bluuebunny/crossref_metadata_2025 huggingface dataset:
Anesthesia Method, Tourniquet Use, and Persistent Postsurgical Pain after Total Knee Arthroplasty: A Prespecified Secondary Analysis of a Randomized Trial
Authors: Palanne Riku A. , Rantasalo Mikko T. , Vakkuri Anne P. , Madanat Rami , Olkkola Klaus T. , Reponen Elina M. , Linko Rita , Vahlberg Tero J. , Skants Noora K. A.
Published: July 2021

Background

Persistent postsurgical pain after total knee arthroplasty is a common problem and a major reason for patient dissatisfaction. This secondary analysis aimed to investigate the effects of anesthesia (spinal vs. general) and tourniquet use on persistent pain after total knee arthroplasty.

Methods

In this secondary analysis of a previously presented parallel, single-center, randomized trial, 404 patients scheduled for total knee arthroplasty were randomized to spinal versus general anesthesia and no-tourniquet versus tourniquet groups. Patients assessed pain using the Brief Pain Inventory–short form preoperatively and 3 and 12 months postoperatively. The prespecified main outcome was the change in “average pain” measured with numerical 0 to 10 rating scale 1 yr postoperatively. The threshold for clinical importance between groups was set to 1.0.

Results

The change in average pain scores 1 yr postoperatively did not differ between the spinal and general anesthesia groups (–2.6 [SD 2.5] vs. –2.3 [SD 2.5], respectively; mean difference, –0.4; 95% CI, –0.9 to 0.1; P = 0.150). The no-tourniquet group reported a smaller decrease in the average pain scores than the tourniquet group (–2.1 [SD 2.7] vs. –2.8 [SD 2.3]; mean difference, 0.6; 95% CI, 0.1 to 1.1; P = 0.012). After 1 yr, the scores concerning the mean of four pain severity variables (numerical rating scale) decreased more in the spinal than in the general anesthesia group (–2.3 [SD 2.2] vs. –1.8 [SD 2.1]; mean difference, –0.5; 95% CI, –0.9 to –0.05; P = 0.029) and less in the no-tourniquet than in the tourniquet group (–1.7 [SD 2.3] vs. –2.3 [SD 2.0]; mean difference, 0.6; 95% CI, 0.2 to 1.0; P = 0.005). None of the differences in pain scores reached the threshold for clinical importance.

Conclusions

The type of anesthesia (spinal vs. general) or tourniquet use has no clinically important effect on persistent postsurgical pain after total knee arthroplasty.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Knowledge, perception and practice of Québec nurses for ambulatory and clinic blood pressure measurement methods: are we there yet?
Authors: Todkar Shweta , Padwal Raj , Cloutier Lyne
Published: July 2021

Background:

Guidelines regarding blood pressure measurement (BPM) methods, namely home (HBPM), ambulatory (ABPM), office (OBPM) and automated (AOBP) are published by Hypertension Canada and rely on accurate measurement technique. Nurses commonly perform BPM but their knowledge, perception and practice considering all methods is understudied. This study is the first to establish the picture of Québec nurses working in primary care settings concerning the four BPM methods.

Methods:

All nurses licensed to practice in primary care in Québec were targeted in our survey. Data were collected using a validated and pretested investigator-initiated questionnaire in English and French. A personalized e-mail invitation, and two reminders, including a link to a secured platform was sent in December 2019. A certificate of ethics was issued by UQTR.

Results:

A total of 453 nurses participated in the study. Median age was 40 ± 11 years, and 92% were women. The overall score on BPM methods knowledge was slightly below 50% (46% ± 23). The perception was mostly positive, with an overall score above 50% (73% ± 8). In practice, HBPM was recommended by 47% of nurses, and ABPM by 18%. Although AOBP is the preferred method in Canada, only 25% of the nurses use it, including the 57% that use an oscillometric device and 11% that use manual auscultation.

Conclusion:

Nurses working in primary care play a central role in BPM. Our results highlight that overall knowledge and practice are suboptimal. Resources should, therefore, be allocated to ensure that initial training and continuing education are addressed.
Corneal stromal thickness changes after myopic laser corneal refractive surgery
Authors: Alió del Barrio Jorge L. , Canto-Cerdan Mario , El Bahrawy Mohamed , Casanova Laura , García María J. , Cavas Francisco , Alió Jorge L.
Published: July 2021

Purpose:

To evaluate the postoperative behavior of the central corneal stromal thickness after myopic femto–laser-assisted in-situ keratomileusis (LASIK) and small-incision lenticule extraction (SMILE) by using combined anterior segment optical coherence tomography and a Placido disk topographer and to compare the accuracy of both laser machines in predicting the real stromal change.

Setting:

Vissum Miranza, Alicante, Spain.

Study design:

Prospective, observational, comparative study.

Methods:

The VisuMax 500 kHz femtosecond laser (FS) and the Amaris 750 excimer laser were used for the correction of myopia with or without myopic astigmatism. Central and paracentral stromal thicknesses (ST) and 6.0 mm corneal aberrometry were obtained with the MS39 topographer. Laser-predicted stromal consumption was recorded (maximum lenticule thickness for SMILE and central ablation depth for LASIK). Visual and refractive outcomes were also evaluated. Total follow-up was 6 months.

Results:

77 LASIK eyes were matched with 77 SMILE eyes. Mean preoperative spherical equivalent (SE) was −3.92 ± 1.67 diopters (D) for LASIK and −4.02 ± 1.63 D for SMILE (P = .356). After LASIK, ST parameters showed significant rethickening between months 1 and 3 (+4.38 μm for central ST; P < .001), remaining stable thereafter. After SMILE, all ST parameters remained stable from month 1. Stromal ablation prediction was higher for SMILE compared with LASIK for all SE ranges, although postoperatively such differences were significant only for ametropias ≤4 D. At 6 months, mean SMILE laser prediction error was −13.21 ± 7.00 μm, whereas LASIK prediction showed better accuracy (+0.92 ± 8.16 μm; P < .001).

Conclusions:

The accuracy of the Amaris 750 excimer laser in predicting the stromal consumption after LASIK was better than the VisuMax FS laser for SMILE. Although SMILE ST remained stable from month 1, after LASIK, mild stromal rethickening was observed up to the third month.
Regression of Hepatic Fibrosis and Evolution of Cirrhosis: A Concise Review
Authors: Khan Shahbaz , Saxena Romil
Published: July 2021

Fibrosis is not a unidirectional, linear process, but a dynamic one resulting from an interplay of fibrogenesis and fibrolysis depending on the extent and severity of a biologic insult, or lack thereof. Regression of fibrosis has been documented best in patients treated with phlebotomies for hemochromatosis, and after successful suppression and eradication of chronic hepatitis B and C infections. This evidence mandates a reconsideration of the term “cirrhosis,” which implies an inevitable progression towards liver failure. Furthermore, it also necessitates a staging system that acknowledges the bidirectional nature of evolution of fibrosis, and has the ability to predict if the disease process is progressing or regressing. The Beijing classification attempts to fill this gap in contemporary practice. It is based on microscopic features termed “the hepatic repair complex,” defined originally by Wanless and colleagues. The elements of the hepatic repair complex represent the 3 processes of fragmentation and regression of scar, vascular remodeling (resolution), and parenchymal regeneration. However, regression of fibrosis does not imply resolution of cirrhosis, which is more than just a stage of fibrosis. So far, there is little to no evidence to suggest that large regions of parenchymal extinction can be repopulated by regenerating hepatocytes. Similarly, the vascular lesions of cirrhosis persist, and there is no evidence of complete return to normal microcirculation in cirrhotic livers. In addition, the risk of hepatocellular carcinoma is higher compared with the general population and these patients need continued screening and surveillance.
Dedifferentiated Liposarcoma: A Comprehensive Historical Review With Proposed Evidence-based Guidelines Regarding a Diagnosis in Need of Further Clarification
Authors: Kilpatrick Scott E.
Published: July 2021

Among all sarcoma types, liposarcoma is the most common sarcoma that develops “dedifferentiation.” Since its initial description by Dr Harry Evans, the spectrum of what is now acceptably included under the rubric of “dedifferentiated liposarcoma” (DL) has expanded, sometimes supported by cytogenetic and molecular advances. Similarly, the range of morphologic appearances considered to represent the precursor of DL, atypical lipomatous tumor (ALT)/well-differentiated liposarcoma, also has broadened, not uncommonly creating variants with significant, almost indistinguishable, morphologic overlap with occasional forms of DL, especially problematic in small biopsy specimens. More specifically, the precise criteria separating cellular forms of ALT from what some consider “low-grade” variants of DL remains controversial and inconsistently applied, even among individual pathologists within institutions. For this separation, the only objective and reproducible criteria historically shown to accurately predict a statistically significant difference in prognosis and survival is mitotic rate, alone or incorporated into a histologic grade [eg, Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC)], consistently identifying a higher grade neoplasm capable of metastases. While DL may have a better prognosis than other nonmyoid adult pleomorphic soft tissue sarcomas, definitive conclusions are difficult to establish due to nonuniform criteria for staging and establishing tumor size/volume of the high-grade component, compounded by variable definitions and thresholds for rendering the diagnosis of DL. If appropriate therapeutic approaches are to be applied to DL, there needs to uniform agreement regarding the histologic definition, grading, and staging of DL. Herein, is a comprehensive historical perspective on DL and ALT/well-differentiated liposarcoma, seeking to provide insights, updates, and a proposal for uniform, evidence-based guidelines.
Treatment of Severe Excoriation Disorder With Mirtazapine: A Case Report
Authors: Keshtkarjahromi Mitra , Mariscal Jonathan , Dempsey Kendall , Tonarelli Silvina
Published: July 2021

Objective

Excoriation disorder is a disabling behavioral disorder characterized by compulsive and repetitive picking of the skin. Excoriation disorder has a lifetime prevalence of 3% to 5% in the general population, and it is most common in females. Its course is chronic, and it is characterized by fluctuating and frequent periods of exacerbation. Excoriation disorder is commonly comorbid with several psychiatric disorders. The treatment of this disorder is challenging and requires a multidisciplinary approach. Current literature has described an improvement in skin picking when patients are treated with fluoxetine or escitalopram; other studies have involved augmentation strategies using antipsychotics, such as olanzapine and aripiprazole; serotonin norepinephrine reuptake inhibitors; and N-acetyl-cysteine. Other pharmacological therapies include lamotrigine and opioid antagonists. Psychotherapies are additional nonpharmacological treatment modalities to consider in this condition.

Methods

We report the case of a 60-year-old Hispanic woman with severe excoriation disorder and several psychiatric comorbidities who responded remarkably to augmentation treatment with mirtazapine.

Conclusion

Mirtazapine is a noradrenergic and specific serotonergic antidepressant, and its antihistaminergic effect can relieve skin itching and pain.
A Systems-Based Framework for Immunisation System Design: Six Loops, Three Flows, Two Paradigms
Authors: Decouttere Catherine , Vandaele Nico , De Boeck Kim , Banzimana Stany
Published: July 2021

Despite massive progress in vaccine coverage globally, the region of sub-Saharan Africa is lagging behind and not on track for Sustainable Development Goal 3 by 2030. Sub-national under-immunisation, related to geographical and social heterogeneity, is part of the problem. System-wide changes could transform current immunisation systems to become more sustainable, resilient and inclusive. A framework is proposed that captures the complexity of immunisation systems and offers directions for sustainable redesign. Insights were extracted from literature, stakeholder workshops, and field research in Rwanda and Kenya. A conceptual model of the national immunisation system was co-developed and validated with stakeholders. Leverage points were suggested for intervention scenario building. The Immunisation System Diagram assembles the paradigms of planned and emergency immunisation in one system and emphasizes the synchronized flows of vaccine receiver, vaccinator and vaccine. Six feedback loops capture the main subsystems. Sustainability and resilience are assessed based on loop dominance and dependency on exogenous factors such as donor funding and vaccine stockpiles. In group model building workshops, the diagram invites stakeholders to share their mental models, to assess the system’s performance and to trigger detection of root causes and leverage points. The framework provides a systems-approach for problem structuring and policy design.
A regression discontinuity analysis of the social distancing recommendations for older adults in Sweden during COVID-19
Authors: Bonander Carl , Stranges Debora , Gustavsson Johanna , Almgren Matilda , Inghammar Malin , Moghaddassi Mahnaz , Nilsson Anton , Franks Paul W , Gomez Maria , Fall Tove , Björk Jonas ,   COVID Symptom Study Sweden
Published: July 2021

Objectives

To study the impact of non-mandatory, age-specific social distancing recommendations for older adults (70+ years) in Sweden on isolation behaviors and disease outcomes during the first wave of the COVID-19 pandemic.

Methods

Our study relies on self-reported isolation data from COVID Symptom Study Sweden (n = 96,053) and national register data on COVID-19 hospitalizations, deaths, and confirmed cases. We use a regression discontinuity design to account for confounding factors, exploiting the fact that exposure to the recommendation was a discontinuous function of age.

Results

By comparing individuals just above to those just below the age limit for the policy, our analyses revealed a sharp drop in the weekly number of visits to crowded places at the 70-year-threshold (−13%). Severe COVID-19 cases (hospitalizations or deaths) also dropped abruptly by 16% at the 70-year-threshold. Our data suggest that the age-specific recommendations prevented approximately 1,800 to 2,700 severe COVID-19 cases, depending on model specification.

Conclusion

The non-mandatory, age-specific recommendations helped control the COVID-19 pandemic in Sweden.
A comprehensive evaluation methodology for the publicly accessible AI services for medical diagnostics
Authors: Morozov Sergey P. , Gombolevskiy Victor A. , Blokhin Ivan A. , Semenov Serafim S. , Logunova Tatiana A. , Andreychenko Anna E.
Published: July 2021

Online AI in telemedicine for radiology became widely available and valuable in the pandemic, particularly for chest CT analysis. On the other hand, the potentially harmful consequences of such services′ inappropriate usage cannot be neglected. Thus, a suitable methodology for quality assurance and quality control has to be established.
A study′s purpose was to develop and test an original methodology for a complex evaluation of open–access AI services in teleradiology. The approach included assessing the user experience, accessibility, safety, and diagnostic accuracy on the independent reference dataset. The methodology was applied to assess seven AI services for the detection of COVID-19 on a CT scan. A comparative analysis of this assessment is presented in this work. The analysis allowed us to draw conclusions about AI services′ quality and their value for different users – patients, physicians, and healthcare data scientists. The originality of the findings, timeliness, and interdisciplinary approach make this quality assurance methodology of particular interest for further application and spreading.
FAIR-IFICATION OF STRUCTURED CLINICAL DATA
Authors: Gouthamchand Varsha , Dekker Andre , Wee Leonard , van Soest Johan
Published: July 2021

One of the common concerns in clinical research is improving the infrastructure to facilitate the reuse of clinical data and deal with interoperability issues. FAIR (Findable, Accessible, Interoperable and Reusable) Data Principles enables reuse of data by providing us with descriptive metadata, explaining what the data represents and where the data can be found. In addition to aiding scholars, FAIR guidelines also help in enhancing the machine-readability of data, making it easier for machine algorithms to find and utilize the data. Hence, the feasibility of accurate interpretation of data is higher and this helps in obtaining maximum results from research work. FAIR-ification is done by embedding knowledge on data. This could be achieved by annotating the data using terminologies and concepts from Web Ontology Language (OWL). By attaching a terminological value, we add semantics to a specific data element, increasing the interoperability and reuse. However, this FAIR-ification of data can be a complicated and a time-consuming process. Our main objective is to disentangle the process of making data FAIR by using both domain and technical expertise. We apply this process in a workflow which involves FAIR-ification of four independent public HNSCC datasets from The Cancer Imaging Archive (TCIA). This approach converts the data from the four datasets into Linked Data using RDF triples, and finally annotates these datasets using standardized terminologies. By annotating them, we link all the four datasets together using their semantics and thus a single query would get the intended information from all the datasets.
Estimated Veterans Health Administration costs for Alzheimer’s disease treatment with aducanumab
Authors: Haimovich Adrian D. , Goulet Joseph L. , Brandt Cynthia A. , Tarabar Asim , Patwa Huned S , Hwang Ula
Published: July 2021

The approval of aducanumab for the treatment of Alzheimer’s disease has been met with significant public concern. Projections of annual cost across United States Medicare beneficiaries are in the tens of billions of dollars. Here, we performed an electronic health record review of Veterans Affairs beneficiaries, identifying 151,921 individuals (1.7%) with diagnosis codes for Alzheimer’s disease. We estimate that treatment for this cohort will cost in excess of $4 billion annually with further expenditures for associated screening, consultations, imaging, and therapeutic monitoring. The magnitude of projected expenditures necessitates early assessment of drug cost effectiveness.
Predictors of Premature Discontinuation of Opioid Use Disorder Treatment in the United States
Authors: Stafford Celia , Marrero Wesley , Naumann Rebecca B. , Lich Kristen Hassmiller , Wakeman Sarah , Jalali Mohammad S.
Published: July 2021

Over the last few decades, opioid use disorder (OUD) and overdose have dramatically increased. Evidence shows that treatment for OUD, particularly medication for OUD, is highly effective; however, despite decreases in barriers to treatment, retention in OUD treatment remains a challenge. Therefore, understanding key risk factors for OUD treatment discontinuation remains a critical priority. We built a machine learning model using the Treatment Episode Data Set – Discharge (TEDS-D). Included were 2,446,710 treatment episodes for individuals in the U.S. discharged between January 1, 2015 and December 31, 2018 (the most recent available data). Exposures contain 32 potential risk factors, including treatment characteristics, substance use history, socioeconomic status, and demographic characteristics. Our findings show that the most influential risk factors include characteristics of treatment service setting, geographic region, primary source of payment, referral source, and health insurance status. Importantly, several factors previously reported as influential predictors, such as age, living situation, age of first substance use, race and ethnicity, and sex had far weaker predictive impacts. The influential factors identified in this study should be more closely explored to inform targeted interventions and improve future models of care.
Amygdala connectivity as a predisposing neural feature of stress-induced behaviour during the COVID-2019 outbreak in Hubei
Authors: Zhou Yuan , He Yuwen , Jin Yuening , Rong Bei , Zeidman Peter , Huang Huan , Feng Yuan , Cui Jian , Zhang Shudong , Wang Yun , Wang Gang , Xiang Yutao , Wang Huiling
Published: July 2021

The amygdala plays an important role in the regulation of stress and anxiety. However, little is known about the relationship between amygdala connectivity and subsequent stress-induced behavior. The current study investigated whether amygdala connectivity measured before experiencing stress is a predisposing neural feature of subsequent stress-induced behavior while individuals face an emergent and unexpected event like the COVID-19 outbreak. Using an fMRI cohort established before the pandemic in Wuhan, Hubei, we found that resting-state functional connectivity (rsFC) of the right amygdala with the dorsomedial prefrontal cortex (dmPFC) was negatively correlated with the stress-induced behavior of these volunteers during the COVID-2019 outbreak in Hubei. Furthermore, the self-connection of the right amygdala, inferred using dynamic causal modeling, was negatively correlated with stress-induced behavior in this cohort. A significant correlation between the right amygdala-dmPFC rsFC and self-connection of the right amygdala was found. Additionally, after three months of the COVID-19 outbreak in Hubei when the stressor weakened - and in another cohort collected in regions outside Hubei where the individuals experienced a lower level of stress - the relationship between the amygdala-dmPFC rsFC and the stress-induced behavior disappeared. Our findings support that amygdala connectivity is a predisposing neural feature of stress-induced behavior in the COVID-19 outbreak in Hubei, suggesting the amygdala connectivity before stress predicts subsequent behavior while facing an emergent and unexpected event. And thus our findings provide an avenue for identifying individuals vulnerable to stress using intrinsic brain function before stress as an indicator.
Distinct pancreatic and neuronal Lung Carcinoid molecular subtypes revealed by integrative omic analysis
Authors: Domingo-Sabugo Clara , Willis-Owen Saffron A.G. , Mandal Amit , Nastase Anca , Dwyer Sarah , Brambilla Cecilia , Gálvez José Héctor , Zhuang Qinwei , Popat Sanjay , Eveleigh Robert , Munter Markus , Lim Eric , Nicholson Andrew G. , Lathrop Mark , Cookson William O.C. , Moffatt Miriam F.
Published: July 2021

Lung Carcinoids (L-CDs) are uncommon low-grade neuroendocrine tumours that are only recently becoming characterised at the molecular level. Notably data on the molecular events that precipitate altered gene expression programmes are very limited. Here we have identified two discrete L-CD subtypes from transcriptomic and whole-genome DNA methylation data, and comprehensively defined their molecular profiles using Whole-Exome Sequencing (WES) and Single Nucleotide Polymorphism (SNP) genotyping. Subtype (Group) 1 features upregulation of neuronal markers (L-CD-NeU) and is characterised by focal spindle cell morphology, peripheral location (71%), high mutational load (P=3.4×10−4), recurrent copy number alterations and is enriched for Atypical Lung Carcinoids. Group 2 (L-CD-PanC) are centrally located and feature upregulation of pancreatic and metabolic pathway genes concordant with promoter hypomethylation of beta cell and genes related to insulin secretion (P<1×10−6). L-CD-NeU tumours harbour mutations in chromatin remodelling and in SWI/SNF complex members, while L-CD-PanC tumours show aflatoxin mutational signatures and significant DNA methylation loss genome-wide, particularly enriched in repetitive elements (P<2.2 × 10−16). Our findings provide novel insights into the distinct mechanisms of epigenetic dysregulation in these lung malignancies, potentially opening new avenues for biomarker selection and treatment in L-CD patients.
Duchenne muscular dystrophy patients lacking the dystrophin isoforms Dp140 and Dp71 and mouse models lacking Dp140 have a more severe motor phenotype
Authors: Chesshyre Mary , Ridout Deborah , Hashimoto Yasumasa , Ookubo Yoko , Torelli Silvia , Maresh Kate , Ricotti Valeria , Abbott Lianne , Gupta Vandana Ayyar , Main Marion , Scoto Mariacristina , Baranello Giovanni , Manzur Adnan , Aoki Yoshitsugu , Muntoni Francesco
Published: July 2021

Background

Duchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full length Dp427 is the primary dystrophin isoform expressed in skeletal muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS co-morbidities is well known, relationships between lack of Dp140 and Dp71 and DMD motor outcomes are not. We have conducted a series of investigations addressing this.

Methods

Functional outcome data from 387 DMD boys aged 4.0-15.4 years was subdivided by DMD mutation expected effect on isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n=201); group 2 (Dp427/Dp140 absent, Dp71 present, n=152); and group 3 (Dp427/Dp140/Dp71 absent, n=34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10m walk/run and rise times were explored using regression analysis. We used Capillary Western immunoassay (Wes) analysis to study Dp427, Dp140 and Dp71 production in wild-type and DMD skeletal muscle and myogenic cultures. Grip strength was studied in wild-type, mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD-null (lacking all isoforms) mice.

Results

In DMD boys, we found a strong association between isoform group and motor function. In DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in group 3 than group 1 (p<0.01) and 4.9 points lower in group 3 than group 2 (p=0.05). Mean peak NSAA scores were 4.0 points lower in group 3 than group 1 (p<0.01), 2.4 points lower in group 3 than group 2 (p=0.09) and 1.6 points lower in group 2 than group 1 (p=0.04).

Average grip strength in peak force at 3 months of age was higher in mdx than mdx52 mice (p=0.01).

Dp427, but not Dp71, was produced in normal skeletal muscle; low levels of Dp71 were detected in DMD skeletal muscle. High Dp71 levels were present in wild-type and DMD myogenic cultures.

Conclusions

DMD boys lacking Dp140 and Dp140/Dp71 displayed worse motor function with a cumulative effect of isoform loss. DMD mouse models lacking Dp427 and Dp140 had lower grip strength than those lacking Dp427 but not Dp140. Our results highlight the importance of considering the effects of dystrophin isoform loss on DMD motor impairment, with important implications for understanding the complex relationship between brain and muscle function in DMD and patient stratification for clinical trials.
Semantic modelling of Common Data Elements for Rare Disease registries, and a prototype workflow for their deployment over registry data
Authors: Kaliyaperumal Rajaram , Wilkinson Mark D. , Alarcón Moreno Pablo , Benis Nirupama , Cornet Ronald , dos Santos Vieira Bruna , Dumontier Michel , Bernabé César Henrique , Jacobsen Annika , Le Cornec Clémence M. A. , Godoy Mario Prieto , Queralt-Rosinach Núria , Schultze Kool Leo J , Swertz Morris A. , van Damme Philip , van der Velde K. Joeri , van Lin Nawel , Zhang Shuxin , Roos Marco
Published: July 2021

Background

The European Platform on Rare Disease Registration (EU RD Platform) aims to address the fragmentation of European rare disease (RD) patient data, scattered among hundreds of independent and non-coordinating registries, by establishing standards for integration and interoperability. The first practical output of this effort was a set of 16 Common Data Elements (CDEs) that should be implemented by all RD registries. Interoperability, however, requires decisions beyond data elements - including data models, formats, and semantics. Within the European Joint Programme on Rare Disease (EJP RD), we aim to further the goals of the EU RD Platform by generating reusable RD semantic model templates that follow the FAIR (Findable, Accessible, Interoperable, and Reusable) Data Principles.

Results

Through a team-based iterative approach, we created semantically grounded models to represent each of the CDEs, using the SemanticScience Integrated Ontology (SIO) as the core framework for representing the entities and their relationships. Within that framework, we mapped the concepts represented in the CDEs, and their possible values, into domain ontologies such as the Orphanet Rare Disease Ontology, Human Phenotype Ontology and National Cancer Institute Thesaurus. Finally, we created an exemplar, reusable ETL pipeline that we will be deploying over these non-coordinating data repositories to assist them in creating model-compliant FAIR data without requiring site-specific coding nor expertise in Linked Data or FAIR.

Conclusions

Within the EJP RD project, we determined that creating reusable, expert-designed templates reduced or eliminated the requirement for our participating biomedical domain experts and rare disease data hosts to understand description logic semantics. This enabled them to publish highly expressive FAIR data using tools and approaches that were already familiar to them.
A highly sensitive and specific SARS-CoV-2 spike- and nucleoprotein-based fluorescent multiplex immunoassay (FMIA) to measure IgG, IgA and IgM class antibodies
Authors: Solastie Anna , Virta Camilla , Haveri Anu , Ekström Nina , Kantele Anu , Miettinen Simo , Lempainen Johanna , Jalkanen Pinja , Kakkola Laura , Dub Timothée , Julkunen Ilkka , Melin Merit
Published: July 2021

Background

Validation and standardization of accurate serological assays are crucial for the surveillance of the coronavirus disease 2019 (COVID-19) pandemic and population immunity.

Methods

We describe the analytical and clinical performance of an in-house fluorescent multiplex immunoassay (FMIA) for simultaneous quantification of antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein and spike glycoprotein. Furthermore, we calibrated IgG-FMIA against World Health Organisation (WHO) International Standard and compared FMIA results to an in-house enzyme immunoassay (EIA) and a microneutralisation test (MNT). We also compared the MNT results of two laboratories.

Results

IgG-FMIA displayed 100% specificity and sensitivity for samples collected 13-150 days post-onset of symptoms (DPO). For IgA- and IgM-FMIA 100% specificity and sensitivity were obtained for a shorter time window (13-36 and 13-28 DPO for IgA- and IgM-FMIA, respectively). FMIA and EIA results displayed moderate to strong correlation, but FMIA was overall more specific and sensitive. IgG-FMIA identified 100% of samples with neutralising antibodies (NAbs). Anti-spike IgG concentrations correlated strongly (ρ=0.77-0.84, P<2.2×10−16) with NAb titers. The NAb titers of the two laboratories displayed a very strong correlation (ρ=0.95, P<2.2×10−16).

Discussion

Our results indicate good correlation and concordance of antibody concentrations measured with different types of in-house SARS-CoV-2 antibody assays. Calibration against WHO international standard did not, however, improve the comparability of FMIA and EIA results.
Determining the stability of genome-wide factors in BMI between ages 40 to 69 years
Authors: Gillespie Nathan A , Gentry Amanda Elswick , Kirkpatrick Robert M , Maes Hermine H , Reynolds Chandra A , Mathur Ravi , Kendler Kenneth S , Peterson Roseann E. , Webb Bradley T.
Published: July 2021

Genome-wide association studies (GWAS) have successfully identified common variants associated with BMI. However, the stability of genetic variation influencing BMI from midlife and beyond is unknown. By analyzing BMI data collected from 165,717 men and 193,073 women from the UKBiobank, we performed BMI GWAS on six independent five-year age intervals between 40 and 73 years. We then applied genomic structural equation modeling (gSEM) to test competing hypotheses regarding the stability of genetic effects for BMI. LDSR genetic correlations between BMI assessed between ages 40 to 73 were all very high and ranged 0.89 to 1.00. Genomic structural equation modeling revealed that genetic variance in BMI at each age interval could not be explained by the accumulation of any age-specific genetic influences or autoregressive processes. Instead, a common set of stable genetic influences appears to underpin variation in BMI from middle to early old age in men and women alike.
EEG Alpha Power and Pupil Diameter Reflect Endogenous Auditory Attention Switching and Listening Effort
Authors: Haro Stephanie , Rao Hrishikesh M. , Quatieri Thomas F. , Smalt Christopher J.
Published: July 2021

Auditory attention describes a listeners focus on an acoustic source while they ignore other competing sources that might be present. In an environment with multiple talkers and background noise (i.e. the cocktail party effect), auditory attention can be difficult, requiring the listener to expend measurable cognitive effort. A listener will naturally interrupt sustained attention on a source when switching towards another source during conversation. This change in attention is potentially even more taxing than maintaining sustained attention due to the limits of human working memory, and this additional effort required has not been well studied. In this work, we evaluated an attention decoder algorithm for detecting the change in attention and investigated cognitive effort expended during attentional switching and sustained attention. Two variants of endogenous attention switching were explored: the switches either had in-the-moment decision making or a pre-defined attentional switch time. A least-squares, EEG-based, attention decoding algorithm achieved 64.1% accuracy with a 5-second correlation window and illustrated smooth transitions in the attended talker prediction through switches in sustained attention at approximately half of the analysis window size (2.2 seconds). The expended listening effort, as measured by simultaneous electroencephalography (EEG) and pupillometry, was also a strong indicator of switching. Specifically, centrotemporal alpha power [F(2, 18) = 7.473, P = 0.00434] and mean pupil diameter [F(2, 18) = 9.159, P = 0.0018] were significantly different for trials that contained a switch in comparison to sustained trials. We also found that relative attended and ignored talker locations modulate the EEG alpha topographic response. This alpha lateralization was found to be impacted by the interaction between experimental condition and whether the measure was computed before or after the switch [F(2,18) = 3.227, P = 0.0634]. These results suggest that expended listening effort is a promising feature that should be pursued in a decoding context, in addition to speech and location-based features.
Multiplexed Imaging Mass Cytometry of Chemokine Milieus in Metastatic Melanoma Characterizes Features of Response to Immunotherapy
Authors: Hoch Tobias , Schulz Daniel , Eling Nils , Gómez Julia Martínez , Levesque Mitchell P. , Bodenmiller Bernd
Published: July 2021

Intratumoral immune cells are crucial for tumor control and anti-tumor responses during immunotherapy. Immune cell trafficking into tumors is mediated by chemokines, which are expressed and secreted upon various stimuli and interact with specific receptors. To broadly characterize chemokine expression and function in tumors, we have used multiplex mass cytometry-based imaging of protein markers and RNA transcripts to analyze the chemokine landscape and immune infiltration in metastatic melanoma samples. Tumors that lacked immune infiltration were devoid of most chemokines and exhibited particularly low levels of antigen presentation and inflammation. Infiltrated tumors were characterized by expression of multiple chemokines. CXCL9 and CXCL10 were often localized in patches associated with dysfunctional T cells expressing CXCL13 which was strongly associated with B cell patches and follicles. TCF7+ naïve-like T cells, which predict response to immunotherapy, were enriched in the vicinity of B cell patches and follicles. Our data highlight the strength of RNA and protein co-detection which was critical to deconvolve specialized immune microenvironments in inflamed tumors based on chemokine expression. Our findings further suggest that the formation of tertiary lymphoid structures is accompanied by naïve and naive- like T cell recruitment, which ultimately boosts anti-tumor activity.

One sentence summary

Inflammatory chemokine milieus in metastatic melanoma are hotspots of T cell dysfunction and CXCL13 expression, which likely guide the recruitment of B cells and the formation of B cell follicles responsible for anti-tumor immunity.
Adipogenic activity of chemicals used in plastic consumer products
Authors: Voelker Johannes , Ashcroft Felicity , Vedoy Asa , Zimmermann Lisa , Wagner Martin
Published: July 2021

Bisphenols and phthalates, chemicals frequently used in plastic products, promote obesity in cell and animal models. However, these well-known metabolism disrupting chemicals (MDCs) represent only a minute fraction of all compounds found in plastics. To gain a comprehensive understanding of plastics as a source of exposure to MDCs, we characterized all chemicals present in 34 everyday products using nontarget high-resolution mass spectrometry and analyzed their joint adipogenic activities by high-content imaging. We detected 55,300 chemical features and tentatively identified 629 unique compounds, including 11 known MDCs. Importantly, chemicals that induced proliferation, growth, and triglyceride accumulation in 3T3-L1 adipocytes were found in one third of the products. Since the majority did not target peroxisome proliferator-activated receptor γ, the effects are likely to be caused by unknown MDCs. Our study demonstrates that daily-use plastics contain potent mixtures of MDCs and can, therefore, be a relevant yet underestimated environmental factor contributing to obesity.
m6A-mediated Cell-cell Communication Controls Planarian Regeneration
Authors: Cui Guanshen , Zhou Jia-Yi , Ge Xin-Yang , Sun Bao-Fa , Song Ge-Ge , Wang Xing , Wang Xiu-Zhi , Zhang Rui , Wang Hai-Lin , Jing Qing , Zhao Yongliang , Koziol Magdalena J , Zeng An , Zhang Wei-Qi , Han Da-Li , Yang Ying , Yang Yun-Gui
Published: July 2021

Regeneration is the regrowth of damaged tissues or organs, a vital mechanism responding to damages from primitive organisms to higher mammals. Planarian possesses active whole-body regenerative capability owning to its vast reservoir of adult stem cells, neoblasts, thus provides an ideal model to delineate the underlying mechanisms for regeneration. N6-methyladenosine (m6A) regulates stem cell renewal and differentiation. However, how m6A controls regeneration at whole-organism level remains largely unknown. Here, we demonstrate that the depletion of m6A methyltransferase regulatory subunit wtap abolishes planarian regeneration, through regulating cell-cell communication and cell cycle. scRNA-Seq analysis unveils that the wtap knockdown induces a unique type of neural progenitor-like cells (NP-like cells), characterized by specific expression of the cell-cell communication ligand grn. Intriguingly, the depletion of m6A-modified transcripts grn/cdk9 (or cdk7) axis rescues the defective regeneration of planarian without wtap. Overall, our study reveals an indispensable role of m6A-dependent cell-cell communication essential for whole-organism regeneration.
Across-population genomic prediction in grapevine opens up promising prospects for breeding
Authors: Brault Charlotte , Segura Vincent , This Patrice , Cunff Loïc Le , Flutre Timothée , François Pierre , Pons Thierry , Péros Jean-Pierre , Doligez Agnès
Published: July 2021

Crop breeding involves two selection steps: choosing progenitors and selecting offspring within progenies. Genomic prediction, based on genome-wide marker estimation of genetic values, could facilitate these steps. However, its potential usefulness in grapevine (Vitis viniferaL.) has only been evaluated in non-breeding contexts mainly through cross-validation within a single population. We tested across-population genomic prediction in a more realistic breeding configuration, from a diversity panel to ten bi-parental crosses connected within a half-diallel mating design. Prediction quality was evaluated over 15 traits of interest (related to yield, berry composition, phenology and vigour), for both the average genetic value of each cross (cross mean) and the genetic values of individuals within each cross (individual values). Genomic prediction in these conditions was found useful: for cross mean, average per-trait predictive ability was 0.6, while per-cross predictive ability was halved on average, but reached a maximum of 0.7. Mean predictive ability for individual values within crosses was 0.26, about half the within-half-diallel value taken as a reference. For some traits and/or crosses, these across-population predictive ability values are promising for implementing genomic selection in grapevine breeding. This study also provided key insights on variables affecting predictive ability. Per-cross predictive ability was well predicted by genetic distance between parents and when this predictive ability was below 0.6, it was improved by training set optimization. For individual values, predictive ability mostly depended on trait-related variables (magnitude of the cross effect and heritability). These results will greatly help designing grapevine breeding programs assisted by genomic prediction.
METTL18-mediated histidine methylation on RPL3 modulates translation elongation for proteostasis maintenance
Authors: Matsuura-Suzuki Eriko , Shimazu Tadahiro , Takahashi Mari , Kotoshiba Kaoru , Suzuki Takehiro , Kashiwagi Kazuhiro , Sohtome Yoshihiro , Akakabe Mai , Sodeoka Mikiko , Dohmae Naoshi , Ito Takuhiro , Shinkai Yoichi , Iwasaki Shintaro
Published: July 2021

Protein methylation occurs predominantly on lysine and arginine residues, but histidine also serves as a substrate for the modification. However, a limited number of enzymes responsible for this modification have been reported. Moreover, the biological role of histidine methylation has remained poorly understood. Here, we report that human METTL18 is a histidine methyltransferase for the ribosomal protein RPL3 and that the modification specifically slows ribosome traverse on tyrosine codons, allowing the proper folding of synthesized proteins. By performing an in vitro methylation assay with a methyl donor analog and quantitative mass spectrometry, we found that His245 of RPL3 is methylated at the τ-N position by METTL18. Structural comparison of the modified and unmodified ribosomes showed stoichiometric modification and suggested a role in translation tuning. Indeed, genome-wide ribosome profiling revealed suppressed ribosomal translocation at tyrosine codons by RPL3 methylation. Because the slower elongation provides enough time for nascent protein folding, RPL3 methylation protects cells from the cellular aggregation of Tyr-rich proteins. Our results reveal histidine methylation as an example of a “ribosome code” that ensures proteome integrity in cells.
HGFAC is a ChREBP Regulated Hepatokine that Enhances Glucose and Lipid Homeostasis
Authors: Sargsyan Ashot , Doridot Ludivine , Hannou Sarah A. , Tong Wenxin , Srinivasan Harini , Ivison Rachael , Monn Ruby , Kou Henry H. , Haldeman Jonathan M. , Arlotto Michelle , White Phillip J. , Grimsrud Paul A. , Astapova Inna , Tsai Linus , Herman Mark A.
Published: July 2021

Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, in part, through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of an HGFAC-HGF-PPARγ signaling axis in the liver to preserve glucose and lipid homeostasis.
Calcium-binding protein S100A6 interaction with VEGF receptors integrates signaling and trafficking pathways
Authors: Bao Leyuan , Fearnley Gareth W. , Lin Chi-Chuan , Odell Adam F. , Redondo Ana C. , Kinsella Gemma K. , Findlay John B. C. , Ladbury John E. , Harrison Michael A. , Ponnambalam Sreenivasan
Published: July 2021

The mammalian endothelium which lines all blood vessels responds to soluble factors which control vascular development and sprouting. Endothelial cells bind to vascular endothelial growth factor A via two different receptor tyrosine kinases (VEGFR1, VEGFR2) which regulate such cellular responses. The integration of VEGFR signal transduction and membrane trafficking is not well understood. Here, we used a yeast-based membrane protein screen to identify VEGFR-interacting factor(s) which modulate endothelial cell function. By screening a human endothelial cDNA library, we identified a calcium-binding protein, S100A6, which can interact with either VEGFR. We found that S100A6 binds in a calcium-dependent manner to either VEGFR1 or VEGFR2. S100A6 binding was mapped to the VEGFR2 tyrosine kinase domain. Depletion of S100A6 impacts on VEGF-A-regulated signaling through the canonical mitogen-activated protein kinase (MAPK) pathway. Furthermore, S100A6 depletion caused contrasting effects on biosynthetic VEGFR delivery to the plasma membrane. Co-distribution of S100A6 and VEGFRs on tubular profiles suggest the presence of transport carriers that facilitate VEGFR trafficking. We propose a mechanism whereby S100A6 acts as a calcium-regulated switch which facilitates biosynthetic VEGFR trafficking from the TGN-to-plasma membrane. VEGFR-S100A6 interactions thus enable integration of signaling and trafficking pathways in controlling the endothelial response to VEGF-A.