (T2W) and T2*-weighted (T2*W) imaging, followed by ex vivo diffusion-weighted imaging (DWI) and T2*W MR-microscopy to enhance the detection of microstructural features.

Results

Structural changes observed in the mouse brain with aging included reduced cortical grey matter volume and enlargement of the brain ventricles. A remarkable age-related change in the brains was the development of CMBs found starting at 18 mo and increasing in total volume at 24 mo, primarily in the thalamus. CMBs presence was confirmed with high resolution ex vivo MRI and histology. DWI detected further brain tissue changes in the aged mice including reduced fractional anisotropy, increased radial diffusion, increased mean diffusion, and changes in the white matter fibers visualized by color-coded tractography, including around a large cortical CMB.

Conclusions

The mouse is a valuable model of age-related vascular contributions to cognitive impairment and dementia (VCID). In composite, these methods and results reveal brain aging in older mice as a multifactorial process including CMBs and tissue diffusion alterations that can be well characterized by high field MRI.
Count data regression modeling: an application to spontaneous abortion
Authors: Verma Prashant , Swain Prafulla Kumar , Singh Kaushalendra Kumar , Khetan Mukti
Published: July 2020

Background

In India, around 20,000 women die every year due to abortion-related complications. In count data modeling, there is sometimes a prevalence of zero counts. This article is concerned with the estimation of various count regression models to predict the average number of spontaneous abortions among women in Punjab and few northern states in India. The study also assesses the factors associated with the number of spontaneous abortions.

Methods

This study includes 27,173 married women of Punjab obtained from the DLHS-4 survey (2012–13) to train the count models. The study predicts the average number of spontaneous abortions using various count regression models, and also identifies the determinants affecting the spontaneous abortions. Further, the best model is validated with other northern states of India using the latest data (NFHS-4, 2015–16).

Results

Statistical comparisons among four estimation methods reveals that the ZINB model provides the best prediction for the number of spontaneous abortions. The study suggests total children born to a woman, antenatal care (ANC) place, place of residence, woman’s education, and economic status are the most significant factors affecting the instance of spontaneous abortion.

Conclusions

This article offers a practical demonstration of techniques designed to handle count outcome variables. The statistical comparisons among four estimation models revealed that the ZINB model provides the best prediction for the number of spontaneous abortions, and it suggests policymakers to use this model to predict the number of spontaneous abortions. The study recommends promoting higher education among women in Punjab and other northern states of India. It also suggests that women must receive institutional antenatal care and have a limited number of children.
Transcranial direct current stimulation (tDCS) for improving aphasia after stroke: a systematic review with network meta-analysis of randomized controlled trials
Authors: Elsner Bernhard , Kugler Joachim , Mehrholz Jan
Published: July 2020

Background

Transcranial Direct Current Stimulation (tDCS) is an emerging approach for improving aphasia after stroke. However, it remains unclear what type of tDCS stimulation is most effective. Our aim was to give an overview of the evidence network regarding the efficacy and safety of tDCS and to estimate the effectiveness of the different stimulation types.

Methods

This is a systematic review of randomized controlled trials with network meta-analysis (NMA). We searched the following databases until 4 February 2020: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, Web of Science, and four other databases. We included studies with adult people with stroke. We compared any kind of active tDCS (anodal, cathodal, or dual, that is applying anodal and cathodal tDCS concurrently) regarding improvement of our primary outcome of functional communication, versus control, after stroke. PROSPERO ID: CRD42019135696.

Results

We included 25 studies with 471 participants. Our NMA showed that tDCS did not improve our primary outcome, that of functional communication. There was evidence of an effect of anodal tDCS, particularly over the left inferior frontal gyrus, in improving our secondary outcome, that of performance in naming nouns (SMD = 0.51; 95% CI 0.11 to 0.90). There was no difference in safety between tDCS and its control interventions, measured by the number of dropouts and adverse events.

Conclusion

Comparing different application/protocols of tDCS shows that the anodal application, particularly over the left inferior frontal gyrus, seems to be the most promising tDCS treatment option to improve performance in naming in people with stroke.
Longitudinal transcriptomic characterization of viral genes in HSV-1 infected tree shrew trigeminal ganglia
Authors: Wang Erlin , Ye Yunshuang , Zhang Ke , Yang Jinlong , Gong Daohua , Zhang Jianhua , Hong Renjun , Zhang Huan , Li Lihong , Chen Guijun , Yang Liping , Liu Jianmei , Cao Hanyu , Du Ting , Fraser Nigel W. , Cheng Le , Cao Xia , Zhou Jumin
Published: July 2020

Background

Following acute infection, Herpes Simplex virus-1 (HSV-1) establishes lifelong latency and recurrent reactivation in the sensory neurons of trigeminal ganglia (TG). Infected tree shrew differs from mouse and show characteristics similar to human infection. A detailed transcriptomic analysis of the tree shrew model could provide mechanistic insights into HSV-1 infection in humans.

Methods

We sequenced the transcriptome of infected TGs from tree shrews and mice, and 4 human donors, then examined viral genes expression up to 58 days in infected TGs from mouse and tree shrew, and compare the latency data with that in human TGs.

Results

Here, we found that all HSV-1 genes could be detected in mouse TGs during acute infection, but 22 viral genes necessary for viral transcription, replication and viral maturation were not expressed in tree shrew TGs during this stage. Importantly, during latency, we found that LAT could be detected both in mouse and tree shrew, but the latter also has an ICP0 transcript signal absent in mouse but present in human samples. Importantly, we observed that infected human and tree shrew TGs have a more similar LAT region transcription peak. More importantly, we observed that HSV-1 spontaneously reactivates from latently infected tree shrews with relatively high efficiency.

Conclusions

These results represent the first longitudinal transcriptomic characterization of HSV-1 infection in during acute, latency and recurrent phases, and revealed that tree shrew infection has important similar features with human infection.
A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis
Authors: Coelho Teresa , Adams David , Conceição Isabel , Waddington-Cruz Márcia , Schmidt Hartmut H. , Buades Juan , Campistol Josep , Berk John L. , Polydefkis Michael , Wang Jing Jing , Chen Jihong , Sweetser Marianne T. , Gollob Jared , Suhr Ole B.
Published: July 2020

Background

Patisiran, an RNA interference therapeutic, has demonstrated robust reduction of wild-type and mutant transthyretin protein and was able to improve polyneuropathy and quality of life following 18 months of treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis.In this 24-month Phase II open-label extension study, we evaluated the effects of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) on safety, serum transthyretin levels, and clinical parameters. Efficacy assessments included modified Neuropathy Impairment Score +7 (mNIS+7) and multiple disease-relevant measures. Cardiac assessments were performed in a pre-specified cardiac subgroup.

Results

Twenty-seven patients entered this study, including 12 (44%) with ambulation difficulties due to their neuropathy and 11 (41%) who met criteria for the cardiac subgroup. During treatment, the majority of adverse events were mild/moderate in severity; there were no drug-related adverse events leading to treatment discontinuation. The most common drug-related adverse events were flushing and infusion-related reactions (22% each). Patisiran resulted in rapid, robust (~ 82%), and sustained reduction of mean transthyretin levels over 24 months. A mean 6.95-point decrease (improvement) in mNIS+7 from baseline was observed at 24 months. Patisiran’s impact on mNIS+7 was irrespective of concomitant tafamidis or diflunisal use, sex, or age. Clinical assessments of motor function, autonomic symptoms, disease stage, and quality of life remained stable over 24 months. No significant changes were observed for echocardiographic measures or cardiac biomarkers in the cardiac subgroup. Exploratory analyses demonstrated improvements in nerve-fiber density with corresponding reductions in amyloid burden observed in skin biopsies over 24 months.

Conclusions

Long-term treatment with patisiran had an acceptable safety profile and was associated with halting/improvement of polyneuropathy progression in patients with hATTR amyloidosis.

Trial registration

The study was registered atClinicalTrials.gov(identifier:NCT01961921) on October 14, 2013.
Exome sequencing for diagnosis of congenital hemolytic anemia
Authors: Mansour-Hendili Lamisse , Aissat Abdelrazak , Badaoui Bouchra , Sakka Mehdi , Gameiro Christine , Ortonne Valérie , Wagner-Ballon Orianne , Pissard Serge , Picard Véronique , Ghazal Khaldoun , Bahuau Michel , Guitton Corinne , Mansour Ziad , Duplan Mylène , Petit Arnaud , Costedoat-Chalumeau Nathalie , Michel Marc , Bartolucci Pablo , Moutereau Stéphane , Funalot Benoît , Galactéros Frédéric
Published: July 2020

Background

Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis.

Results

A probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients.

Conclusion

The rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients’ healthcare and probably has to be democratized notably for complex cases.
Merging microarray studies to identify a common gene expression signature to several structural heart diseases
Authors: Fajarda Olga , Duarte-Pereira Sara , Silva Raquel M. , Oliveira José Luís
Published: July 2020

Background

Heart disease is the leading cause of death worldwide. Knowing a gene expression signature in heart disease can lead to the development of more efficient diagnosis and treatments that may prevent premature deaths. A large amount of microarray data is available in public repositories and can be used to identify differentially expressed genes. However, most of the microarray datasets are composed of a reduced number of samples and to obtain more reliable results, several datasets have to be merged, which is a challenging task. The identification of differentially expressed genes is commonly done using statistical methods. Nonetheless, these methods are based on the definition of an arbitrary threshold to select the differentially expressed genes and there is no consensus on the values that should be used.

Results

Nine publicly available microarray datasets from studies of different heart diseases were merged to form a dataset composed of 689 samples and 8354 features. Subsequently, the adjustedp-value and fold change were determined and by combining a set of adjustedp-values cutoffs with a list of different fold change thresholds, 12 sets of differentially expressed genes were obtained. To select the set of differentially expressed genes that has the best accuracy in classifying samples from patients with heart diseases and samples from patients with no heart condition, the random forest algorithm was used. A set of 62 differentially expressed genes having a classification accuracy of approximately 95% was identified.

Conclusions

We identified a gene expression signature common to different cardiac diseases and supported our findings by showing their involvement in the pathophysiology of the heart. The approach used in this study is suitable for the identification of gene expression signatures, and can be extended to different diseases.
Prone positioning in severe ARDS requiring extracorporeal membrane oxygenation
Authors: Rilinger Jonathan , Zotzmann Viviane , Bemtgen Xavier , Schumacher Carin , Biever Paul M. , Duerschmied Daniel , Kaier Klaus , Stachon Peter , von zur Mühlen Constantin , Zehender Manfred , Bode Christoph , Staudacher Dawid L. , Wengenmayer Tobias
Published: July 2020

Background

Prone positioning (PP) has shown to improve survival in patients with severe acute respiratory distress syndrome (ARDS). To this point, it is unclear if PP is also beneficial for ARDS patients treated with veno-venous extracorporeal membrane oxygenation (VV ECMO) support.

Methods

We report retrospective data of a single-centre registry of patients with severe ARDS requiring VV ECMO support between October 2010 and May 2018. Patients were allocated to the PP group if PP was performed during VV ECMO treatment or the supine positioning group. VV ECMO weaning success and hospital survival were analysed before and after propensity score matching.

Results

A total of 158 patients could be analysed, and 38 patients (24.1%) received PP. There were no significant differences in VV ECMO weaning rate (47.4% vs. 46.7%, p = 0.94) and hospital survival (36.8% vs. 36.7%, p = 0.98) between the prone and supine groups, respectively. The analysis of 38 propensity score matched pairs also showed no difference in hospital survival (36.8% vs. 36.8%, p = 1.0) or VV ECMO weaning rate (47.4% vs. 44.7%, p = 0.82). Hospital survival was superior in the subgroup of patients treated with early PP (cutoff < 17 h via Youden’s Index) as compared to late or no PP (81.8% vs. 33.3%, p = 0.02).

Conclusion

In this propensity score matched cohort of severe ARDS patients requiring VV ECMO support, prone positioning at any time was not associated with improved weaning or survival. However, early initiation of prone positioning was linked to a significant reduction of hospital mortality.
Outcome reporting recommendations for clinical trial protocols and reports: a scoping review
Authors: Butcher Nancy J. , Mew Emma J. , Monsour Andrea , Chan An-Wen , Moher David , Offringa Martin
Published: July 2020

Background

Clinicians, patients, and policy-makers rely on published evidence from clinical trials to help inform decision-making. A lack of complete and transparent reporting of the investigated trial outcomes limits reproducibility of results and knowledge synthesis efforts, and contributes to outcome switching and other reporting biases. Outcome-specific extensions for the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT-Outcomes) and Consolidated Standards of Reporting Trials (CONSORT-Outcomes) reporting guidelines are under development to facilitate harmonized reporting of outcomes in trial protocols and reports. The aim of this review was to identify and synthesize existing guidance for trial outcome reporting to inform extension development.

Methods

We searched for documents published in the last 10 years that provided guidance on trial outcome reporting using: an electronic bibliographic database search (MEDLINE and the Cochrane Methodology Register); a grey literature search; and solicitation of colleagues using a snowballing approach. Two reviewers completed title and abstract screening, full-text screening, and data charting after training. Extracted trial outcome reporting guidance was compared with candidate reporting items to support, refute, or refine the items and to assess the need for the development of additional items.

Results

In total, 1758 trial outcome reporting recommendations were identified within 244 eligible documents. The majority of documents were published by academic journals (72%). Comparison of each recommendation with the initial list of 70 candidate items led to the development of an additional 62 items, producing 132 candidate items. The items encompassed outcome selection, definition, measurement, analysis, interpretation, and reporting of modifications between trial documents. The total number of documents supporting each candidate item ranged widely (median 5, range 0–84 documents per item), illustrating heterogeneity in the recommendations currently available for outcome reporting across a large and diverse sample of sources.

Conclusions

Outcome reporting guidance for clinical trial protocols and reports lacks consistency and is spread across a large number of sources that may be challenging to access and implement in practice. Evidence and consensus-based guidance, currently in development (SPIRIT-Outcomes and CONSORT-Outcomes), may help authors adequately describe trial outcomes in protocols and reports transparently and completely to help reduce avoidable research waste.
Efficacy of chloroquine versus lopinavir/ritonavir in mild/general COVID-19 infection: a prospective, open-label, multicenter, randomized controlled clinical study
Authors: Liu Xi , Chen Huili , Shang Yuqi , Zhu Hongqiong , Chen Gongqi , Chen Yuanli , Liu Shaoxuan , Zhou Yaoyong , Huang Mingxing , Hong Zhongsi , Xia Jinyu
Published: July 2020

Background

The outbreak of COVID-19 (caused by SARS-Cov-2) is very serious, and no effective antiviral treatment has yet been confirmed. The adage “old drug, new trick” in this context may suggest the important therapeutic potential of existing drugs. We found that the lopinavir/ritonavir treatment recommended in the fifth edition of the Treatment Plan of China can only help to improve a minority of throat-swab nucleic-acid results (3/15) in hospitals. Our previous use of chloroquine to treat patients with COVID-19 infection showed an improvement in more throat-swab nucleic-acid results (5/10) than the use of lopinavir/ritonavir.

Methods/design

This is a prospective, open-label, randomized controlled, multicenter clinical study. The study consists of three phases: a screening period, a treatment period of no more than 10 days, and a follow-up period for each participant. Participants with COVID-19 infection who are eligible for selection for the study will be randomly allocated to the trial group or the control group. The control group will be given lopinavir/ritonavir treatment for no more than 10 days. The trial group will be given chloroquine phosphate treatment for no more than 10 days. The primary outcome is the clinical recovery time at no more than 28 days after the completion of therapy and follow-up. The secondary outcomes include the rate of treatment success after the completion of therapy and follow-up, the time of treatment success after no more than 28 days, the rate of serious adverse events during the completion of therapy and follow-up, and the time to return to normal temperature (calculated from the onset of illness) during the completion of therapy and follow-up. Comparisons will be performed using two-sided tests with a statistical significance level of 5%.

Discussion

This experiment should reveal the efficacy and safety of using chloroquine versus lopinavir/ritonavir for patients with mild/general COVID-19 infection. If the new treatment including chloroquine shows a higher rate of throat-swab SARS-CoV-2 real-time fluorescent reverse transcription polymerase chain reaction (RT-PCR) negativity and is safe, it could be tested as a future COVID-19 treatment.

Trial registration

Chinese Clinical Trial Registry, ID: ChiCTR2000029741. Registered on 11 February 2020.
Generate-Boost: study protocol for a prospective, multicenter, randomized controlled, double-blinded phase II trial to evaluate efficacy and safety of bortezomib in patients with severe autoimmune encephalitis
Authors: Wickel Jonathan , Chung Ha-Yeun , Platzer Stephanie , Lehmann Thomas , Prüss Harald , Leypoldt Frank , Günther Albrecht , Scherag André , Geis Christian ,   on behalf of the GENERATE Study Group
Published: July 2020

Background

Autoimmune encephalitis is a new spectrum of autoimmune disorders of the central nervous system (CNS), which are characterized by pathogenic autoantibodies against neuronal surface antigens. Clinical presentations range from acute to subacute encephalopathy with neurological and psychiatric symptoms, and life-threatening autonomic dysfunction in severe cases. There exist no approved therapies nor is data available from controlled clinical trials. Patients are usually treated with diverse combinations of immunotherapy. However, effect of immunotherapy on antibody-producing cells and thus on levels of pathogenic autoantibodies is insufficient. Therefore, therapeutic response is sometimes prolonged with necessity of long-time intensive care treatment and also irreversible deficits occur in severe cases. This trial will investigate the efficacy and safety of bortezomib, a proteasome inhibitor known to selectively deplete plasma cells, in patients with severe autoimmune encephalitis who have been treated with rituximab with insufficient response.

Methods

Generate-Boost is an investigator-initiated, multicenter, double-blinded, randomized controlled phase II trial which will be conducted in specialized neurological hospitals within the GENERATE (GErman NEtwork for Research on AuToimmune Encephalitis) network in Germany. Adult patients with severe autoimmune encephalitis (modified Rankin scale, mRS ≥ 3), autoantibodies against neuronal surface antigens, and pretreatment with rituximab are eligible for study participation. Fifty patients will be randomized 1:1 and undergo up to 3 cycles (each 21 days with 4 s. c. applications) of bortezomib or placebo. All patients will receive concomitant medication with dexamethasone, acyclovir and co-trimoxazole. The primary efficacy endpoint is the mRS score 17 weeks after first treatment application. Secondary endpoints are neurocognitive function, antibody titers, markers of neuronal cell damage, length of ICU/hospital stay, and mRS and Glasgow coma scale scores throughout the trial up to week 17. General and bortezomib-specific adverse events are monitored continuously.

Discussion

The expected outcome of the study is to obtain first reliable data on a hypothesis-driven therapeutic option in severe and difficult-to-treat autoimmune encephalitis. If treatment with bortezomib is beneficial in these cases, this will be the basis for implementation in the current guidelines.

Trial registration

Clinicaltrials.gov, NCT03993262. Registered June 20, 2019;

German Clinical Trials Register, DRKS00017497.
Impacts of chest compression cycle length and real-time feedback with a CPRmeter® on chest compression quality in out-of-hospital cardiac arrest: study protocol for a multicenter randomized controlled factorial plan trial
Authors: Buléon Clément , Parienti Jean-Jacques , Morilland-Lecoq Elodie , Halbout Laurent , Cesaréo Eric , Dubien Pierre-Yves , Jardel Benoit , Boyer Christophe , Husson Kévin , Andriamirado Florian , Benet Xavier , Morel-Marechal Emmanuel , Aubrion Antoine , Muntean Catalin , Dupire Erwan , Roupie Eric , Hubert Hervé , Vilhelm Christian , Gueugniaud Pierre-Yves ,   on behalf of the CILICA-HS study group
Published: July 2020

Background

With a survival rate of 6 to 11%, out-of-hospital cardiac arrest (OHCA) remains a healthcare challenge with room for improvement in morbidity and mortality. The guidelines emphasize the highest possible quality of cardiopulmonary resuscitation (CPR) and chest compressions (CC). It is essential to minimize CC interruptions, and therefore increase the chest compression fraction (CCF), as this is an independent factor for survival. Survival is significantly and positively correlated with the suitability of CCF targets, CC frequency, CC depth, and brief predefibrillation pause. CC guidance improves adherence to recommendations and allows closer alignment with the CC objectives. The possibility of improving CCF by lengthening the time between two CC relays and the effect of real-time feedback on the quality of the CC must be investigated.

Methods

Using a 2 × 2 factorial design in a multicenter randomized trial, two hypotheses will be tested simultaneously: (i) a 4-min relay rhythm improves the CCF (reducing the no-flow time) compared to the currently recommended 2-min relay rate, and (ii) a guiding tool improves the quality of CC. Primary outcomes (i) CCF and (ii) correct compression score will be recorded by a real-time feedback device. Five hundred adult nontraumatic OHCAs will be included over 2 years. Patients will be randomized in a 1:1:1:1 distribution receiving advanced CPR as follows: 2-min blind, 2 min with guidance, 4-min blind, or 4 min with guidance. Secondary outcomes are the depth, frequency, and release of CC; length (care, no-flow, and low-flow); rate of return of spontaneous circulation; characteristics of advanced CPR; survival at hospital admission; survival and neurological state on days 1 and 30 (or intensive care discharge); and dosage of neuron-specific enolase on days 1 and 3.

Discussion

This study will contribute to assessing the impact of real-time feedback on CC quality in practical conditions of OHCA resuscitation. It will also provide insight into the feasibility of extending the relay rhythm between two rescuers from the currently recommended 2 to 4 min.

Trial registration

ClinicalTrials.gov, NCT03817892. Registered on 28 January 2019
Azithromycin added to hydroxychloroquine for patients admitted to intensive care due to coronavirus disease 2019 (COVID-19)—protocol of randomised controlled trial AZIQUINE-ICU
Authors: Duška František , Waldauf Petr , Halačová Milada , Zvoníček Václav , Bala Jakub , Balík Martin , Beneš Jan , Klementová Olga , Kozáková Irena , Kubricht Viktor , Le Roy Anne , Vymazal Tomáš , Řehořová Veronika , Černý Vladimír ,   on behalf of Czech Anaesthesia Clinical Trials and Audit Network
Published: July 2020

Background

Novel coronavirus SARS-CoV-2 is known to be susceptible in vitro to exposure to hydroxychloroquine and its effect has been found to be potentiated by azithromycin. We hypothesise that early administration of hydroxychloroquine alone or in combination with azithromycin can prevent respiratory deterioration in patients admitted to intensive care due to rapidly progressive COVID-19 infection.

Methods

Design: Prospective, multi-centre, double-blind, randomised, controlled trial (RCT). Participants: Adult (> 18 years) within 24 h of admission to the intensive care unit with proven or suspected COVID-19 infection, whether or not mechanically ventilated. Exclusion criteria include duration symptoms of febrile disease for ≥ 1 week, treatment limitations in place or moribund patients, allergy or intolerance of any study treatment, and pregnancy. Interventions: Patients will be randomised in 1:1:1 ratio to receive Hydroxychloroquine 800 mg orally in two doses followed by 400 mg daily in two doses and azithromycin 500 mg orally in one dose followed by 250 mg in one dose for a total of 5 days (HC-A group) or hydroxychloroquine + placebo (HC group) or placebo + placebo (C-group) in addition to the best standard of care, which may evolve during the trial period but will not differ between groups. Primary outcome is the composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14. Secondary outcomes: The percentage of patients who were prevented from needing intubation until day 14, ICU length of stay, and mortality (in hospital) at day 28 and 90.

Discussion

Although both investigational drugs are often administered off label to patients with severe COVID-19, at present, there is no data from RCTs on their safety and efficacy. In vitro and observational trial suggests their potential to limit viral replication and the damage to lungs as the most common reason for ICU admission. Therefore, patients most likely to benefit from the treatment are those with severe but early disease. This trial is designed and powered to investigate whether the treatment in this cohort of patients leads to improved clinical patient-centred outcomes, such as mechanical ventilation-free survival.

Trial registration

Clinical trials.gov: NCT04339816 (Registered on 9 April 2020, amended on 22 June 2020); Eudra CT number: 2020-001456-18 (Registered on 29 March 2020).
Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults
Authors: Hillary Robert F. , Trejo-Banos Daniel , Kousathanas Athanasios , McCartney Daniel L. , Harris Sarah E. , Stevenson Anna J. , Patxot Marion , Ojavee Sven Erik , Zhang Qian , Liewald David C. , Ritchie Craig W. , Evans Kathryn L. , Tucker-Drob Elliot M. , Wray Naomi R. , McRae Allan F. , Visscher Peter M. , Deary Ian J. , Robinson Matthew R. , Marioni Riccardo E.
Published: July 2020

Background

The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets.

Methods

In this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares- (OLS) and mixed model-based approaches).

Results

We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified 3 CpG sites spread across 3 proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to 1 polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease and between IL12B and Crohn’s disease.

Conclusions

Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease.
Potential roles of psychological and oxidative stress in insulin resistance: a cohort-based study
Authors: Janczura Miroslaw , Dropinski Jerzy , Gielicz Anna , Kotula-Horowitz Katarzyna , Iwaniec Teresa , Stanisz Andrzej , Rosa Rafal , Domagala Teresa B.
Published: July 2020

Background

The present study investigated the relationships between psychological stress indices and oxidative stress marker, also when combined with emergent insulin resistance (IR), in the non-diabetic, middle-aged subjects, exposed to frequent/chronic psychological stressors.

Methods

Cross-sectional data from a cohort of non-diabetic police officers (n = 234; 19F), aged 27–56 years, were used. Plasma inflammatory (CRP, TNF-α), oxidative stress (free 8-iso-prostaglandin F2α; 8-iso-PGF2α) markers, and insulin were measured. The value of homeostasis model assessment of IR index (HOMA-IR) was assumed the threshold value of IR, i.e. 2.04. Free cortisol in urine and perceived stress (psychological stress indices) were also measured.

Results

In the IR subjects, most biochemical variables, inflammatory markers and urine cortisol were significantly higher, as compared to the non-IR ones. Psychological stress indices were associated with plasma 8-iso-PGF2α[B = 0.139, 95% CI (0.048, 0.230), p = 0.002, and B = 0.007, 95% CI (0.0006, 0.014), p = 0.03; for perceived stress level and cortisol, respectively]. Positive associations were established between plasma 8-iso-PGF2α[B = 0.069, 95% CI (0.016–0.120), p = 0.01] and urine cortisol [B = 0.003, 95% CI (0.0003, 0.005), p = 0.02] with HOMA-IR. Metabolic syndrome, as defined by IDF criteria, was established in 110 study subjects, whereas 136 of them were hypertensive. Waist circumference [B = 0.056, 95% CI (0.039, 0.074), p < 0.0001], and systolic blood pressure [B = 0.009, 95% CI (0.00003, 0.018), p = 0.04] were positively associated with HOMA-IR, whereas the association of HDL cholesterol [B = − 0.597, 95% CI (− 1.139, − 0.055), p = 0.03] was a negative one. Cortisol [OR = 1.007, 95% CI (1.002, 1.012), p = 0.006], and 8-iso-PGF2α[OR = 1.103, 95% CI (1.010, 1.201), p = 0.02] affected the incidence of IR. After adjustment for metabolic syndrome (or its components), age, sex, and current smoking, the effects became non-significant. Out of metabolic syndrome components, waist circumference [OR 4.966, 95% CI (2.29, 10.751), p = 0.00004] and hypertriglyceridemia [OR 1.993, 95% CI (1.063, 3.736), p = 0.03] increased the chance of IR incidence.

Conclusions

Both psychological stress indices were associated with oxidative stress, but only cortisol with HOMA-IR. In the subjects exposed to frequent/chronic psychological stressors, cortisol and oxidative stress marker affected IR incidence, being statistically attenuated, though, following adjustment for metabolic syndrome, or its components.
The MLH1 polymorphism rs1800734 and risk of endometrial cancer with microsatellite instability
Authors: Russell Holly , Kedzierska Katarzyna , Buchanan Daniel D. , Thomas Rachael , Tham Emma , Mints Miriam , Keränen Anne , Giles Graham G. , Southey Melissa C. , Milne Roger L. , Tomlinson Ian , Church David , Spurdle Amanda B. , O’Mara Tracy A. , Lewis Annabelle
Published: July 2020

Both colorectal (CRC, 15%) and endometrial cancers (EC, 30%) exhibit microsatellite instability (MSI) due to MLH1 hypermethylation and silencing. The MLH1 promoter polymorphism, rs1800734 is associated with MSI CRC risk, increased methylation and reduced MLH1 expression. In EC samples, we investigated rs1800734 risk using MSI and MSS cases and controls. We found no evidence that rs1800734 or other MLH1 SNPs were associated with the risk of MSI EC. We found the rs1800734 risk allele had no effect on MLH1 methylation or expression in ECs. We propose that MLH1 hypermethylation occurs by different mechanisms in CRC and EC.
Transient elevation of serum ferritin in a Sri Lankan with homozygosity for H63D mutation in the HFE gene: a case report
Authors: Wickramasinghe Wasanthi , Karunathilaka Chathurika , Jayasinghe Saroj , Gooneratne Lallindra
Published: July 2020

Introduction

Hereditary hemochromatosis is an inherited disorder of iron metabolism, characterized by excessive iron deposition in major organs of the body, leading to multi-organ dysfunction. It is a genetically heterogeneous disease caused by mutations in one or more different genes, the most common being mutations in the HFE gene. HFE hereditary hemochromatosis is mostly found in Europeans and is almost always a result of two mutations: C282Y and H63D. The H63D mutation is not as penetrant as the C282Y mutation, but there are rare reported cases of hereditary hemochromatosis with homozygous H63D genotype. While the C282Y mutation is primarily confined to persons of Northern European origin, the H63D mutation is spread worldwide. Other types of hereditary hemochromatosis are rare and broadly defined as non-HFE hereditary hemochromatosis and include mutations in the hemojuvelin gene, hepcidin (HAMP gene), transferrin receptor 2 gene, and ferroportin gene.

Hereditary hemochromatosis is commonly found in populations of European origin; in contrast, it is rare and less well understood in Asia. It can be masked by the presence of concurrent iron deficiency or secondary iron overload in thalassemias.

Case presentation

We report the case of a 42-year-old Sri Lankan man investigated for fatigue during a brief upper respiratory tract infection and found to have high liver transaminases and high serum ferritin, which persisted even after complete resolution of the infection. Homozygosity for H63D mutation in the HFE gene was detected. Liver enzymes, serum ferritin, and transferrin saturation normalized following venesections.

Conclusion

This case adds to the literature on the importance of being vigilant and investigating patients suspected for iron overload, including genetic studies for hereditary hemochromatosis, even though it is a rare clinical entity in Asians.
Pathogenic characteristics of a QX-like infectious bronchitis virus strain SD in chickens exposed at different ages and protective efficacy of combining live homologous and heterologous vaccination
Authors: Shao Lei , Zhao Jing , Li Lihua , Huang Xiuying , Yang Huiming , Cheng Jinlong , Liu Changqing , Zhang Guozhong
Published: July 2020

Continued reports of infections with infectious bronchitis virus (IBV) variants have occurred since its first isolation in the 1930s. Currently, QX-like IBVs are the predominant circulating genotype around the world. Here, the pathogenicity of QX-like IBV strain SD was characterized in chickens at different ages of exposure to the virus, and the protection efficacy of available vaccine combinations against IBV was evaluated. The results revealed that QX-like IBV strain SD was severely pathogenic in chickens, causing respiratory, urinary and reproductive infections, irrespective of age, based on clinical observations, viral distribution in tissues and a ciliostasis study. Severe respiratory signs, tracheal cilia injury, nephritis and abnormal development of the oviduct and ovarian follicles were evident throughout the experiment. A challenge experiment demonstrated that the homologous QX vaccine showed superior protection efficacy compared with other available vaccines, confirming the importance of IBV vaccine seed homology against the circulating IBV strains. Our findings aid an understanding of the pathogenicity of QX-like IBVs that may help to further control the infection.
Innate immune responses to duck Tembusu virus infection
Authors: Li Ning , Zhao Jun , Yang Yudong , Zeng Yongqing , Liu Sidang
Published: July 2020

The disease caused by duck Tembusu virus (DTMUV) is characterized by severe egg-drop in laying ducks. Currently, the disease has spread to most duck-raising areas in China, leading to great economic losses in the duck industry. In the recent years, DTMUV has raised some concerns, because of its expanding host range and increasing pathogenicity, as well as the potential threat to public health. Innate immunity is crucial for defending against invading pathogens in the early stages of infection. Recently, studies on the interaction between DTMUV and host innate immune response have made great progress. In the review, we provide an overview of DTMUV and summarize current advances in our understanding of the interaction between DTMUV and innate immunity, including the host innate immune responses to DTMUV infection through pattern recognition receptors (PRRs), signaling transducer molecules, interferon-stimulated genes (ISGs), and the immune evasion strategies employed by DTMUV. The aim of the review is to gain an in-depth understanding of DTMUV pathogenesis to facilitate future studies.
A comprehensive descriptive assessment of obesity related chronic morbidity and estimated annual cost burden from a population-based electronic health record database
Authors: Reges Orna , Leibowitz Morton , Hirsch Avital , Dicker Dror , Finer Nick , Haase Christiane Lundegaard , Satylganova Altynai , Leventer-Roberts Maya , Feldman Becca
Published: July 2020

Background

The growing prevalence of obesity and its complications pose a huge burden on the individual and health care systems worldwide. This study presents the frequency of multiple prevalent co-morbidities and estimated annual cost burden by body mass index (BMI) groups, age, and sex among the Israeli adult population to provide policy makers with further evidence to appropriately target interventions.

Methods

This cross-sectional study utilized population-based electronic medical records from the largest payer-provider health fund in Israel. The population included individuals ≥25 years as of 01/01/2014. A new approach assessing body system-related morbidity (BSRM) prevalence was assessed along with estimated annual cost burden for the year 2015 and presented across BMI group, age, and sex via heat maps.

Results

Among 1,756,791 adults, 65% had an elevated BMI (BMI > 25 kg/m2). Heat map analysis demonstrated a higher multi-BSRM prevalence and relative estimated annual cost burden among participants with obesity in all age groups. There was a notably higher multi-BSRM prevalence among men and women aged 25–29 with class III obesity (26 and 30%, respectively) compared to the corresponding BMI groups between 18·5- < 25 kg/m2 (5 and 9%, respectively). Healthcare costs were 1·72 times higher among men aged 25–29 with class III obesity and 2·75 times among women aged 25–29 with class III obesity compared to those of healthy weight.

Conclusions

The detailed analysis describes the uneven distribution of burdens across BMI groups, age, and sex allowing policy makers to identify sub-populations for targeted interventions.
Comparison of the proximal and distal approaches for axillary vein catheterization under ultrasound guidance (PANDA) in cardiac surgery patients susceptible to bleeding: a randomized controlled trial
Authors: Su Ying , Hou Jun-yi , Ma Guo-guang , Hao Guang-wei , Luo Jing-chao , Yu Shen-ji , Liu Kai , Zheng Ji-li , Xue Yan , Luo Zhe , Tu Guo-wei
Published: July 2020

Background

The present study aimed at comparing the success rate and safety of proximal versus distal approach for ultrasound (US)-guided axillary vein catheterization (AVC) in cardiac surgery patients susceptible to bleeding.

Methods

In this single-center randomized controlled trial, cardiac surgery patients susceptible to bleeding and requiring AVC were randomized to either the proximal or distal approach group for US-guided AVC. Patients susceptible to bleeding were defined as those who received oral antiplatelet drugs or anticoagulants for at least 3 days. Success rate, catheterization time, number of attempts, and mechanical complications within 24 h were recorded for each procedure.

Results

A total of 198 patients underwent randomization: 99 patients each to the proximal and distal groups. The proximal group had the higher first puncture success rate (75.8% vs. 51.5%, p < 0.001) and site success rate (93.9% vs. 83.8%, p = 0.04) than the distal group. However, the overall success rates between the two groups were similar (99.0% vs. 99.0%; p = 1.00). Moreover, the proximal group had fewer average number of attempts (p < 0.01), less access time (p < 0.001), and less successful cannulation time (p < 0.001). There was no significant difference in complications between the two groups, such as major bleeding, minor bleeding, arterial puncture, pneumothorax, nerve injuries, and catheter misplacements.

Conclusions

For cardiac surgery patients susceptible to bleeding, both proximal and distal approaches for US-guided AVC can be considered as feasible and safe methods of central venous cannulation. In terms of the first puncture success rate and cannulation time, the proximal approach is superior to the distal approach. Trial registration Clinicaltrials.gov, NCT03395691. Registered January 10, 2018, https://clinicaltrials.gov/ct2/show/NCT03395691?cond=NCT03395691&draw=1&rank=1.