bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationships of Prescription Opioid Sales to Opiate Treatment Admissions and Overdose Deaths: A Reanalysis of Relationships -- United States 2010-2019
Authors: Aubry Larry , Carr B. Thomas 
Published: March 2022

ABSTRACTBackgroundIn 2016, the United States Centers for Disease Control and Prevention (CDC) issued “CDC Guideline for Prescribing Opioids for Chronic Pain”. The guideline used data from 1999 to 2010 that related Opioid Sales to Opiate Treatment Admissions (a measure of drug addiction rates) Opioid Deaths. The CDC’s analysis indicated that opioid prescriptions are directly correlated1-8 with drug addiction and overdose mortality outcomes. As a result, prescription opioid sales have been curtailed, making it difficult for sufferers of severe chronic pain to access an effective treatment option. In this paper, the relationships between opioid sales, drug addiction, and opioid deaths are reexamined using data from 2010 to 2019.MethodsLinear regression models were fit to each response separately. Opioid sales (measured as MME per capita) was the independent variable. Total overdose deaths (TOD), any opioid overdose deaths (AOD), prescription opioid overdose deaths (POD) and opiate treatment admissions (OTA) were the dependent, response variables. The models were assessed using three criteria: the statistical significance of the model (Overall P-Value), the quality of the fit (R2), and the sign of the slope coefficient.ResultsThe analyses revealed that the direct correlations (significant, positive slopes) reported by the CDC based on data from 1999 to 2010 no longer exist based on data from 2010 to 2019. The relationships either have reversed (i.e., significant negative slopes) or are non-existent (no significant model).ConclusionsThe basis for the CDC guideline no longer holds. The guideline should be updated or annulled based on the current relationships that have existed for a decade. This is especially relevant for people suffering from severe, chronic pain, whose access to prescription opioids has been severely curtailed under the current guideline and to ensure that government resources are directed to an effective approach to reducing overdose deaths.
Clinical prediction of pathogenic variants in non-coding regions of the human genome
Authors: Petrazzini Ben O. , López-Bello Fernando , Naya Hugo , Spangenberg Lucia 
Published: March 2022

AbstractWhole genome sequencing has become a wide-spread diagnostic tool for rare diseases patients. This broadens analyses to non-coding regions of the genome showing strong evidence of clinical significance for human Mendelian diseases. Notwithstanding its importance, current in-silico prediction tools are restricted to coding sequences which limits its applicability. Additionally, lack of power in discriminating variants of uncertain significance (VUS) limits its clinical utility. Here we present PANCO, a genome-wide pathogenicity prediction tool aiming at reclassification of VUS with a rigorous imputation workflow adapted for non-coding variants. PANCO integrates functional, evolutionary and population frequency information to capture emerging biological signals correctly reclassifying VUS. Importantly, PANCO shows remarkable power in an external validation set, on VUS (AUROC=0.99 and AUROC=0.89, respectively).
High cardiomyocyte diversity in human early prenatal heart development
Authors: Sylvén Christer , Wärdell Eva , Månsson-Broberg Agneta , Cingolani Eugenio , Ampatzis Konstantinos , Larsson Ludvig , Björklund Åsa , Giacomello Stefania 
Published: March 2022

SummaryCardiomyocytes play key roles during cardiogenesis, but have poorly understood features, especially in prenatal stages. Thus, we have characterized human prenatal cardiomyocytes, 6.5– 7 weeks post-conception, in detail by integrating single-cell RNA sequencing, spatial transcriptomics, and ligand–receptor interaction information. Using a computational workflow developed to dissect cell type heterogeneity, localize cell types, and explore their molecular interactions, we identified eight types of developing cardiomyocyte, more than double compared to the ones identified in the Human Developmental Cell Atlas. These have high variability in cell cycle activity, mitochondrial content, and connexin gene expression, and are differentially distributed in the ventricles, including outflow tract, and atria, including sinoatrial node. Moreover, cardiomyocyte ligand–receptor crosstalk is mainly with non-cardiomyocyte cell types, encompassing cardiogenesis-related pathways. Thus, early prenatal human cardiomyocytes are highly heterogeneous and develop unique location-dependent properties, with complex ligand–receptor crosstalk. Further elucidation of their developmental dynamics may give rise to new therapies.Graphical abstract
OLFACTORY TRAINING EFFICIENCY IN POST-COVID-19 PERSISTENT OLFACTORY DISORDERS
Authors: Vandersteen Clair , Payne Magali , Dumas Louise-Émilie , Cancian Élisa , Plonka Alexandra , D’Andrea Grégoire , Chirio David , Demonchy Élisa , Risso Karine , Askenazy-Gittard Florence , Savoldelli Charles , Guevara Nicolas , Robert Philippe , Castillo Laurent , Manera Valeria , Gros Auriane 
Published: March 2022

ABSTRACTBackgroundPersistent post-viral olfactory disorders (PPVOD) are widely reported after a COVID-19 and estimate to 30% one year after infection. Parosmias are the main qualitative dysosmia associated with olfaction recovery. No treatment is, to date, significantly efficient on PPVOD except olfactory training (OT). The main objective of this work was to evaluate OT efficiency on post-COVID-19 PPVOD.MethodsConsecutive patients consulting to the ENT department with post-COVID-19 PPVOD were included after mainly clinical examination, the complete Sniffin’ Stick Test (TDI), the short version of the Questionnaire of olfactory disorders and the SF-36. Patients were trained to practice a self-olfactory training (professional manufactured olfactory training kit) twice a day for 6 months before coming back and undergo the same complete evaluation.ResultsForty-three patients were included and performed 3,5 months of OT in average. There was a significant improvement in the mean TDI score increasing from 24,7 (±8,9) before the OT to 30,9 (±9,8) (p<0,001). Parosmias increased significantly from 8 (18,6%) to 27 (62.8%) (p<0,001). Based on normative data divided by sex and age, a significant increase in the number of normosmic participants was only found for the Threshold values (p<0,001). Specific and general olfaction-related quality of life improved after the OT.ConclusionsOT seems to be efficient in post-COVID-19 PPVOD, probably on the peripheral regenerative part of the olfactory recovery. Future therapeutic strategies may focus on the central aspects of the post-COVID-19 PPVOD.
Resting-State Amygdala Subregion and Precuneus Connectivity Provide Evidence for a Dimensional Approach to Studying Social Anxiety Disorder
Authors: Mizzi Simone , Pedersen Mangor , Rossell Susan L , Rendell Peter , Terrett Gill , Heinrichs Markus , Labuschagne Izelle 
Published: March 2022

AbstractBackgroundSocial anxiety disorder (SAD) is a prevalent and disabling mental health condition, characterized by excessive fear and anxiety in social situations. Resting-state functional magnetic resonance imaging (fMRI) paradigms have been increasingly used to understand the neurobiological underpinnings of SAD in the absence of threat-related stimuli. Previous studies have primarily focused on the role of the amygdala in SAD. However, the amygdala consists of functionally and structurally distinct subregions, and recent studies have highlighted the importance of investigating the role of these subregions independently.MethodUsing multiband fMRI, we analyzed resting-state data from 135 participants (42 SAD, 93 healthy controls). By employing voxel-wise permutation testing, we examined group differences of fMRI connectivity and associations between fMRI connectivity and social anxiety symptoms to further investigate the classification of SAD as a categorical or dimensional construct.ResultsSeed-to-whole brain functional connectivity analysis using multiple ‘seeds’ including the amygdala and its subregions and the precuneus, revealed no statistically significant group differences. However, social anxiety severity was significantly negatively correlated with functional connectivity of the precuneus - perigenual anterior cingulate cortex and positively correlated with functional connectivity of the amygdala (specifically the superficial subregion) - parietal/cerebellar areas.ConclusionOur findings demonstrate clear links between symptomatology and brain connectivity in the absence of diagnostic differences, with evidence of amygdala subregion-specific alterations. The observed brain-symptom associations did not include disturbances in the brain’s fear circuitry (i.e., disturbances in connectivity between amygdala - prefrontal regions) likely due to the absence of threat-related stimuli.
A strategy to optimize the peptide-based inhibitors against different mutants of the spike protein of SARS-CoV-2
Authors: Priya Prerna , Basit Abdul , Bandyopadhyay Pradipta 
Published: March 2022

AbstractSARS-CoV-2 virus has caused high-priority health concerns at a global level. Vaccines have stalled the proliferation of viruses to some extent. Yet, the emergence of newer, potentially more infectious, and dangerous mutants such as delta and omicron are among the major challenges in finding a more permanent solution for this pandemic. The effectiveness of antivirals Molnupiravir and Paxlovid, authorized for emergency use by the FDA, are yet to be assessed at larger populations. Patients with a high risk of disease progression or hospitalization have received treatment with a combination of antibodies (antibody-cocktail). Most of the mutations leading to the new lineage of SARS-CoV-2 are found in the spike protein of this virus that plays a key role in facilitating host entry. The current study has investigated how to modify a promising peptide-based inhibitor of spike protein, LCB3, against common mutations in the target protein so that it retains its efficacy against the spike protein. LCB3 being a prototype for protein-based inhibitors is an ideal testing system to learn about protein-based inhibitors. Two common mutations N501Y and K417N are considered in this work. Using a structure-based approach that considers free energy decomposition of residues, distance, and the interactions between amino acids, we propose the substitutions of amino acid residues of LCB3 inhibitors. Our binding free energy calculations suggest a possible improvement in the binding affinity of existing inhibitor LCB3 to the mutant forms of the S-protein using simple substitutions at specific positions of the inhibitor. This approach, being general, can be used in different inhibitors and other mutations and help in fighting against SARS-CoV-2.
Achieving pan-microbiome biological insights via the dbBact knowledge base
Authors: Amir Amnon , Ozel Eitan , Haberman Yael , Shental Noam 
Published: March 2022

Abstract16S rRNA amplicon sequencing provides a relatively inexpensive culture-independent method for studying the microbial world. Although thousands of such studies have examined diverse habitats, it is difficult for researchers to use this vast trove of experiments when analyzing their findings and interpret them in a broader context. To bridge this gap, we introduce dbBact, an open wiki-like bacterial knowledge base. dbBact combines information from hundreds of studies across diverse habitats, creating a collaborative central repository where 16S rRNA amplicon sequence variants (ASVs) are manually extracted from each study and assigned multiple ontology-based terms. Using the >900 studies of dbBact, covering more than 1,400,000 associations between 345,000 ASVs and 6,500 ontology terms, we show how the dbBact statistical and programmatic pipeline can augment standard microbiome analysis. We use multiple examples to demonstrate how dbBact leads to formulating novel hypotheses regarding inter-host similarities, intra-host sources of bacteria, and commonalities across different diseases, and helps detect environmental sources and identify contaminants.
Design, Synthesis and Evaluation of Inhibitors of the SARS-CoV2 nsp3 Macrodomain
Authors: Sherrill Lavinia M. , Joya Elva E. , Walker AnnMarie , Roy Anuradha , Alhammad Yousef M. , Atobatele Moriama , Wazir Sarah , Abbas George , Keane Patrick , Zhuo Junlin , Leung Anthony K.L. , Johnson David K. , Lehtiö Lari , Fehr Anthony R. , Ferraris Dana 
Published: March 2022

AbstractA series of amino acid based7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized to discern the structure activity relationships against the SARS-CoV-2 nsp3 macrodomain (Mac1), an ADP-ribosylhydrolase that is critical for coronavirus replication and pathogenesis. Structure activity studies identified compound15cas a low-micromolar inhibitor of Mac1 in two ADP-ribose binding assays. This compound also demonstrated inhibition in an enzymatic assay of Mac1 and displayed a thermal shift comparable to ADPr in the melting temperature of Mac1 supporting binding to the target protein. A structural model reproducibly predicted a binding mode where the pyrrolo pyrimidine forms a hydrogen bonding network with Asp22and the amide backbone NH of Ile23in the adenosine binding pocket and the carboxylate forms hydrogen bonds to the amide backbone of Phe157and Asp156, part of the oxyanion subsite of Mac1. Compound15calso demonstrated notable selectivity for coronavirus macrodomains when tested against a panel of ADP-ribose binding proteins. Together, this study identified several low MW, low μM Mac1 inhibitors to use as small molecule chemical probes for this potential anti-viral target and offers starting points for further optimization.Graphical Abstract
AI based pre-screening of large bowel cancer via weakly supervised learning of colorectal biopsy histology images
Authors: Bilal Mohsin , Tsang Yee Wah , Ali Mahmoud , Graham Simon , Hero Emily , Wahab Noorul , Dodd Katherine , Sahota Harvir , Lu Wenqi , Jahanifar Mostafa , Robinson Andrew , Azam Ayesha , Benes Ksenija , Nimir Mohammed , Bhalerao Abhir , Eldaly Hesham , Ahmed Raza Shan E , Gopalakrishnan Kishore , Minhas Fayyaz , Snead David , Rajpoot Nasir 
Published: March 2022

AbstractHistopathological examination is a pivotal step in the diagnosis and treatment planning of many major diseases. To facilitate the diagnostic decision-making and reduce the workload of pathologists, we present an AI-based pre-screening tool capable of identifying normal and neoplastic colon biopsies. To learn the differential histological patterns from whole slides images (WSIs) stained with hematoxylin and eosin (H&E), our proposed weakly supervised deep learning method requires only slide-level labels and no detailed cell or region-level annotations. The proposed method was developed and validated on an internal cohort of biopsy slides (n=4 292) from two hospitals labeled with corresponding diagnostic categories assigned by pathologists after reviewing case reports. Performance of the proposed colon cancer pre-screening tool was evaluated in a cross-validation setting using the internal cohort (n=4 292) and also by an external validation on The Cancer Genome Atlas (TCGA) cohort (n=731). With overall cross-validated classification accuracy (AUROC = 0.9895) and external validation accuracy (AUROC = 0.9746), the proposed tool promises high accuracy to assist with the pre-screening of colorectal biopsies in clinical practice. Analysis of saliency maps confirms the representation of disease heterogeneity in model predictions and their association with relevant pathological features. The proposed AI tool correctly reported some slides as neoplastic while clinical reports suggested they were normal. Additionally, we analyzed genetic mutations and gene enrichment analysis of AI-generated neoplastic scores to gain further insight into the model predictions and explore the association between neoplastic histology and genetic heterogeneity through representative genes and signaling pathways.
Medium-term impacts of the waves of the COVID-19 epidemic on treatments for non-COVID-19 patients in intensive care units: a retrospective cohort study in Japan
Authors: Watanabe Shusuke , Shin Jung-ho , Okuno Takuya , Morishita Tetsuji , Takada Daisuke , Kunisawa Susumu , Imanaka Yuichi 
Published: March 2022

ABSTRACTBackgroundMaintaining critical care for non-Coronavirus-disease-2019 (non-COVID-19) patients is a key pillar of tackling the impact of the COVID-19 pandemic. This study aimed to reveal the medium-term impacts of the COVID-19 epidemic on case volumes and quality of intensive care for critically ill non-COVID-19 patients.MethodsAdministrative data were used to investigate the trends in case volumes of admissions to intensive care units (ICUs) compared with the previous years. Standardized mortality ratios (SMRs) of non-COVID-19 ICU patients were calculated in each wave of the COVID-19 epidemic in Japan.ResultsThe ratios of new ICU admissions of non-COVID-19 patients to those in the corresponding months before the epidemic: 21% in May 2020, 8% in August 2020, 9% in February 2021, and 14% in May 2021, approximately concurrent with the peaks in COVID-19 infections. The decrease was greatest for new ICU admissions of non-COVID patients receiving mechanical ventilation (MV) on the first day of ICU admission: 26%, 15%, 19%, and 19% in the first, second, third, and fourth waves, respectively. No statistically significant change in SMR was observed in any wave of the epidemic; SMRs were 0.990 (95% confidence interval (CI), 0.962-1.019), 0.979 (95% CI, 0.953-1.006), 0.996 (95% CI, 0.980-1.013), and 0.989 (95% CI, 0.964-1.014), in the first, second, third, and fourth waves of the epidemic, respectively.ConclusionsCompared to the previous years, the number of non-COVID-19 ICU patients continuously decreased over the medium term during the COVID-19 epidemic. The decrease in case volumes was larger in non-COVID-19 ICU patients initially receiving MV than those undergoing other initial treatments. The standardized in-hospital mortality of non-COVID-19 ICU patients did not change in any waves of the epidemic.EYWORDSIntensive care unit, COVID-19, mechanical ventilation, in-hospital mortality
Structural analysis of the bacterial amyloid curli
Authors: Sleutel Mike , Pradhan Brajabandhu , Remaut Han 
Published: March 2022

AbstractTwo decades have passed since the initial proposition that amyloids are not only (toxic) byproducts of an unintended aggregation cascade, but that they can also be produced by an organism to serve a defined biological function. That revolutionary idea was borne out of the realization that a large fraction of the extracellular matrix that holds Gram-negative cells into a persistent biofilm is composed of protein fibers (curli; tafi) with cross-β architecture, nucleation-dependent polymerization kinetics and classic amyloid tinctorial properties. The list of proteins shown to form so-called ‘functional’ amyloid fibers in vivo has greatly expanded over the years, but detailed structural insights have not followed at a similar pace, in part due to the associated experimental barriers. Here we combine extensive AlphaFold2 modelling and cryo-electron transmission microscopy to propose an atomic model of curli protofibrils, and their higher modes of organization. We uncover an unexpected structural diversity of curli building blocks and fibril architectures. Our results allow for a rationalization of the extreme physico-chemical robustness of curli, as well as earlier observations of inter-species curli promiscuity, and should facilitate further engineering efforts to expand the repertoire of curli-based functional materials.
Inhibition of advanced glycation end product formation and serum protein infiltration in bioprosthetic heart valve leaflets: Investigations of anti-glycation agents
Authors: Zakharchenko Andrey , Rock Christopher A. , Thomas Tina , Keeney Samuel , Hall Emily , Takano Hajime , Krieger Abba M. , Ferrari Giovanni , Levy Robert J. 
Published: March 2022

AbstractBioprosthetic heart valves (BHV) fabricated from glutaraldehyde pretreated heterograft tissue, such as bovine pericardium (BP) are the most commonly used heart valve replacements. However, BHV durability is limited by structural valve degeneration (SVD) resulting from both calcification and advanced glycation end product (AGE) deposition together with serum protein infiltration. In the present study we investigated the hypothesis that anti-AGE agents, Aminoguanidine (AG), Pyridoxamine (PYR), and N-Acetylcysteine (NAC) could mitigate AGE-serum protein mechanisms in model studies, both in vitro and in vivo, using rat subdermal implants of BP. In vitro studies demonstrated that each of these agents could significantly inhibit AGE formation in BP. However, in rat 28 days BP subdermal implants, only PYR demonstrated both significant inhibition of AGE and serum albumin accumulation per immunostaining. BHV calcification was not mitigated by PYR. It is concluded that AGE-serum protein pathophysiology contributing to SVD can be ameliorated by PYR.
Impact of stakeholder management on efficient construction waste management
Authors: Frempong-Jnr Emmanuel Yaw , Ametepey Simon Ofori , Cobbina John Edward 
Published: March 2022

PurposeThe construction industry’s contribution to environmental deterioration is widely established in the literature, implying that addressing this issue will require a coordinated effort from all stakeholders. According to literature, stakeholder involvement without stakeholder management (SKM) is not enough, in ensuring efficient construction waste management (CWM). This study investigates the impact of SKM on efficient CWM by aggregating all relevant SKM variables and measuring their degree of influence on efficient CWM.Design/methodology/approachThis study used a four-stage research approach that included a literature review, a pilot study, a questionnaire survey and statistical analysis. After a thorough examination of the literature, nine essential SKM factors were identified and tested by a questionnaire survey following a pilot study. A total of 310 questionnaires were filled out and returned for analysis (exploratory and confirmatory factor analysis).FindingsThe study established that SKM is a unidimensional construct since all the variables extracted unto one underlying component with total variance explained (TVE), accounting for 58.938% of the total Variance in the measure of SKM in efficient CWM. Additionally, the reliability and validity test results satisfied the recommended thresholds, thus justifying the factorability of the construct. Furthermore, the hypothesis test revealed that SKM has a statistically significant impact on efficient CWM, implying that increasing SKM will have a beneficial impact on efficient CWM.Research limitations/implicationsThe study is limited to material waste management in the construction industry and the outcome was determined solely by a field survey in Ghana. Extending the study to other jurisdictions would have improved its findings and made them easier to generalise.Practical implicationsThe study’s findings are helpful for practitioners and researchers, especially regarding the influence of the eight SKM variables on efficient CWM.Social implicationsThe study’s findings will reduce pollution, thus enhancing public health and encouraging social inclusion through the creation of jobs in the waste management chain.Originality/valueThe uniqueness of this study is anchored on the fact that no CWM study has considered all the eight SKM variables measured in this study at the same time. Also, this study has contributed to the literature by establishing the determinants of SKM in efficient CWM in Ghana.