bluuebunny/crossref_metadata_2025 huggingface dataset:
A Tale of Two Countries: DiaSorin Molecular’s Rapid Response to the COVID-19 Pandemic
Authors: Tabb Michelle M. , Minnucci Giulia , Albano Vincenzo
Published: April 2022

In the summer of 2019, DiaSorin Molecular started designing a multiplex respiratory panel with pan-coronavirus detection as one of the planned targets. The R&D team in Gerenzano, Italy was already searching databases, performing alignments and assessing preliminary target regions for common coronavirus RT-PCR, including SARS and MERS-CoV. In December 2019, we were vigilant and following a cluster of pneumonia cases with undetermined etiology in Wuhan, China. As we now know, the cause of the respiratory infections was the new SARS-CoV-2 virus. DiaSorin Molecular swiftly responded in line with our heritage and company history in detecting emerging infectious diseases. Early in the pandemic and in record time, using research and development teams in both Italy and the U.S. together with the U.S. manufacturing team, we were able to develop and commercialize a new diagnostic test, Simplexa™ COVID-19 Direct, to detect SARS-CoV-2. Our unique platform allowed development of a rapid diagnostic test without the need for extraction reagents. Challenges with control materials, quarantines, clinical samples, raw materials and production were overcome and the entire company worked side by side for accelerated delivery of this assay to clinical labs in Europe, the U.S. and Canada.
Climate-Informed Decision-Making in Data-Poor Environments: Managing Climate Risk Through Citizen Science Networks
Authors: Manteaw Bob O. , Amoah Antwi-Bosiako , Ayittah Bernard , Enu Kirk B.
Published: April 2022

Climate change impacts have become a verifiable reality in most communities in Africa and have already shown its ruthlessness in derailing modest gains made toward sustainable development. While evidence of climate change impacts abounds, especially in key climate-sensitive sectors, not many people living in affected communities have the requisite knowledge, understanding and capacity to respond to emerging impacts. Most communities in Ghana and Africa, broadly, lack the requisite climate change knowledge resources to inform adaptation choices. Adaptation decision-making, in most cases, is reactive, speculative, and based on flawed assumptions and understandings of the climate change phenomenon. This is essentially because most countries lack the capacity to make climate-informed decisions which is also a function of the pervasive lack of efficient climate information services regime across Africa. The paucity of climate change knowledge and associated climate information services is undoubtedly an issue of institutional capacity; however, it is also a function of an enduring culture—a poor attitude toward data collection and application—in decision-making processes. Data-poor environment, or data-poverty, as implied in this work, therefore, broadly describes the absence of a data management culture in decision-making processes; however, specifically to climate change, it describes the lack of functional climate information services regime in local communities in Africa and how such omissions impede the ability of countries to make climate-informed decisions to support adaptation and resilience building. Focusing on Ghana, the paper problematizes the lack of climate information in local communities. The paper argues that Africa's climate crisis is as much a knowledge and learning challenge which requires new and innovative learning approaches to build capacities to facilitate the making of data-driven and climate-informed adaptation decisions in local communities. The paper, therefore, foregrounds citizen-science networks as avenues for community-focused and community-based climate knowledge co-producing mechanisms.
Endothelial Cell Phenotype, a Major Determinant of Venous Thrombo-Inflammation
Authors: Pilard Marion , Ollivier Estelle L. , Gourdou-Latyszenok Virginie , Couturaud Francis , Lemarié Catherine A.
Published: April 2022

Reduced blood flow velocity in the vein triggers inflammation and is associated with the release into the extracellular space of alarmins or damage-associated molecular patterns (DAMPs). These molecules include extracellular nucleic acids, extracellular purinergic nucleotides (ATP, ADP), cytokines and extracellular HMGB1. They are recognized as a danger signal by immune cells, platelets and endothelial cells. Hence, endothelial cells are capable of sensing environmental cues through a wide variety of receptors expressed at the plasma membrane. The endothelium is then responding by expressing pro-coagulant proteins, including tissue factor, and inflammatory molecules such as cytokines and chemokines involved in the recruitment and activation of platelets and leukocytes. This ultimately leads to thrombosis, which is an active pro-inflammatory process, tightly regulated, that needs to be properly resolved to avoid further vascular damages. These mechanisms are often dysregulated, which promote fibrinolysis defects, activation of the immune system and irreversible vascular damages further contributing to thrombotic and inflammatory processes. The concept of thrombo-inflammation is now widely used to describe the complex interactions between the coagulation and inflammation in various cardiovascular diseases. In endothelial cells, activating signals converge to multiple intracellular pathways leading to phenotypical changes turning them into inflammatory-like cells. Accumulating evidence suggest that endothelial to mesenchymal transition (EndMT) may be a major mechanism of endothelial dysfunction induced during inflammation and thrombosis. EndMT is a biological process where endothelial cells lose their endothelial characteristics and acquire mesenchymal markers and functions. Endothelial dysfunction might play a central role in orchestrating and amplifying thrombo-inflammation thought induction of EndMT processes. Mechanisms regulating endothelial dysfunction have been only partially uncovered in the context of thrombotic diseases. In the present review, we focus on the importance of the endothelial phenotype and discuss how endothelial plasticity may regulate the interplay between thrombosis and inflammation. We discuss how the endothelial cells are sensing and responding to environmental cues and contribute to thrombo-inflammation with a particular focus on venous thromboembolism (VTE). A better understanding of the precise mechanisms involved and the specific role of endothelial cells is needed to characterize VTE incidence and address the risk of recurrent VTE and its sequelae.
Recent Advances in Direct Adhesive Restoration Resin-Based Dental Materials With Remineralizing Agents
Authors: Mai Sui , Zhang Qi , Liao Muzi , Ma Xinyue , Zhong Yewen
Published: April 2022

Resin-based dental materials are popular restorative materials especially in direct adhesive restoration because of the excellent mechanical and esthetic properties. Toward the realization of minimally invasive dental procedures, direct composite resin adhesive restoration has become the main treatment for dental defects. In addition, for caries-affected dentin close to the pulp, conservation remineralization has been advocated to save the living pulp. However, the resin–dentin interface can be destabilized by various factors, especially the enzymatic degradation of collagen fibrils within the hybrid layer and polymer hydrolysis. Furthermore, for resin-based restorative materials, the marginal gap remains a major problem that can lead to the occurrence of secondary caries. To address these issues, research efforts have focused on the remineralization of mineral-depleted dental hard tissues using remineralizing bioactive substances. In this review, we first described various bioactive agents with remineralizing properties. Furthermore, we discussed recent advances in resin-based dental materials for enamel or dentin remineralization. Finally, we examined the current challenges and prospects of these emerging materials. This work aims to provide a theoretical foundation for the future development of resin-based dental materials in direct adhesive restoration with remineralizing agents.
Examining the Conceptual and Measurement Overlap of Body Dissatisfaction and Internalized Weight Stigma in Predominantly Female Samples: A Meta-Analysis and Measurement Refinement Study
Authors: Saunders Jessica F. , Nutter Sarah , Russell-Mayhew Shelly
Published: April 2022

Both body dissatisfaction and internalized weight stigma have been identified as risk factors for many negative health outcomes for women, including depression and eating disorders. In addition to these contributions, these concepts have been found to overlap to various degrees in existing literature. We conducted a systematic review and meta-analysis on articles published prior to February 2022 to demonstrate the conceptual and measurement overlap between body dissatisfaction and internalized weight stigma as currently quantified. We identified 48 studies examining the interrelation between body dissatisfaction and internalized weight stigma in predominantly female samples. Stronger correlations between these two constructs, some bordering on multicollinearity, were prevalent in community samples compared to clinical samples and with some but not all the commonly used measures in the body image and weight stigma fields. Body mass index (BMI) moderated these relations such that individuals with higher self-reported BMI were more likely to report lower correlations between the constructs. This concept proliferation, stronger for individuals with lower BMIs and community samples, necessitates the need change how we conceptualize and measure body dissatisfaction and internalized weight stigma. To this end, we conducted study two to refine existing measures and lessen the degree of measurement overlap between internalized weight stigma and body dissatisfaction, particularly in community samples of women. We aimed to clarify the boundaries between these two concepts, ensuring measurement error is better accounted for. Female university students completed existing measures of body satisfaction and internalized weight stigma, which were analyzed using an exploratory followed by a confirmatory factor analysis. In our attempts to modify two existing measures of internalized weight stigma and body dissatisfaction, the majority of the internalized weight stigma items were retained. In contrast, most of the body dissatisfaction items either cross-loaded onto both factors or loaded on to the internalized weight stigma factor despite being intended for the body dissatisfaction factor, suggesting that the measurement issues identified in recent prior research may be due not only to the way we conceptualize and quantify weight stigma, but also the ways in which we quantify body dissatisfaction, across the existing corpus of body dissatisfaction scales.
The Pathogenesis of Ischemia-Reperfusion Induced Acute Kidney Injury Depends on Renal Neutrophil Recruitment Whereas Sepsis-Induced AKI Does Not
Authors: Li Zhenhan , Ludwig Nadine , Thomas Katharina , Mersmann Sina , Lehmann Martin , Vestweber Dietmar , Pittet Jean-Francois , Gomez Hernando , Kellum John A. , Rossaint Jan , Zarbock Alexander
Published: April 2022

Acute kidney injury (AKI) may be induced by different causes, including renal ischemia-reperfusion injury and sepsis, which represent the most common reasons for AKI in hospitalized patients. AKI is defined by reduced urine production and/or increased plasma creatinine. However, this definition does not address the molecular mechanisms of different AKI entities, and uncertainties remain regarding distinct pathophysiological events causing kidney injury in the first place. In particular, sepsis-induced AKI is considered not to be associated with leukocyte infiltration into the kidney, but a direct investigation of this process is missing to this date. In this study, we used two murine AKI models induced by either renal ischemia-reperfusion injury (IRI) or cecal ligation and puncture (CLP) to investigate the contribution of neutrophils to tissue injury and kidney function. By using VEC-Y731F mice, in which neutrophil recruitment is impaired, we analyzed the specific contribution of neutrophil recruitment to the pathogenesis of IRI- and CLP-induced AKI. We observed that the degree of renal injury evaluated by plasma creatinine, urinary biomarkers and histological analyses, following IRI-induction was dependent on neutrophil migration into the kidney, whereas the pathogenesis of CLP-induced AKI was independent of neutrophil recruitment. Furthermore, plasma transfer experiments suggest that the pathogenesis of CLP-induced AKI relies on circulating inflammatory mediators. These results extend our knowledge of the AKI pathogenesis and may help in the development of prophylactic and therapeutic treatments for AKI patients.
Impact of Dietary Protein Restriction on the Immunogenicity and Efficacy of Whole-Sporozoite Malaria Vaccination
Authors: Nunes-Cabaço Helena , Moita Diana , Rôla Catarina , Mendes António M. , Prudêncio Miguel
Published: April 2022

Malaria remains one of the world’s most prevalent infectious diseases. Several vaccination strategies currently under investigation aim at hampering the development of the Plasmodium parasite during the clinically silent liver stage of its life cycle in the mammalian host, preventing the subsequent disease-associated blood stage of infection. Immunization with radiation-attenuated sporozoites (RAS), the liver-infecting parasite forms, can induce sterile protection against malaria. However, the efficacy of vaccine candidates in malaria-naïve individuals in high-income countries is frequently higher than that found in populations where malaria is endemic. Malnutrition has been associated with immune dysfunction and with a delay or impairment of the immune response to some vaccines. Since vaccine efficacy depends on the generation of competent immune responses, and malaria-endemic regions are often associated with malnutrition, we hypothesized that an inadequate host nutritional status, specifically resulting from a reduction in dietary protein, could impact on the establishment of an efficient anti-malarial immune response. We developed a model of RAS immunization under low protein diet to investigate the impact of a reduced host protein intake on the immunogenicity and protective efficacy of this vaccine. Our analysis of the circulating and tissue-associated immune compartments revealed that a reduction in dietary protein intake during immunization resulted in a decrease in the frequency of circulating CD4+ T cells and of hepatic NK cells. Nevertheless, the profile of CD8+ T cells in the blood, liver and spleen was robust and minimally affected by the dietary protein content during RAS immunization, as assessed by supervised and in-depth unsupervised X-shift clustering analysis. Although mice immunized under low protein diet presented higher parasite liver load upon challenge than those immunized under adequate protein intake, the two groups displayed similar levels of protection from disease. Overall, our data indicate that dietary protein reduction may have minimal impact on the immunogenicity and efficacy of RAS-based malaria vaccination. Importantly, this experimental model can be extended to assess the impact of other nutrient imbalances and immunization strategies, towards the refinement of future translational interventions that improve vaccine efficacy in malnourished individuals.
Using Deep Learning Radiomics to Distinguish Cognitively Normal Adults at Risk of Alzheimer’s Disease From Normal Control: An Exploratory Study Based on Structural MRI
Authors: Jiang Jiehui , Zhang Jieming , Li Zhuoyuan , Li Lanlan , Huang Bingcang ,   Alzheimer’s Disease Neuroimaging Initiative
Published: April 2022

Objectives

We proposed a novel deep learning radiomics (DLR) method to distinguish cognitively normal adults at risk of Alzheimer’s disease (AD) from normal control based on T1-weighted structural MRI images.

Methods

In this study, we selected MRI data from the Alzheimer’s Disease Neuroimaging Initiative Database (ADNI), which included 417 cognitively normal adults. These subjects were divided into 181 individuals at risk of Alzheimer’s disease (preAD group) and 236 normal control individuals (NC group) according to standard uptake ratio >1.18 calculated by amyloid Positron Emission Tomography (PET). We further divided the preaAD group into APOE+ and APOE− subgroups according to whether APOE ε4 was positive or not. All data sets were divided into one training/validation group and one independent test group. The proposed DLR method included three steps: (1) the pre-training of basic deep learning (DL) models, (2) the extraction, selection and fusion of DLR features, and (3) classification. The support vector machine (SVM) was used as the classifier. In the comparative experiments, we compared our proposed DLR method with three existing models: hippocampal model, clinical model, and traditional radiomics model. Ten-fold cross-validation was performed with 100 time repetitions.

Results

The DLR method achieved the best classification performance between preAD and NC than other models with an accuracy of 89.85% ± 1.12%. In comparison, the accuracies of the other three models were 72.44% ± 1.37%, 82.00% ± 4.09% and 79.65% ± 2.21%. In addition, the DLR model also showed the best classification performance (85.45% ± 9.04% and 92.80% ± 2.61%) in the subgroup experiment.

Conclusion

The results showed that the DLR method provided a potentially clinical value to distinguish preAD from NC.
The Intricacy of the Viral-Human Protein Interaction Networks: Resources, Data, and Analyses
Authors: Saha Deeya , Iannuccelli Marta , Brun Christine , Zanzoni Andreas , Licata Luana
Published: April 2022

Viral infections are one of the major causes of human diseases that cause yearly millions of deaths and seriously threaten global health, as we have experienced with the COVID-19 pandemic. Numerous approaches have been adopted to understand viral diseases and develop pharmacological treatments. Among them, the study of virus-host protein-protein interactions is a powerful strategy to comprehend the molecular mechanisms employed by the virus to infect the host cells and to interact with their components. Experimental protein-protein interactions described in the scientific literature have been systematically captured into several molecular interaction databases. These data are organized in structured formats and can be easily downloaded by users to perform further bioinformatic and network studies. Network analysis of available virus-host interactomes allow us to understand how the host interactome is perturbed upon viral infection and what are the key host proteins targeted by the virus and the main cellular pathways that are subverted. In this review, we give an overview of publicly available viral-human protein-protein interactions resources and the community standards, curation rules and adopted ontologies. A description of the main virus-human interactome available is provided, together with the main network analyses that have been performed. We finally discuss the main limitations and future challenges to assess the quality and reliability of protein-protein interaction datasets and resources.
Contribution of Clinical Metagenomics to the Diagnosis of Bone and Joint Infections
Authors: d’Humières Camille , Gaïa Nadia , Gueye Signara , de Lastours Victoire , Leflon-Guibout Véronique , Maataoui Naouale , Duprilot Marion , Lecronier Marie , Rousseau Marc-Antoine , Gamany Naura , Lescure François-Xavier , Senard Olivia , Deconinck Laurène , Dollat Marion , Isernia Valentina , Le Hur Anne-Claire , Petitjean Marie , Nazimoudine Anissa , Le Gac Sylvie , Chalal Solaya , Ferreira Stéphanie , Lazarevic Vladimir , Guigon Ghislaine , Gervasi Gaspard , Armand-Lefèvre Laurence , Schrenzel Jacques , Ruppé Etienne
Published: April 2022

Bone and joint infections (BJIs) are complex infections that require precise microbiological documentation to optimize antibiotic therapy. Currently, diagnosis is based on microbiological culture, sometimes complemented by amplification and sequencing of the 16S rDNA gene. Clinical metagenomics (CMg), that is, the sequencing of the entire nucleic acids in a sample, was previously shown to identify bacteria not detected by conventional methods, but its actual contribution to the diagnosis remains to be assessed, especially with regard to 16S rDNA sequencing. In the present study, we tested the performance of CMg in 34 patients (94 samples) with suspected BJIs, as compared to culture and 16S rDNA sequencing. A total of 94 samples from 34 patients with suspicion of BJIs, recruited from two sites, were analyzed by (i) conventional culture, (ii) 16S rDNA sequencing (Sanger method), and (iii) CMg (Illumina Technology). Two negative controls were also sequenced by CMg for contamination assessment. Based on the sequencing results of negative controls, 414 out of 539 (76.7%) bacterial species detected by CMg were considered as contaminants and 125 (23.2%) as truly present. For monomicrobial infections (13 patients), the sensitivity of CMg was 83.3% as compared to culture, and 100% as compared to 16S rDNA. For polymicrobial infections (13 patients), the sensitivity of CMg was 50% compared to culture, and 100% compared to 16S rDNA. For samples negative in culture (8 patients, 21 samples), CMg detected 11 bacteria in 10 samples from 5 different patients. In 5/34 patients, CMg brought a microbiological diagnosis where conventional methods failed, and in 16/34 patients, CMg provided additional information. Finally, 99 antibiotic resistance genes were detected in 24 patients (56 samples). Provided sufficient genome coverage (87.5%), a correct inference of antibiotic susceptibility was achieved in 8/8 bacteria (100%). In conclusion, our study demonstrated that the CMg provides complementary and potentially valuable data to conventional methods of BJIs diagnosis.
A Review and Meta-Analysis of Influenza Interactome Studies
Authors: Chua Sonja Courtney Jun Hui , Cui Jianzhou , Engelberg David , Lim Lina Hsiu Kim
Published: April 2022

Annually, the influenza virus causes 500,000 deaths worldwide. Influenza-associated mortality and morbidity is especially high among the elderly, children, and patients with chronic diseases. While there are antivirals available against influenza, such as neuraminidase inhibitors and adamantanes, there is growing resistance against these drugs. Thus, there is a need for novel antivirals for resistant influenza strains. Host-directed therapies are a potential strategy for influenza as host processes are conserved and are less prone mutations as compared to virus-directed therapies. A literature search was performed for papers that performed viral–host interaction screens and the Reactome pathway database was used for the bioinformatics analysis. A total of 15 studies were curated and 1717 common interactors were uncovered among all these studies. KEGG analysis, Enrichr analysis, STRING interaction analysis was performed on these interactors. Therefore, we have identified novel host pathways that can be targeted for host-directed therapy against influenza in our review.
Mechanisms of Action of Ozone Therapy in Emerging Viral Diseases: Immunomodulatory Effects and Therapeutic Advantages With Reference to SARS-CoV-2
Authors: Cenci Alessandra , Macchia Iole , La Sorsa Valentina , Sbarigia Clemente , Di Donna Valentina , Pietraforte Donatella
Published: April 2022

Medical oxygen-ozone (O2-O3) is a successful therapeutic approach accounting on the assessed beneficial action of ozone in the range 30–45 μg/ml (expanded range 10–80 μg/ml according to different protocols), as in this dosage range ozone is able to trigger a cellular hormetic response via the modulating activity of reactive oxygen species (ROS), as signaling molecules. The ozone-dependent ROS-mediated fatty acid oxidation leads to the formation of lipid ozonization products (LOPs), which act as signal transducers by triggering ROS signaling and therefore mitohormetic processes. These processes ultimately activate survival mechanisms at a cellular level, such as the Nrf2/Keap1/ARE system activation, the AMPK/FOXO/mTOR/Sir1 pathway and the Nrf2/NF-kB cross talk. Furthermore, indirectly, via these pathways, LOPs trigger the HIF-1α pathway, the HO-1 signaling and the NO/iNOS biochemical machinery. Ozone-driven shift of cytokine activation pathways, from pro-inflammatory to anti-inflammatory immediately afterwards, also exert direct immunoregulatory effects on regulatory T lymphocytes as well as on the intestinal microbiota, which in turn can affect immune response thus influencing the progression of the disease. In this review, we will describe the biological and biochemical mechanisms of action of ozone therapy with the aim of evaluating both positive and critical aspects of ozone use as a therapeutic adjuvant in the light of emerging viral infections, such as SARS-CoV-2 and microbiome-associated disorders related to SARS-CoV-2.
Single-Neuron Labeling in Fixed Tissue and Targeted Volume Electron Microscopy
Authors: Turegano-Lopez Marta , Santuy Andrea , Kastanauskaite Asta , Rodriguez Jose-Rodrigo , DeFelipe Javier , Merchan-Perez Angel
Published: April 2022

The structural complexity of nervous tissue makes it very difficult to unravel the connectivity between neural elements at different scales. Numerous methods are available to trace long-range projections at the light microscopic level, and to identify the actual synaptic connections at the electron microscopic level. However, correlating mesoscopic and nanoscopic scales in the same cell, cell population or brain region is a problematic, laborious and technically demanding task. Here we present an effective method for the 3D reconstruction of labeled subcellular structures at the ultrastructural level, after single-neuron labeling in fixed tissue. The brain is fixed by intracardial perfusion of aldehydes and thick vibratome sections (250 μm) are obtained. Single cells in these vibratome sections are intracellularly injected with horseradish peroxidase (HRP), so that the cell body and its processes can be identified. The thick sections are later flat-embedded in epoxy resin and re-sectioned into a series of thinner (7 μm) sections. The sections containing the regions of interest of the labeled cells are then imaged with automated focused ion beam milling and scanning electron microscopy (FIB-SEM), acquiring long series of high-resolution images that can be reconstructed, visualized, and analyzed in 3D. With this methodology, we can accurately select any cellular segment at the light microscopic level (e.g., proximal, intermediate or distal dendrites, collateral branches, axonal segments, etc.) and analyze its synaptic connections at the electron microscopic level, along with other ultrastructural features. Thus, this method not only facilitates the mapping of the synaptic connectivity of single-labeled neurons, but also the analysis of the surrounding neuropil. Since the labeled processes can be located at different layers or subregions, this method can also be used to obtain data on the differences in local synaptic organization that may exist at different portions of the labeled neurons.
The Global Burden of Motor Neuron Disease: An Analysis of the 2019 Global Burden of Disease Study
Authors: Park Jin , Kim Jee-Eun , Song Tae-Jin
Published: April 2022

Up-to-date, accurate information on the disease burden of motor neuron disease (MND) is the cornerstone for evidence-based resource allocation and healthcare planning. We aimed to estimate the burden of MND globally from 1990 to 2019, as part of the Global Burden of Disease, Injuries and Risk Factor (GBD) study. Amyotrophic lateral sclerosis, progressive muscular atrophy, primary lateral sclerosis, pseudobulbar palsy, spinal muscular atrophy and hereditary spastic paraplegia- were included for analysis as MNDs. We measured age-standardized incidence, prevalence, death, and disability-adjusted life-years (DALYs) in 204 countries and territories worldwide from 1990 to 2019 using spatial Bayesian analyses. The effects of age, sex, and the sociodemographic index (measures of income per capita, education, and fertility) on incidence, prevalence, death, and disability-adjusted life-years due to MNDs were explored. According to 2019 GBD estimates, there were ~268,673 [95% uncertainty interval (UI), 213,893–310,663] prevalent cases and 63,700 (95% UI, 57,295–71,343) incident cases of MND worldwide. In 2019, MND caused 1,034,606 (95% UI, 979,910–1,085,401) DALYs and 39,081 (95% UI, 36,566–41,129) deaths worldwide. The age-standardized rates of prevalence, incidence, death, and DALYs for MNDs in 2019 were 3.37 (95% UI, 2.9–3.87) per 100,000 people, 0.79 (95% UI, 0.72–0.88) per 100,000 people, 0.48 (95% UI, 0.45–0.51) per 100,000 people, and 12.66 (95% UI, 11.98–13.29) per 100,000 people, respectively. The global prevalence and deaths due to MND in 2019 were increased (1.91% [95% UI, 0.61–3.42] and 12.39% [95% UI, 5.81–19.27], respectively) compared to 1990, without significant change in incidence. More than half of the prevalence and deaths due to MND occurred in three high-income regions (North America, Western Europe, and Australasia). In most cases, the prevalence, incidence, and DALYs of MNDs were high in regions with high sociodemographic index; however, in high-income East Asia, these were relatively low compared to similar sociodemographic index groups elsewhere. The burden of MND increased between 1990 and 2019. Its expected increase in the future highlights the importance of global and national healthcare planning using more objective evidence. Geographical heterogeneity in the MND burden might suggest the influences of sociodemographic status and genetic background in various regions.
A Transfer Learning Algorithm to Reduce Brain-Computer Interface Calibration Time for Long-Term Users
Authors: Giles Joshua , Ang Kai Keng , Phua Kok Soon , Arvaneh Mahnaz
Published: April 2022

Current motor imagery-based brain-computer interface (BCI) systems require a long calibration time at the beginning of each session before they can be used with adequate levels of classification accuracy. In particular, this issue can be a significant burden for long term BCI users. This article proposes a novel transfer learning algorithm, called r-KLwDSA, to reduce the BCI calibration time for long-term users. The proposed r-KLwDSA algorithm aligns the user's EEG data collected in previous sessions to the few EEG trials collected in the current session, using a novel linear alignment method. Thereafter, the aligned EEG trials from the previous sessions and the few EEG trials from the current sessions are fused through a weighting mechanism before they are used for calibrating the BCI model. To validate the proposed algorithm, a large dataset containing the EEG data from 11 stroke patients, each performing 18 BCI sessions, was used. The proposed framework demonstrated a significant improvement in the classification accuracy, of over 4% compared to the session-specific algorithm, when there were as few as two trials per class available from the current session. The proposed algorithm was particularly successful in improving the BCI accuracy of the sessions that had initial session-specific accuracy below 60%, with an average improvement of around 10% in the accuracy, leading to more stroke patients having meaningful BCI rehabilitation.
The Association Between Consumption of 100% Fruit Juice and Risk of Age-Related Macular Degeneration: Data From the National Health and Nutrition Examination Survey Database
Authors: Song Mi , Chen Baihua
Published: April 2022

Age-related macular degeneration (AMD) is the main irreversible blindness disease worldwide. The current study aimed to investigate whether the consumption of 100% fruit juice increases the risk of age-related macular degeneration and find approaches to prevent and reduce the development of age-related macular degeneration from the aspect of dietary habits. A cross-sectional clinical study design was adopted. We screened participants from the 2005 to 2006 NHANES database. The logistic regression model was used to evaluate the relationship between 100% fruit juice consumption and advanced AMD and to adjust variables such as demographics, general health status, body mass index (BMI), health-related behaviors, systemic complications, and ophthalmic complications. The results show that 100% fruit juice consumption did not affect early AMD and any AMD. High consumers of 100% fruit juice are more likely to develop advanced age-related macular degeneration than those who never drink 100% fruit juice.
Low Carbohydrate Diets for Diabetic Cardiomyopathy: A Hypothesis
Authors: Kleissl-Muir Sabine , Rasmussen Bodil , Owen Alice , Zinn Caryn , Driscoll Andrea
Published: April 2022

Elevated blood glucose levels, insulin resistance (IR), hyperinsulinemia and dyslipidemia the key aspects of type 2 diabetes mellitus (T2DM), contribute to the development of a certain form of cardiomyopathy. This cardiomyopathy, also known as diabetic cardiomyopathy (DMCM), typically occurs in the absence of overt coronary artery disease (CAD), hypertension or valvular disease. DMCM encompasses a variety of pathophysiological processes impacting the myocardium, hence increasing the risk for heart failure (HF) and significantly worsening outcomes in this population. Low fat (LF), calorie-restricted diets have been suggested as the preferred eating pattern for patients with HF. However, LF diets are naturally higher in carbohydrates (CHO). We argue that in an insulin resistant state, such as in DMCM, LF diets may worsen glycaemic control and promote further insulin resistance (IR), contributing to a physiological and functional decline in DMCM. We postulate that CHO restriction targeting hyperinsulinemia may be able to improve tissue and systemic IR. In recent years low carbohydrate diets (LC) including ketogenic diets (KD), have emerged as a safe and effective tool for the management of various clinical conditions such as T2DM and other metabolic disorders. CHO restriction achieves sustained glycaemic control, lower insulin levels and successfully reverses IR. In addition to this, its pleiotropic effects may present a metabolic stress defense and facilitate improvement to cardiac function in patients with HF. We therefore hypothesize that patients who adopt a LC diet may require less medications and experience improvements in HF-related symptom burden.
Exploring Tumor Immune Microenvironment and Its Associations With Molecular Characteristics in Melanoma
Authors: Wang Jiangyuan , Peng Cong , Dai Wentao , Chen Xiang , Meng Jing , Jiang Taijiao
Published: April 2022

Background

The tumor microenvironment (TME), which involves infiltration of multiple immune cells into the tumor tissues, plays an essential role in clinical benefit to therapy. The chemokines and their receptors influence migration and functions of both tumor and immune cells. Also, molecular characteristics are associated with the efficacy of melanoma therapy. However, there lacked exploration of immune characteristics and the association with molecular characteristics.

Methods

We collected the currently available 569 melanoma samples that had both the genomic and transcriptional data from TCGA and SRA databases. We first identified TME subtypes based on the developed immune signatures, and then divided the samples into two immune cohorts based on the immune score. Next, we estimated the compositions of the immune cells of the two cohorts, and performed differential expression genes (DEGs) and functional enrichments. In addition, we investigated the interactions of chemokines and their receptors under immune cells. Finally, we explored the genomic characteristics under different immune subtypes.

Results

TME type D had a better prognosis among the four subtypes. The high-immunity cohort had significantly high 16 immune cells. The 63 upregulated and 384 downregulated genes in the high-immunity cohort were enriched in immune-related biological processes, and keratin, pigmentation and epithelial cells, respectively. The correlations of chemokines and their receptors with immune cell infiltration, such as CCR5-CCL4/CCL5 and CXCR3-CXCL9/CXCL10/CXCL11/CXCL13 axis, showed that the recruitments of 11 immune cells, such as CD4T cells and CD8T cells, were modulated by chemokines and their receptors. The proportions of the four TME subtypes in each molecular subtype were comparable. The two driver genes, CDKN2A and PRB2, had significantly different MAFs between the high-immunity and low-immunity.

Conclusion

We dissected the characteristics of immune infiltration, the interactions of chemokines and their receptors under immune cells, and the correlation of molecular and immune characteristics. Our work will enable the reasonable selection of anti-melanoma treatments and accelerate the development of new therapeutic strategies for melanoma.
Development and Validation of a Prognostic Model to Predict Recurrence-Free Survival After Curative Resection for Perihilar Cholangiocarcinoma: A Multicenter Study
Authors: Liu Zhi-Peng , Chen Wei-Yue , Wang Zi-Ran , Liu Xing-Chao , Fan Hai-Ning , Xu Lei , Pan Yu , Zhong Shi-Yun , Xie Dan , Bai Jie , Jiang Yan , Zhang Yan-Qi , Dai Hai-Su , Chen Zhi-Yu
Published: April 2022

Background

Recurrence is the main cause of death in perihilar cholangiocarcinoma (pCCA) patients after surgery. Identifying patients with a high risk of recurrence is important for decision-making regarding neoadjuvant therapy to improve long-term outcomes.

Aim

The objective of this study was to develop and validate a prognostic model to predict recurrence-free survival (RFS) after curative resection of pCCA.

Methods

Patients following curative resection for pCCA from January 2008 to January 2016 were identified from a multicenter database. Using random assignment, 70% of patients were assigned to the training cohort, and the remaining 30% were assigned to the validation cohort. Independent predictors of RFS after curative resection for pCCA were identified and used to construct a prognostic model. The predictive performance of the model was assessed using calibration curves and the C-index.

Results

A total of 341 patients were included. The median overall survival (OS) was 22 months, and the median RFS was 14 months. Independent predictors associated with RFS included lymph node involvement, macrovascular invasion, microvascular invasion, maximum tumor size, tumor differentiation, and carbohydrate antigen 19-9. The model incorporating these factors to predict 1-year RFS demonstrated better calibration and better performance than the 8th American Joint Committee on Cancer (AJCC) staging system in both the training and validation cohorts (C-indexes: 0.723 vs. 0.641; 0.743 vs. 0.607).

Conclusions

The prognostic model could identify patients at high risk of recurrence for pCCA to inform patients and surgeons, help guide decision-making for postoperative adjuvant therapy, and improve survival.
Efficacy and Safety of TACE Combined With Lenvatinib Plus PD-1 Inhibitors Compared With TACE Alone for Unresectable Hepatocellular Carcinoma Patients: A Prospective Cohort Study
Authors: Qu Shuping , Zhang Xiaobing , Wu Yutian , Meng Yan , Pan Hongyu , Fang Qiang , Hu Lei , Zhang Jin , Wang Ruoyu , Wei Lixin , Wu Dong
Published: April 2022

Purpose

To compare the efficacy and safety of the combination of transcatheter arterial chemoembolization (TACE), Lenvatinib, and programmed cell death protein-1 (PD-1) inhibitors (combination group) with TACE (TACE group) in the treatment of patients with unresectable hepatocellular carcinoma (uHCC).

Methods

We consecutively enrolled 110 patients with uHCC in this prospective cohort study, with 56 patients receiving combination treatment and 54 patients receiving TACE from November 2017 to September 2020. The differences in tumor response, survival benefit, and adverse events (AEs) were compared between the two groups. Factors affecting survival were identified via Cox regression analysis.

Results

Compared with the TACE group, the combination group had a higher objective response rate (ORR) (67.9% vs. 29.6%, p < 0.001), longer median progression-free survival (mPFS) (11.9 vs. 6.9 months, P = 0.003) and overall survival (mOS) (23.9 vs. 15.3 months, p < 0.001). Multivariate analysis showed that the neutrophil-to-lymphocyte ratio (NLR) and the treatment option were independent factors associated with the PFS and OS. Further subgroup analysis showed that patients with low NLR (≤median 3.11) receiving combination therapy had better mPFS (20.1 vs. 6.2 months, P < 0.001) and mOS (28.9 vs. 15.2 months, P < 0.001) than those receiving TACE, while no obvious difference in PFS or OS was observed between the two groups in patients with high NLR (> 3.11). There were no unexpected toxicities in the combination group.

Conclusion

Compared with TACE, the combination treatment demonstrated an improved clinical efficacy and manageable safety profile in patients with uHCC. Combination treatment showed better therapeutic efficacy in patients with low NLR; therefore, this ratio could be used to identify patients who will benefit from this treatment.
Predicting the Risk of Microtia From Prenatal Factors: A Hospital-Based Case-Control Study
Authors: Chen Wei , Sun Manqing , Zhang Yue , Zhang Qun , Xu Xiaolin
Published: April 2022

Background

Although a wide range of risk factors for microtia were identified, the limitation of these studies, however, is that risk factors were not estimated in comparison with one another or from different domains. Our study aimed to uncover which factors should be prioritized for the prevention and intervention of non-syndromic microtia via tranditonal and meachine-learning statistical methods.

Methods

293 pairs of 1:1 matched non-syndromic microtia cases and controls who visited Shanghai Ninth People's Hospital were enrolled in the current study during 2017-2019. Thirty-nine risk factors across four domains were measured (i.e., parental sociodemographic characteristics, maternal pregnancy history, parental health conditions and lifestyles, and parental environmental and occupational exposures). Lasso regression model and multivariate conditional logistic regression model were performed to identify the leading predictors of microtia across the four domains. The area under the curve (AUC) was used to calculate the predictive probabilities.

Results

Eight predictors were identified by the lasso regression, including abnormal pregnancy history, genital system infection, teratogenic drugs usage, folic acid supplementation, paternal chronic conditions history, parental exposure to indoor decoration, paternal occupational exposure to noise and maternal acute respiratory infection. The additional predictors identified by the multivariate conditional logistic regression model were maternal age and maternal occupational exposure to heavy metal. Predictors selected from the conditional logistic regression and lasso regression both yielded AUCs (95% CIs) of 0.83 (0.79–0.86).

Conclusion

The findings from this study suggest some factors across multiple domains are key drivers of non-syndromic microtia regardless of the applied statistical methods. These factors could be used to generate hypotheses for further observational and clinical studies on microtia and guide the prevention and intervention strategies for microtia.
Biologics for Non-Cancer Dermatological Diseases: Analysis on China’s Clinical Trial Registration Trend From 2016 to 2020
Authors: Zhu Beibei , Liu Yi , Li Jing , Ni Qi , Yin Zheng , Zhu Junli , Chen Ken , Yang Xueyuan
Published: April 2022

Background: In the past 5 years, China has quickly followed US’s steps to approve the new drug application of biologics for dermatological diseases. There is an increasing interest in the current biologic landscape and further potentials in China. Our study aims to analyze features of clinical trials on non-cancer dermatological biologics and synthesize recent achievements and impediments, in order to forecast the development trends in China.

Methods: Three registers (the Chinese Clinical Trial Registry, Center for Drug Evaluation, and ClinicalTrials.gov) were searched for clinical trials of non-cancer dermatological biologics initiated between 2016 and 2020 in mainland China. Trial information (the first posted year, sponsor type, study phase and site, recruitment status, disease, drug target, and drug registration type) and certain study design (selection of the control group, primary efficacy outcome, and inclusion of patient-reported outcome for non–phase I or II trials only) information were extracted and analyzed.

Results: A total of 60 trials were identified. The number of registered dermatological biologic trials significantly increased with an annual increase of 59% from 2016 to 2020, primarily driven by psoriasis (47/60, 78.3%) and atopic dermatitis (6/60, 10.0%) trials. The tumor necrosis factor (TNF)-α and interleukin (IL)-17 remained the hottest drug targets (17/60, 28.3% for TNF-α and 18/60, 30.0% for IL-17). In addition to TNF-α and IL-17, many new psoriasis drug targets came into place since 2018 (IL-12/23) and 2019 (IL-36 and glucagon-like peptide-1 (GLP-1)). Thirty percent (18/60) of the trials were conducted for biosimilar products, all of which were sponsored by local pharmaceutical companies and 88.9% of which were targeting on TNF-α. Targets of IL-36, IL-5, and IgE were only available in trials sponsored by global companies.

Conclusion: There was great progress on the innovation of dermatological biologics in the past 5 years in China in terms of surged number of clinical trials, increased biosimilars and “me-too” drugs which greatly improved patient access to novel treatments, execution of parallel clinical trials, and improved hospital GCP office and regulatory environment. Further efforts for local pharmaceutical companies should include relocating resources to exploring novel drug targets and dermatological diseases other than psoriasis or atopic dermatitis.

Systematic Review Registration: [website], identifier [registration number].
Pharmacology of Kappa Opioid Receptors: Novel Assays and Ligands
Authors: Sturaro Chiara , Malfacini Davide , Argentieri Michela , Djeujo Francine M. , Marzola Erika , Albanese Valentina , Ruzza Chiara , Guerrini Remo , Calo’ Girolamo , Molinari Paola
Published: April 2022

The present study investigated the in vitro pharmacology of the human kappa opioid receptor using multiple assays, including calcium mobilization in cells expressing chimeric G proteins, the dynamic mass redistribution (DMR) label-free assay, and a bioluminescence resonance energy transfer (BRET) assay that allows measurement of receptor interaction with G protein and β-arrestin 2. In all assays, dynorphin A, U-69,593, and [D-Pro10]dyn(1-11)-NH2 behaved as full agonists with the following rank order of potency [D-Pro10]dyn(1-11)-NH2 > dynorphin A ≥ U-69,593. [Dmt1,Tic2]dyn(1-11)-NH2 behaved as a moderate potency pure antagonist in the kappa-β-arrestin 2 interaction assay and as low efficacy partial agonist in the other assays. Norbinaltorphimine acted as a highly potent and pure antagonist in all assays except kappa-G protein interaction, where it displayed efficacy as an inverse agonist. The pharmacological actions of novel kappa ligands, namely the dynorphin A tetrameric derivative PWT2-Dyn A and the palmitoylated derivative Dyn A-palmitic, were also investigated. PWT2-Dyn A and Dyn A-palmitic mimicked dynorphin A effects in all assays showing similar maximal effects but 3–10 fold lower potency. In conclusion, in the present study, multiple in vitro assays for the kappa receptor have been set up and pharmacologically validated. In addition, PWT2-Dyn A and Dyn A-palmitic were characterized as potent full agonists; these compounds are worthy of further investigation in vivo for those conditions in which the activation of the kappa opioid receptor elicits beneficial effects e.g. pain and pruritus.