bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure of a trapped radical transfer pathway within a ribonucleotide reductase holocomplex
Authors: Kang Gyunghoon , Taguchi Alexander T. , Stubbe JoAnne , Drennan Catherine L.
Published: March 2020

Caught in the act

Proton-coupled electron transfer (PCET) is an important process for moving electrons through proteins and requires precise positioning of suitable proton and electron carriers. Kang
et al.
determined a cryo–electron microscopy structure of the active complex formed by ribonucleotide reductase that allows for PCET between two protein subunits over a total distance of ∼35 angstroms. Several interventions that stabilized the radical en route also stabilized the complex and allowed for visualization of the interface between the two subunits and the full network of residues that permit PCET.

Science
, this issue p.
424
An ocular glymphatic clearance system removes β-amyloid from the rodent eye
Authors: Wang Xiaowei , Lou Nanhong , Eberhardt Allison , Yang Yujia , Kusk Peter , Xu Qiwu , Förstera Benjamin , Peng Sisi , Shi Meng , Ladrón-de-Guevara Antonio , Delle Christine , Sigurdsson Björn , Xavier Anna L. R. , Ertürk Ali , Libby Richard T. , Chen Lu , Thrane Alexander S. , Nedergaard Maiken
Published: March 2020

Glymphatic pathway clears retinal β-amyloid in rodents via optic nerve and is impaired in glaucoma.
Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape
Authors: Martin Constance J. , Datta Abhishek , Littlefield Christopher , Kalra Ashish , Chapron Christopher , Wawersik Stefan , Dagbay Kevin B. , Brueckner Christopher T. , Nikiforov Anastasia , Danehy Francis T. , Streich Frederick C. , Boston Christopher , Simpson Allison , Jackson Justin W. , Lin Susan , Danek Nicole , Faucette Ryan R. , Raman Pichai , Capili Allan D. , Buckler Alan , Carven Gregory J. , Schürpf Thomas
Published: March 2020

Inhibiting a specific isoform of TGFβ augments the effectiveness of checkpoint blockade therapy in cancer treatment.
Out of the frying pan into the fire: IFN-γ in post-sepsis immunosuppression
Authors: Billi Allison C.
Published: March 2020

Secretion of IFN-γ in sepsis contributes to post-sepsis immunosuppression and secondary candidemia.
Complete Genomic Sequences of Three Salmonella enterica subsp.
enterica
Serovar Muenchen Strains from an Orchard in San Joaquin County, California
Authors: Tran Thao D. , Huynh Steven , Parker Craig T. , Hnasko Robert , Gorski Lisa , Khalsa Sat Darshan S. , Brown Patrick H. , McGarvey Jeffery A.
Published: March 2020

We present here the complete genome sequences of three
Salmonella enterica
subsp.
enterica
serovar Muenchen strains, LG24, LG25, and LG26. All three strains were isolated from almond drupes grown in an orchard in San Joaquin County, California, in 2016. These genomic sequences are nonidentical and will contribute to our understanding of
S. enterica
genomics.
Complete Genome Sequences of Clinical Pandoraea fibrosis Isolates
Authors: Pitt Miranda E. , Nguyen Son H. , Duarte Tânia P. S. , Roddam Louise F. , Blaskovich Mark A. T. , Cooper Matthew A. , Coin Lachlan J. M.
Published: March 2020

Pandoraea fibrosis
is a newly identified Gram-negative bacterial species that was isolated from the respiratory tract of an Australian cystic fibrosis patient. The complete assembled genome sequences of two consecutive isolates (second isolate collected 11 months after antibiotic treatment) from the same individual are presented here.
Rare case of EBV-induced colitis in an immunocompetent individual
Authors: Choi Catherine , Yu Qi , Deb Pratik Q , Wang Weizheng
Published: March 2020

Epstein-Barr virus (EBV) is a member of the herpes virus family and affects people worldwide. EBV-infected colitis can occur in patients in immunocompromised states. However, EBV-induced colitis in immunocompetent patients is extremely rare. A 34-year-old man with a prior history of possible intussusception, and who underwent a right hemicolectomy, presented with abdominal pain and rectal bleeding. Laboratory investigations were unremarkable, and the patient underwent a colonoscopy, which showed EBV-infected colitis. Both infectious and inflammatory bowel disease (IBD) workups were negative. The patient’s symptoms were resolved with supportive therapy. A repeat colonoscopy showed normal colonic mucosa with an absence of EBV infection. Without evidence of IBD or infectious aetiologies, EBV-associated colitis is a rare finding in an immunocompetent patient.
Study protocol for SFX-01 after subarachnoid haemorrhage (SAS): a multicentre randomised double-blinded, placebo controlled trial
Authors: Zolnourian Ardalan H , Franklin Stephen , Galea Ian , Bulters Diederik Oliver
Published: March 2020

Introduction

Subarachnoid haemorrhage (SAH) from a ruptured cerebral aneurysm carries high morbidity and mortality. Despite huge advances in techniques to secure the aneurysm, there has been little progress in the treatment of the deleterious effects of the haemorrhage.

Sulforaphane is an Nrf2 inducer with anti-oxidant and anti-inflammatory properties. It has been shown to improve clinical outcome in experimental models of SAH, but is unstable. SFX-01 (Evgen Pharma) is a novel composition comprised of synthetic sulforaphane stabilised within an α-cyclodextrin complex. On ingestion, the complex releases sulforaphane making SFX-01 an ideal vehicle for delivery of sulforaphane.

Methods and analysis

The objective of the study is to assess the safety, pharmacokinetics and efficacy of SFX-01. This is a prospective, multicentre, randomised, double-blind placebo-controlled trial in patients aged 18–80 years with aneurysmal subarachnoid haemorrhage in the previous 48 hours. 90 patients will be randomised to receive SFX-01 (300 mg) or placebo two times per day for up to 28 days.

Safety will be assessed using blood tests and adverse event reporting.

Pharmacokinetics will be assessed based on paired blood and cerebrospinal fluid (CSF) sulforaphane levels on day 7. A subgroup will have hourly samples taken during 6 hours post-dosing on days 1 and 7. Pharmacodynamics will be assessed by haptoglobin and malondialdehyde levels, and maximum flow velocity of middle cerebral artery will be measured by transcranial Doppler ultrasound.

Clinical outcomes will be assessed at days 28, 90 and 180 with modified Rankin Scale, Glasgow Outcome Score, SAH Outcome Tool, Short Form-36, Brain Injury Community Rehabilitation Outcome Scales and Check List for Cognitive and Emotional consequences following stroke. MRI at 6 months including quantitative susceptibility mapping and volumetric T1 will measure iron deposition and cortical volume.

Safety, CSF sulforaphane concentration and middle cerebral artery flow velocity will be primary outcomes and all others secondary.

Ethics and dissemination

Ethical approval was obtained from South Central Hampshire A committee. Outcomes of the trial will be submitted for publication in a peer-reviewed journal.

Trial registration number

NCT02614742.
Effect of face-to-face verbal feedback compared with no or alternative feedback on the objective workplace task performance of health professionals: a systematic review and meta-analysis
Authors: Johnson Christina Elizabeth , Weerasuria Mihiri P , Keating Jennifer L
Published: March 2020

Objective

Verbal face-to-face feedback on clinical task performance is a fundamental component of health professions education. Experts argue that feedback is critical for performance improvement, but the evidence is limited. The aim of this systematic review was to investigate the effect of face-to-face verbal feedback from a health professional, compared with alternative or no feedback, on the objective workplace task performance of another health professional.

Design

Systematic review and meta-analysis.

Methods

We searched the full holdings of Ovid MEDLINE, CENTRAL, Embase, CINAHL and PsycINFO up to 1 February 2019 and searched references of included studies. Two authors independently undertook study selection, data extraction and quality appraisal. Studies were included if they were randomised controlled trials investigating the effect of feedback, in which health professionals were randomised to individual verbal face-to-face feedback compared with no feedback or alternative feedback and available as full-text publications in English. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations approach. For feedback compared with no feedback, outcome data from included studies were pooled using a random effects model.

Results

In total, 26 trials met the inclusion criteria, involving 2307 participants. For the effect of verbal face-to-face feedback on performance compared with no feedback, when studies at high risk of bias were excluded, eight studies involving 392 health professionals were included in a meta-analysis: the standardised mean difference (SMD) was 0.7 (95% CI 0.37 to 1.03; p<0.001) in favour of feedback. The calculated SMD prediction interval was −0.06 to 1.46. For feedback compared with alternative feedback, studies could not be pooled due to substantial design and intervention heterogeneity. All included studies were summarised, and key factors likely to influence performance were identified including components within feedback interventions, instruction and practice opportunities.

Conclusions

Verbal face-to-face feedback in the health professions may result in a moderate to large improvement in workplace task performance, compared with no feedback. However, the quality of evidence was low, primarily due to risk of bias and publication bias. Further research is needed. In particular, we found a lack of high-quality trials that clearly reported key components likely to influence performance.

Trial registration number

CRD42017081796.
Neighbourhood effects on obesity: scoping review of time-varying outcomes and exposures in longitudinal designs
Authors: Letarte Laurence , Pomerleau Sonia , Tchernof André , Biertho Laurent , Waygood Edward Owen D , Lebel Alexandre
Published: March 2020

Context and objectives

Neighbourhood effect research on obesity took off in the early 2000s and was composed of mostly cross-sectional observational studies interested in various characteristics of the built environment and the socioeconomic environment. To limit biases related to self-selection and life course exposures, many researchers apply longitudinal designs in their studies. Until now, no review has specifically and exclusively examined longitudinal studies and the specific designs of these studies. In this review, we intend to answer the following research question: how are the temporal measurements of contextual exposure and obesity outcomes integrated into longitudinal studies that explore how neighbourhood-level built and socioeconomic environments impact adult obesity?

Design

A systematic search strategy was designed to address the research question. The search was performed in Embase, Web of Science and PubMed, targeting scientific papers published before 1 January 2018. The eligible studies reported results on adults, included exposure that was limited to neighbourhood characteristics at the submunicipal level, included an outcome limited to obesity proxies, and reported a design with at least two exposure measurements or two outcome measurements.

Results

This scoping review identified 66 studies that fit the eligibility criteria. A wide variety of neighbourhood characteristics were also measured, making it difficult to draw general conclusions about associations between neighbourhood exposure and obesity. We applied a typology that classified studies by whether exposure and outcome were measured as varying or fixed. Using this typology, we found that 32 studies reported both neighbourhood exposure and obesity outcomes that were varying in time; 28 reported varying outcomes but fixed exposures; and 6 had fixed outcomes and varying exposures.

Conclusion

Our typology illustrates the variety of longitudinal designs that were used in the selected studies. In the light of our results, we make recommendations on how to better report longitudinal designs and facilitate comparisons between studies.
Management of haemorrhoids: protocol of an umbrella review of systematic reviews and meta-analyses
Authors: Chen Min , Tang Tai-Chun , He Tao-Hong , Du Yong-Jun , Qin Di , Zheng Hui
Published: March 2020

Introduction

The prevalence of haemorrhoidal diseases was high in general population, and many treatments are proposed for the management of haemorrhoids. The treatments include conservative and surgical interventions; the credibility and strength of current evidence of their effectiveness are not comprehensively evaluated. We aim to evaluate the credibility of systematic reviews and meta-analyses that assess the effectiveness of the treatments for haemorrhoidal diseases through an umbrella review.

Methods and analysis

We will search Ovid Medline, Embase, Cochrane library and Web of Science from inception to March 2020 without any language restriction. We will include meta-analyses that examine the effectiveness of treatments in the management of haemorrhoids. Two reviewers will independently screen the titles and abstracts of retrieved articles, and they will extract data from the included meta-analyses. For each meta-analysis, we will estimate the effect size of a treatment through the random-effect model and the fixed-effect model, and we will evaluate between-study heterogeneity (Cochrane’s Q and I2statistics) and small-study effect (Egger’s test); we will also estimate the evidence of excess significance bias. Evidence of each treatment will be graded according to prespecified criteria. Methodological quality of each meta-analysis will be evaluated by using Assessment of Multiple Systematic Reviews 2. The corrected cover area method will be used to assess the impact of overlap in reviews on the findings of the umbrella review.

Ethics and dissemination

We will present the results of the umbrella review at conferences and publish the final report in a peer-reviewed journal. The umbrella review does not require ethical approval.

PROSPERO registration number

CRD42019140702.
Investigation of an extensive outbreak of HIV infection among children in Sindh, Pakistan: protocol for a matched case–control study
Authors: Siddiqui Amna R , Ali Nathwani Apsara , Abidi Syed H , Mahmood Syed Faisal , Azam Iqbal , Sawani Sobiya , Kazi Abdul M , Hotwani Aneeta , Memon Sikander Ali , Soomro Jamila , Shaikh Saqib Ali , Achakzai Baseer , Saeed Quaid , Simms Victoria , Khan Palwasha , Ferrand Rashida , Mir Fatima
Published: March 2020

Introduction

In April 2019, 14 children were diagnosed with HIV infection by a private healthcare provider in Larkana district, Sindh province, Pakistan. Over the next 3 months, 930 individuals were diagnosed with HIV, >80% below 16 years, the largest ever outbreak of HIV in children in Pakistan. In this protocol paper, we describe research methods for assessing likely modes of HIV transmission in this outbreak and investigate spatial and molecular epidemiology.

Methods and analysis

A matched case–control study will be conducted with 406 cases recruited. Cases will be children aged below 16 years registered for care at the HIV treatment centre at Shaikh Zayed Children Hospital in Larkana City. Controls will be children who are HIV-uninfected (confirmed by a rapid HIV test) matched 1:1 by age (within 1 year), sex and neighbourhood. Following written informed consent from the guardian, a structured questionnaire will be administered to collect data on sociodemographic indices and exposure to risk factors for parenteral, vertical and sexual (only among those aged above 10 years) HIV transmission. A blood sample will be collected for hepatitis B and C serology (cases and controls) and HIV lineage studies (cases only). Mothers of participants will be tested for HIV to investigate the possibility of mother-to-child transmission. Conditional logistic regression will be used to investigate the association of a priori defined risk factors with HIV infection. Phylogenetic analyses will be conducted. Global positioning system coordinates of participants’ addresses will be collected to investigate concordance between the genetic and spatial epidemiology.

Ethics and dissemination

Ethical approval was granted by the Ethics Review Committee of the Aga Khan University, Karachi. Study results will be shared with Sindh and National AIDS Control Programs, relevant governmental and non-governmental organisations, presented at national and international research conferences and published in international peer-reviewed scientific journals.
Improving the documentation quality of point-of-care ultrasound scans in the emergency department
Authors: Aziz Shadman , Bottomley James , Mohandas Vasant , Ahmad Arif , Morelli Gemma , Thenabadu Sam
Published: March 2020

A point-of-care ultrasound scan (POCUS) is a core element of the Royal College of Emergency Medicine (RCEM) specialty training curriculum. However, POCUS documentation quality can be poor, especially in the time-pressured environment of the emergency department (ED). A survey of 10 junior ED clinicians at the Princess Royal University Hospital (PRUH) found that total POCUS documentation was as low as 38% in some examinations.

This quality improvement project aimed to increase the coverage and quality of POCUS documentation in the ED. This was done by using a plan-do-study-act (PDSA) regime to improve the quality of POCUS documentation from the original baseline to 80%. There were three discreet PDSA cycles and the interventions included improving education and training about POCUS documentation and the introduction of an original proforma, which incorporated six minimum requirements for POCUS documentation as per the joint RCEM and Royal College of Radiologists (RCR) guidelines for POCUS documentation (patient details, indications, findings, conclusions, signature and date).

The project team audited the quality of all documented scans in the resuscitation department of the PRUH against the RCEM/RCR guidelines at baseline and following three discrete PDSA cycles. This was done over an 8-week period, spanning 696 attendances to the resuscitation area of the ED and 42 documented POCUS examinations.

Quality recording of the six RCEM/RCR elements of POCUS documentation was poor at baseline but improved following three successful PDSA cycles. There was a demonstrated improvement in five of six documentation elements: patient details on POCUS documentation increased from 53.3% to the 66.7%, indication from 60.0% to 66.7%, conclusion from 13.0% to 83.0%, signature from 86.7% to 100.0% and date from 46.7% to 66.7%.

These results suggest that the introduction of a proforma and a vigorous education strategy are effective ways to improve the quality of documentation of ED POCUS.
Testicular cancer: improving outcomes with national quality performance indicators
Authors: Baxter Mark A , MacDonald Graham , Malik Jahangeer , Law Alistair , Dahle-Smith Åsa , Mmeka Walter , Donat Roland , Shukla Cj , Connor John , Houston Colin , Waterston Ashita , White Jeff
Published: March 2020

Testicular cancer is the most common malignancy in young adult men. The prognosis is excellent in limited disease and cure is possible even in advanced disease. Quality performance indicators (QPI) are used in many developed countries as a measure of healthcare performance. We report and discuss the development of a national set of QPIs in Scotland for testicular cancer as a method of gathering demographic data and driving improvement in nationwide testicular cancer outcomes.
Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms
Authors: Jin Xi , Lian Jiang-Shan , Hu Jian-Hua , Gao Jianguo , Zheng Lin , Zhang Yi-Min , Hao Shao-Rui , Jia Hong-Yu , Cai Huan , Zhang Xiao-Li , Yu Guo-Dong , Xu Kai-Jin , Wang Xiao-Yan , Gu Jue-Qing , Zhang Shan-Yan , Ye Chan-Yuan , Jin Ci-Liang , Lu Ying-Feng , Yu Xia , Yu Xiao-Peng , Huang Jian-Rong , Xu Kang-Li , Ni Qin , Yu Cheng-Bo , Zhu Biao , Li Yong-Tao , Liu Jun , Zhao Hong , Zhang Xuan , Yu Liang , Guo Yong-Zheng , Su Jun-Wei , Tao Jing-Jing , Lang Guan-Jing , Wu Xiao-Xin , Wu Wen-Rui , Qv Ting-Ting , Xiang Dai-Rong , Yi Ping , Shi Ding , Chen Yanfei , Ren Yue , Qiu Yun-Qing , Li Lan-Juan , Sheng Jifang , Yang Yida
Published: March 2020

Objective

The SARS-CoV-2-infected disease (COVID-19) outbreak is a major threat to human beings. Previous studies mainly focused on Wuhan and typical symptoms. We analysed 74 confirmed COVID-19 cases with GI symptoms in the Zhejiang province to determine epidemiological, clinical and virological characteristics.

Design

COVID-19 hospital patients were admitted in the Zhejiang province from 17 January 2020 to 8 February 2020. Epidemiological, demographic, clinical, laboratory, management and outcome data of patients with GI symptoms were analysed using multivariate analysis for risk of severe/critical type. Bioinformatics were used to analyse features of SARS-CoV-2 from Zhejiang province.

Results

Among enrolled 651 patients, 74 (11.4%) presented with at least one GI symptom (nausea, vomiting or diarrhoea), average age of 46.14 years, 4-day incubation period and 10.8% had pre-existing liver disease. Of patients with COVID-19 with GI symptoms, 17 (22.97%) and 23 (31.08%) had severe/critical types and family clustering, respectively, significantly higher than those without GI symptoms, 47 (8.14%) and 118 (20.45%). Of patients with COVID-19 with GI symptoms, 29 (39.19%), 23 (31.08%), 8 (10.81%) and 16 (21.62%) had significantly higher rates of fever >38.5°C, fatigue, shortness of breath and headache, respectively. Low-dose glucocorticoids and antibiotics were administered to 14.86% and 41.89% of patients, respectively. Sputum production and increased lactate dehydrogenase/glucose levels were risk factors for severe/critical type. Bioinformatics showed sequence mutation of SARS-CoV-2 with m6A methylation and changed binding capacity with ACE2.

Conclusion

We report COVID-19 cases with GI symptoms with novel features outside Wuhan. Attention to patients with COVID-19 with non-classic symptoms should increase to protect health providers.
Preoperative detection of malignancy in fine-needle aspiration cytology (FNAC) smears with indeterminate cytology (Bethesda III, IV) by a combined molecular classifier
Authors: Titov Sergei , Demenkov Pavel S , Lukyanov Sergei A , Sergiyko Sergei V , Katanyan Gevork A , Veryaskina Yulia A , Ivanov Mikhail K
Published: March 2020

Aims

Analysis of molecular markers in addition to cytological analysis of fine-needle aspiration (FNA) samples is a promising way to improve the preoperative diagnosis of thyroid nodules. Previously, we have developed an algorithm for the differential diagnosis of thyroid nodules by means of a small set of molecular markers. Here, we aimed to validate this approach using FNA cytology samples of Bethesda categories III and IV, in which preoperative detection of malignancy by cytological analysis is impossible.

Methods

A total of 122 FNA smears from patients with indeterminate cytology (Bethesda III: 13 patients, Bethesda IV: 109 patients) were analysed by real-time PCR regarding the preselected set of molecular markers (theBRAFV600E mutation, normalised concentrations ofHMGA2mRNA, 3 microRNAs, and the mitochondrial/nuclear DNA ratio). The decision tree–based classifier was used to discriminate between benign and malignant tumours.

Results

The molecular testing detected malignancy in FNA smears of indeterminate cytology with 89.2% sensitivity, 84.6% positive predictive value, 92.9% specificity and 95.2% negative predictive value; these characteristics are comparable with those of more complicated commercial tests. Residual risk of malignancy for the thyroid nodules that were shown to be benign by this molecular method did not exceed the reported risk of malignancy for Bethesda II histological diagnosis. Analytical-accuracy assessment revealed required nucleic-acid input of ≥5 ng.

Conclusions

The study shows feasibility of preoperative differential diagnosis of thyroid nodules of indeterminate cytology using a small panel of molecular markers of different types by a simple PCR-based method using stained FNA smears.
CSF levels of glutamine synthetase and GFAP to explore astrocytic damage in seronegative NMOSD
Authors: Kleerekooper Iris , Herbert Megan K , Kuiperij H Bea , Sato Douglas Kazutoshi , Fujihara Kazuo , Callegaro Dagoberto , Marignier Romain , Saiz Albert , Senel Makbule , Tumani Hayrettin , De Jong Brigit A , Trip S Anand , Nakashima Ichiro , Verbeek Marcel M , Petzold Axel
Published: March 2020

Objective

To explore levels of astrocytopathy in neuromyelitis optica spectrum disorder (NMOSD) by measuring levels of the astrocytic enzyme glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), an established astrocytic biomarker known to be associated with disease activity in multiple sclerosis.

Methods

Cerebrospinal fluid concentrations of GS and GFAP were measured by ELISA in patients with NMOSD (n=39, 28 aquaporin-4 (AQP4)-Ab-seropositive, 3 double-Ab-seronegative, 4 myelin oligodendrocyte glycoprotein (MOG)-Ab-seropositive and 4 AQP4-Ab-seronegative with unknown MOG-Ab-serostatus), multiple sclerosis (MS) (n=69), optic neuritis (n=5) and non-neurological controls (n=37).

Results

GFAP and GS concentrations differed significantly across groups (both p<0.001), showing a similar pattern of elevation in patients with AQP4-Ab-seropositive NMOSD. GS and GFAP were significantly correlated, particularly in patients with AQP4-Ab-seropositive NMOSD (rs=0.70, p<0.001). Interestingly, GFAP levels in some patients with double-Ab-seronegative NMOSD were markedly increased.

Conclusions

Our data indicate astrocytic injury occurs in some patients with double-Ab-seronegative NMOSD, which hints at the possible existence of yet undiscovered astrocytic autoimmune targets. We hypothesise that elevated GS and GFAP levels could identify those double-Ab-seronegative patients suitable to undergo in-depth autoimmune screening for astrocytic antibodies.
Visual hallucinations in neurological and ophthalmological disease: pathophysiology and management
Authors: O'Brien John , Taylor John Paul , Ballard Clive , Barker Roger A , Bradley Clare , Burns Alistair , Collerton Daniel , Dave Sonali , Dudley Rob , Francis Paul , Gibbons Andrea , Harris Kate , Lawrence Vanessa , Leroi Iracema , McKeith Ian , Michaelides Michel , Naik Chaitali , O'Callaghan Claire , Olsen Kirsty , Onofrj Marco , Pinto Rebecca , Russell Gregor , Swann Peter , Thomas Alan , Urwyler Prabitha , Weil Rimona Sharon , ffytche Dominic
Published: March 2020

Visual hallucinations are common in older people and are especially associated with ophthalmological and neurological disorders, including dementia and Parkinson’s disease. Uncertainties remain whether there is a single underlying mechanism for visual hallucinations or they have different disease-dependent causes. However, irrespective of mechanism, visual hallucinations are difficult to treat. The National Institute for Health Research (NIHR) funded a research programme to investigate visual hallucinations in the key and high burden areas of eye disease, dementia and Parkinson’s disease, culminating in a workshop to develop a unified framework for their clinical management. Here we summarise the evidence base, current practice and consensus guidelines that emerged from the workshop.

Irrespective of clinical condition, case ascertainment strategies are required to overcome reporting stigma. Once hallucinations are identified, physical, cognitive and ophthalmological health should be reviewed, with education and self-help techniques provided. Not all hallucinations require intervention but for those that are clinically significant, current evidence supports pharmacological modification of cholinergic, GABAergic, serotonergic or dopaminergic systems, or reduction of cortical excitability. A broad treatment perspective is needed, including carer support. Despite their frequency and clinical significance, there is a paucity of randomised, placebo-controlled clinical trial evidence where the primary outcome is an improvement in visual hallucinations. Key areas for future research include the development of valid and reliable assessment tools for use in mechanistic studies and clinical trials, transdiagnostic studies of shared and distinct mechanisms and when and how to treat visual hallucinations.
How to set up a clinical trial
Authors: Thomas Rachel A B , Aitken Emma Louise , Antonelli Jean , Marson Lorna
Published: March 2020

Clinical trials are considered the gold-standard method for the evaluation of healthcare interventions. However, randomised control trials are complex to perform and many researchers, especially those in the early stages of their career, can find it challenging to know where to start set up, contribute to or lead a trial. This guide provides an introduction to trials and also practical advice to help potential investigators complete their clinical trial to time and to budget by signposting the pathway through the complex regulatory landscape. The authors draw on their own recent experiences of running clinical trials and provide tips and tricks for troubleshooting common problems encountered including trial design and documentation.
Probing new physics signals with symmetry-restored Yukawa textures
Authors: Li Shao-Ping , Li Xin-Qiang
Published: March 2020

We implement a symmetry violation guideline into a two-Higgs-doublet model embedded with three right-handed neutrinos, and exploit the generic Yukawa structures of the model via a hypothetical symmetry restoration of a global $$U_Q(1)^3\times U_L(1)^3$$UQ(1)3×UL(1)3 symmetry. We then apply a mass-powered parametrization to construct the phenomenologically motivated Yukawa interactions, which enables us to incorporate correlatively the neutrino mass, dark matter, as well as the lepton-flavor universality violations in $$R_{K^{(*)}}$$RK(∗) and $$R_{D^{(*)}}$$RD(∗). Specifically, two atmospheric-scale neutrino masses are generated by a low-scale seesaw mechanism, while the much lighter one, being of $$\mathcal {O}(10^{-6})~{{\mathrm{eV}}}$$O(10-6)eV, is fixed by a $$7.1~{\mathrm{keV}}$$7.1keV sterile neutrino dark matter produced primordially by the freeze-in mechanism. On the other hand, the neutrino and the charged-lepton mass hierarchies encoded in the mass-powered textures can naturally account for the $$R_{K^{(*)}}$$RK(∗) and the $$R_{D^{(*)}}$$RD(∗) anomalies, respectively. As a further application, a milder discrepancy of the muon $$g{-}2$$g-2 is observed, which has also been implied by the recently refined lattice results.
Anisotropic Karmarkar stars in f(R, T)-gravity
Authors: Rahaman Monsur , Singh Ksh. Newton , Errehymy Abdelghani , Rahaman Farook , Daoud Mohammed
Published: March 2020

The main aim of this work is devoted to studying the existence of compact spherical systems representing anisotropic matter distributions within the scenario of alternative theories of gravitation, specificallyf(R, T) gravity theory. Besides, a noteworthy and achievable choice on the formulation off(R, T) gravity is made. To provide the complete set of field equations for the anisotropic matter distribution, it is considered that the functional form off(R, T) as$$f(R, T)=R+2\chi T$$f(R,T)=R+2χT, whereRandTcorrespond to scalar curvature and trace of the stress–energy tensor, respectively. Following the embedding class one approach employing the Eisland condition to get a full space–time portrayal interior the astrophysical structure. When the space–time geometry is identified, we construct a suitable anisotropic model by using a new gravitational potential$$g_{rr}$$grrwhich often yields physically motivated solutions that describe the anisotropic matter distribution interior the astrophysical system. The physical availability of the obtained model, represents the physical characteristics of the solution is affirmed by performing several physical tests. It merits referencing that with the help of the observed mass values for six compact stars, we have predicted the exact radii for different values of$$\chi $$χ-coupling parameter. From this one can convince that the solution predicted the radii in good agreement with the observed values. Since the radius of MSP J0740+6620, the most massive neutron star observed yet is still unknown, we have predicted its radii for different values of$$\chi $$χ-coupling parameter. These predicted radii exhibit a monotonic diminishing nature as the parameter$$\chi $$χgoing from$$-1$$-1to 1 gradually. TheM–Rcurve generated from our solution can accommodate a variety of compact stars from the less massive (Her X-1) to super massive (MSP J0740+6620). So the present study uncovers that the modifiedf(R, T) gravity is an appropriate theory to clarify massive astrophysical systems, in any case, for$$\chi =0.0$$χ=0.0the standard consequences of the general relativity are recovered.
Natural philosophy versus philosophy of naturalness
Authors: Senjanović Goran
Published: March 2020

I reflect on some of the basic aspects of present day Beyond the Standard Model particle physics, focusing mostly on the issues of naturalness, in particular on the so-called hierarchy problem. To all of us, physics as natural science emerged with Galileo and Newton, and led to centuries of unparalleled success in explaining and often predicting new phenomena of nature. I argue here that the long-standing obsession with the hierarchy problem as a guiding principle for the future of our field has had the tragic consequence of deviating high energy physics from its origins as natural philosophy, and turning it into a philosophy of naturalness.
STABILITY AND BIFURCATION ANALYSIS OF A DISCRETE PREY–PREDATOR MODEL WITH SQUARE-ROOT FUNCTIONAL RESPONSE AND OPTIMAL HARVESTING
Authors: CHAKRABORTY PRABIR , GHOSH UTTAM , SARKAR SUSMITA
Published: March 2020

In this paper, we have considered a discrete prey–predator model with square-root functional response and optimal harvesting policy. This type of functional response is used to study the dynamics of the prey–predator model where the prey population exhibits herd behavior, i.e., the interaction between prey and predator occurs along the boundary of the population. The considered population model has three fixed points; one is trivial, the second one is axial and the last one is an interior fixed point. The first two fixed points are always feasible but the last one depends on the parameter value. The interior fixed point experiences the flip and Neimark–Sacker bifurcations depending on the predator harvesting coefficient. Finally, an optimal harvesting policy has been introduced and the optimal value of the harvesting coefficient is determined.
Effects of Additives on Structural and Magnetic Properties of Iron Oxide
Authors: Deshmane Vikas V. , Patil Arun V.
Published: March 2020

This paper analyzes the effects of additives on the properties of Iron oxide. The Iron oxide was synthesized using the co-precipitation method. The X-ray diffraction (XRD) peaks of resultant Iron oxide perfectly matched with JCPDS #860550 ([Formula: see text] phase of Iron oxide / Hematite). The additives like Cobalt oxide, Nickel metal, Indium oxide and Tin metal with diverse properties procured in readymade forms were mechanically mixed with Iron oxide in 1:99, 3:97, 5:95 and 7:93 weight ratios, respectively. The XRD peaks for additives were prominent for 7:93 (Additive: Base Material) weight % ratio samples. Therefore, for further studies, only these samples were used. In this study, variations in XRD intensity, lattice parameters, unit cell volume, grain size, micro-strains (W-H analysis), dislocation density and stacking fault probability were analyzed. The specific surface area of particles was calculated by scanning electron microscope analysis. The presence of additives was also confirmed by energy dispersive spectra (EDS). The M-H loops (Vibrating Sample Magnetometer analysis) for samples under investigation showed rare vertical shifts. The weak magnetic behavior of bare Hematite (1.0 emu/gm) sample improved to antiferromagnetic behavior due to the addition of Cobalt oxide (7.89 emu/gm) and Nickel metal (2.76 emu/gm). The addition of Indium oxide (0.65 emu/gm) and Tin metal (0.73 emu/gm) samples showed a decreased magnetic saturation.
Modelling the evolution of seal integrity in deepwater toe thrust anticlines
Authors: Grant Neil T.
Published: March 2020

This paper describes the results of an empirical one-dimensional model for toe thrust structures that enables both fluid pressure expectations and seal integrity to be evaluated. The growth of a deepwater thrust anticline is forward modelled with calibration made to a present-day structure. Two locations are used to describe the structural evolution: the crest of the anticline and the floor of the adjacent syncline. These locations are followed through structural growth and burial. Pore pressures in the evolving toe thrust are modelled by employing a centroid model for a pre-tectonic target reservoir interval, with shale pressures modelled using the concept of a variable fluid retention depth. A shale compaction model based on critical state soil mechanics is used to model top seal porosity and to aid the evaluation of the capillary top seal. Together with mechanical seal analysis this enables the controls on trapped hydrocarbon column heights to be assessed. Application of the model to two recently drilled toe thrusts is discussed, and results compared to model predictions. The model can be used to offer a generic seal integrity scheme for a toe thrust that may help focus attention on the key exploration risks.
Online Optimization in Cloud Resource Provisioning
Authors: Comden Joshua , Yao Sijie , Chen Niangjun , Xing Haipeng , Liu Zhenhua
Published: March 2020

Due to mainstream adoption of cloud computing and its rapidly increasing usage of energy, the efficient management of cloud computing resources has become an important issue. A key challenge in managing the resources lies in the volatility of their demand. While there have been a wide variety of online algorithms (e.g. Receding Horizon Control, Online Balanced Descent) designed, it is hard for cloud operators to pick the right algorithm. In particular, these algorithms vary greatly on their usage of predictions and performance guarantees. This paper aims at studying an automatic algorithm selection scheme in real time. To do this, we empirically study the prediction errors from real-world cloud computing traces. Results show that prediction errors are distinct from different prediction algorithms, across virtual machines, and over the time horizon. Based on these observations, we propose a simple prediction error model and prove upper bounds on the dynamic regret of several online algorithms. We then apply the empirical and theoretical results to create a simple online meta-algorithm that chooses the best algorithm on the fly. Numerical simulations demonstrate that the performance of the designed policy is close to that of the best algorithm in hindsight.
Quantifying Target Occupancy of Small Molecules Within Living Cells
Authors: Robers M.B. , Friedman-Ohana R. , Huber K.V.M. , Kilpatrick L. , Vasta J.D. , Berger B.-T. , Chaudhry C. , Hill S. , Müller S. , Knapp S. , Wood K.V.
Published: March 2020

The binding affinity and kinetics of target engagement are fundamental to establishing structure–activity relationships (SARs) for prospective therapeutic agents. Enhancing these binding parameters for operative targets, while minimizing binding to off-target sites, can translate to improved drug efficacy and a widened therapeutic window. Compound activity is typically assessed through modulation of an observed phenotype in cultured cells. Quantifying the corresponding binding properties under common cellular conditions can provide more meaningful interpretation of the cellular SAR analysis. Consequently, methods for assessing drug binding in living cells have advanced and are now integral to medicinal chemistry workflows. In this review, we survey key technological advancements that support quantitative assessments of target occupancy in cultured cells, emphasizing generalizable methodologies able to deliver analytical precision that heretofore required reductionist biochemical approaches.
The kynurenine connection: how exercise shifts muscle tryptophan metabolism and affects energy homeostasis, the immune system, and the brain
Authors: Martin Kyle S. , Azzolini Michele , Lira Ruas Jorge
Published: March 2020

Tryptophan catabolism through the kynurenine pathway generates a variety of bioactive metabolites. Physical exercise can modulate kynurenine pathway metabolism in skeletal muscle and thus change the concentrations of select compounds in peripheral tissues and in the central nervous system. Here we review recent advances in our understanding of how exercise alters tryptophan-kynurenine metabolism in muscle and its subsequent local and distal effects. We propose that the effects of kynurenine pathway metabolites on skeletal muscle, adipose tissue, immune system, and the brain suggest that some of these compounds could qualify as exercise-induced myokines. Indeed, some of the more recently discovered biological activities for kynurenines include many of the best-known benefits of exercise: improved energy homeostasis, promotion of an anti-inflammatory environment, and neuroprotection. Finally, by considering the tissue expression of the different membrane and cytosolic receptors for kynurenines, we discuss known and potential biological activities for these tryptophan metabolites.
Mitochondrial 8-oxoguanine DNA glycosylase mitigates alveolar epithelial cell PINK1 deficiency, mitochondrial DNA damage, apoptosis, and lung fibrosis
Authors: Kim Seok-Jo , Cheresh Paul , Jablonski Renea P. , Rachek Lyudmila , Yeldandi Anjana , Piseaux-Aillon Raul , Ciesielski Mark J. , Ridge Karen , Gottardi Cara , Lam Anna P. , Pardo Annie , Selman Moises , Natarajan Viswanathan , Kamp David W.
Published: March 2020

Alveolar epithelial cell (AEC) apoptosis, arising from mitochondrial dysfunction and mitophagy defects, is important in mediating idiopathic pulmonary fibrosis (IPF). Our group established a role for the mitochondrial (mt) DNA base excision repair enzyme, 8-oxoguanine-DNA glycosylase 1 (mtOGG1), in preventing oxidant-induced AEC mtDNA damage and apoptosis and showed that OGG1-deficient mice have increased lung fibrosis. Herein, we determined whether mice overexpressing the mtOGG1 transgene ( mtOgg1tg) are protected against lung fibrosis and whether AEC mtOGG1 preservation of mtDNA integrity mitigates phosphatase and tensin homolog-induced putative kinase 1 (PINK1) deficiency and apoptosis. Compared with wild type (WT), mtOgg1tg mice have diminished asbestos- and bleomycin-induced pulmonary fibrosis that was accompanied by reduced lung and AEC mtDNA damage and apoptosis. Asbestos and H2O2 promote the MLE-12 cell PINK1 deficiency, as assessed by reductions in the expression of PINK1 mRNA and mitochondrial protein expression. Compared with WT, Pink1-knockout ( Pink1-KO) mice are more susceptible to asbestos-induced lung fibrosis and have increased lung and alveolar type II (AT2) cell mtDNA damage and apoptosis. AT2 cells from Pink1-KO mice and PINK1-silenced (siRNA) MLE-12 cells have increased mtDNA damage that is augmented by oxidative stress. Interestingly, mtOGG1 overexpression attenuates oxidant-induced MLE-12 cell mtDNA damage and apoptosis despite PINK1 silencing. mtDNA damage is increased in the lungs of patients with IPF as compared with controls. Collectively, these findings suggest that mtOGG1 maintenance of AEC mtDNA is crucial for preventing PINK1 deficiency that promotes apoptosis and lung fibrosis. Given the key role of AEC apoptosis in pulmonary fibrosis, strategies aimed at preserving AT2 cell mtDNA integrity may be an innovative target.
Gradual cold acclimation induces cardioprotection without affecting β-adrenergic receptor-mediated adenylyl cyclase signaling
Authors: Tibenska V. , Benesova A. , Vebr P. , Liptakova A. , Hejnová L. , Elsnicová B. , Drahota Z. , Hornikova D. , Galatík F. , Kolar D. , Vybiral S. , Alánová P. , Novotný J. , Kolar F. , Novakova O. , Zurmanova J. M.
Published: March 2020

Novel strategies are needed that can stimulate endogenous signaling pathways to protect the heart from myocardial infarction. The present study tested the hypothesis that appropriate regimen of cold acclimation (CA) may provide a promising approach for improving myocardial resistance to ischemia/reperfusion (I/R) injury without negative side effects. We evaluated myocardial I/R injury, mitochondrial swelling, and β-adrenergic receptor (β-AR)-adenylyl cyclase-mediated signaling. Male Wistar rats were exposed to CA (8°C, 8 h/day for a week, followed by 4 wk at 8°C for 24 h/day), while the recovery group (CAR) was kept at 24°C for an additional 2 wk. The myocardial infarction induced by coronary occlusion for 20 min followed by 3-h reperfusion was reduced from 56% in controls to 30% and 23% after CA and CAR, respectively. In line, the rate of mitochondrial swelling at 200 μM Ca2+was decreased in both groups. Acute administration of metoprolol decreased infarction in control group and did not affect the CA-elicited cardiprotection. Accordingly, neither β1-AR-Gsα-adenylyl cyclase signaling, stimulated with specific ligands, nor p-PKA/PKA ratios were affected after CA or CAR. Importantly, Western blot and immunofluorescence analyses revealed β2- and β3-AR protein enrichment in membranes in both experimental groups. We conclude that gradual cold acclimation results in a persisting increase of myocardial resistance to I/R injury without hypertension and hypertrophy. The cardioprotective phenotype is associated with unaltered adenylyl cyclase signaling and increased mitochondrial resistance to Ca2+-overload. The potential role of upregulated β2/β3-AR pathways remains to be elucidated.

NEW & NOTEWORTHY We present a new model of mild gradual cold acclimation increasing tolerance to myocardial ischemia/reperfusion injury without hypertension and hypertrophy. Cardioprotective phenotype is accompanied by unaltered adenylyl cyclase signaling and increased mitochondrial resistance to Ca2+-overload. The potential role of upregulated β2/β3-adrenoreceptor activation is considered. These findings may stimulate the development of novel preventive and therapeutic strategies against myocardial ischemia/reperfusion injury.
Early gamma-oscillations as correlate of localized nociceptive processing in primary sensorimotor cortex
Authors: Heid C. , Mouraux A. , Treede R.-D. , Schuh-Hofer S. , Rupp A. , Baumgärtner U.
Published: March 2020

Gamma-band oscillations show hand-foot somatotopy compatible with generation in primary sensorimotor cortex and are present following nociceptive but not tactile stimulation of the hand and foot in humans.