bluuebunny/crossref_metadata_2025 huggingface dataset:
Overall survival and factors predicting long-term outcome after thoracic aortic endovascular repair
Authors: Coster Bruno De , Houthoofd Sabrina , Laenen Annouschka , Fourneau Inge , Maleux Geert
Published: March 2020

Purposes:

To assess overall survival and to determine factors predicting outcome after thoracic endovascular aortic repair.

Materials and methods:

A Retrospective analysis was performed on a cohort of 212 consecutive patients (165 men and 47 women; mean age 64 years) who underwent thoracic endovascular aortic repair in a tertiary referral center for aortic disease. Main indications were true thoracic aortic aneurysm (n = 58; 27.6%), traumatic aortic rupture (n = 33; 15.7%), anastomotic pseudoaneurysms (n = 23; 10.9%), chronic type B aortic dissection (n = 22; 10.5%), and symptomatic, acute type B dissection (n = 21; 10.0%). In 79 patients (37.3%), a hybrid procedure, including supra-aortic rerouting, was performed. Kaplan–Meier estimates were used for overall survival and Cox regression models were used for univariable analysis of the association between risk factors and survival.

Results:

Proximal landing zones were predominantly zone 3 (n = 66; 31.3%), zone 2 (n = 63; 29.9%), and zone 1 (n = 38; 18%). In-hospital mortality was n = 18 (8.5%). Overall survival was 79.6%, 65.9%, and 51.1% at 2, 5, and 10 years, respectively; better overall survival was shown for traumatic aortic rupture, anastomotic pseudoaneurysms, and chronic posttraumatic pseudoaneurysms (p < 0.05). Clinical risk factors influencing overall survival include prior coronary bypass surgery, atrial flutter, arterial hypertension, renal failure, chronic obstructive pulmonary disease, and associated abdominal aortic aneurysm (p < 0.05).

Conclusions:

Thoracic endovascular aortic repair is an effective treatment option for various thoracic aortic diseases with highest survival rates for traumatic aortic rupture and anastomotic pseudoaneurysms. Several clinical parameters are identified as risk factors for overall survival.
The disconcerting potential of online disinformation: Persuasive effects of astroturfing comments and three strategies for inoculation against them
Authors: Zerback Thomas , Töpfl Florian , Knöpfle Maria
Published: March 2020

This study is the first to scrutinize the psychological effects of online astroturfing in the context of Russia’s digitally enabled foreign propaganda. Online astroturfing is a communicative strategy that uses websites, “sock puppets,” or social bots to create the false impression that a particular opinion has widespread public support. We exposed N = 2353 subjects to pro-Russian astroturfing comments and tested: (1) their effects on political opinions and opinion certainty and (2) the efficiency of three inoculation strategies to prevent these effects. All effects were investigated across three issues and from a short- and long-term perspective. Results show that astroturfing comments can indeed alter recipients’ opinions, and increase uncertainty, even when subjects are inoculated before exposure. We found exclusively short-term effects of only one inoculation strategy (refutational-same). As these findings imply, preemptive media literacy campaigns should deploy (1) continuous rather than one-time efforts and (2) issue specific rather than abstract inoculation messages.
The United Kingdom has spoken: The receding impact of European jurisprudence on the UK interpretation of the common VAT system
Authors: Zu Yige , Krever Richard
Published: March 2020

Post-Brexit, UK law conforming to Directives of the European Union such as the value added tax (VAT) Directive will remain in effect and UK courts will be permitted to consider decisions of the Court of Justice of the European Union (CJEU) when interpreting that law. How UK common law courts, steeped in the tradition of the doctrine of precedent, will use CJEU judgments in the post-Brexit era has been the subject of much speculation. This article considers the question in the context of a case study, looking at the application by UK courts of CJEU decisions in an important area of VAT law, the treatment of customer loyalty plan benefits. The evidence suggests that, even prior to Brexit, UK courts had started to pursue a separate path, declining to follow CJEU precedents that yielded clearly inappropriate policy outcomes. If the results of the case study are replicated more widely in UK rulings, it can be expected that the influence of CJEU judgments may taper off where formalistic and literalist CJEU interpretations have led to outcomes inconsistent with the recognized policy intent of UK law.
Methylome Variation Predicts Exemestane Resistance in Advanced ER+ Breast Cancer
Authors: Liu Xiao-ran , Zhang Ru-yan , Gong Hao , Rugo Hope S. , Chen Ling-bo , Fu Yuan , Che Jian-wei , Tie Jian , Shao Bin , Wan Feng-ling , Kong Wei-yao , Song Guo-hong , Jiang Han-fang , Xu Guo-bing , Li Hui-ping
Published: March 2020

Background:

More than 30% of estrogen receptor-positive breast cancers are resistant to primary hormone therapy, and about 40% that initially respond to hormone therapy eventually acquire resistance. Although the mechanisms of hormone therapy resistance remain unclear, aberrant DNA methylation has been implicated in oncogenesis and drug resistance.

Purpose:

We investigated the relationship between methylome variations in circulating tumor DNA and exemestane resistance, to track hormone therapy efficacy.

Methods:

We prospectively recruited 16 patients who were receiving first-line therapy in our center. All patients received exemestane-based hormone therapy after enrollment. We collected blood samples at baseline, first follow-up (after 2 therapeutic cycles) and at detection of disease progression. Disease that progressed within 6 months under exemestane treatment was considered exemestane resistance but was considered relatively exemestane-sensitive otherwise. We obtained circulating tumor DNA-derived methylomes using the whole-genome bisulfide sequencing method. Methylation calling was done by BISMARK software; differentially methylated regions for exemestane resistance were calculated afterward.

Results:

Median follow-up for the 16 patients was 19.0 months. We found 7 exemestane resistance-related differentially methylated regions, located in different chromosomes, with both significantly different methylation density and methylation ratio. Baseline methylation density and methylation ratio of chromosome 6 [32400000-32599999] were both high in exemestane resistance. High baseline methylation ratios of chromosome 3 [67800000-67999999] ( P = .013), chromosome 3 [140200000-140399999] ( P = .037), and chromosome 12 [101200000-101399999] ( P = .026) could also predict exemestane resistance. During exemestane treatment, synchronized changes in methylation density and methylation ratio in chromosome 6 [32400000-32599999] could accurately stratify patients in terms of progression-free survival ( P = .000033). Cutoff values of methylation density and methylation ratio for chromosome 6 [149600000-149799999] were 0.066 and 0.076, respectively.

Conclusion:

Methylation change in chromosome 6 [149600000-149799999] is an ideal predictor of exemestane resistance with great clinical potential.
Measurement of push-rim forces during racing wheelchair propulsion using a novel attachable force sensor system
Authors: Miyazaki Yusuke , Iida Kazuki , Nakashima Motomu , Maruyama Takeo , Yamanobe Kaohru
Published: March 2020

To improve competitive skills, it is important to clarify the relationship between the propulsion motion (the propulsive force in the use of racing wheelchairs optimized for athletes) and aerodynamic drag, which can change during propulsive motion. Therefore, the purpose of this research was to construct a novel force sensor system that is attachable to racing wheelchairs for individual athletes and usable in a wind tunnel facility to examine differences in the push-rim force characteristics of athletes based on the measured results. The system was composed of four two-dimensional component force sensors, batteries, and radio transmitters. From the output of the four two-dimensional component sensors, tangential and radial components of the push-rim force were measured. Three top-class long-distance wheelchair athletes participated in this study, which required each athlete to push a racing wheelchair at 5.56 m/s on a wheelchair roller system in a wind tunnel facility. The force sensor system was mounted on the participants’ individual racing wheelchairs. The measured tangential force waveforms were classified as either bimodal or unimodal depending on the athletes’ propulsion styles. Although two athletes showed similar propulsion style characteristics, the athlete with more years of experience showed better propulsive work efficiency and repeatability. Therefore, a difference in skill for applying propulsive force during the push phase, which is difficult to estimate by kinematic analysis, could be estimated by using the force sensor system.
Effective enforcement of EU labour law: A comparative example
Authors: Gotthardt Michael
Published: March 2020

The article looks at the outcome of the two legal proceedings in the Schüth and IR cases. In both cases employees of the Catholic Church – a choirmaster and organist in a Catholic parish and a trained physician working as Head of the Internal Medicine Department of a Catholic hospital - were dismissed because of the violation of the Basic Regulations on Employment Relationships in the Service of the Church. In the Schüth case Article 8 of the European Convention on Human Rights (ECHR), which protects the right to private and family life, had been violated. In the IR case the Charter of Fundamental Rights of the European Union and the Directive establishing a general framework for equal treatment in employment and occupation were applicable. The dismissal in IR was held to be unequal treatment in employment. But the outcome of both cases was very different. We find that Union law and in particular Article 47 of the Charter of Fundamental Rights of the European Union makes all the difference. In the Schüth case, the employment relationship was terminated and the claimant’s only consolation was a claim for damages from the State. In the IR case, on the other hand, the termination was declared invalid and the employment relationship continued, i.e. the head physician did not lose his job. The comparison of the cases demonstrates that European law, backed by Article 47 of the Charter of Fundamental Rights of the European Union, has not only permeated procedural law, it has also led to an increase in judicial reviews of substantive law which in the application of Union law is a far cry from a mere plausibility review.
Exploring lecturer and student perceptions and use of a learning management system in a postgraduate public health environment
Authors: Kite James , Schlub Timothy E , Zhang Ying , Choi Silvia , Craske Sarah , Dickson Michelle
Published: March 2020

Learning management systems have become a key component of teaching and learning in higher education. However, the evidence on the importance of learning management systems to learning is still in its infancy. Therefore, we aimed to investigate the role that the Canvas learning management system played in the Sydney School of Public Health at the University of Sydney, Australia. To do this, we conducted interviews with lecturers ( n = 9) and postgraduate coursework students ( n = 7) from the School during Semester 2, 2018. We analysed the interviews thematically, identifying one overarching theme: that Canvas is predominantly used and perceived as an information repository by teaching academics and students. This means that lecturers place course materials on the learning management system for students to use and are making limited use of other, more interactive features of the learning management system, despite interaction being seen as essential to effective teaching and learning. This use of Canvas was explained by two factors: (1) face-to-face learning is perceived as superior to online learning and (2) the existence of skill and capacity barriers that hinder improved online teaching and learning practice, even where professional development opportunities exist for lecturers. We argue that this represents suboptimal use of a learning management system, especially when online learning is likely to become more significant in the coming years. To address this issue, we recommend employing and appropriately resourcing educational designers within higher education settings. These specialists can aid lecturers in the creation of genuinely interactive online environments so that the benefits of online teaching and learning can be fully realised.
Systematic Coronary Risk Evaluation estimated risk and prevalent subclinical atherosclerosis in coronary and carotid arteries: A population-based cohort analysis from the Swedish Cardiopulmonary Bioimage Study
Authors: Östgren Carl J , Söderberg Stefan , Festin Karin , Angerås Oskar , Bergström Göran , Blomberg Anders , Brandberg John , Cederlund Kerstin , Eliasson Mats , Engström Gunnar , Erlinge David , Fagman Erika , Hagström Emil , Lind Lars , Mannila Maria , Nilsson Ulf , Oldgren Jonas , Ostenfeld Ellen , Persson Anders , Persson Jonas , Persson Margaretha , Rosengren Annika , Sundström Johan , Swahn Eva , Engvall Jan E , Jernberg Tomas
Published: March 2020

Background

It is not clear if the European Systematic Coronary Risk Evaluation algorithm is useful for identifying prevalent subclinical atherosclerosis in a population of apparently healthy individuals. Our aim was to explore the association between the risk estimates from Systematic Coronary Risk Evaluation and prevalent subclinical atherosclerosis.

Design

The design of this study was as a cross-sectional analysis from a population-based study cohort.

Methods

From the general population, the Swedish Cardiopulmonary Bioimage Study randomly invited individuals aged 50–64 years and enrolled 13,411 participants mean age 57 (standard deviation 4.3) years; 46% males between November 2013–December 2016. Associations between Systematic Coronary Risk Evaluation risk estimates and coronary artery calcification and plaques in the carotid arteries by using imaging data from a computed tomography of the heart and ultrasonography of the carotid arteries were examined.

Results

Coronary calcification was present in 39.5% and carotid plaque in 56.0%. In men, coronary artery calcium score >0 ranged from 40.7–65.9% and presence of carotid plaques from 54.5% to 72.8% in the age group 50–54 and 60–65 years, respectively. In women, the corresponding difference was from 17.1–38.9% and from 41.0–58.4%. A doubling of Systematic Coronary Risk Evaluation was associated with an increased probability to have coronary artery calcium score >0 (odds ratio: 2.18 (95% confidence interval 2.07–2.30)) and to have >1 carotid plaques (1.67 (1.61–1.74)).

Conclusion

Systematic Coronary Risk Evaluation estimated risk is associated with prevalent subclinical atherosclerosis in two major vascular beds in a general population sample without established cardiovascular disease or diabetes mellitus. Thus, the Systematic Coronary Risk Evaluation risk chart may be of use for estimating the risk of subclinical atherosclerosis.
Do Dr. Google and Health Apps Have (Comparable) Side Effects? An Experimental Study
Authors: Jungmann Stefanie M. , Brand Sebastian , Kolb Johanna , Witthöft Michael
Published: March 2020

Googling and using apps for health-related information are highly prevalent worldwide. So far, little is known about the emotional, body-related, and behavioral effects of using both Google and health-related apps. In our experimental study, bodily symptoms were first provoked by a standardized hyperventilation test. A total of 147 participants (96.6% students) were then randomly assigned to one of three conditions: Googling for the causes of the currently experienced bodily symptoms, using a medical app to diagnose the experienced symptoms, and a waiting control condition. Health-related Internet use for symptoms led to stronger negative affect, increased health anxiety, and increased need to consult a physician compared with the control condition. Googling and using the medical app showed comparable adverse emotional and behavioral effects. The findings are in line with current models of cyberchondria in which health-related Internet use represents an essential factor in maintaining and amplifying emotional distress.
Assessment of minimal residual disease using multiparametric flow cytometry in patients with AL amyloidosis
Authors: Staron Andrew , Burks Eric J. , Lee John C. , Sarosiek Shayna , Sloan J. Mark , Sanchorawala Vaishali
Published: March 2020

Despite achieving a hematologic complete response after treatment, many patients with AL amyloidosis do not attain recovery of organ function and/or experience hematologic relapse. A persistent plasma cell clone producing amyloidogenic light chains at levels below the detection threshold of traditional serologic methods is hypothesized to impede organ response in some patients. Assessment of minimal residual disease (MRD) may therefore have clinical importance as a more stringent treatment response tool for patients in a hematologic complete response. We used 2-tube, 10-color combination multiparametric flow cytometry to assess for MRD at a minimum sensitivity of 1 in 105 nucleated cells. Of 65 patients in hematologic complete response, 36 (55%) were found to have a residual clonal plasma cell population in the bone marrow. Comparing the MRD-negative and MRD-positive groups, renal response was observed in 88% vs 64% (P = .06), cardiac response in 75% vs 59% (P = .45), and any organ response in 90% vs 75% (P = .20) of patients. Depth of organ response as measured by the percent decrease in 24-hour proteinuria and brain natriuretic peptide was 96% vs 91% (P = .16) and 55% vs 46% (P = .66), respectively. These data suggest a possible correlation between MRD negativity and higher probability of organ response after treatment in AL amyloidosis. Future prospective studies with a larger cohort are needed to determine the clinical relevance of these improvements. This trial was registered at www.clinicaltrials.gov as #NCT00898235.
Tracing cross species transmission of Mycobacterium bovis at the wildlife/livestock interface in South Africa
Authors: Sichewo Petronillah R. , Hlokwe Tiny M. , Etter Eric M. C. , Michel Anita L.
Published: March 2020

Background

Bovine tuberculosis (bTB) affects cattle and wildlife in South Africa with the African buffalo (Syncerus caffer) as the principal maintenance host. The presence of a wildlife maintenance host at the wildlife/livestock interface acting as spill-over host makes it much more challenging to control and eradicate bTB in cattle. Spoligotyping and mycobacterial interspersed repetitive unit-variable number of tandem repeat (MIRU-VNTR) genotyping methods were performed to investigate the genetic diversity of Mycobacterium bovis (M. bovis) isolates from cattle and wildlife, their distribution and transmission at the wildlife/livestock interface in northern Kwa-Zulu Natal (KZN), South Africa.

Results

SB0130 was identified as the dominant spoligotype pattern at this wildlife/livestock interface, while VNTR typing revealed a total of 29 VNTR profiles (strains) in the KZN province signifying high genetic variability. The detection of 5 VNTR profiles shared between cattle and buffalo suggests M. bovis transmission between species. MIRU-VNTR confirmed co-infection in one cow with three strains of M. bovis that differed at a single locus, with 2 being shared with buffalo, implying pathogen introduction from most probably unrelated wildlife sources.

Conclusion

Our findings highlight inter and intra species transmission of bTB at the wildlife/livestock interface and the need for the implementation of adequate bTB control measures to mitigate the spread of the pathogen responsible for economic losses and a public health threat.
Fast, simple and highly specific molecular detection of Vibrio alginolyticus pathogenic strains using a visualized isothermal amplification method
Authors: Dong Yu , Zhao Panpan , Chen Li , Wu Huahua , Si Xinxin , Shen Xin , Shen Hui , Qiao Yi , Zhu Shanyuan , Chen Qiong , Jia Weiwei , Dong Jingquan , Li Juan , Gao Song
Published: March 2020

Background

Vibrio alginolyticus is an important pathogen that has to be closely monitored and controlled in the mariculture industry because of its strong pathogenicity, quick onset after infection and high mortality rate in aquatic animals. Fast, simple and specific methods are needed for on-site detection to effectively control outbreaks and prevent economic losses. The detection specificity towards the pathogenic strains has to be emphasized to facilitate pointed treatment and prevention. Polymerase chain reaction (PCR)-based molecular approaches have been developed, but their application is limited due to the requirement of complicated thermal cycling machines and trained personnel.

Results

A fast, simple and highly specific detection method for V. alginolyticus pathogenic strains was established based on isothermal recombinase polymerase amplification (RPA) and lateral flow dipsticks (LFD). The method targeted the virulence gene toxR, which is reported to have good coverage for V. alginolyticus pathogenic strains. To ensure the specificity of the method, the primer-probe set of the RPA system was carefully designed to recognize regions in the toxR gene that diverge in different Vibrio species but are conserved in V. alginolyticus pathogenic strains. The primer-probe set was determined after a systematic screening of amplification performance, primer-dimer formation and false positive signals. The RPA-LFD method was confirmed to have high specificity for V. alginolyticus pathogenic strains without any cross reaction with other Vibrio species or other pathogenic bacteria and was able to detect as little as 1 colony forming unit (CFU) per reaction without DNA purification, or 170 fg of genomic DNA, or 6.25 × 103 CFU/25 g in spiked shrimp without any enrichment. The method finishes detection within 30 min at temperatures between 35 °C and 45 °C, and the visual signal on the dipstick can be directly read by the naked eye. In an application simulation, randomly spiked shrimp homogenate samples were 100% accurately detected.

Conclusions

The RPA-LFD method developed in this study is fast, simple, highly specific and does not require complicated equipment. This method is applicable for on-site detection of V. alginolyticus pathogenic strains for the mariculture industry.
Compositional analysis of the associations between 24-h movement behaviours and cardio-metabolic risk factors in overweight and obese adults with pre-diabetes from the PREVIEW study: cross-sectional baseline analysis
Authors: Swindell Nils , Rees Paul , Fogelholm Mikael , Drummen Mathijs , MacDonald Ian , Martinez J. Alfredo , Navas-Carretero Santiago , Handjieva-Darlenska Teodora , Boyadjieva Nadka , Bogdanov Georgi , Poppitt Sally D. , Gant Nicholas , Silvestre Marta P. , Brand-Miller Jennie , Schlicht Wolfgang , Muirhead Roslyn , Brodie Shannon , Tikkanen Heikki , Jalo Elli , Westerterp-Plantenga Margriet , Adam Tanja , Vestentoft Pia Siig , Larsen Thomas M. , Raben Anne , Stratton Gareth
Published: March 2020

Background

Physical activity, sedentary time and sleep have been shown to be associated with cardio-metabolic health. However, these associations are typically studied in isolation or without accounting for the effect of all movement behaviours and the constrained nature of data that comprise a finite whole such as a 24 h day. The aim of this study was to examine the associations between the composition of daily movement behaviours (including sleep, sedentary time (ST), light intensity physical activity (LIPA) and moderate-to-vigorous activity (MVPA)) and cardio-metabolic health, in a cross-sectional analysis of adults with pre-diabetes. Further, we quantified the predicted differences following reallocation of time between behaviours.

Methods

Accelerometers were used to quantify daily movement behaviours in 1462 adults from eight countries with a body mass index (BMI) ≥25 kg·m− 2, impaired fasting glucose (IFG; 5.6–6.9 mmol·l− 1) and/or impaired glucose tolerance (IGT; 7.8–11.0 mmol•l− 1 2 h following oral glucose tolerance test, OGTT). Compositional isotemporal substitution was used to estimate the association of reallocating time between behaviours.

Results

Replacing MVPA with any other behaviour around the mean composition was associated with a poorer cardio-metabolic risk profile. Conversely, when MVPA was increased, the relationships with cardiometabolic risk markers was favourable but with smaller predicted changes than when MVPA was replaced. Further, substituting ST with LIPA predicted improvements in cardio-metabolic risk markers, most notably insulin and HOMA-IR.

Conclusions

This is the first study to use compositional analysis of the 24 h movement composition in adults with overweight/obesity and pre-diabetes. These findings build on previous literature that suggest replacing ST with LIPA may produce metabolic benefits that contribute to the prevention and management of type 2 diabetes. Furthermore, the asymmetry in the predicted change in risk markers following the reallocation of time to/from MVPA highlights the importance of maintaining existing levels of MVPA.

Trial registration

ClinicalTrials.gov (NCT01777893).
Qishen granules exerts cardioprotective effects on rats with heart failure via regulating fatty acid and glucose metabolism
Authors: Gao Kuo , Zhang Jian , Gao Pengrong , Wang Qiyan , Liu Ying , Liu Junjie , Zhang Yili , Li Yan , Chang Hong , Ren Ping , Liu Jinmin , Wang Yong , Wang Wei
Published: March 2020

Background

Qishen granules (QSG) has been applied to treat heart failure (HF) for decades. Our previous transcriptomics study has suggested that Qishen granules (QSG) could regulate the pathways of cardiac energy metabolism in HF, but the specific regulatory mechanism has not yet been clarified. This study was to investigate the potential mechanism of QSG in regulating myocardial fatty acid (FA) and glucose metabolism in a rat model of HF.

Methods

The model of HF was induced by left anterior descending coronary artery ligation. Cardiac structure and function were assessed by cine magnetic resonance imaging (MRI) and echocardiography. Level of glucose metabolism was non-invasively evaluated by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT). Blood lipid levels were determined by enzymatic analysis. The mitochondrial ultrastructure was observed with a transmission electron microscope. The critical proteins related to FA metabolism, glucose metabolism and mitochondrial function were measured by western blotting. The ANOVA followed by a Fisher’s LSD test was used for within-group comparisons.

Results

QSG ameliorated cardiac functions and attenuated myocardial remodeling in HF model. The levels of serum TC, TG and LDL-C were significantly reduced by QSG. The proteins mediating FA uptake, transportation into mitochondria and β-oxidation (FAT/CD36, CPT1A, ACADL, ACADM, ACAA2 and SCP2) as well as the upstreaming transcriptional regulators of FA metabolism (PPARα, RXRα, RXRβ and RXRγ) were up-regulated by QSG. As to glucose metabolism, QSG inhibited glycolytic activity by decreasing LDHA, while stimulated glucose oxidation by decreasing PDK4. Furthermore, QSG could facilitate tricarboxylic acid cycle, promote the transportation of ATP from mitochondria to cytoplasm and restore the mitochondrial function by increasing SUCLA2, CKMT2 and PGC-1α and decreasing UCP2 simultaneously.

Conclusion

QSG improved myocardial energy metabolism through increasing FA metabolism,inhibiting uncoupling of glycolysis from glucose oxidation.
Experienced complaints, activity limitations and loss of motor capacities in patients with pure hereditary spastic paraplegia: a web-based survey in the Netherlands
Authors: van Lith Bas J. H. , Kerstens Hans C. J. W. , van den Bemd Laura A. C. , der Sanden Maria W. G. Nijhuis-van , Weerdesteyn Vivian , Smeets Rob J. E. M. , Fheodoroff Klemens , van de Warrenburg Bart P. C. , Geurts Alexander C. H.
Published: March 2020

Background

Hereditary spastic paraplegia (HSP) is a group of inherited disorders characterized by progressive spastic paresis of the lower limbs. Treatment is often focused on reducing spasticity and its physical consequences. To better address individual patients’ needs, we investigated a broad range of experienced complaints, activity limitations, and loss of motor capacities in pure HSP. In addition, we aimed to identify patient characteristics that are associated with increased fall risk and/or reduced walking capacity.

Methods

We developed and distributed an HSP-specific online questionnaire in the Netherlands. A total of 109 out of 166 questionnaires returned by participants with pure HSP were analyzed.

Results

Participants experienced the greatest burden from muscle stiffness and limited standing and walking activities, while 72% reported leg and/or back pain. Thirty-five and 46% reported to use walking aids (e.g. crutches) indoors and outdoors, respectively; 57% reported a fall incidence of at least twice a year (‘fallers’); in 51% a fall had led to an injury at least once; and 73% reported fear of falling. Duration of spasticity and incapacity to rise from the floor were positively associated with being a ‘faller’, whereas non-neurological comorbidity and wheelchair use were negatively associated. Higher age, experienced gait problems, not being able to stand for 10 min, and incapacity to open a heavy door showed a negative association with being a ‘walker without aids’ (> 500 m).

Conclusions

Our results emphasize the large impact of spastic paraparesis on the lives of people with pure HSP and contribute to a better understanding of possible targets for rehabilitation.
Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers
Authors: Federici Giulia , Soddu Silvia
Published: March 2020

The promising expectations about personalized medicine have opened the path to routine large-scale sequencing and increased the importance of genetic counseling for hereditary cancers, among which hereditary breast and ovary cancers (HBOC) have a major impact. High-throughput sequencing, or Next-Generation Sequencing (NGS), has improved cancer patient management, ameliorating diagnosis and treatment decisions. In addition to its undeniable clinical utility, NGS is also unveiling a large number of variants that we are still not able to clearly define and classify, the variants of uncertain significance (VUS), which account for about 40% of total variants. At present, VUS use in the clinical context is challenging. Medical reports may omit this kind of data and, even when included, they limit the clinical utility of genetic information. This has prompted the scientific community to seek easily applicable tests to accurately classify VUS and increase the amount of usable information from NGS data. In this review, we will focus on NGS and classification systems for VUS investigation, with particular attention on HBOC-related genes and in vitro functional tests developed for ameliorating and accelerating variant classification in cancer.
Efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in mechanically ventilated intensive care patients—a randomized clinical trial
Authors: Adlbrecht Christopher , Wurm Raphael , Depuydt Pieter , Spapen Herbert , Lorente Jose A. , Staudinger Thomas , Creteur Jacques , Zauner Christian , Meier-Hellmann Andreas , Eller Philipp , Laenen Margot Vander , Molnár Zsolt , Várkonyi István , Schaaf Bernhard , Héjja Mária , Šrámek Vladimír , Schneider Hauke , Kanesa-thasan Niranjan , Eder-Lingelbach Susanne , Klingler Anton , Dubischar Katrin , Wressnigg Nina , Rello Jordi
Published: March 2020

Background

Pseudomonas aeruginosa infections are a serious threat in intensive care units (ICUs). The aim of this confirmatory, randomized, multicenter, placebo-controlled, double-blind, phase 2/3 study was to assess the efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in non-surgical ICU patients.

Methods

Eight hundred patients aged 18 to 80 years admitted to the ICU with expected need for mechanical ventilation for ≥ 48 h were randomized 1:1 to either IC43 100 μg or saline placebo, given in two vaccinations 7 days apart. The primary efficacy endpoint was all-cause mortality in patients 28 days after the first vaccination. Immunogenicity and safety were also evaluated.

Findings

All-cause mortality rates at day 28 were 29.2% vs 27.7% in the IC43 and placebo groups, respectively (P = .67). Overall survival (Kaplan-Meier survival estimates, P = .46) and proportion of patients with ≥ one confirmed P. aeruginosa invasive infection or respiratory tract infection also did not differ significantly between both groups. The geometric mean fold increase in OprF/I titers was 1.5 after the first vaccination, 20 at day 28, after the second vaccination, and 2.9 at day 180. Significantly more patients in the placebo group (96.5%) had ≥ one adverse event (AE) versus the IC43 100 μg group (93.1%) (P = .04). The most frequently reported severe AEs in the IC43 and placebo groups were respiratory failure (6.9% vs 5.7%, respectively), septic shock (4.1% vs 6.5%), cardiac arrest (4.3% vs 5.7%), multiorgan failure (4.6% vs 5.5%), and sepsis (4.6% vs 4.2%). No related serious AEs were reported in the IC43 group.

Interpretation

The IC43 100 μg vaccine was well tolerated in this large population of medically ill, mechanically ventilated patients. The vaccine achieved high immunogenicity but provided no clinical benefit over placebo in terms of overall mortality.

Trial registration

https://clinicaltrials.gov (NCT01563263). Registration was sent to ClinicalTrials.gov on March 14, 2012, but posted by ClinicalTrials.gov on March 26, 2012. The first subject was included in the trial on March 22, 2012.
Therapeutic iloprost for the treatment of acute respiratory distress syndrome (ARDS) (the ThIlo trial): a prospective, randomized, multicenter phase II study
Authors: Haeberle Helene , Prohaska Stefanie , Martus Peter , Straub Andreas , Zarbock Alexander , Marx Gernot , Zago Manola , Giera Martin , Koeppen Michael , Rosenberger Peter
Published: March 2020

Background

Acute respiratory distress syndrome (ARDS) is caused by rapid-onset (within hours) acute inflammatory processes in lung tissue, and it is a life-threatening condition with high mortality. The treatment of ARDS to date is focused on the prevention of further iatrogenic damage of the lung rather than the treatment of the initial inflammatory process. Several preclinical studies have revealed a beneficial effect of iloprost on the control of pulmonary inflammation, and in a small number of patients with ARDS, iloprost treatment resulted in improved oxygenation. Therefore, we plan to conduct a large multicenter trial to evaluate the effect of iloprost on ARDS.

Methods

The Therapeutic Iloprost during ARDS trial (ThIlo trial) is a multicenter, randomized, single blinded, clinical phase II trial assessing the efficacy of inhaled iloprost for the prevention of the development and progression of ARDS in critically ill patients. One hundred fifty critically ill patients suffering from acute ARDS will be treated either by nebulized iloprost or NaCl 0.9% for 5 days. Blood samples will be drawn at defined time points to elucidate the serum levels of iloprost and inflammatory markers during treatment. Mechanical ventilation will be standardized. In follow-up visits at days 28 and 90 as well as 6 months after enrollment, functional status according to the Barthel Index and a health care-related questionnaire, and frailty (Vulnerable Elders Survey) will be evaluated. The primary endpoint is the improvement of oxygenation, defined as the ratio of PaO2/FiO2. Secondary endpoints include 90-day all-cause mortality, Sequential Organ Failure Assessment scores during the study period up to day 90, the duration of mechanical ventilation, the length of intensive care unit (ICU) stay, ventilator-associated pneumonia, delirium, ICU-acquired weakness, and discharge localization. The study will be conducted in three university ARDS centers in Germany.

Discussion

The results of the ThIlo trial will highlight the anti-inflammatory effect of iloprost on early inflammatory processes during ARDS, resulting in the improvement of outcome parameters in patients with ARDS.

Trial registration

EUDRA-CT: 2016-003168-37. Registered on 12 April 2017. ClinicalTrials.gov: NCT03111212. Registered on 4 June 2017.
Small-angle X-ray scattering characterization of a $$\beta $$-amyloid model in phantoms
Authors: Breedlove Sophya , Crentsil Jasson , Dahal Eshan , Badano Aldo
Published: March 2020

Objective

We present a method to prepare an amyloid model at scalable quantities for phantom studies to evaluate small-angle x-ray scattering systems for amyloid detection. Two amyloid models were made from a plasma protein with and without heating. Both models mimic the $$\beta $$β-sheet structure of the $$\beta $$β-amyloid ($$\beta \text {A}$$βA) plaques in Alzheimer’s disease. Amyloid detection is based on the distinct peaks in the scattering signature of the $$\beta $$β-sheet structure. We characterized the amyloid models using a spectral small-angle x-ray scattering (sSAXS) prototype with samples in a plastic syringe and within a cylindrical polymethyl methacrylate (PMMA) phantom.

Results

sSAXS data show that we can detect the scattering peaks characteristic of amyloid $$\beta $$β-sheet structure in both models around 6 and 13 $$\text {nm}^{-1}$$nm-1. The $$\beta \text {A}$$βA model prepared without heating provides a stronger signal in the PMMA phantom. The methods described can be used to prepare models in sufficiently large quantities and used in samples with different packing density to assess the performance of $$\beta \text {A}$$βA quantification systems.
Research progress on the role of type I vesicular glutamate transporter (VGLUT1) in nervous system diseases
Authors: Du Xianchao , Li Jiashuo , Li Minghui , Yang Xinxin , Qi Zhipeng , Xu Bin , Liu Wei , Xu Zhaofa , Deng Yu
Published: March 2020

Glutamate (Glu) is the predominant excitatory neurotransmitter in the central nervous system (CNS). Glutamatergic transmission is critical for controlling neuronal activity. In presynaptic neurons, Glu is stored in synaptic vesicles and released by stimulation. The homeostasis of glutamatergic system is maintained by a set of transporters in the membrane of synaptic vesicles. The family of vesicular Glu transporters in mammals is comprised of three highly homologous proteins: VGLUT1-3. Among them, VGLUT1 accounts for the largest proportion. However, most of the Glu is transported into the synaptic vesicles via the type 1 vesicle Glu transporter (VGLUT1). So, the expression of particular VGLUT1 is largely complementary with limited overlap and so far it is most specific markers for neurons that use Glu as neurotransmitter. Controlling the activity of VGLUT1 could potentially modulate the efficiency of excitatory neuro-transmission and change the filling level of synaptic vesicles. This review summarizes the recent knowledge concerning molecular and functional characteristic of VGLUT1, their development, contribution to a series of central nervous system and peripheral nervous system diseases such as learning and memory disorders, Alzheimer’s disease, Parkinson’s disease and sensitized nociception or pain pathology et al.
Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study
Authors:   the OPTIPARK investigators, Reichmann Heinz , Lees Andrew , Rocha José-Francisco , Magalhães Diogo , Soares-da-Silva Patrício
Published: March 2020

Background

The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials.

Methods

OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).

Results

Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients.

Conclusions

Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice.

Trial registration

Registered in July 2016 at clinicaltrials.gov (NCT02847442).
Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy
Authors: Zheng Jin , Akbari Mansour , Schirmer Claire , Reynaert Marie-Line , Loyens Anne , Lefebvre Bruno , Buée Luc , Croteau Deborah L. , Galas Marie-Christine , Bohr Vilhelm A.
Published: March 2020

Insoluble intracellular aggregation of tau proteins into filaments and neurodegeneration are histopathological hallmarks of Alzheimer disease (AD) and other tauopathies. Recently, prefibrillar, soluble, oligomeric tau intermediates have emerged as relevant pathological tau species; however, the molecular mechanisms of neuronal responses to tau oligomers are not fully understood. Here, we show that hippocampal neurons in six-month-old transgenic mouse model of tauopathy, THY-Tau22, are enriched with oligomeric tau, contain elongated mitochondria, and display cellular stress, but no overt cytotoxicity compared to the control mice. The levels of several key mitochondrial proteins were markedly different between the THY-Tau22 and control mice hippocampi including the mitochondrial SIRT3, PINK1, ANT1 and the fission protein DRP1. DNA base excision repair (BER) is the primary defense system against oxidative DNA damage and it was elevated in six-month-old transgenic mice. DNA polymerase β, the key BER DNA polymerase, was enriched in the cytoplasm of hippocampal neurons in six-month-old transgenic mice and localized with and within mitochondria. Polβ also co-localized with mitochondria in human AD brains in neurons containing oligomeric tau. Most of these altered mitochondrial and DNA repair events were specific to the transgenic mice at 6 months of age and were not different from control mice at 12 months of age when tau pathology reaches its maximum and oligomeric forms of tau are no longer detectable. In summary, our data suggests that we have identified key cellular stress responses at early stages of tau pathology to preserve neuronal integrity and to promote survival. To our knowledge, this work provides the first description of multiple stress responses involving mitochondrial homeostasis and BER early during the progression of tau pathology, and represents an important advance in the etiopathogenesis of tauopathies.
Imaging of polymer:fullerene bulk-heterojunctions in a scanning electron microscope: methodology aspects and nanomorphology by correlative SEM and STEM
Authors: Li Yonghe , Müller Erich , Sprau Christian , Colsmann Alexander , Gerthsen Dagmar
Published: March 2020

Scanning transmission electron microscopy (STEM) at low energies (≤ 30 keV) in a scanning electron microscope is well suited to distinguish weakly scattering materials with similar materials properties and analyze their microstructure. The capabilities of the technique are illustrated in this work to resolve material domains in PTB7:PC71BM bulk-heterojunctions, which are commonly implemented for light-harvesting in organic solar cells. Bright-field (BF-) and high-angle annular dark-field (HAADF-) STEM contrast of pure PTB7 and PC71BM was first systematically analyzed using a wedge-shaped sample with well-known thickness profile. Monte-Carlo simulations are essential for the assignment of material contrast for materials with only slightly different scattering properties. Different scattering cross-sections were tested in Monte-Carlo simulations with screened Rutherford scattering cross-sections yielding best agreement with the experimental data. The STEM intensity also depends on the local specimen thickness, which can be dealt with by correlative STEM and scanning electron microscopy (SEM) imaging of the same specimen region yielding additional topography information. Correlative STEM/SEM was applied to determine the size of donor (PTB7) and acceptor (PC71BM) domains in PTB7:PC71BM absorber layers that were deposited from solution with different contents of the processing additive 1,8-diiodooctane (DIO).
In vitro anthelmintic activity and phytochemical characterization of Corallocarpus epigaeus (Rottler) Hook. f. tuber from ethyl acetate extracts
Authors: Ishnava Kalpesh B. , Konar Priya S.
Published: March 2020

Background

Helminth infections occur in poverty-stricken areas and developing countries with warm and humid environments and where sanitary conditions are poor. Only few drugs are regularly used for the treatment of these parasite infections.

Results

For checking the anthelmintic activity, taking Corallocarpus epigaeus extracts and their composition was done using organic solvents, namely methanol, chloroform, ethyl acetate and hexane against Pheretima posthuma (earthworms). Four different concentrations (25, 50, 75, and 100 mg/ml, respectively) while normal saline and albendazole (20 mg/ml) were taken as the control and standard drug, respectively. Time of paralysis and death of the worms were determined. The result depict that the ethyl acetate extract showed finest activity. The minimum inhibition concentration (MIC) was found out to be 12.5 mg/ml against albendazole drug (20 mg/ml). The preliminary phytochemical qualitative analysis of the promising ethyl acetate extract showed the presence of alkaloid, flavonoid, saponin, phenol, tannins and steroids. HPTLC analysis of ethyl acetate extract showed 6 bands. GC–MS results analysis of ethyl acetate extract showed 6 bands, the identified compounds were n-hexadecanoic acid and octadecanoic acid.

Conclusion

Identified bioactive compounds were n-hexadecanoic acid and 1-octadecanoic acid which may be useful for the treatment of helminthiasis.