bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance of Lactate and CO2-Derived Parameters in Predicting Major Postoperative Complications After Cardiac Surgery With Cardiopulmonary Bypass: Protocol of a Diagnostic Accuracy Study
Authors: Zhou Xiao-Fen , Yu Rong-Guo , Chen Qian , Xue Yi-Min , Chen Han
Published: October 2021

Background:CO2-derived parameters are increasingly used to identify either low-flow status or anaerobic metabolism in shock resuscitation. However, the performance of CO2-derived parameters in cardiac surgical patients is poorly understood. This study aims to compare the performance of lactate and CO2-derived parameters in predicting major postoperative complications after cardiac surgery with cardiopulmonary bypass.

Methods:This is a prospective, single-center, diagnostic accuracy study. All patients who receive elective cardiac surgery involving cardiopulmonary bypass will be screened for study eligibility. Blood samples will be taken for the calculation of CO2-derived parameters, including the venous-arterial difference in CO2partial pressure (PCO2gap), venous-arterial difference in CO2content to arterial-venous O2content ratio (Cv-aCO2/Ca-vO2), and venous-arterial difference in CO2partial pressure to arterial-venous O2content ratio (Pv-aCO2/Ca-vO2) at ICU admission, and 3, 6, and 12 h later. Baseline, perioperative data will be collected daily for 7 days; patients will be followed up for 28 days to collect outcome data. The primary endpoint is the occurrence of major postoperative complications. Receiver-operating characteristics (ROC) curve analysis will be carried out to assess the predictive performance of lactate and CO2-derived parameters. The performance of the ROC curves will be compared.

Discussion:The performance of lactate and CO2-derived parameters in predicting major postoperative complications will be investigated in the non-sepsis population, which has not been extensively investigated. Our study will compare the two surrogates of respiratory quotient directly, which is an important strength.

Trial Registration:ChiCTR, ChiCTR2000029365. Registered January 26th, 2020,http://www.chictr.org.cn/showproj.aspx?proj=48744.
Effect of Digoxin Therapy on Mortality in Patients With Atrial Fibrillation: An Updated Meta-Analysis
Authors: Wang Xiaoxu , Luo Yi , Xu Dan , Zhao Kun
Published: October 2021

Background: Whether digoxin is associated with increased mortality in atrial fibrillation (AF) remains controversial. We aimed to assess the risk of mortality and clinical effects of digoxin use in patients with AF.

Methods: PubMed, Embase, and the Cochrane library were systematically searched to identify eligible studies comparing all-cause mortality of patients with AF taking digoxin with those not taking digoxin, and the length of follow-up was at least 6 months. Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted and pooled.

Results: A total of 29 studies with 621,478 patients were included. Digoxin use was associated with an increased risk of all-cause mortality in all patients with AF (HR 1.17, 95% CI 1.13–1.22, P < 0.001), especially in patients without HF (HR 1.28, 95% CI 1.11–1.47, P < 0.001). There was no significant association between digoxin and mortality in patients with AF and HF (HR 1.06, 95% CI 0.99–1.14, P = 0.110). In all patients with AF, regardless of concomitant HF, digoxin use was associated with an increased risk of sudden cardiac death (SCD) (HR 1.40, 95% CI 1.23–1.60, P < 0.001) and cardiovascular (CV) mortality (HR 1.27, 95% CI 1.08–1.50, P < 0.001), and digoxin use had no significant association with all-cause hospitalization (HR 1.13, 95% CI 0.92–1.39, P = 0.230).

Conclusion: We conclude that digoxin use is associated with an increased risk of all-cause mortality, CV mortality, and SCD, and it does not reduce readmission for AF, regardless of concomitant HF. Digoxin may have a neutral effect on all-cause mortality in patients with AF with concomitant HF.

Systematic Review Registration:https://www.crd.york.ac.ukPROSPERO.
Case Report: A Primary Right Ventricular Vascular Malformation Presenting as a Mass
Authors: Liu Hongduan , Li Xin , Zhang Cuiwei , Fan Chengming , Liu Liming , Wan Juyi
Published: October 2021

Primary right ventricular vascular malformation is a rare primary benign anomaly in heart in nature. Due to the extremely low incidence and the progress on the classification of vascular malformation, a few cases were reported in the literatures. In the current case study, a 55-year-old women presented with a cardiac mass that was identified in right ventricle during a routine medical checkup. Magnetic resonance imaging demonstrated a well-circumscribed mass attached to the interventricular septum. Median sternotomy for the surgical resection of the mass and a cardiopulmonary bypass were performed. The intraoperative transesophageal echocardiogram showed that the mass had been successfully removed. The patient recovered well and was discharged from hospital 9 days after the surgery. The pathological diagnosis was primary cardiac arteriovenous malformation. No mass recurrence was shown by echocardiography during the 13 months' follow-up.
Debris Emergence Elevations and Glacier Change
Authors: Shea Joseph M. , Kraaijenbrink Philip D. A. , Immerzeel Walter W. , Brun Fanny
Published: October 2021

Debris-covered glaciers represent potentially significant stores of freshwater in river basins throughout High Mountain Asia (HMA). Direct glacier mass balance measurements are extremely difficult to maintain on debris-covered glaciers, and optical remote sensing techniques to evaluate annual equilibrium line altitudes (ELAs) do not work in regions with summer-accumulation type glaciers. Surface elevation and glacier velocity change have been calculated previously for debris-covered glaciers across the region, but the response of debris cover itself to climate change remains an open question. In this research we propose a new metric, i.e. the debris emergence elevation (ZDE), which can be calculated from a combination of optical and thermal imagery and digital elevation data. We quantify ZDE for 975 debris-covered glaciers in HMA over three compositing periods (1985–1999, 2000–2010, and 2013–2017) and compare ZDE against median glacier elevations, modelled ELAs, and observed rates of both mass change and glacier velocity change. Calculated values of ZDE for individual glaciers are broadly similar to both median glacier elevations and modelled ELAs, but slightly lower than both. Across the HMA region, the average value of ZDE increased by 70 +/− 126 m over the study period, or 2.7 +/− 4.1 m/yr. Increases in ZDE correspond with negative mass balance rates and decreases in glacier velocity, while glaciers and regions that show mass gains and increases in glacier velocity experienced decreases in ZDE. Regional patterns of ZDE, glacier mass balance, and glacier velocities are strongly correlated, which indicates continued overall increases in ZDEE and expansion of debris-covered areas as glaciers continue to lose mass. Our results suggest that ZDE is a useful metric to examine regional debris-covered glacier changes over decadal time scales, and could potentially be used to reconstruct relative mass and ELA changes on debris-covered glaciers using historical imagery or reconstructed debris cover extents.
Case Report: Severe Neonatal Course in Paternally Derived Familial Hypocalciuric Hypercalcemia
Authors: Höppner Jakob , Lais Sabrina , Roll Claudia , Wegener-Panzer Andreas , Wieczorek Dagmar , Högler Wolfgang , Grasemann Corinna
Published: October 2021

Familial hypocalciuric hypercalcemia (FHH, [OMIM #145980]) is recognized as a benign endocrine condition affecting PTH and calcium levels due to heterozygous inactivating mutations in the calcium sensing receptor (CaSR). The condition is often un- or misdiagnosed but may have a prevalence as high as 74 in 100.000. Here, the neonatal courses of two brothers with paternally inherited FHH (CaSRc.554G>A; p.(Arg185Gln)) are described. The older brother was born preterm at 25 weeks gestation with hypercalcemia and hyperparathyroidism. The younger brother, born full-term, had severe hyperparathyroidism, muscular hypotonia, thrombocytopenia, failure to thrive and multiple metaphyseal fractures. Treatment with cinacalcet was initiated, which resulted in subsequent reduction of PTH levels and prompt clinical improvement. While it is known that homozygous mutations inCaSRmay lead to life-threatening forms of neonatal severe hyperparathyroidism (NSHPT), few reports have described a severe clinical course in neonates with FHH due to heterozygous mutations. However, based on the pathophysiological framework, inde novoor paternally transmitted FHH the differing calcium needs of mother and fetus can be expected to induce fetal hyperparathyroidism and may result in severe perinatal complications as described in this report. In summary, FHH is a mostly benign condition, but transient neonatal hyperparathyroidism may occur in affected neonates if the mutation is paternally inherited. If severe, the condition can be treated successfully with cinacalcet. Patients with FHH should be informed about the risk of neonatal disease manifestation in order to monitor pregnancies and neonates.
No Evidence for Effects of Ecological and Behavioral Factors on Eye Size Evolution in Anurans
Authors: Chen Chuan , Jiang Ying , Jin Long , Liao Wen Bo
Published: October 2021

Eye size varies markedly among taxonomic levels, and this variation is often related to the patterns shaped by phylogeny and ecological and behavioral factors. The selective pressures underlying eye size evolution are especially studied in fishes, anurans, birds, and mammals. However, selective pressures underlying the eye size evolution in anurans have inconsistent scaling rules. Here, we investigated the links between eye size and both ecological (e.g., light availability and habitat type) and behavioral factors (e.g., activity time, foraging mobility, defensive strategy, and mating system) among 252 species of anurans by using phylogenetically controlled generalized least-squared (PGLS) regression. Results show that anuran eye size scales hypo-allometrically with body size. However, eye size was not significantly influenced by ecological and behavioral factors, including habitat type, activity time, light availability, foraging mobility, defensive strategy, and mating system. Therefore, neither ecology nor behavior plays a key role in promoting eye size evolution in frogs.
Tracing the Distribution of European Lactase Persistence Genotypes Along the Americas
Authors: Guimarães Alves Ana Cecília , Sukow Natalie Mary , Adelman Cipolla Gabriel , Mendes Marla , Leal Thiago P. , Petzl-Erler Maria Luiza , Lehtonen Rodrigues Souza Ricardo , Rainha de Souza Ilíada , Sanchez Cesar , Santolalla Meddly , Loesch Douglas , Dean Michael , Machado Moara , Moon Jee-Young , Kaplan Robert , North Kari E. , Weiss Scott , Barreto Mauricio L. , Lima-Costa M. Fernanda , Guio Heinner , Cáceres Omar , Padilla Carlos , Tarazona-Santos Eduardo , Mata Ignacio F. , Dieguez Elena , Raggio Víctor , Lescano Andres , Tumas Vitor , Borges Vanderci , Ferraz Henrique B. , Rieder Carlos R. , Schumacher-Schuh Artur , Santos-Lobato Bruno L. , Chana-Cuevas Pedro , Fernandez William , Arboleda Gonzalo , Arboleda Humberto , Arboleda-Bustos Carlos E. , O’Connor Timothy D. , Beltrame Marcia Holsbach , Borda Victor
Published: October 2021

In adulthood, the ability to digest lactose, the main sugar present in milk of mammals, is a phenotype (lactase persistence) observed in historically herder populations, mainly Northern Europeans, Eastern Africans, and Middle Eastern nomads. As the –13910∗T allele in the MCM6 gene is the most well-characterized allele responsible for the lactase persistence phenotype, the –13910C > T (rs4988235) polymorphism is commonly evaluated in lactase persistence studies. Lactase non-persistent adults may develop symptoms of lactose intolerance when consuming dairy products. In the Americas, there is no evidence of the consumption of these products until the arrival of Europeans. However, several American countries’ dietary guidelines recommend consuming dairy for adequate human nutrition and health promotion. Considering the extensive use of dairy and the complex ancestry of Pan-American admixed populations, we studied the distribution of –13910C > T lactase persistence genotypes and its flanking haplotypes of European origin in 7,428 individuals from several Pan-American admixed populations. We found that the –13910∗T allele frequency in Pan-American admixed populations is directly correlated with allele frequency of the European sources. Moreover, we did not observe any overrepresentation of European haplotypes in the –13910C > T flanking region, suggesting no selective pressure after admixture in the Americas. Finally, considering the dominant effect of the –13910∗T allele, our results indicate that Pan-American admixed populations are likely to have higher frequency of lactose intolerance, suggesting that general dietary guidelines deserve further evaluation across the continent.
Tree-Based Co-Clustering Identifies Chromatin Accessibility Patterns Associated With Hematopoietic Lineage Structure
Authors: George Thomas B. , Strawn Nathaniel K. , Leviyang Sivan
Published: October 2021

Chromatin accessibility, as measured by ATACseq, varies between hematopoietic cell types in different lineages of the hematopoietic differentiation tree, e.g. T cells vs. B cells, but methods that associate variation in chromatin accessibility to the lineage structure of the differentiation tree are lacking. Using an ATACseq dataset recently published by the ImmGen consortium, we construct associations between chromatin accessibility and hematopoietic cell types using a novel co-clustering approach that accounts for the structure of the hematopoietic, differentiation tree. Under a model in which all loci and cell types within a co-cluster have a shared accessibility state, we show that roughly 80% of cell type associated accessibility variation can be captured through 12 cell type clusters and 20 genomic locus clusters, with the cell type clusters reflecting coherent components of the differentiation tree. Using publicly available ChIPseq datasets, we show that our clustering reflects transcription factor binding patterns with implications for regulation across cell types. We show that traditional methods such as hierarchical and kmeans clusterings lead to cell type clusters that are more dispersed on the tree than our tree-based algorithm. We provide a python package, chromcocluster, that implements the algorithms presented.
From GWAS to Gene: Transcriptome-Wide Association Studies and Other Methods to Functionally Understand GWAS Discoveries
Authors: Li Binglan , Ritchie Marylyn D.
Published: October 2021

Since their inception, genome-wide association studies (GWAS) have identified more than a hundred thousand single nucleotide polymorphism (SNP) loci that are associated with various complex human diseases or traits. The majority of GWAS discoveries are located in non-coding regions of the human genome and have unknown functions. The valley between non-coding GWAS discoveries and downstream affected genes hinders the investigation of complex disease mechanism and the utilization of human genetics for the improvement of clinical care. Meanwhile, advances in high-throughput sequencing technologies reveal important genomic regulatory roles that non-coding regions play in the transcriptional activities of genes. In this review, we focus on data integrative bioinformatics methods that combine GWAS with functional genomics knowledge to identify genetically regulated genes. We categorize and describe two types of data integrative methods. First, we describe fine-mapping methods. Fine-mapping is an exploratory approach that calibrates likely causal variants underneath GWAS signals. Fine-mapping methods connect GWAS signals to potentially causal genes through statistical methods and/or functional annotations. Second, we discuss gene-prioritization methods. These are hypothesis generating approaches that evaluate whether genetic variants regulate genes via certain genetic regulatory mechanisms to influence complex traits, including colocalization, mendelian randomization, and the transcriptome-wide association study (TWAS). TWAS is a gene-based association approach that investigates associations between genetically regulated gene expression and complex diseases or traits. TWAS has gained popularity over the years due to its ability to reduce multiple testing burden in comparison to other variant-based analytic approaches. Multiple types of TWAS methods have been developed with varied methodological designs and biological hypotheses over the past 5 years. We dive into discussions of how TWAS methods differ in many aspects and the challenges that different TWAS methods face. Overall, TWAS is a powerful tool for identifying complex trait-associated genes. With the advent of single-cell sequencing, chromosome conformation capture, gene editing technologies, and multiplexing reporter assays, we are expecting a more comprehensive understanding of genomic regulation and genetically regulated genes underlying complex human diseases and traits in the future.
Genome-Wide Association Mapping of Late Blight Tolerance Trait in Potato (Solanum tuberosum L.)
Authors: Wang Fang , Zou Meiling , Zhao Long , Xia Zhiqiang , Wang Jian
Published: October 2021

Uncovering the genetic basis and optimizing the late blight tolerance trait in potatoes (Solanum tuberosum L.) are crucial for potato breeding. Late blight disease is one of the most significant diseases hindering potato production. The traits of late blight tolerance were evaluated for 284 potato cultivars to identify loci significantly associated with the late blight tolerance trait. Of all, 37 and 15 were the most tolerant to disease, and 107 and 30 were the most susceptible. A total of 22,489 high-quality single-nucleotide polymorphisms and indels were identified in 284 potato cultivars. All the potato cultivars were clustered into eight subgroups using population structure analysis and principal component analysis, which were consistent with the results of the phylogenetic tree analysis. The average genetic diversity for all 284 potato cultivars was 0.216, and the differentiation index of each subgroup was 0.025–0.149. Genome-wide linkage disequilibrium (LD) analysis demonstrated that the average LD was about 0.9 kb. A genome-wide association study using a mixed linear model identified 964 loci significantly associated with the late blight tolerance trait. Fourteen candidate genes for late blight tolerance traits were identified, including genes encoding late blight tolerance protein, chitinase 1, cytosolic nucleotide-binding site–leucine-rich repeat tolerance protein, protein kinase, ethylene-responsive transcription factor, and other potential plant tolerance-related proteins. This study provides novel insights into the genetic architecture of late blight tolerance traits and will be helpful for late blight tolerance in potato breeding.
Rare Co-Occurrence of Visual Snow in a Female Carrier With RPGRORF15-Associated Retinal Disorder
Authors: Tuekprakhon Aekkachai , Pawestri Aulia Rahmi , Suvannaboon Ragkit , Thongyou Ketwarin , Trinavarat Adisak , Atchaneeyasakul La-Ongsri
Published: October 2021

X-linked retinitis pigmentosa (XLRP), a rare form of retinitis pigmentosa (RP), is predominantly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. Affected males often present with severe phenotypes and early disease onset. In contrast, female carriers are usually asymptomatic or show stationary phenotypes. Herein, we reported an 8-year-old female carrier, a daughter of a confirmed RP father with RPGR mutation, with an early onset of progressive cone-rod pattern retinal dystrophy. Additionally, the carrier experienced visual snow-like symptom as long as she recalled. Ophthalmological examination showed the reduction of visual acuity and attenuation of photoreceptor functions since the age of 5 years. Further analysis revealed a heterozygous pathogenic variant of the RPGR gene and a random X-inactivation pattern. Although she harboured an identical RPGR variant as the father, there were phenotypic intrafamilial variations. The information on the variety of genotypic and phenotypic presentations in XLRP carriers is essential for further diagnosis, management, and monitoring of these cases, including the design of future gene therapy trials.
An Efficient Score Test Integrated with Empirical Bayes for Genome-Wide Association Studies
Authors: Xiao Jing , Zhou Yang , He Shu , Ren Wen-Long
Published: October 2021

Many methods used in multi-locus genome-wide association studies (GWAS) have been developed to improve statistical power. However, most existing multi-locus methods are not quicker than single-locus methods. To address this concern, we proposed a fast score test integrated with Empirical Bayes (ScoreEB) for multi-locus GWAS. Firstly, a score test was conducted for each single nucleotide polymorphism (SNP) under a linear mixed model (LMM) framework, taking into account the genetic relatedness and population structure. Then, all of the potentially associated SNPs were selected with a less stringent criterion. Finally, Empirical Bayes in a multi-locus model was performed for all of the selected SNPs to identify the true quantitative trait nucleotide (QTN). Our new method ScoreEB adopts the similar strategy of multi-locus random-SNP-effect mixed linear model (mrMLM) and fast multi-locus random-SNP-effect EMMA (FASTmrEMMA), and the only difference is that we use the score test to select all the potentially associated markers. Monte Carlo simulation studies demonstrate that ScoreEB significantly improved the computational efficiency compared with the popular methods mrMLM, FASTmrEMMA, iterative modified-sure independence screening EM-Bayesian lasso (ISIS EM-BLASSO), hybrid of restricted and penalized maximum likelihood (HRePML) and genome-wide efficient mixed model association (GEMMA). In addition, ScoreEB remained accurate in QTN effect estimation and effectively controlled false positive rate. Subsequently, ScoreEB was applied to re-analyze quantitative traits in plants and animals. The results show that ScoreEB not only can detect previously reported genes, but also can mine new genes.
Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Autoimmunity 1 Year Later: The Era of Vaccines
Authors: Picchianti Diamanti Andrea , Rosado Maria Manuela , Nicastri Emanuele , Sesti Giorgio , Pioli Claudio , Laganà Bruno
Published: October 2021

Impressive efforts have been made by researchers worldwide in the development of target vaccines against the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and in improving the management of immunomodulating agents. Currently, different vaccine formulations, such as viral vector, mRNA, and protein-based, almost all directed toward the spike protein that includes the domain for receptor binding, have been approved. Although data are not conclusive, patients affected by autoimmune rheumatic diseases (ARDs) seem to have a slightly higher disease prevalence, risk of hospitalization, and death from coronavirus disease-2019 (COVID-19) than the general population. Therefore, ARD patients, under immunosuppressive agents, have been included among the priority target groups for vaccine administration. However, specific cautions are needed to optimize vaccine safety and effectiveness in these patients, such as modification in some of the ongoing immunosuppressive therapies and the preferential use of mRNA other than vector-based vaccines. Immunomodulating agents can be a therapeutic opportunity for the management of COVID-19 patients; however, their clinical impact depends on how they are handled. To place in therapy immunomodulating agents in the correct window of opportunity throughout the identification of surrogate markers of disease progression and host immune response is mandatory to optimize patient’s outcome.
B Cells Control Mucosal-Associated Invariant T Cell Responses to Salmonella enterica Serovar Typhi Infection Through the CD85j HLA-G Receptor
Authors: Salerno-Gonçalves Rosângela , Rezwan Tasmia , Luo David , Tettelin Hervé , Sztein Marcelo B.
Published: October 2021

Mucosal-associated invariant T (MAIT) cells are an innate-like population of T cells that display a TCR Vα7.2+ CD161+ phenotype and are restricted by the nonclassical MHC-related molecule 1 (MR1). Although B cells control MAIT cell development and function, little is known about the mechanisms underlying their interaction(s). Here, we report, for the first time, that duringSalmonella entericaserovar Typhi (S. Typhi) infection, HLA-G expression on B cells downregulates IFN-γ production by MAIT cells. In contrast, blocking HLA-G expression onS. Typhi-infected B cells increases IFN-γ production by MAIT cells. After interacting with MAIT cells, kinetic studies show that B cells upregulate HLA-G expression and downregulate the inhibitory HLA-G receptor CD85j on MAIT cells resulting in their loss. These results provide a new role for HLA-G as a negative feedback loop by which B cells control MAIT cell responses to antigens.
Characterization of Exosome-Related Gene Risk Model to Evaluate the Tumor Immune Microenvironment and Predict Prognosis in Triple-Negative Breast Cancer
Authors: Qiu Pengjun , Guo Qiaonan , Yao Qingzhi , Chen Jianpeng , Lin Jianqing
Published: October 2021

Background

As a kind of small membrane vesicles, exosomes are secreted by most cell types from multivesicular endosomes, including tumor cells. The relationship between exosomes and immune response plays a vital role in the occurrence and development of tumors. Nevertheless, the interaction between exosomes and the microenvironment of tumors remains unclear. Therefore, we set out to study the influence of exosomes on the triple-negative breast cancer (TNBC) microenvironment.

Method

One hundred twenty-one exosome-related genes were downloaded from ExoBCD database, and IVL, CXCL13, and AP2S1 were final selected because of the association with TNBC prognosis. Based on the sum of the expression levels of these three genes, provided by The Cancer Genome Atlas (TCGA), and the regression coefficients, an exosome risk score model was established. With the median risk score value, the patients in the two databases were divided into high- and low-risk groups. R clusterProfiler package was employed to compare the different enrichment ways between the two groups. The ESTIMATE and CIBERSORT methods were employed to analyze ESTIMATE Score and immune cell infiltration. Finally, the correlation between the immune checkpoint-related gene expression levels and exosome-related risk was analyzed. The relationship between selected gene expression and drug sensitivity was also detected.

Results

Different risk groups exhibited distinct result of TNBC prognosis, with a higher survival rate in the low-risk group than in the high-risk group. The two groups were enriched by immune response and biological process pathways. A better overall survival (OS) was demonstrated in patients with high scores of immune and ESTIMATE rather than ones with low scores. Subsequently, we found that CD4+-activated memory T cells and M1 macrophages were both upregulated in the low-risk group, whereas M2 macrophages and activated mast cell were downregulated in the low-risk group in patients from the TCGA and GEO databases, respectively. Eventually, four genes previously proposed to be targets of immune checkpoint inhibitors were evaluated, resulting in the expression levels of CD274, CTLA4, LAG3, and TIM3 being higher in the low-risk group than high-risk group.

Conclusion

The results of our study suggest that exosome-related risk model was related to the prognosis and ratio of immune cell infiltration in patients with TNBC. This discovery may make contributions to improve immunotherapy for TNBC.
Environmental Determinants of Type 1 Diabetes: From Association to Proving Causality
Authors: Quinn Lauren M. , Wong F. Susan , Narendran Parth
Published: October 2021

The rising incidence of type 1 diabetes (T1D) cannot be ascribed to genetics alone, and causative environmental triggers and drivers must also be contributing. The prospective TEDDY study has provided the greatest contributions in modern time, by addressing misconceptions and refining the search strategy for the future. This review outlines the evidence to date to support the pathways from association to causality, across all stages of T1D (seroconversion to beta cell failure). We focus on infections and vaccinations; infant growth and childhood obesity; the gut microbiome and the lifestyle factors which cultivate it. Of these, the environmental determinants which have the most supporting evidence are enterovirus infection, rapid weight gain in early life, and the microbiome. We provide an infographic illustrating the key environmental determinants in T1D and their likelihood of effect. The next steps are to investigate these environmental triggers, ideally though gold-standard randomised controlled trials and further prospective studies, to help explore public health prevention strategies.
Current Status of Cell-Based Therapies for COVID-19: Evidence From Mesenchymal Stromal Cells in Sepsis and ARDS
Authors: Xu Zhiheng , Huang Yongbo , Zhou Jianmeng , Deng Xiumei , He Weiqun , Liu Xiaoqing , Li Yimin , Zhong Nanshan , Sang Ling
Published: October 2021

The severe respiratory consequences of the coronavirus disease 2019 (COVID-19) pandemic have prompted the urgent need for novel therapies. Cell-based therapies, primarily using mesenchymal stromal cells (MSCs), have demonstrated safety and potential efficacy in the treatment of critical illness, particularly sepsis and acute respiratory distress syndrome (ARDS). However, there are limited preclinical data for MSCs in COVID-19. Recent studies have shown that MSCs could decrease inflammation, improve lung permeability, enhance microbe and alveolar fluid clearance, and promote lung epithelial and endothelial repair. In addition, MSC-based therapy has shown promising effects in preclinical studies and phase 1 clinical trials in sepsis and ARDS. Here, we review recent advances related to MSC-based therapy in the context of sepsis and ARDS and evaluate the potential value of MSCs as a therapeutic strategy for COVID-19.
Clinical Experience of Proteasome Inhibitor Bortezomib Regarding Efficacy and Safety in Severe Systemic Lupus Erythematosus: A Nationwide Study
Authors: Walhelm Tomas , Gunnarsson Iva , Heijke Rebecca , Leonard Dag , Trysberg Estelle , Eriksson Per , Sjöwall Christopher
Published: October 2021

As treatment options in advanced systematic lupus erythematosus (SLE) are limited, there is an urgent need for new and effective therapeutic alternatives for selected cases with severe disease. Bortezomib (BTZ) is a specific, reversible, inhibitor of the 20S subunit of the proteasome. Herein, we report clinical experience regarding efficacy and safety from all patients receiving BTZ as therapy for SLE in Sweden during the years 2014−2020. 8 females and 4 males were included with a mean disease duration at BTZ initiation of 8.8 years (range 0.7–20 years). Renal involvement was the main target for BTZ. Reduction of global disease activity was recorded by decreasing SLEDAI-2K scores over time and remained significantly reduced at the 6-month (p=0.007) and the 12-month (p=0.008) follow-up visits. From BTZ initiation, complement protein 3 (C3) levels increased significantly after the 2nd treatment cycle (p=0.05), the 6-month (p=0.03) and the 12-month (p=0.04) follow-up visits. The urine albumin/creatinine ratio declined over time and reached significance at the 6-month (p=0.008) and the 12-month follow-up visits (p=0.004). Seroconversion of anti-dsDNA (27%), anti-C1q (50%) and anti-Sm (67%) was observed. 6 of 12 patients experienced at least one side-effect during follow-up, whereof the most common adverse events were infections. Safety parameters (C-reactive protein, blood cell counts) mainly remained stable over time. To conclude, we report favorable therapeutic effects of BTZ used in combination with corticosteroids in a majority of patients with severe SLE manifestations irresponsive to conventional immunosuppressive agents. Reduction of proteinuria was observed over time as well as seroconversion of some autoantibody specificities. In most patients, tolerance was acceptable but mild adverse events was not uncommon. Special attention should be paid to infections and hypogammaglobinemia.
Regional Variation in Winter Foraging Strategies by Weddell Seals in Eastern Antarctica and the Ross Sea
Authors: Harcourt Rob , Hindell Mark A. , McMahon Clive R. , Goetz Kimberly T. , Charrassin Jean-Benoit , Heerah Karine , Holser Rachel , Jonsen Ian D. , Shero Michelle R. , Hoenner Xavier , Foster Rose , Lenting Baukje , Tarszisz Esther , Pinkerton Matthew Harry
Published: October 2021

The relative importance of intrinsic and extrinsic determinants of animal foraging is often difficult to quantify. The most southerly breeding mammal, the Weddell seal, remains in the Antarctic pack-ice year-round. We compared Weddell seals tagged at three geographically and hydrographically distinct locations in East Antarctica (Prydz Bay, Terre Adélie, and the Ross Sea) to quantify the role of individual variability and habitat structure in winter foraging behaviour. Most Weddell seals remained in relatively small areas close to the coast throughout the winter, but some dispersed widely. Individual utilisation distributions (UDi, a measure of the total area used by an individual seal) ranged from 125 to 20,825 km2. This variability was not due to size or sex but may be due to other intrinsic states for example reproductive condition or personality. The type of foraging (benthic vs. pelagic) varied from 56.6 ± 14.9% benthic dives in Prydz Bay through 42.1 ± 9.4% Terre Adélie to only 25.1 ± 8.7% in the Ross Sea reflecting regional hydrographic structure. The probability of benthic diving was less likely the deeper the ocean. Ocean topography was also influential at the population level; seals from Terre Adélie, with its relatively narrow continental shelf, had a core (50%) UD of only 200 km2, considerably smaller than the Ross Sea (1650 km2) and Prydz Bay (1700 km2). Sea ice concentration had little influence on the time the seals spent in shallow coastal waters, but in deeper offshore water they used areas of higher ice concentration. Marine Protected Areas (MPAs) in the Ross Sea encompass all the observed Weddell seal habitat, and future MPAs that include the Antarctic continental shelf are likely to effectively protect key Weddell seal habitat.
Multilevel Resilience of Fishing Communities of Coastal Bangladesh Against Covid-19 Pandemic and 65-Day Fishing Ban
Authors: Sultana Rumana , Irfanullah Haseeb Md. , Selim Samiya A. , Raihan Syed Tauheed , Bhowmik Joy , Ahmed Shaikh Giasuddin
Published: October 2021

The unusual situation that arose due to the COVID-19 pandemic and the 65-day fishing ban (national policy to boost depleted fish stocks) affected the lower-income fishing communities in coastal Bangladesh. Shocks and stresses were posed, and community people adopted strategies to adapt to the changes. In the process of adaptation, social-ecological systems resilience at different levels plays a crucial role. Though resilience is acknowledged as multilevel feature, studies on the interaction between the levels while understanding communities’ responses to shock and stress are limited. Thus, in this study, we explored the shocks and stresses the fishing community faced and their views on the resilience feature at different levels (i.e., individual, household, and community level) in coastal Bangladesh during the COVID-19 pandemic and 65-day fishing ban period. The study found that the most resilience promoting features (e.g., diversified livelihood, friendship, and network of supports) were adopted at the individual and household levels. However, positive and negative interactions were explored between resilience features at all levels. Low community-level resilience was not translated into a lack of household-level resilience, and strong individual-level resilience did not mean high household-level resilience. It was noted that the increased resilience of a particular individual or household could negatively affect community resilience. Resilience features showed inconsistent interactions within or among the three levels’ resilience features. The study also revealed that multilevel resilience features stressed the importance of combining persistence (i.e., keeping fishing as the main livelihood) and adaptation process (e.g., livelihood diversification). The study showcases the importance of considering multilevel resilience that offers insight into crucial resilience factors which would not be evident if only one level were studied. The overall finding of this study will contribute to framing governance strategies to ensure sustainable coastal management even in the time of any abrupt or expected changes, such as the COVID-19 pandemic and the fishing ban policy.
Comparative Study of the Feeding Characteristics and Digestion Physiology of Haliotis discus hannai and Haliotis gigantea
Authors: Lyu Mingxin , Gao Xiaolong , Zhang Mo , Lin Shihui , Luo Xuan , You Weiwei , Ke Caihuan
Published: October 2021

Abalone (Haliotis spp.) are typical nocturnal creatures but Haliotis discus hannai is bold and active in the nighttime whereas H. gigantea tends to be timid and inactive. In this study, we quantified and compared differences in movement, feeding, and digestive physiology between H. discus hannai and H. gigantea as well as the potential molecular mechanisms on the basis of video observations and expression levels of genes related to feeding regulation. The feeding behaviors of both species were characterized by significant circadian rhythms (P < 0.05). However, the distance moved and the cumulative duration of movement were 2.61 and 1.94 times higher, respectively, in H. discus hannai than in H. gigantea over the 24-h cycle. The cumulative duration of feeding by H. discus hannai was only 1.15 times that by H. gigantea, but the feeding time as a percentage of the cumulative duration of movement (FTP) was up to 94.6% for H. gigantea and only 56.0% for H. discus hannai. The peaks for α-amylase activity and NPF expression levels in both species as well as the peak OX2R expression level in H. gigantea occurred during 20:00–00:00 h. By contrast, the peaks for alginate lyase activity and NPYR expression levels in H. discus hannai occurred at 16:00 h, when the FTP was significantly higher for H. discus hannai than for H. gigantea. These initial findings quantify specific behavior parameters and thus provide a reference for the selection of appropriate feeding strategies and the proliferation of abalone via bottom sowing.
The MicroRNA Prediction Models as Ancillary Diagnosis Biomarkers for Urothelial Carcinoma in Patients With Chronic Kidney Disease
Authors: Li An-Lun , Chou Che-Yi , Chen Chien-Lung , Wu Kun-Lin , Lin Shih-Chieh , Chen Hung-Chun , Wang Ming-Cheng , Chang Chia-Chu , Hsu Bang-Gee , Wu Mai-Szu , Ma Nianhan , Huang Chiu-Ching
Published: October 2021

Urothelial carcinoma is a common urological cancer in chronic kidney disease patients. Cystoscopy and urine cytology are the clinical diagnostic tools for UC. However, cystoscopy is an invasive procedure, while urine cytology showed low sensitivity for low-grade urothelial tumors. High accuracy with non-invasive tools for UC is needed for CKD patients. Our study collected a total of 272 urine and 138 plasma samples to detect the miRNA expression levels for establishing UC signatures from CKD patients. Seventeen candidate miRNAs of biofluids were selected and confirmed by qRT-PCR. Our results showed that urinary miR-1274a and miR-30a-5p expression levels were significantly lower but miR-19a-5p expression levels were higher in UC when compared with CKD. In plasma samples, miR-155-5p, miR-19b-1-5p, miR-378, and miR-636 showed significantly lower expression in UC compared to those with CKD. The Kaplan-Meier curve showed that lower expression of miR-19a, miR-19b, miR-636 and miR-378, and higher expression of miR-708-5p were associated with poor prognosis in patients with bladder cancer. In addition, we produced classifiers for predicting UC by multiple logistic regression. The urine signature was developed with four miRNAs, and the AUC was 0.8211. Eight miRNA expression levels from both urine and plasma samples were examined, and the AUC was 0.8595. Two miRNA classifiers and the nomograms could improve the drawbacks of current UC biomarker screenings for patients with CKD.
Case Report: Extracorporeal Membrane Oxgenation for Rapidly Progressive Interstitial Lung Disease Associated With Clinically Amyopathic Dermatomyositis in a Post-partum Woman
Authors: Gu Qiao , Diao MengYuan , Hu Wei , Huang Man , Zhu Ying
Published: October 2021

Background: Clinically amyopathic dermatomyositis (CADM) presented with rapid progressive interstitial lung disease (RP-ILD) is rare. Here, we present a case of a post-partum female with CADM complicated by severe RP-ILD managed with venovenous extracorporeal membrane oxygenation (V-V ECMO).

Case Summary: A 36-year-old woman was referred to a local hospital with cough and fever. She had a history of facial erythema and cough since an induction of labor for a stillborn fetus 2 months ago. Her status developed into RP-ILD with mediastinal emphysema and subcutaneous emphysema after admission, and V-V ECMO was initiated. After several failed attempts to wean the patient from ECMO, a decision was made to place the patient on the lung transplant waitlist. She underwent a double lung transplant on ECMO day 31 and received tacrolimus as an immunosuppressive regimen. The patient presented with positive anti-MDA5 and anti-Ro-52 antibodies and a high ferritin level, all of which indicated the presence of clinically amyopathic dermatomyositis (CADM). The patient was weaned from ECMO at 3 days after transplantation, but the patient's state of consciousness deteriorated, and head CT was considered for posterior reversible encephalopathy syndrome (PRES). After the temporary cessation of calcineurin inhibitors and a dosage reduction, the patient's state of consciousness returned to normal. Because of another disturbance of consciousness, the patient declined further treatment and was discharged 14 days after transplantation.

Conclusion: Early recognition of CADM can effectively improve patients' prognosis. ECMO should be considered as a supportive therapy in patients in acute respiratory failure secondary to RP-ILD.
Effects of Rotations With Legume on Soil Functional Microbial Communities Involved in Phosphorus Transformation
Authors: Yu Hui , Wang Fenghua , Shao Minmin , Huang Ling , Xie Yangyang , Xu Yuxin , Kong Lingrang
Published: October 2021

Including legumes in the cereal cropping could improve the crop yield and the uptake of nitrogen (N) and phosphorus (P) of subsequent cereals. The effects of legume-cereal crop rotations on the soil microbial community have been studied in recent years, the impact on soil functional genes especially involved in P cycling is raising great concerns. The metagenomic approach was used to investigate the impacts of crop rotation managements of soybean-wheat (SW) and maize-wheat (MW) lasting 2 and 7years on soil microbial communities and genes involved in P transformation in a field experiment. Results indicated that SW rotation increased the relative abundances ofFirmicutesandBacteroidetes, reducedActinobacteria,Verrucomicrobia, andChloroflexicompared to MW rotation.gcd,phoR,phoD, andppxpredominated in genes involved in P transformation in both rotations. Genes ofgcd,ppa, andugpABCEshowed higher abundances in SW rotation than in MW rotation, whereasgadACandpstSshowed less abundances.Proteobacteria,Acidobacteria, andGemmatimonadetesplayed predominant roles in microbial P cycling. Our study provides a novel insight into crop P, which requires strategy and help to understand the mechanism of improving crop nutrient uptake and productivity in different rotations.
Whole-Genome Assessment of Clinical Acinetobacter baumannii Isolates Uncovers Potentially Novel Factors Influencing Carbapenem Resistance
Authors: Javkar Kiran , Rand Hugh , Hoffmann Maria , Luo Yan , Sarria Saul , Thirunavukkarasu Nagarajan , Pillai Christine A. , McGann Patrick , Johnson J. Kristie , Strain Errol , Pop Mihai
Published: October 2021

Carbapenems—one of the important last-line antibiotics for the treatment of gram-negative infections—are becoming ineffective for treating Acinetobacter baumannii infections. Studies have identified multiple genes (and mechanisms) responsible for carbapenem resistance. In some A. baumannii strains, the presence/absence of putative resistance genes is not consistent with their resistance phenotype—indicating the genomic factors underlying carbapenem resistance in A. baumannii are not fully understood. Here, we describe a large-scale whole-genome genotype-phenotype association study with 349 A. baumannii isolates that extends beyond the presence/absence of individual antimicrobial resistance genes and includes the genomic positions and pairwise interactions of genes. Ten known resistance genes exhibited statistically significant associations with resistance to imipenem, a type of carbapenem: blaOXA-23, qacEdelta1, sul1, mphE, msrE, ant(3”)-II, aacC1, yafP, aphA6, and xerD. A review of the strains without any of these 10 genes uncovered a clade of isolates with diverse imipenem resistance phenotypes. Finer resolution evaluation of this clade revealed the presence of a 38.6 kbp conserved chromosomal region found exclusively in imipenem-susceptible isolates. This region appears to host several HTH-type DNA binding transcriptional regulators and transporter genes. Imipenem-susceptible isolates from this clade also carried two mutually exclusive plasmids that contain genes previously known to be specific to imipenem-susceptible isolates. Our analysis demonstrates the utility of using whole genomes for genotype-phenotype correlations in the context of antibiotic resistance and provides several new hypotheses for future research.