bluuebunny/crossref_metadata_2025 huggingface dataset:
CPI-613 rewires lipid metabolism to enhance pancreatic cancer apoptosis via the AMPK-ACC signaling
Authors: Gao Lixia , Xu Zhigang , Huang Zheng , Tang Yan , Yang Donglin , Huang Jiuhong , He Leilei , Liu Manran , Chen Zhongzhu , Teng Yong
Published: April 2020

Background

Pancreatic cancer remains one of the most rapidly progressive and deadly malignancies worldwide. Current treatment regimens only result in small improvements in overall survival for patients with this cancer type. CPI-613 (Devimistat), a novel lipoate analog inhibiting mitochondrial metabolism, shows the new hope for pancreatic cancer treatment as an efficient and well-tolerated therapeutic option treated alone or in combination with chemotherapy.

Methods

Pancreatic cancer cells growing in planar 2D cultures and 3D scaffold were used as research platforms. Cell viability was measured by MTT and alamarBlue, and apoptosis was assessed by JC-1 staining and flow cytometry with Annexin V-FITC/PI staining. The mechanism behind CPI-613 action was analyzed by western blot, transmission electron microscopy, and lipolysis assay kits, in the presence or absence of additional signaling pathway inhibitors or gene modifications.

Results

CPI-613 exhibits anticancer activity in pancreatic cancer cells by triggering ROS-associated apoptosis, which is accompanied by increased autophagy and repressed lipid metabolism through activating the AMPK signaling. Intriguingly, ACC, the key enzyme modulating lipid metabolism, is identified as a vital target of CPI-613, which is inactivated in an AMPK-dependent manner and influences apoptotic process upon CPI-613. Blockade or enhancement of autophagic process does not increase or blunt apoptosis to CPI-613, but inhibition of the AMPK-ACC signaling significantly attenuates apoptosis induced by CPI-613, suggesting CPI-613-mediated lipid metabolism reduction contributes to its cytotoxicity in pancreatic cancer cells.

Conclusions

These findings explore the critical role of lipid metabolism in apoptosis, providing new insights into the AMPK-ACC signaling axis in crosstalk between lipid metabolism and apoptosis in CPI-613 treatment.
REPIC: a database for exploring the N6-methyladenosine methylome
Authors: Liu Shun , Zhu Allen , He Chuan , Chen Mengjie
Published: April 2020

The REPIC (RNA EPItranscriptome Collection) database records about 10 million peaks called from publicly available m6A-seq and MeRIP-seq data using our unified pipeline. These data were collected from 672 samples of 49 studies, covering 61 cell lines or tissues in 11 organisms. REPIC allows users to query N6-methyladenosine (m6A) modification sites by specific cell lines or tissue types. In addition, it integrates m6A/MeRIP-seq data with 1418 histone ChIP-seq and 118 DNase-seq data tracks from the ENCODE project in a modern genome browser to present a comprehensive atlas of m6A methylation sites, histone modification sites, and chromatin accessibility regions. REPIC is accessible at https://repicmod.uchicago.edu/repic.
ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data
Authors: Dolzhenko Egor , Bennett Mark F. , Richmond Phillip A. , Trost Brett , Chen Sai , van Vugt Joke J. F. A. , Nguyen Charlotte , Narzisi Giuseppe , Gainullin Vladimir G. , Gross Andrew M. , Lajoie Bryan R. , Taft Ryan J. , Wasserman Wyeth W. , Scherer Stephen W. , Veldink Jan H. , Bentley David R. , Yuen Ryan K. C. , Bahlo Melanie , Eberle Michael A.
Published: April 2020

Repeat expansions are responsible for over 40 monogenic disorders, and undoubtedly more pathogenic repeat expansions remain to be discovered. Existing methods for detecting repeat expansions in short-read sequencing data require predefined repeat catalogs. Recent discoveries emphasize the need for methods that do not require pre-specified candidate repeats. To address this need, we introduce ExpansionHunter Denovo, an efficient catalog-free method for genome-wide repeat expansion detection. Analysis of real and simulated data shows that our method can identify large expansions of 41 out of 44 pathogenic repeats, including nine recently reported non-reference repeat expansions not discoverable via existing methods.
Origin of the nuclear proteome on the basis of pre-existing nuclear localization signals in prokaryotic proteins
Authors: Lisitsyna Olga M. , Kurnaeva Margarita A. , Arifulin Eugene A. , Shubina Maria Y. , Musinova Yana R. , Mironov Andrey A. , Sheval Eugene V.
Published: April 2020

Background

The origin of the selective nuclear protein import machinery, which consists of nuclear pore complexes and adaptor molecules interacting with the nuclear localization signals (NLSs) of cargo molecules, is one of the most important events in the evolution of eukaryotic cells. How proteins were selected for import into the forming nucleus remains an open question.

Results

Here, we demonstrate that functional NLSs may be integrated in the nucleotide-binding domains of both eukaryotic and prokaryotic proteins and may coevolve with these domains.

Conclusion

The presence of sequences similar to NLSs in the DNA-binding domains of prokaryotic proteins might have created an advantage for nuclear accumulation of these proteins during evolution of the nuclear-cytoplasmic barrier, influencing which proteins accumulated and became compartmentalized inside the forming nucleus (i.e., the content of the nuclear proteome).

Reviewers

This article was reviewed by Sergey Melnikov and Igor Rogozin.

Open peer review

Reviewed by Sergey Melnikov and Igor Rogozin. For the full reviews, please go to the Reviewers’ comments section.
Intense versus standard regimens of intermittent occlusion therapy for unilateral moderate amblyopia in children: study protocol for a randomized controlled trial
Authors: Wang Jingyun , Malik Ayesha , Jin Jing , Pang Yi , Yin Kelly , Allen Megan , Grigorian Adriana , Scombordi Brandy , Bailey Joann , Aljohani Saeed , Funari Katharine , Shoge Ruth , Meiyeppen Siva , Myung Jenny , Soni Ajay , Neely Daniel E.
Published: April 2020

Background

We reported that in our previous study that wearing intermittent occlusion therapy glasses (IO-therapy) for 4 hours (h) was non-inferior to patching for 2 h in 3 to 8-year-old children with amblyopia. We hypothesize that an intense regimen of 12-h IO-therapy per day for 4 weeks could be as effective as the standard regimen of 4-h IO-therapy per day for 12 weeks in treating moderate amblyopia in 3 to 8-year-old children.

Methods/Design

A total of 56 children between 3 and 8 years of age with amblyopia in association with anisometropia and/or strabismus will be enrolled. All participants will be prescribed IO-therapy glasses (Amblyz™), set at 30-s opaque/transparent intervals (i.e., occluded 50% of wear time). They will be randomized to receive the standard regimen for 12 weeks or the intense regimen for 4 weeks. Adherence to using the IO-therapy glasses will be objectively monitored in each participant by means of a microsensor dose monitor. The primary study objective is to compare the effectiveness of an intense regimen to a standard regimen of IO-therapy in 3 to 8-year-old children with moderate amblyopia. The secondary study objectives are to determine whether adherence differs between an intense regimen and a standard regimen of IO-therapy, and to determine the dose-response relationship of IO-therapy.

Discussion

In addition to testing the effectiveness, this study will test for the first time the association between treatment adherence and the visual outcome of IO-therapy, which will enhance our understanding of the dose-response relationship of IO-therapy. If an intense regimen is shown to be effective, it would alter amblyopia treatment strategies and improve visual outcomes.

Trial registration

ClinicalTrials.gov: NCT02767856. Registered on 10 May 2016.
Protocol for a randomized multicenter study for isolated skin vasculitis (ARAMIS) comparing the efficacy of three drugs: azathioprine, colchicine, and dapsone
Authors:   for the Vasculitis Clinical Research Consortium, Micheletti Robert G. , Pagnoux Christian , Tamura Roy N. , Grayson Peter C. , McAlear Carol A. , Borchin Renee , Krischer Jeffrey P. , Merkel Peter A.
Published: April 2020

Background

Skin-limited forms of vasculitis, while lacking systemic manifestations, can persist or recur indefinitely, cause pain, itch, or ulceration, and be complicated by infection or scarring. High-quality evidence on how to treat these conditions is lacking. The aim of this comparative effectiveness study is to determine the optimal management of patients with chronic skin-limited vasculitis.

Methods

ARAMIS is a multicenter, sequential, multiple assignment randomized trial with an enrichment design (SMARTER) aimed at comparing the efficacy of three drugs—azathioprine, colchicine, and dapsone—commonly used to treat various forms of isolated skin vasculitis. ARAMIS will enroll patients with isolated cutaneous small or medium vessel vasculitis, including cutaneous small vessel vasculitis, immunoglobulin A (IgA) vasculitis (skin-limited Henoch-Schönlein purpura), and cutaneous polyarteritis nodosa. Patients not responding to the initial assigned therapy will be re-randomized to one of the remaining two study drugs (Stage 2). Those with intolerance or contraindication to a study drug can be randomized directly into Stage 2. Target enrollment is 90 participants, recruited from international centers affiliated with the Vasculitis Clinical Research Consortium. The number of patients enrolled directly into Stage 2 of the study will be capped at 10% of the total recruitment target. The primary study endpoint is the proportion of participants from the pooled study stages with a response to therapy at month 6, according to the study definition.

Discussion

ARAMIS will help identify effective agents for skin-limited forms of vasculitis, an understudied group of diseases. The SMARTER design may serve as an example for future trials in rare diseases.

Trial registration

ClinicalTrials.gov: NCT02939573. Registered on 18 October 2016.
Lay-therapist-delivered, low-intensity, psychosocial intervention for refugees and asylum seekers (PROSPER): protocol for a pilot randomised controlled trial
Authors: Rawlinson Rebecca , Aslam Rabeea’h W. , Burnside Girvan , Chiumento Anna , Eriksson-Lee Malena , Humphreys Amy , Khan Naila , Lawrence Daniel , McCluskey Rachel , Mackinnon Annette , Orton Lois , Rahman Atif , Roberts Ewan , Rosala-Hallas Anna , Edwards Rhiannon Tudor , Uwamaliya Philomene , White Ross G. , Winrow Eira , Dowrick Christopher
Published: April 2020

Background

Asylum seekers and refugees (AS&Rs) experience impaired mental health and wellbeing, related to stresses in their country of origin, experiences in transit and reception on arrival, including significant barriers to accessing mainstream services. Their contact with health care is often crisis-driven and mediated through non-governmental organisations (NGOs).

Problem Management Plus (PM+) is a psychosocial intervention recommended by the World Health Organisation to address distress experienced by adults affected by humanitarian crises. We are investigating its application for the first time in a high-income country.

Methods

In a pilot randomised controlled trial (RCT), PM+ will be delivered to AS&Rs in contact with NGOs in Liverpool City Region, UK by lay therapists who have lived experience of forced migration. Following systematic review and stakeholder engagement, PM+ has been adapted to the local context, and lay therapists have been trained in its delivery.

We will assess the feasibility of conducting a three-arm RCT of five 90-min sessions of PM+, delivered individually or in groups by lay therapists to AS&Rs experiencing emotional distress and functional impairment, compared with each other and with usual support offered by local NGOs. Distress and impairment at baseline will be measured by the Hospital Anxiety and Depression Scale (HADS) and the WHO Disability Assessment Schedule (WHO-DAS). We aim to recruit 105 participants, 35 per arm.

Primary health outcomes are anxiety and depressive symptoms at 3 months, measured by HADS. Secondary outcomes include subjective wellbeing, functional status, progress on identified problems, presence of post-traumatic stress disorder and depressive disorder and service usage. Longer-term impact will be assessed at 6 months post baseline, on the same parameters.

We will assess the feasibility of conducting a full RCT in relation to the following elements: recruitment and retention of lay therapists and study participants; fidelity of delivery of PM+; and suitability of the study measures, including any linguistic or cultural barriers.

Discussion

We will use these findings to specify the parameters for a full RCT to test the effectiveness and cost-effectiveness of PM+ in reducing emotional distress and health inequalities, and improving functional ability and wellbeing, amongst asylum seekers and refugees.

Trial registration

ISRCTN, ID: ISRCTN15214107. Registered on 10 September 2019.
Nonexistence and existence of positive radial solutions to a class of quasilinear Schrödinger equations in $\mathbb{R}^{N}$
Authors: Li Jing , Wang Ying
Published: April 2020

This paper aims to investigate the class of quasilinear Schrödinger equations $$\begin{aligned} \begin{aligned}[b] &-\Delta u-\bigl[\Delta \bigl(1+u^{2}\bigr)^{\frac{\gamma }{2}}\bigr] \frac{\gamma u}{2(1+u^{2})^{\frac{2-\gamma }{2}}}\\ &\quad =\alpha h\bigl( \vert x \vert \bigr) \vert u \vert ^{p-1}u+ \beta H\bigl( \vert x \vert \bigr) \vert u \vert ^{q-1}u, \quad x\in \mathbb{R}^{N}, \end{aligned} \end{aligned}$$ −Δu−[Δ(1+u2)γ2]γu2(1+u2)2−γ2=αh(|x|)|u|p−1u+βH(|x|)|u|q−1u,x∈RN, where $N >2$N>2, $1 \le \gamma \le 2$1≤γ≤2, $\alpha ,\beta \in \mathbb{R}$α,β∈R and either $0< p<1<q$0<p<1<q or $1< p< q$1<p<q. Functions $h(|x|)$h(|x|), $H(|x|)$H(|x|) are continuous and positive in $\mathbb{R}^{N} $RN. Relying on some special arguments and the Schauder–Tychonoff fixed point theorem, nonexistence criteria, existence of positive ground state solutions and blow-up solutions to Eq. (0.1) with $0< p<1<q$0<p<1<q or $1< p< q$1<p<q will be obtained.
The controllability of nonlinear fractional differential system with pure delay
Authors: Nawaz Musarrat , Jiang Wei , Sheng Jiale
Published: April 2020

In this study, we are currently investigating the controllability of nonlinear fractional differential control systems with delays in the state function. The solution representations of fractional delay differential equations have been established by using the delayed Mittag-Leffler function. Firstly we obtain the result of the controllability of a linear fractional control system with delay. Then, for the controllability criteria of nonlinear fractional delay system, we establish the set of sufficient conditions of nonlinear fractional differential systems with delay in their state function by using Schauder’s fixed point theorem. In the end, a numerical example is constructed to support the results.
Local fractional Newton’s inequalities involving generalized harmonic convex functions
Authors: Iftikhar Sabah , Erden Samet , Kumam Poom , Awan Muhammad Uzair
Published: April 2020

A new auxiliary result based on a three step quadratic kernel utilizing the concepts of local fractional calculus is obtained. Using this new auxiliary result we have several new Newton type inequalities whose power q of local fractional derivative in modulus is a generalized harmonic convex function.
Correction to: 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: April 2020

An amendment to this paper has been published and can be accessed via the original article.
Enhanced accumulation of N-terminally truncated Aβ with and without pyroglutamate-11 modification in parvalbumin-expressing GABAergic neurons in idiopathic and dup15q11.2-q13 autism
Authors: Frackowiak Janusz , Mazur-Kolecka Bozena , Mehta Pankaj , Wegiel Jerzy
Published: April 2020

Autism, the most frequent neurodevelopmental disorder of a very complex etiopathology, is associated with dysregulation of cellular homeostatic mechanisms, including processing of amyloid-β precursor protein (APP). Products of APP processing — N-terminally truncated amyloid-β peptide (N-tr-Aβ) species — are accumulated in autism in neurons and glia in the cortex, cerebellum, and subcortical structures of the brain. This process in neurons is correlated with increased oxidative stress. Because abnormally high levels of N-tr-Aβ are detected in only a fraction of neurons in the prefrontal cortex, we applied immunohistochemical staining and confocal microscopy in autopsy brain material from idiopathic and chromosome 15q11.2-q13 duplication (dup-15) autism to measure the load of N-tr-Aβ in the cells and synapses and to identify the subpopulation of neurons affected by these pathophysiological processes. The peptides accumulated in autism are N-terminally truncated; therefore, we produced a new antibody against Aβ truncated at N-terminal amino acid 11 modified to pyroglutamate to evaluate the presence and distribution of this peptide species in autism. We also quantified and characterized the oligomerization patterns of the Aβ-immunoreactive peptides in autism and control frozen brain samples. We provide morphological evidence, that in idiopathic and dup-15 autism, accumulation of N-tr-Aβ with and without pyroglutamate-11 modified N-terminus affects mainly the parvalbumin-expressing subpopulation of GABAergic neurons. N-tr-Aβ peptides are accumulated in neurons’ cytoplasm and nucleus as well as in GABAergic synapses. Aβ peptides with both C-terminus 40 and 42 were detected by immunoblotting in frozen cortex samples, in the form of dimers and complexes of the molecular sizes of 18–24kD and 32–34kD. We propose that deposition of N-tr-Aβ specifically affects the functions of the parvalbumin-expressing GABAergic neurons and results in a dysregulation of brain excitatory–inhibitory homeostasis in autism. This process may be the target of new therapies.
Validation of machine learning models to detect amyloid pathologies across institutions
Authors: Vizcarra Juan C. , Gearing Marla , Keiser Michael J. , Glass Jonathan D. , Dugger Brittany N. , Gutman David A.
Published: April 2020

Semi-quantitative scoring schemes like the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) are the most commonly used method in Alzheimer’s disease (AD) neuropathology practice. Computational approaches based on machine learning have recently generated quantitative scores for whole slide images (WSIs) that are highly correlated with human derived semi-quantitative scores, such as those of CERAD, for Alzheimer’s disease pathology. However, the robustness of such models have yet to be tested in different cohorts. To validate previously published machine learning algorithms using convolutional neural networks (CNNs) and determine if pathological heterogeneity may alter algorithm derived measures, 40 cases from the Goizueta Emory Alzheimer’s Disease Center brain bank displaying an array of pathological diagnoses (including AD with and without Lewy body disease (LBD), and / or TDP-43-positive inclusions) and levels of Aβ pathologies were evaluated. Furthermore, to provide deeper phenotyping, amyloid burden in gray matter vs whole tissue were compared, and quantitative CNN scores for both correlated significantly to CERAD-like scores. Quantitative scores also show clear stratification based on AD pathologies with or without additional diagnoses (including LBD and TDP-43 inclusions) vs cases with no significant neurodegeneration (control cases) as well as NIA Reagan scoring criteria. Specifically, the concomitant diagnosis group of AD + TDP-43 showed significantly greater CNN-score for cored plaques than the AD group. Finally, we report that whole tissue computational scores correlate better with CERAD-like categories than focusing on computational scores from a field of view with densest pathology, which is the standard of practice in neuropathological assessment per CERAD guidelines. Together these findings validate and expand CNN models to be robust to cohort variations and provide additional proof-of-concept for future studies to incorporate machine learning algorithms into neuropathological practice.
Preoperative tumor size measurement in breast cancer patients: which threshold is appropriate on computer-aided detection for breast MRI?
Authors: Song Sung Eun , Seo Bo Kyoung , Cho Kyu Ran , Woo Ok Hee , Park Eun Kyung , Cha Jaehyung , Han Seungju
Published: April 2020

Background

Computer-aided detection (CAD) can detect breast lesions by using an enhancement threshold. Threshold means the percentage of increased signal intensity in post-contrast imaging compared to precontrast imaging. If the pixel value of the enhanced tumor increases above the set threshold, CAD provides the size of the tumor, which is calculated differently depending on the set threshold. Therefore, CAD requires the accurate setting of thresholds. We aimed to compare the diagnostic accuracy of tumor size measurement using MRI and CAD with 3 most commonly used thresholds and to identify which threshold is appropriate on CAD in breast cancer patients.

Methods

A total of 130 patients with breast cancers (80 invasive cancers and 50 ductal carcinoma in situ [DCIS]) who underwent preoperative MRI with CAD and surgical treatment were included. Tumor size was manually measured on first contrast-enhanced MRI and acquired by CAD using 3 different thresholds (30, 50, and 100%) for each tumor. Tumor size measurements using MRI and CAD were compared with pathological sizes using Spearman correlation analysis. For comparison of size discrepancy between imaging and pathology, concordance was defined as estimation of size by imaging within 5 mm of the pathological size. Concordance rates were compared using Chi-square test.

Results

For both invasive cancers and DCIS, correlation coefficient rho (r) between tumor size on imaging and pathology was highest at CAD with 30% threshold, followed by MRI, CAD with 50% threshold, and CAD with 100% threshold (all p <  0.05). For invasive cancers, the concordance rate of 72.5% at CAD with 30% threshold showed no difference with that of 62.5% at MRI (p = 0.213). For DCIS, the concordance rate of 30.0% at CAD with 30% threshold showed no difference with that of 36.0% at MRI (p = 0.699). Compared to MRI, higher risk of underestimation was noted when using CAD with 50% or 100% threshold for invasive cancers and when using CAD with 100% threshold for DCIS.

Conclusion

For CAD analysis, 30% threshold is the most appropriate threshold whose accuracy is comparable to manual measurement on MRI for tumor size measurement. However, clinicians should be aware of the higher risk of underestimation when using CAD with 50% threshold for tumor staging in invasive cancers.
Groundwater NO3 concentration and its potential health effects in Beni Moussa perimeter (Tadla plain, Morocco)
Authors: Barakat Ahmed
Published: April 2020

In this research, the concentrations of nitrates were investigated in well water sampled from the irrigated perimeter of Beni Moussa (Tadla plain, Morocco), and human health risks via ingestion and dermal pathways for individuals in different age brackets were assessed using the chronic daily intake, the dermal absorbed dose and hazard index (HI).

The results showed that the groundwater NO3 contents were between 4.20 to 80.46 mg L− 1, with an average of 32.11 mg L− 1, indicating anthropogenic inputs caused by the infiltration of nitrates not consumed by plants or surface industrial and domestic wastewater into the shallow aquifer. Compared to the Moroccan standard, 17.78%, 40.00%, 37.78% and 4.44% of sampled wells showed poor, fair, good or excellent quality, respectively. For non-carcinogenic risk, the oral ingestion of nitrate appeared to be the main exposure pathway for local human receptors causing the high non-carcinogenic risk, and the dermal exposure met within the accepted precautionary criterion. Infants in the study area are more likely to experience adverse effects to higher nitrate level in groundwater (3.04E-01 < HI < 1.80E+ 00), followed by female (2.39E-01 < HI < 1.41E+ 00), then male (2.22E-01 < HI < 1.31E+ 00) and finally children (2.08E-01 < HI < 1.23E+ 00). The resulting spatial variation in HI values was greatly influenced by human activities and population density.

The results of this study could help to shape effective environmental management measures for enhancing the groundwater quality and ensuring safe drinking water.
Negativity about the outcomes of extreme prematurity a persistent problem - a survey of health care professionals across the North Queensland region
Authors: Ireland Susan , Larkins Sarah , Ray Robin , Woodward Lynn
Published: April 2020

Background

Extremely preterm babies are at risk of significant mortality and morbidity due to their physiological immaturity. At periviable gestations decisions may be made to either provide resuscitation and intensive care or palliation based on assessment of the outlook for the baby and the parental preferences. Health care professionals (HCP) who counsel parents will influence decision making depending on their individual perceptions of the outcome for the baby. This paper aims to explore the knowledge and attitudes towards extremely preterm babies of HCP who care for women in pregnancy in a tertiary, regional and remote setting in North Queensland.

Methods

A cross sectional electronic survey of HCP was performed. Perceptions of survival, severe disability and intact survival data were collected for each gestational age from 22 to 27 completed weeks gestation. Free text comment enabled qualitative content analysis.

Results

Almost all 113 HCP participants were more pessimistic than the actual outcome data suggests. HCP caring for women antenatally were the most pessimistic for survival (p = 0.03 at 23 weeks, p = 0.02 at 25,26 and 27 weeks), severe disability (p = 0.01 at 24 weeks) and healthy outcomes (p = 0.01 at 24 weeks), whilst those working in regional and remote centres were more negative than those in tertiary unit for survival (p = 0.03 at 23,24,25 weeks). Perception became less negative as gestational age increased.

Conclusion

Pessimism of HCP may be negatively influencing decision making and will negatively affect the way in which parents perceive the chances of a healthy outcome for their offspring.
Study protocol for a cluster randomised controlled feasibility trial evaluating personalised care planning for older people with frailty: PROSPER V2 27/11/18
Authors: Heaven Anne , Bower Peter , Cundill Bonnie , Farrin Amanda , Foster Marilyn , Foy Robbie , Hartley Suzanne , Hawkins Rebecca , Hulme Claire , Humphrey Sara , Lawton Rebecca , Parker Catriona , Pendleton Neil , West Robert , Young John , Clegg Andrew
Published: April 2020

Background

Frailty is characterised by increased vulnerability to falls, disability, hospitalisation and care home admission. However, it is relatively reversible in the early stages. Older people living with frailty often have multiple health and social issues which are difficult to address but could benefit from proactive, person-centred care. Personalised care planning aims to improve outcomes through better self-management, care coordination and access to community resources.

Methods

This feasibility cluster randomised controlled trial aims to recruit 400 participants from 11 general practice clusters across Bradford and Leeds in the north of England. Eligible patients will be aged over 65 with an electronic frailty index score of 0.21 (identified via their electronic health record), living in their own homes, without severe cognitive impairment and not in receipt of end of life care. After screening for eligible patients, a restricted 1:1 cluster-level randomisation will be used to allocate practices to the PROSPER intervention, which will be delivered over 12 weeks by a personal independence co-ordinator worker, or usual care. Following initial consent, participants will complete a baseline questionnaire in their own home including measures of health-related quality of life, activities of daily living, depression and health and social care resource use. Follow-up will be at six and 12 months. Feasibility outcomes relate to progression criteria based around recruitment, intervention delivery, retention and follow-up. An embedded process evaluation will contribute to iterative intervention optimisation and logic model development by examining staff training, intervention implementation and contextual factors influencing delivery and uptake of the intervention.

Discussion

Whilst personalised care planning can improve outcomes in long-term conditions, implementation in routine settings is poor. We will evaluate the feasibility of conducting a cluster randomised controlled trial of personalised care planning in a community population based on frailty status. Key objectives will be to test fidelity of trial design, gather data to refine sample size calculation for the planned definitive trial, optimise data collection processes and optimise the intervention including training and delivery.

Trial registration

ISRCTN12363970 – 08/11/18.
Taking guidance from parents involved in a longitudinal birth cohort – the ROLO family advisory committee
Authors: Walsh N. M. , O’Brien E. C. , Geraghty A. A. , Byrne D. F. , Whelan A. , Reilly S. , Murray S. , Reilly C. , Adams E. , Farnan P. M. , McAuliffe F. M.
Published: April 2020

Background

The ROLO Study (Randomised cOntrol trial of a Low glycaemic index diet in pregnancy to prevent macrosomia) was a randomised control trial conducted between 2007 and 2011 to examine if a low glycaemic index (GI) diet could reduce the incidence of macrosomia. The ROLO Family Advisory Committee is a self-selected group of parents who are involved in the longitudinal follow-up of the ROLO Study. The committee was established in 2017 and the goal is to achieve a partnership between ROLO families and researchers, leading to improved research quality, relevance, and outcomes. This research method is termed “Public and patient involvement (PPI)” and describes how researchers collaborate and engage with the public in order to make research more relevant to them.

Methods

The ROLO study mothers and children have been prospectively followed-up at multiple time points post-pregnancy. In October 2017, all women were invited to join the ROLO Family Advisory Committee via email or via advertisement on the ROLO Study Facebook page. Fathers and other guardians of the study children were also invited to join. Two annual meetings with the research team and parents were held in 2018 and 2019. The meetings were recorded, transcribed verbatim by researchers, and thematically analysed.

Results

Parents provided opinions on the areas they felt should be explored within the ROLO study using information that was collected up to the current follow-up point. They also shared views on research interests which were of importance to them. These topics included; child mental health, fussy eating in childhood and healthy eating policies in schools. Mothers were much more concerned about factors which influenced their child’s health rather than their own. Incorporating an element of PPI to this study was found to be a positive learning experience for participants and researchers.

Conclusion

The involvement of parents has enriched the research agenda at the UCD Perinatal Research Centre. We will continue to engage with the parents of the ROLO Study and plan to involve the children to explore their opinions at the next opportunity.
A bibliometric analysis of socially responsible investment sukuk literature
Authors: Rahman Mahfuzur , Isa Che Ruhana , Tu Teng-Tsai , Sarker Moniruzzaman , Masud Md. Abdul Kaium
Published: April 2020

Despite the impressive growth of socially responsible investment (SRI) Sukuk (Islamic bond) over the last five years, a handful of comprehensive research is documented in literature. Hence, the aim of this study is to systematically explore and cluster the SRI Sukuk literature to offer comprehensive guidelines for future research. A total of 232 peer reviewed papers fromWeb of Sciencedatabase were considered for bibliometric analysis (usingVOSviewer software) which are published over the period of 1970-May 2019. This analysis shows SRI Sukuk literature mainly falls in three research clusters: (1) nature of SRI Sukuk, (2) competitiveness of SRI Sukuk, and (3) determinants of SRI Sukuk. However, very few studies have explored the determinants of SRI Sukuk investment. The literature also indicates that, SRI Sukuk research are highly collaborated between Malaysia, Australia, and the USA yet the number is trifling. Thus, exploring motivational factors of SRI Sukuk investment and its impact on the nation’s economic development in a cross-country setting would be worthwhile researching.
Estimating some demographic parameters of Aphidius matricariae Haliday (Hymenoptera: Braconidae), the parasitoid of the greenbug aphid, Schizaphis graminum (Rondani) (Hemiptera: Aphididae), at different temperatures
Authors: Rashki Maryam , Shirvani Asghar , Hajrahmatollahi Fatemeh
Published: April 2020

Some demographic parameters of the indigenous parasitoid,Aphidius matricariaeHaliday (Hymenoptera: Braconidae) parasitizing the greenbug,Schizaphis graminum(Rondani) (Hemiptera: Aphididae), were estimated at 3 different temperatures (20, 25, and 30 ± 1 °C; 70 ± 5% RH; 16 L:8D). According to age-specific theory, the demographic parameters of the parasitoid were computed by related formulas. The results showed that duration of mummy’s formation to adult emergence and oviposition to adult emergence were significantly prolonged at 30 °C. The high temperature (30 °C) markedly shortened the longevity and lifespan of the wasp. The lowest value of fecundity (6.35 ± 0.85) significantly occurred when the female wasps were exposed to 30 °C. The estimated values ofrmwere remarkably high when the female wasps were exposed to 20 (0.320 ± 0.011) and 25 °C (0.310 ± 0.009). The lowest and highest values of theR0significantly occurred at 30 (6.167 ± 0.754) and 20 °C (55.306 ± 6.316). Theλ,T,DT, andrwvalues were noticeably decreased at high temperature, and there was non-significant difference between the two other temperatures. High temperature decreased the number of females produced per female per day (mx) and survival rate (lx) of the parasitoid wasp. The highestmxandlxhappened at 20 and 25 °C, respectively. Therefore, the results showed that the parasitoid wasp was sensitive to the high temperature, as its low reproduction, survival, and short adult longevity were recorded. Considering the characteristics, the wasp appeared to be well-adapt with the temperatures below 30 °C. Understanding the optimal temperatures for the life history traits ofA. matricariaecould promote the performance of the parasitoid wasp in different climatic regions, and this might advance the mass production of the parasitoid applied in IPM program for successful biological control ofS. graminum.
Ovarian carcinoma in patients with BRCA mutation - a correlation between the growing pattern of peritoneal implants evaluated by CT/MRI and the genotype BRCA1 and BRCA2
Authors: Vieira Ana Catarina , Antunes Natalie , Damasceno Eduarda , Ramalho Madalena , Esteves Susana , Vaz Fátima , Félix Ana , Cunha Teresa Margarida
Published: April 2020

Background

Ovarian cancer is the leading cause of death from gynecologic cancer. The risk of developing ovarian cancer is significantly increased in patients that carry a genetic mutation of tumor suppressor gene BRCA1 or BRCA2. The majority of BRCA-associated ovarian/fallopian tube cancers are high-grade serous carcinomas (HGSC). The recognition of patterns of disease is crucial to identify distinctive imaging features that could be useful for predicting prognosis and therapeutic response.

Results

An institutional review board-approved retrospective study was performed and included 34patients (23 BRCA-mutated and 11 BRCA wild-type) with HGSC FIGO III/IV who underwent pre-operative or pre-chemotherapy contrast-enhanced CT/MRI of the abdomen and pelvis between January 2003 and December 2017. Three radiologists independently reviewed the imaging studies and looked for qualitative features of the primary tumor and peritoneal metastases (nodular versus infiltrative pattern). Two pathologists also assessed the histopathologic characteristics of the surgical specimens, with emphasis on the growth pattern of metastatic deposits (expansive/nodular and infiltrative) and inflammatory infiltrate (intra- and/or peritumoral).

No significant associations were found between the different groups of patients (BRCA1-mutant HGSC, BRCA2-mutant HGSC. and BRCA wild-type) and CT/MRI features of ovarian tumors, morphology of peritoneal metastasis, and pathologic characteristics.

Conclusion

Identification of specific imaging and pathologic features is important to pursue an optimal personalized cancer treatment strategy and to develop precision medicine in the future.
Immune Checkpoint Blockade for Prostate Cancer: Niche Role or Next Breakthrough?
Authors: de Almeida Daniel Vargas P. , Fong Lawrence , Rettig Matthew B. , Autio Karen A.
Published: April 2020

A number of trials have evaluated the use of single-agent immune checkpoint inhibitors for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The benefit appears to be limited to a small subset of patients, such as those with tumors with microsatellite instability, highlighting the importance of biomarkers to identify which patients may be more likely to respond. Given the lack of efficacy for most patients with mCRPC, our understanding of the mechanisms of primary resistance to checkpoint inhibitors and of the tumor immune microenvironment in prostate cancer is critical. Knowledge gained in these key areas will allow for the identification of novel combination therapies that will circumvent resistance mechanisms and should be tested in clinical trials. Improving our understanding of the effects of androgen deprivation therapy on immune cells and of the most favorable disease setting (e.g., biochemically recurrent vs. castration-resistant prostate cancer) may aid in the optimal use of checkpoint inhibitors in combination with other agents. If successful, this may move immune checkpoint inhibitors into the treatment armamentarium of prostate cancer management.
Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients With Acute Myeloid Leukemia: A Report From the Children’s Oncology Group
Authors: Getz Kelly D. , Sung Lillian , Alonzo Todd A. , Leger Kasey J. , Gerbing Robert B. , Pollard Jessica A. , Cooper Todd , Kolb E. Anders , Gamis Alan S. , Ky Bonnie , Aplenc Richard
Published: April 2020

PURPOSE

To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens.

PATIENTS AND METHODS

This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children’s Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF < 28% or EF < 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure.

RESULTS

A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% v 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; P = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% v 45.1%; P = .534) and OS (65.0% v 61.9%; P = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% v 12.7%; P = .068).

CONCLUSION

Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.
The Presence of Active Brown Adipose Tissue Determines Cold-Induced Energy Expenditure and Oxylipin Profiles in Humans
Authors: Kulterer Oana C , Niederstaetter Laura , Herz Carsten T , Haug Alexander R , Bileck Andrea , Pils Dietmar , Kautzky-Willer Alexandra , Gerner Christopher , Kiefer Florian W
Published: April 2020

Background

Accumulating evidence links brown adipose tissue (BAT) to increased cold-induced energy expenditure (CIEE) and regulation of lipid metabolism in humans. BAT has also been proposed as a novel source for biologically active lipid mediators including polyunsaturated fatty acids (PUFAs) and oxylipins. However, little is known about cold-mediated differences in energy expenditure and various lipid species between individuals with detectable BAT positive (BATpos) and those without BAT negative (BATneg).

Methods

Here we investigated a unique cohort of matched BATpos and BATneg individuals identified by 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography ([18F]-FDG PET/CT). BAT function, CIEE, and circulating oxylipins, were analyzed before and after short-term cold exposure using [18F]-FDG PET/CT, indirect calorimetry, and high-resolution mass spectrometry, respectively.

Results

We found that active BAT is the major determinant of CIEE since only BATpos individuals experienced significantly increased energy expenditure in response to cold. A single bout of moderate cold exposure resulted in the dissipation of an additional 20 kcal excess energy in BATpos but not in BATneg individuals. The presence of BAT was associated with a unique systemic PUFA and oxylipin profile characterized by increased levels of anti-inflammatory omega-3 fatty acids as well as cytochrome P450 products but decreased concentrations of some proinflammatory hydroxyeicosatetraenoic acids when compared with BATneg individuals. Notably, cold exposure raised circulating levels of various lipids, including the recently identified BAT-derived circulating factors (BATokines) DiHOME and 12-HEPE, only in BATpos individuals.

Conclusions

In summary, our data emphasize that BAT in humans is a major contributor toward cold-mediated energy dissipation and a critical organ in the regulation of the systemic lipid pool.
Salt-inducible Kinases Are Critical Determinants of Female Fertility
Authors: Armouti Marah , Winston Nicola , Hatano Osamu , Hobeika Elie , Hirshfeld-Cytron Jennifer , Liebermann Juergen , Takemori Hiroshi , Stocco Carlos
Published: April 2020

Follicle development is the most crucial step toward female fertility and is controlled mainly by follicle-stimulating hormone (FSH). In ovarian granulosa cells (GCs), FSH activates protein kinase A by increasing 3′,5′-cyclic adenosine 5′-monophosphate (cAMP). Since cAMP signaling is impinged in part by salt-inducible kinases (SIKs), we examined the role of SIKs on the regulation of FSH actions. Here, we report that SIKs are essential for normal ovarian function and female fertility. All SIK isoforms are expressed in human and rodent GCs at different levels (SIK3>SIK2>SIK1). Pharmacological inhibition of SIK activity potentiated the stimulatory effect of FSH on markers of GC differentiation in mouse, rat, and human GCs and estradiol production in rat GCs. In humans, SIK inhibition strongly enhanced FSH actions in GCs of patients with normal or abnormal ovarian function. The knockdown of SIK2, but not SIK1 or SIK3, synergized with FSH on the induction of markers of GC differentiation. SIK inhibition boosted gonadotropin-induced GC differentiation in vivo, while the genomic knockout of SIK2 led to a significant increase in the number of ovulated oocytes. Conversely, SIK3 knockout females were infertile, FSH insensitive, and had abnormal folliculogenesis. These findings reveal novel roles for SIKs in the regulation of GC differentiation and female fertility, and contribute to our understanding of the mechanisms regulated by FSH. Furthermore, these data suggest that specific pharmacological modulation of SIK2 activity could be of benefit to treat ovulatory defects in humans and to increase the propagation of endangered species and farm mammals.
“Bread and Roses”
Authors: Juravich Tom
Published: April 2020

This paper traces the history of the song “Bread and Roses” to examine labor culture and the role of song in the labor movement. In the late 1930s and early 1940s, “Bread and Roses” was included in several of the first generation song books produced by unions that reflected an expansive and inclusive labor culture closely connected with the Left. With the ascendance of business unionism and the blacklisting of the Left after the war, labor culture took a heavy blow, and labor songbooks became skeletons of the full-bodied versions they had once been. Unions began to see singing not as part of the process of social change but as a vehicle to bring people together, and songs such as “Bread and Roses” and other more class-based songs were jettisoned in favor of a few labor standards and American sing-along songs. “Bread and Roses” was born anew to embody a central concept in the women’s movement and rode the wave of new music, art, and film that were part of new social movements and new constituencies that challenged business unionism and reshaped union culture in the 1980s.
Reduced immune responsiveness contributes to winter energy conservation in an Arctic bird
Authors: Nord Andreas , Hegemann Arne , Folkow Lars P.
Published: April 2020

Animals in seasonal environments must prudently manage energy expenditure to survive the winter. This may be achieved through reductions in the allocation of energy for various purposes (e.g. thermoregulation, locomotion, etc.). We studied whether such trade-offs also include suppression of the innate immune response, by subjecting captive male Svalbard ptarmigan (Lagopus muta hyperborea) to bacterial lipopolysaccharide (LPS) during exposure to either mild temperature (0°C) or cold snaps (acute exposure to −20°C), in constant winter darkness when birds were in energy-conserving mode, and in constant daylight in spring. The innate immune response was mostly unaffected by temperature. However, energy expenditure was below baseline when birds were immune challenged in winter, but significantly above baseline in spring. This suggests that the energetic component of the innate immune response was reduced in winter, possibly contributing to energy conservation. Immunological parameters decreased (agglutination, lysis, bacteriostatic capacity) or did not change (haptoglobin/PIT54) after the challenge, and behavioural modifications (anorexia, mass loss) were lengthy (9 days). While we did not study the mechanisms explaining these weak, or slow, responses, it is tempting to speculate they may reflect the consequences of having evolved in an environment where pathogen transmission rate is presumably low for most of the year. This is an important consideration if climate change and increased exploitation of the Arctic would alter pathogen communities at a pace outwith counter-adaption in wildlife.