bluuebunny/crossref_metadata_2025 huggingface dataset:
Putting the Self in Self-Correction: Findings From the Loss-of-Confidence Project
Authors: Rohrer Julia M. , Tierney Warren , Uhlmann Eric L. , DeBruine Lisa M. , Heyman Tom , Jones Benedict , Schmukle Stefan C. , Silberzahn Raphael , Willén Rebecca M. , Carlsson Rickard , Lucas Richard E. , Strand Julia , Vazire Simine , Witt Jessica K. , Zentall Thomas R. , Chabris Christopher F. , Yarkoni Tal
Published: March 2021

Science is often perceived to be a self-correcting enterprise. In principle, the assessment of scientific claims is supposed to proceed in a cumulative fashion, with the reigning theories of the day progressively approximating truth more accurately over time. In practice, however, cumulative self-correction tends to proceed less efficiently than one might naively suppose. Far from evaluating new evidence dispassionately and infallibly, individual scientists often cling stubbornly to prior findings. Here we explore the dynamics of scientific self-correction at an individual rather than collective level. In 13 written statements, researchers from diverse branches of psychology share why and how they have lost confidence in one of their own published findings. We qualitatively characterize these disclosures and explore their implications. A cross-disciplinary survey suggests that such loss-of-confidence sentiments are surprisingly common among members of the broader scientific population yet rarely become part of the public record. We argue that removing barriers to self-correction at the individual level is imperative if the scientific community as a whole is to achieve the ideal of efficient self-correction.
The India–China Confrontation: A View from Seawards
Authors: Prakash Admiral (Retd) Arun
Published: March 2021

Most Indians assumed that India’s humiliating military defeat at China’s hands in 1962 had jolted its political leadership out of its complacency, engendered by naïve beliefs in the commonality of China’s and India’s aims and aspirations. The current tense confrontation between Indian and Chinese forces in the remote Himalayan wastes of Ladakh, climaxing in the June 2020 sanguinary clash, therefore, came as a rude re-awakening for the Indian public. It is now obvious that over the past three decades, India’s politico-diplomatic establishment has been lulled into the false belief that parleys and summit meetings could ensure peace and tranquillity across the undefined ‘line of actual control’. They also seem oblivious of the fact that growing naval pressure from the south, coupled with existing military pressure in the north, could have ominous security implications for India. Amidst the prevailing perplexity, this essay is a modest attempt to cast some light on the rationale and motivation behind China’s actions and its long-term strategic objectives with a focus on its grandiose maritime ambitions.
Cognitive impairment in patients with cerebrovascular disease: A white paper from the links between stroke ESO Dementia Committee
Authors: Verdelho Ana , Wardlaw Joanna , Pavlovic Aleksandra , Pantoni Leonardo , Godefroy Olivier , Duering Marco , Charidimou Andreas , Chabriat Hugues , Biessels Geert Jan
Published: March 2021

Purpose

Many daily-life clinical decisions in patients with cerebrovascular disease and cognitive impairment are complex. Evidence-based information sustaining these decisions is frequently lacking. The aim of this paper is to propose a practical clinical approach to cognitive impairments in patients with known cerebrovascular disease.

Methods

The document was produced by the Dementia Committee of the European Stroke Organisation (ESO), based on evidence from the literature where available and on the clinical experience of the Committee members. This paper was endorsed by the ESO.

Findings

Many patients with stroke or other cerebrovascular disease have cognitive impairment, but this is often not recognized. With improvement in acute stroke care, and with the ageing of populations, it is expected that more stroke survivors and more patients with cerebrovascular disease will need adequate management of cognitive impairment of vascular etiology. This document was conceived for the use of strokologists and for those clinicians involved in cerebrovascular disease, with specific and practical hints concerning diagnostic tools, cognitive impairment management and decision on some therapeutic options. Discussion and conclusions: It is essential to consider a possible cognitive deterioration in every patient who experiences a stroke. Neuropsychological evaluation should be adapted to the clinical status. Brain imaging is the most informative biomarker concerning prognosis. Treatment should always include adequate secondary prevention.
Antivascular Endothelial Growth Factor Dosing Frequency and Visual Outcomes in Macular Edema Following Central Retinal Vein Occlusion
Authors: Modi Yasha S. , Goduni Lediana , Moini Hadi , Gibson Andrea , Boucher Nick , Lucas Genevieve , Dhoot Dilsher S.
Published: March 2021

Purpose:

We evaluated the relationship between dosing frequency of intravitreal antivascular endothelial growth factor (anti-VEGF) agents and visual acuity (VA) outcomes over 2 years in eyes with macular edema (ME) secondary to central retinal vein occlusion (CRVO) in the US routine clinical practice setting.

Methods:

This retrospective analysis assessed electronic medical records of eyes with ME secondary to CRVO that received their first anti-VEGF injection January 1, 2012, to May 31, 2016, and were followed for 1 year or more in the US-based Vestrum Health Treatment and Outcomes database. Eyes were divided into 2 injection frequency subcohorts (≤6 or ≥7 injections/year).

Results:

Overall, 851 (34.6%) of 2458 eyes with ME secondary to CRVO received 6 or fewer injections, and 1607 (65.4%) received 7 or more injections through 1 year. The mean number of injections in patients receiving 6 or fewer injections and 7 or more injections was 4.7 and 8.8, respectively, and baseline mean VA was 35 and 37 letters, respectively. At year 1, mean letter gain from baseline was less in eyes receiving 6 or fewer injections vs in those receiving 7 or more injections (7.0 vs 12.2, P < .001). Mean VA at year 2 was 50 letters in eyes receiving 6 or fewer injections (n = 50) and 55 letters in eyes receiving 7 or more injections (n = 157).

Conclusions:

In routine clinical practice, more frequent dosing with anti-VEGF agents was associated with greater visual benefits in eyes with ME secondary to CRVO.
A preliminary study of the stone Avatamsaka Sutra in Korea
Authors: Lee Kyoo-Kap
Published: March 2021

This paper is a study of the stone Avatamsaka Sutra（華嚴石經）in Korea. The stone Avatamsaka Sutra is all fragmented and preserved, which is not only of religious value, but also a very important resource for the research of the graphic forms of the characters at the time. Therefore, in this paper, I would like to examine the value of this stone Avatamsaka Sutra in various aspects.
Biocultural nation making: Biopolitics, cultural-territorial belonging, and national protected areas
Authors: Stinson James , Lunstrum Elizabeth
Published: March 2021

While the academic literature on biopolitics has investigated how the life of the population and its biological capacities have increasingly become the target of political concern and intervention largely at the scale of the nation, the literature on nations and nationalism has explored nations as cultural-territorial units including questions of their emergence, ongoing production, and impacts. What these share is a similar if not nearly identical object of analysis: the nation or national population. These, however, are realms of scholarly debate that have largely, and quite surprisingly, bypassed one another. This paper advances the concept of biocultural nation making to bridge these debates and illustrate that nation making is at once biological and cultural-territorial and that these are deeply intertwined. We ground this in the experience of Canadian national parks, highlighting how “natural” environments like national parks are key sites of biocultural, and increasingly neoliberal, national production. Here, state conservation organizations promote park visitation as a means of, first, enabling an active, healthy, and economically productive national population. Second, parks are promoted on the grounds that they enable the experience of distinctively Canadian landscapes and places of national inclusion especially as park visitorship is expanded to include nontraditional visitors including immigrants, urban communities, and the youth. Parks, in short, have become vehicles of biocultural, and increasingly neoliberal, nation making. While there are indeed affirmative aspects to this, we also highlight hidden exclusions tied to the embrace of neoliberal logic, the limits of multiculturalism, and the ongoing erasure of Indigenous communities.
Haploidentical age-adapted myeloablative transplant and regulatory and effector T cells for acute myeloid leukemia
Authors: Pierini Antonio , Ruggeri Loredana , Carotti Alessandra , Falzetti Franca , Saldi Simonetta , Terenzi Adelmo , Zucchetti Claudio , Ingrosso Gianluca , Zei Tiziana , Iacucci Ostini Roberta , Piccinelli Sara , Bonato Samanta , Tricarico Sara , Mancusi Antonella , Ciardelli Sara , Limongello Roberto , Merluzzi Mara , Di Ianni Mauro , Tognellini Rita , Minelli Olivia , Mecucci Cristina , Martelli Maria Paola , Falini Brunangelo , Martelli Massimo Fabrizio , Aristei Cynthia , Velardi Andrea
Published: March 2021

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective treatment in eradicating high-risk acute myeloid leukemia (AML). Here, we present data from a novel HLA-haploidentical HSCT protocol that addressed the 2 remaining major unmet medical needs: leukemia relapse and chronic graft-versus-host disease (cGVHD). Fifty AML patients were enrolled in the study. The conditioning regimen included total body irradiation for patients up to age 50 years and total marrow/lymphoid irradiation for patients age 51 to 65 years. Irradiation was followed by thiotepa, fludarabine, and cyclophosphamide. Patients received an infusion of 2 × 106/kg donor regulatory T cells on day −4 followed by 1 × 106/kg donor conventional T cells on day −1 and a mean of 10.7 × 106 ± 3.4 × 106/kgpurified CD34+ hematopoietic progenitor cells on day 0. No pharmacological GVHD prophylaxis was administered posttransplantation. Patients achieved full donor–type engraftment. Fifteen patients developed grade ≥2 acute GVHD (aGVHD). Twelve of the 15 patients with aGVHD were alive and no longer receiving immunosuppressive therapy. Moderate/severe cGVHD occurred in only 1 patient. Nonrelapse mortality occurred in 10 patients. Only 2 patients relapsed. Consequently, at a median follow-up of 29 months, the probability of moderate/severe cGVHD/relapse-free survival was 75% (95% confidence interval, 71%-78%). A novel HLA-haploidentical HSCT strategy that combines an age-adapted myeloablative conditioning regimen with regulatory and conventional T-cell adoptive immunotherapy resulted in an unprecedented cGVHD/relapse-free survival rate in 50 AML patients with a median age of 53 years. This trial was registered with the Umbria Region Institutional Review Board Public Registry as identification code 02/14 and public registry #2384/14 and at www.clinicaltrials.gov as #NCT03977103.
Phototransformation kinetics of cyanobacterial toxins and secondary metabolites in surface waters
Authors: Natumi Regiane , Marcotullio Sandro , Janssen Elisabeth M.-L.
Published: March 2021

Background

Cyanobacteria and their toxins occur in high concentrations during the so-called bloom events in surface waters. To be able to assess the risks associated with cyanobacterial blooms, we need to understand the persistence and fate processes of these toxins and other bioactive metabolites. In this study, we investigated the photochemical fate of 54 cyanopeptides extracted from two strains of Microcystis aeruginosa (PCC7806 and UV006), Planktothrix rubescens, and Dolichospermum flos aquae. We determined half-lives during sunlight exposure in lake water and inspected the effect of pH on transformation kinetics for 27 microcystins, 8 anabaenopeptins, 14 cyanopeptolins, 2 cyclamides, and 3 aeruginosins.

Results

For cyanopeptides from D. flos aquae and P. rubescens, we observed the highest removal of 28 and 26%, respectively, after 3-h sunlight exposure. Most cyanopeptides produced by the two M. aeruginosa strains were rather persistent with only up to 3% removal. The more reactive cyanopeptides contained amino acids known to undergo phototransformation, including methionine and tyrosine moieties or their derivatives. Photochemical half-lives of 14 tyrosine-containing cyanopeptides decreased by one order of magnitude from nearly persistent conditions at pH 7 (half-life > 70 h) to shorter half-lives at pH 10 (< 10 h).

Conclusions

More work is needed to distinguish the contribution of different photochemical reaction pathways including the contributions to the pH effect. To the best of our knowledge, this is the first assessment of transformation kinetics of such a wide range of cyanopeptides. The abundant and persistent cyanopeptides that have not been studied in detail yet should be prioritized for the evaluation of their ecosystem and human health risks and for their abatement during drinking water treatment.
A Practical Guide to Rodent Islet Isolation and Assessment Revisited
Authors: Corbin Kathryn L. , West Hannah L. , Brodsky Samantha , Whitticar Nicholas B. , Koch William J. , Nunemaker Craig S.
Published: March 2021

Insufficient insulin secretion is a key component of both type 1 and type 2 diabetes. Since insulin is released by the islets of Langerhans, obtaining viable and functional islets is critical for research and transplantation. The effective and efficient isolation of these small islands of endocrine cells from the sea of exocrine tissue that is the rest of the pancreas is not necessarily simple or quick. Choosing and administering the digestive enzyme, separation of the islets from acinar tissue, and culture of islets are all things that must be considered. The purpose of this review is to provide a history of the development of islet isolation procedures and to serve as a practical guide to rodent islet research for newcomers to islet biology. We discuss key elements of mouse islet isolation including choosing collagenase, the digestion process, purification of islets using a density gradient, and islet culture conditions. In addition, this paper reviews techniques for assessing islet viability and function such as visual assessment, glucose-stimulated insulin secretion and intracellular calcium measurements. A detailed protocol is provided that describes a common method our laboratory uses to obtain viable and functional mouse islets for in vitro study. This review thus provides a strong foundation for successful procurement and purification of high-quality mouse islets for research purposes.
Clinical characteristics and treatment outcomes of acute severe autoimmune hepatitis
Authors: Zheng Linhua , Liu Yansheng , Shang Yulong , Han Zheyi , Han Ying
Published: March 2021

Background and aim

Acute severe autoimmune hepatitis (AS-AIH) is a rare cause of acute liver failure (ALF), which is often neglected and delayed in treatment. The purpose of this study was to analyze the clinical characteristics and therapeutic effects of AS-AIH.

Methods

Retrospective analysis was performed. AIH was diagnosed according to the International Autoimmune Hepatitis Group (IAIHG) criteria revised in 1999. AS-AIH was defined as an acute presentation (onset of symptoms to presentation of ≤ 26 weeks) and INR of ≥ 1.5, and no histologic evidence of cirrhosis.

Results

Twelve patients were diagnosed as AS-AIH. At baseline, median immunoglobulin G was 28.35 g/L (range, 11.4–49.2). Ten (83.3%) patients were antinuclear antibodies and/or anti-smooth muscle antibodies positive. The prominent histologic characteristics were lobular necrosis/inflammation (91.7%) and plasma cell infiltration (100%). All patients received corticosteroid therapy. Death occurred in 2 (16.7%) patients within 30 days resulted from ALF. The average interval between the onset of symptoms and initiation of corticosteroid therapy in deceased patients was 65 days, compared with 19 days for survivors.

Conclusions

AS-AIH is an uncommon disease with poor outcomes. Patients with acute severe hepatitis of unknown cause should be minded the possibility of AS-AIH and corticosteroids should be considered as soon as possible.
Physiotherapy in nursing homes. A qualitative study of physiotherapists’ views and experiences
Authors: Sterke Shanty , Nascimento da Cunha Ana Paula , Oomen Hanneke , Voogt Lennard , Goumans Marleen
Published: March 2021

Background

There are distinct differences in the implementation of physiotherapeutic care in nursing homes. Both nationally and internationally staffing levels of physiotherapy differ significantly between and within nursing homes. Since legislation or guidelines that specify the parameters of physiotherapy required in nursing homes are lacking, it is unknown how physiotherapists currently estimate the usefulness and necessity of physiotherapy in individual situations in long-term care. The purpose of this study was to describe how physiotherapists actually work, and how they want to work, in daily practice in Dutch nursing homes.

Methods

We performed a qualitative study with an online questionnaire. We asked 72 physiotherapists working in Dutch nursing homes to describe as accurately as possible usual care in nine different cases in long-term care. Furthermore we asked them to describe their role in the prevention and treatment of a number of indicators that measure the quality of care in nursing homes. Two reviewers thematically analysed the answers to the questionnaires.

Results

Forty-six physiotherapists returned the questionnaire. Physiotherapy services include active exercise therapy aimed to improve mobility and movement dysfunctions, advising on prevention and management of falls, pressure ulcers, incontinence, malnutrition and sarcopenia, overweight, physical restraints, intertrigo, chronic wounds, behavioural and psychological symptoms in dementia, and physical inactivity, and ergonomic and behavioural training. The way and extent in which physiotherapists are involved in the various care- and functional problems differs and depends on organisational and personal factors such as, organisation’s policy, type of ward, time pressure, staffing level, collaboration with other members of the multidisciplinary team, or lack of knowledge.

Conclusion

Physiotherapists in nursing homes are involved in the prevention and management of different care situations and functional problems. The way in which they are involved differs between physiotherapist. Aiming for more uniformity seems necessary. A shared vision can help physiotherapists to work more consistently and will strengthen their position in nursing homes.
Manufacturing and banking canine adipose-derived mesenchymal stem cells for veterinary clinical application
Authors: Luo Huina , Li Dongsheng , Chen Zhisheng , Wang Bingyun , Chen Shengfeng
Published: March 2021

Background

Mesenchymal stem cells (MSCs) have generated a great amount of interest in recent years as a novel therapeutic application for improving the quality of pet life and helping them free from painful conditions and diseases. It has now become critical to address the challenges related to the safety and efficacy of MSCs expanded in vitro. In this study, we establish a standardized process for manufacture of canine adipose-derived MSCs (AD-MSCs), including tissue sourcing, cell isolation and culture, cryopreservation, thawing and expansion, quality control and testing, and evaluate the safety and efficacy of those cells for clinical applications.

Results

After expansion, the viability of AD-MSCs manufactured under our standardized process was above 90 %. Expression of surface markers and differentiation potential was consistent with ISCT standards. Sterility, mycoplasma, and endotoxin tests were consistently negative. AD-MSCs presented normal karyotype, and did not form in vivo tumors. No adverse events were noted in the case treated with intravenously AD-MSCs.

Conclusions

Herein we demonstrated the establishment of a feasible bioprocess for manufacturing and banking canine AD-MSCs for veterinary clinical use.
Beyond national indicators: adapting the Demographic and Health Surveys’ sampling strategies and questions to better inform subnational malaria intervention policy
Authors: Ozodiegwu Ifeoma D. , Ambrose Monique , Battle Katherine E. , Bever Caitlin , Diallo Ousmane , Galatas Beatriz , Runge Manuela , Gerardin Jaline
Published: March 2021

In malaria-endemic countries, prioritizing intervention deployment to areas that need the most attention is crucial to ensure continued progress. Global and national policy makers increasingly rely on epidemiological data and mathematical modelling to help optimize health decisions at the sub-national level. The Demographic and Health Surveys (DHS) Program is a critical data source for understanding subnational malaria prevalence and intervention coverage, which are used for parameterizing country-specific models of malaria transmission. However, data to estimate indicators at finer resolutions are limited, and surveys questions have a narrow scope. Examples from the Nigeria DHS are used to highlight gaps in the current survey design. Proposals are then made for additional questions and expansions to the DHS and Malaria Indicator Survey sampling strategy that would advance the data analyses and modelled estimates that inform national policy recommendations. Collaboration between the DHS Program, national malaria control programmes, the malaria modelling community, and funders is needed to address the highlighted data challenges.
Identification of tumor antigens and immune subtypes of pancreatic adenocarcinoma for mRNA vaccine development
Authors: Huang Xing , Zhang Gang , Tang Tianyu , Liang Tingbo
Published: March 2021

Background

Although mRNA vaccines have been effective against multiple cancers, their efficacy against pancreatic adenocarcinoma (PAAD) remains undefined. Accumulating evidence suggests that immunotyping can indicate the comprehensive immune status in tumors and their immune microenvironment, which is closely associated with therapeutic response and vaccination potential. The aim of this study was to identify potent antigens in PAAD for mRNA vaccine development, and further distinguish immune subtypes of PAAD to construct an immune landscape for selecting suitable patients for vaccination.

Methods

Gene expression profiles and clinical information of 239 PAAD datasets were extracted from ICGC, and RNA-Seq data of 103 samples were retrieved from TCGA. GEPIA was used to calculate differential expression levels and prognostic indices, cBioPortal program was used to compare genetic alterations, and TIMER was used to explore correlation between genes and immune infiltrating cells. Consensus cluster was used for consistency matrix construction and data clustering, DAVID was used for functional annotation, and graph learning-based dimensional reduction was used to depict immune landscape.

Results

Six overexpressed and mutated tumor antigens associated with poor prognosis and infiltration of antigen presenting cells were identified in PAAD, including ADAM9, EFNB2, MET, TMOD3, TPX2, and WNT7A. Furthermore, five immune subtypes (IS1-IS5) and nine immune gene modules of PAAD were identified that were consistent in both patient cohorts. The immune subtypes showed distinct molecular, cellular and clinical characteristics. IS1 and IS2 exhibited immune-activated phenotypes and correlated to better survival compared to the other subtypes. IS4 and IS5 tumors were immunologically cold and associated with higher tumor mutation burden. Immunogenic cell death modulators, immune checkpoints, and CA125 and CA199, were also differentially expressed among the five immune subtypes. Finally, the immune landscape of PAAD showed a high degree of heterogeneity between individual patients.

Conclusions

ADAM9, EFNB2, MET, TMOD3, TPX2, and WNT7A are potent antigens for developing anti-PAAD mRNA vaccine, and patients with IS4 and IS5 tumors are suitable for vaccination.
Fabrication of monodisperse magnetic nanorods for improving hyperthermia efficacy
Authors: Zhao Shan , Hao Nanjing , Zhang John X. J. , Hoopes P. Jack , Shubitidze Fridon , Chen Zi
Published: March 2021

Background

Hyperthermia is one of the promising cancer treatment strategies enabled by local heating with the use of tumor-targeting magnetic nanoparticles (MNP) under a non-invasive magnetic field. However, one of the remaining challenges is how to achieve therapeutic levels of heat (without causing damages to regular tissues) in tumors that cannot be effectively treated with anti-tumor drug delivery.

Results

In this work, we report a facile method to fabricate magnetic nanorods for hyperthermia by one-step wet chemistry synthesis using 3-Aminopropyltrimethoxysilane (APTMS) as the shape-controlling agent and ferric and ferrous ions as precursors. By adjusting the concentration of APTMS, hydrothermal reaction time, ratios of ferric to ferrous ions, magnetic nanorods with aspect ratios ranging from 4.4 to 7.6 have been produced. At the clinically recommended field strength of 300 Oe (or less) and the frequency of 184 kHz, the specific absorption rate (SAR) of these nanorods is approximately 50 % higher than that of commercial Bionized NanoFerrite particles.

Conclusions

This increase in SAR, especially at low field strengths, is crucial for treating deep tumors, such as pancreatic and rectal cancers, by avoiding the generation of harmful eddy current heating in normal tissues.
Sexual function, mental health, and quality of life under strain of COVID-19 pandemic in Iranian pregnant and lactating women: a comparative cross-sectional study
Authors: Mirzaei Negin , Jahanian Sadatmahalleh Shahideh , Bahri Khomami Mahnaz , Moini Ashraf , Kazemnejad Anoshirvan
Published: March 2021

Background

The impact of COVID-19 pandemic on mental health of pregnant and lactating women is unclear. This study aimed to assess the impact of COVID-19 on psychological health, sexual function, and quality of life (QoL) in Iranian pregnant and lactating women and compare the results with non-pregnant/non-lactating women.

Method

This comparative cross-sectional study was carried out on pregnant and lactating women, with non-pregnant/non-lactating women from May to Jun 2020. Patients were asked to complete three questionnaires: Hospital Anxiety and Depression Scale (HADS), Female Sexual Function Index (FSFI), and Short-Form Health Survey (SF-12). One-way ANOVA was used to reveal the statistical differences between the three groups.

Result

The mean age of patients was 20.81 ± 5.92 years old. The mean (SD) score of HADS in pregnant, lactating and non-pregnant / non-lactating women were 12.11 (6.72), 11.98 (8.44) and 9.38 (6.2) respectively, and the results showed that the scores in pregnant, lactating women were higher than non-pregnant / non-lactating women (P < 0.001). Also the mean (SD) score of QOL and FSFI was 68.29 (9.47), 74.18 (12.65), 79.03 (10.48) and 22.71 (8.16), 22.72 (8.16), 26.19 (3.93) in three groups and the scores in pregnant, lactating women were lower than non-pregnant/non-lactating women (P < 0.001).

Conclusion

The COVID-19 epidemic increases the risk of depression, anxiety, FSD, and lowers QoL in pregnant and lactating women, with the general population. This suggests the urgent need for psychological intervention in the maternal population during the epidemic.
Reconciling ACEA and MCDA: is there a way forward for measuring cost-effectiveness in the U.S. healthcare setting?
Authors: Zamora Bernarda , Garrison Louis P. , Unuigbe Aig , Towse Adrian
Published: March 2021

Background

The ISPOR Special Task Force (STF) on US Value Assessment Frameworks was agnostic about exactly how to implement the quality-adjusted life year (QALY) as a key element in an overall cost-effectiveness evaluation. But the STF recommended using the cost-per-QALY gained as a starting point in deliberations about including a new technology in a health plan benefit. The STF offered two major alternative approaches—augmented cost-effectiveness analysis (ACEA) and multi-criteria decision analysis (MCDA)—while emphasizing the need to apply either a willingness-to-pay (WTP) or opportunity cost threshold rule to operationalize the inclusion decision.

Methods

The MCDA model uses the multi-attribute utility function. The ACEA model is based on the expected utility theory. In both ACEA and MCDA models, value trade-offs are derived in a hierarchical model with two high-level objectives which measure overall health gain separately from financial attributes affecting consumption.

Results

Even though value trade-offs can be elicited or revealed without considering budget constraints, we demonstrate that they can be used similarly to WTP-based cost-effectiveness thresholds for resource allocation decisions. The consideration of how costs of medical technology, income, and severity of disease affect value trade-offs demonstrates, however, that reconciling decisions in ACEA and MCDA requires that health and consumption are either complements or independent attributes.

Conclusions

We conclude that value trade-offs derived either from ACEA or MCDA move similarly with changes in main factors considered by enrollees and decision makers—costs of the medical technology, income, and severity of disease. Consequently, this complementarity between health and consumption is a necessary condition for reconciling ACEA and MCDA. Moreover, their similarity would be further enhanced if the QALY is used as the key attribute or anchor in the MCDA value function: the choice between the two is a pragmatic question that is still open.
Aberrant regulation of retinoic acid signaling genes in cerebral arterio venous malformation nidus and neighboring astrocytes
Authors: Thomas Jaya Mary , Sasankan Dhakshmi , Surendran Sumi , Abraham Mathew , Rajavelu Arumugam , Kartha Chandrasekharan C.
Published: March 2021

Background

Cerebral arterio venous malformations (AVM) are a major causal factor for intracranial hemorrhage, which result in permanent disability or death. The molecular mechanisms of AVM are complex, and their pathogenesis remains an enigma. Current research on cerebral AVM is focused on characterizing the molecular features of AVM nidus to elucidate the aberrant signaling pathways. The initial stimuli that lead to the development of AVM nidus structures between a dilated artery and a vein are however not known.

Methods

In order to understand the molecular basis of development of cerebral AVM, we used in-depth RNA sequencing with the total RNA isolated from cerebral AVM nidus. Immunoblot and qRT-PCR assays were used to study the differential gene expression in AVM nidus, and immunofluorescence staining was used to study the expression pattern of aberrant proteins in AVM nidus and control tissues. Immunohistochemistry was used to study the expression pattern of aberrant proteins in AVM nidus and control tissues.

Results

The transcriptome study has identified 38 differentially expressed genes in cerebral AVM nidus, of which 35 genes were upregulated and 3 genes were downregulated. A final modular analysis identified an upregulation of ALDH1A2, a key rate-limiting enzyme of retinoic acid signaling pathway. Further analysis revealed that CYR61, a regulator of angiogenesis, and the target gene for retinoic acid signaling is upregulated in AVM nidus. We observed that astrocytes associated with AVM nidus are abnormal with increased expression of GFAP and Vimentin. Triple immunofluorescence staining of the AVM nidus revealed that CYR61 was also overexpressed in the abnormal astrocytes associated with AVM tissue.

Conclusion

Using high-throughput RNA sequencing analysis and immunostaining, we report deregulated expression of retinoic acid signaling genes in AVM nidus and its associated astrocytes and speculate that this might trigger the abnormal angiogenesis and the development of cerebral AVM in humans.
The psychoactive drug of abuse mephedrone differentially disrupts blood-brain barrier properties
Authors: Buzhdygan Tetyana P. , Rodrigues Cassidy R. , McGary Hannah M. , Khan Jana A. , Andrews Allison M. , Rawls Scott M. , Ramirez Servio H.
Published: March 2021

Background

Synthetic cathinones are a category of psychostimulants belonging to the growing number of designer drugs also known as “Novel Psychoactive Substances” (NPS). In recent years, NPS have gained popularity in the recreational drug market due to their amphetamine-like stimulant effects, low cost, ease of availability, and lack of detection by conventional toxicology screening. All these factors have led to an increase in NPS substance abuse among the young adults, followed by spike of overdose-related fatalities and adverse effects, severe neurotoxicity, and cerebral vascular complications. Much remains unknown about how synthetic cathinones negatively affect the CNS and the status of the blood-brain barrier (BBB).

Methods

We used in vitro models of the BBB and primary human brain microvascular endothelial cells (hBMVEC) to investigate the effects of the synthetic cathinone, 4-methyl methcathinone (mephedrone), on BBB properties.

Results

We showed that mephedrone exposure resulted in the loss of barrier properties and endothelial dysfunction of primary hBMVEC. Increased permeability and decreased transendothelial electrical resistance of the endothelial barrier were attributed to changes in key proteins involved in the tight junction formation. Elevated expression of matrix metalloproteinases, angiogenic growth factors, and inflammatory cytokines can be explained by TLR-4-dependent activation of NF-κB signaling.

Conclusions

In this first characterization of the effects of a synthetic cathinone on human brain endothelial cells, it appears clear that mephedrone-induced damage of the BBB is not limited by the disruption of the barrier properties but also include endothelial activation and inflammation. This may especially be important in comorbid situations of mephedrone abuse and HIV-1 infections. In this context, mephedrone could negatively affect HIV-1 neuroinvasion and NeuroAIDS progression.
Correction to: Long-term survival with sebelipase alfa enzyme replacement therapy in infants with rapidly progressive lysosomal acid lipase deficiency: final results from 2 open-label studies
Authors: Vijay Suresh , Brassier Anais , Ghosh Arunabha , Fecarotta Simona , Abel Florian , Marulkar Sachin , Jones Simon A.
Published: March 2021

An amendment to this paper has been published and can be accessed via the original article.
Pretibial myxedema in a euthyroid patient: a case report
Authors: Ambachew Rediet , Yosef Tizita , Gebremariam Aklilu M. , Demere Lishan , Aberra Theodros , Tarekegn Getahun , Reja Ahmed
Published: March 2021

Background

Pretibial myxedema also known as localized myxedema, thyroid dermopathy, or infiltrative dermopathy and rarely as localized mucinosis is an infrequent manifestation of Graves’ disease. It can appear before, during, or after the thyrotoxic state. Euthyroid pretibial myxedema is a rare presentation with few case reports in the literature. This case highlights the importance of considering pretibial myxedema when characteristic skin lesions are observed in a euthyroid patient.

Case presentation

A 72-year old male Ethiopian patient with a very rare presentation of biopsy-proven pretibial myxedema in a euthyroid state without history of thyroid disease and absence of thyroid autoimmune markers. Resolution of skin lesion was achieved after topical corticosteroid application.

Conclusion

Absence of history of thyroid disorder and normal thyroid function tests should not exclude the diagnosis of pretibial myxedema.
CPSF6 links alternative polyadenylation to metabolism adaption in hepatocellular carcinoma progression
Authors: Tan Sheng , Zhang Ming , Shi Xinglong , Ding Keshuo , Zhao Qiang , Guo Qianying , Wang Hao , Wu Zhengsheng , Kang Yani , Zhu Tao , Sun Jielin , Zhao Xiaodong
Published: March 2021

Background

Alternative polyadenylation (APA) is an important mechanism of gene expression regulation through generation of RNA isoforms with distinct 3′ termini. Increasing evidence has revealed that APA is actively involved in development and disease, including hepatocellular carcinoma (HCC). However, how APA functions in tumor formation and progression remains elusive. In this study, we investigated the role of cleavage factor I (CFIm) subunit CPSF6 in human hepatocellular carcinoma (HCC).

Methods

Expression levels of CPSF6 in clinical tissues and cell lines were determined by qRT-PCR and western blot. Functional assays, including the cell number, MTT, colony formation and transwell, were used to determine the oncogenic role of CPSF6 in HCC. Animal experiments were used to determine the role of CPSF6 in HCC tumorigenicity in vivo. Deep sequencing-based 3 T-seq was used to profile the transcriptome-wide APA sites in both HCC cells and CPSF6 knockdown HCC cells. The function of CPSF6-affected targetNQO1with distinct 3′UTRs was characterized by metabolism assays.

Results

We observed CPSF6 was upregulated in HCC and the high expression of CPSF6 was associated with poor prognosis in patients. Overexpression of CPSF6 promoted proliferation, migration and invasion of HCC cells in vitro and in vivo. Transcriptome-wide APA profiling analysis indicated that high expression of CPSF6 promoted the favorable usage of the proximal poly(A) site in the 3′UTR ofNQO1. We demonstrated CPSF6-induced tumorigenic activities were mediated by theNQO1isoform with short 3′UTR. Furthermore, we found that CPSF6 induced metabolic alterations in liver cells through NQO1.

Conclusion

CPSF6 plays a critical role in HCC progression by upregulating NQO1 expression through APA. These findings provide evidence to demonstrate that APA ofNQO1contributes to HCC progression and may have implications for developing new therapeutic strategy against this disease.
Stem vacuole-targetted sucrose isomerase enhances sugar content in sorghum
Authors: Liu Guoquan , Zhang Yan , Gong Hao , Li Shan , Pan Yunrong , Davis Christopher , Jing Hai-Chun , Wu Luguang , Godwin Ian D.
Published: March 2021

Background

Sugar content is critically important in determining sugar crop productivity. However, improvement in sugar content has been stagnant among sugar crops for decades. Sorghum, especially sweet sorghum with high biomass, shown great potential for biofuel, has lower sugar content than sugarcane. To enhance sugar content, the sucrose isomerase (SI) gene, driven by stem-specific promoters (A2 or LSG) with a vacuole-targetted signal peptide, was transformed into the sorghum inbred line (T×430).

Results

The study demonstrated that transgenic lines of grain sorghum, containing 50–60% isomaltulose, accumulated up to eightfold (1000 mM) more total sugar than the control T×430 did (118 mM) in stalks of T0 generation. Subsequently, the elite engineered lines (A5, and LSG9) were crossed with sweet sorghum (Rio, and R9188). Total sugar contents (over 750 mM), were notably higher in F1, and F2 progenies than the control Rio (480 mM). The sugar contents of the engineered lines (over 750 mM), including T0, T1, F1, and F2, are surprisingly higher than that of the field-grown sugarcane (normal range 600–700 mmol/L). Additionally, analysis of physiological characterization demonstrated that the superior progenies had notably higher rates of photosynthesis, sucrose transportation, and sink strength than the controls.

Conclusions

The genetic engineering approach has dramatically enhanced total sugar content in grain sorghum (T0, and T1) and hybrid sorghum (F1, and F2), demonstrating that sorghum can accumulate as high or higher sugar content than sugarcane. This research illustrates that the SI gene has enormous potential on improvement of sugar content in sorghum, particularly in hybirds and sweet sorghum. The substantial increase on sugar content would lead to significant financial benefits for industrial utilization. This study could have a substantial impact on renewable bioenergy. More importantly, our results demonstrated that the phenotype of high sugar content is inheritable and shed light on improvement for other sugar crops.
Congruent microbiome signatures in fibrosis-prone autoimmune diseases: IgG4-related disease and systemic sclerosis
Authors: Plichta Damian R. , Somani Juhi , Pichaud Matthieu , Wallace Zachary S. , Fernandes Ana D. , Perugino Cory A. , Lähdesmäki Harri , Stone John H. , Vlamakis Hera , Chung Daniel C. , Khanna Dinesh , Pillai Shiv , Xavier Ramnik J.
Published: March 2021

Background

Immunoglobulin G4-related disease (IgG4-RD) and systemic sclerosis (SSc) are rare autoimmune diseases characterized by the presence of CD4+ cytotoxic T cells in the blood as well as inflammation and fibrosis in various organs, but they have no established etiologies. Similar to other autoimmune diseases, the gut microbiome might encode disease-triggering or disease-sustaining factors.

Methods

The gut microbiomes from IgG4-RD and SSc patients as well as healthy individuals with no recent antibiotic treatment were studied by metagenomic sequencing of stool DNA. De novo assembly-based taxonomic and functional characterization, followed by association and accessory gene set enrichment analysis, were applied to describe microbiome changes associated with both diseases.

Results

Microbiomes of IgG4-RD and SSc patients distinctly separated from those of healthy controls: numerous opportunistic pathogenic Clostridium and typically oral Streptococcus species were significantly overabundant, while Alistipes, Bacteroides, and butyrate-producing species were depleted in the two diseases compared to healthy controls. Accessory gene content analysis in these species revealed an enrichment of Th17-activating Eggerthella lenta strains in IgG4-RD and SSc and a preferential colonization of a homocysteine-producing strain of Clostridium bolteae in SSc. Overabundance of the classical mevalonate pathway, hydroxyproline dehydratase, and fibronectin-binding protein in disease microbiomes reflects potential functional differences in host immune recognition and extracellular matrix utilization associated with fibrosis. Strikingly, the majority of species that were differentially abundant in IgG4-RD and SSc compared to controls showed the same directionality in both diseases. Compared with multiple sclerosis and rheumatoid arthritis, the gut microbiomes of IgG4-RD and SSc showed similar signatures; in contrast, the most differentially abundant taxa were not the facultative anaerobes consistently identified in inflammatory bowel diseases, suggesting the microbial signatures of IgG4-RD and SSc do not result from mucosal inflammation and decreased anaerobism.

Conclusions

These results provide an initial characterization of gut microbiome ecology in fibrosis-prone IgG4-RD and SSc and reveal microbial functions that offer insights into the pathophysiology of these rare diseases.
Are seminal vesicles a potential pitfall during pelvic exploration using point-of-care ultrasound (POCUS)?
Authors: Fasseaux Antoine , Pès Philippe , Steenebruggen Françoise , Dupriez Florence
Published: March 2021

Background

Trauma is a major cause of death among the working population. Many countries have now adopted a structured approach to trauma management in which ultrasound is used as a primary evaluation tool. While its use has direct therapeutic benefits, many artifacts and pitfalls are inherent to the technique. Knowledge of the most frequently encountered pitfalls in practice could thus help reduce the risk of error and lead to more accurate trauma assessments.

Objective

This study evaluates a potential pitfall caused by seminal vesicles during focused assessment with sonography for trauma examinations of the male pelvis performed by an emergency physician with experience in point-of-care ultrasound.

Methods

We took five static and five dynamic (3-s loops) transverse ultrasound images of the pelvis in five healthy males. The images and videos were then incorporated into an online survey and emailed through the World Interactive Network Focused On Critical UltraSound (WINFOCUS) in France and the Ultrasound and Emergency Medicine (UEM) Organization in Belgium. A questionnaire asked anonymous participants to assess the presence of free fluid in the static and dynamic images and to share information about their training and experience in point-of-care ultrasound. To validate the static and dynamic images, the survey was sent to three external radiologists for independent verification.

Results

A total of 191 individuals responded fully or partially to the survey, 114 of whom completed it. Among the 114 participants who completed the survey, the misinterpretation rate was 0.55 (95CI 0.51–0.60) for all static and dynamic ultrasound transverse pelvic views. The misinterpretation rate was 0.61 (95CI 0.55–0.66) and 0.50 (95CI 0.45–0.55) for static and dynamic ultrasound transverse pelvic views, respectively. The three external radiologists answered the questionnaire correctly without misinterpreting the survey ultrasound views.

Conclusions

Seminal vesicles are a potential pitfall when interpreting transverse ultrasound images of the male pelvis in the context of point-of-care ultrasound.
The association of group IIB intron with integrons in hypersaline environments
Authors: Sonbol Sarah , Siam Rania
Published: March 2021

Background

Group II introns are mobile genetic elements used as efficient gene targeting tools. They function as both ribozymes and retroelements. Group IIC introns are the only class reported so far to be associated with integrons. In order to identify group II introns linked with integrons and CALINS (cluster of attC sites lacking a neighboring integron integrase) within halophiles, we mined for integrons in 28 assembled metagenomes from hypersaline environments and publically available 104 halophilic genomes using Integron Finder followed by blast search for group II intron reverse transcriptases (RT)s.

Results

We report the presence of different group II introns associated with integrons and integron-related sequences denoted by UHB.F1, UHB.I2, H.ha.F1 and H.ha.F2. The first two were identified within putative integrons in the metagenome of Tanatar-5 hypersaline soda lake, belonging to IIC and IIB intron classes, respectively at which the first was a truncated intron. Other truncated introns H.ha.F1 and H.ha.F2 were also detected in a CALIN within the extreme halophile Halorhodospira halochloris, both belonging to group IIB introns. The intron-encoded proteins (IEP) s identified within group IIB introns belonged to different classes: CL1 class in UHB.I2 and bacterial class E in H.ha.Fa1 and H.ha.F2. A newly identified insertion sequence (ISHahl1) of IS200/605 superfamily was also identified adjacent to H. halochloris CALIN. Finally, an abundance of toxin-antitoxin (TA) systems was observed within the identified integrons.

Conclusion

So far, this is the first investigation of group II introns within integrons in halophilic genomes and metagenomes from hypersaline environments. We report the presence of group IIB introns associated with integrons or CALINs. This study provides the basis for understanding the role of group IIB introns in the evolution of halophiles and their potential biotechnological role.