bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations Between Different Dietary Vitamins and the Risk of Obesity in Children and Adolescents: A Machine Learning Approach
Authors: Tang Weifeng , Zhan Wenqiang , Wei Mengdan , Chen Qian
Published: February 2022

Backgrounds

Simultaneous dietary intake of vitamins is considered as a common and real scenario in daily life. However, limited prospective studies have evaluated the association between multivitamins intake and obesity in children and adolescents.

Objectives

This study aimed to evaluate the relationship between the intake of different dietary vitamins and the risk of obesity in children (6-11 years) and adolescents (12-19 years).

Methods

We conducted a cross-sectional study based on data from U.S. National Health and Nutrition Examination Survey, 2013-2016. A total of 3634 children and adolescents were included who had available data on dietary vitamins, obesity and covariates. We analyzed the dietary intake levels of nine vitamins, including vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K. Multivariate logistic regression was used to model the associations between vitamins and obesity. Bayesian kernel machine regression (BKMR) was employed to explore the joint and independent effects of vitamins on obesity among children and adolescents.

Results

In the multivariate logistic regression model, five vitamins (vitamin A, vitamin B1, vitamin B2, vitamin B12, and vitamin D) were negatively associated with obesity in children and adolescents. BKMR analysis showed that when the concentration of the nine vitamins was at or above the 55th percentile compared with the median value, the combined intake of these vitamins could significantly reduce the risk of obesity in children and adolescents. Potential interactions between vitamin B2 and vitamin B12 in increasing the risk of obesity in children and adolescents were observed.

Conclusions

We determine the combined effects of multivitamins on obesity in children and adolescents, and observe a significant interaction between vitamin B2 and vitamin B12. Further cohort studies are needed to clarify the health effects of multivitamins intake in a larger population.
Comparison of Different Mandibular Jawlines Classifications on Transoral Endoscopic Thyroidectomy for Papillary Thyroid Carcinoma: Experiences of 690 Cases
Authors: Yu Xing , Jiang Yuancong , Li Yujun , He Qionghua , Pan Lei , Zhu Peifeng , Wang Yong , Wang Ping
Published: February 2022

Background

The influences of patients’ different mandibular jawlines on transoral endoscopic thyroidectomy via vestibular approach (TOETVA) have not been described before. The objective of this study was to introduce a new classification to assess different mandibular jawlines, and to evaluate the effects on TOETVA in terms of safety, feasibility, and postoperative feelings in the treatment of papillary thyroid carcinoma (PTC).

Methods

The crossing angle of esthetic plane and mandibular plane was defined as Wang Angle, used to assess patients’ different mandibular jawlines. Mandibular classifications of A (angle: 80° ~ 110°), B (angle > 110°), and C (angle < 80°) types were compared to evaluate the surgical outcomes of TOETVA by a retrospective study. 690 patients of PTC who received TOETVA were included in this study, which were divided into three groups according to mandibular classifications.

Results

Clinicopathological characteristics of the patients including age, gender, body mass index, tumor size, Hashimoto thyroiditis were similar in the three groups. Patients’ length of jay in group C was significantly longer than group A and group B (P < 0.01). The ratios of using suspension system in group C were significantly higher than group A and group B (P < 0.01). The scores of postoperative visual analogue scale (VAS) and ratios of mandibular swell in group C were significantly higher than group A and group B (P < 0.01). There was no significant difference in the three groups regarding surgical outcomes, including postoperative vocal cord paralysis, hypocalcemia, serum white blood cells and C-reactive protein levels.

Conclusions

The Wang angle and mandibular jawline classifications were firstly introduced in TOETVA. All the patients of class A, B, and C mandibular jawline can achieve safe and effective surgical outcomes in the treatment of PTC with TOETVA. Patients of class C need more assistance of suspension system, would experience higher scores of VAS, and higher ratios of mandibular swell compared with class A and B.
Does Carbon Emissions, and Economic Expansion Induce Health Expenditure in China: Evidence for Sustainability Perspective
Authors: Xiu Juhua , Ameer Waqar , Abbas Shujaat , Altuntaş Mehmet
Published: February 2022

The current paper assesses the drivers of health care expenditure such as urbanization, natural resources, economic expansion, and CO2 utilizing quarterly data from 2000Q1 to 2018Q4. The research applied the novel dual adjustment approach to identify the long run association between healthcare expenditure and urbanization, economic growth, natural resource and CO2 emissions. The main novelty of the dual adjustment approach is that the approach offers another way to cointegration analysis by relaxing the implicit assumption of the singular adjustment in cointegration analysis. The outcome of the dual adjustment approach affirmed cointegration among the variables in the long run. Furthermore, we applied fully modified ordinary least square (FMOLS), dynamic ordinary least square (DOLS) and canonical cointegrating regression (CCR) estimators and their results disclosed that economic growth, urbanization, and CO2 emissions increase health care expenditure while natural resource rent mitigates healthcare expenditure in China. Moreover, the spectral causality test uncovered that urbanization, economic growth, natural resource, and CO2 emissions can predict healthcare expenditure at various frequencies. Based on these findings, China’s policymakers should establish strategic environmental management policies that improve healthy and clean air to reduce healthcare costs. In addition, policymakers in China should reevaluate their urban development strategies to avoid negative externalities associated with fast urbanization.
Improving Sustainable Field-Grown Wheat Production With Azospirillum brasilense Under Tropical Conditions: A Potential Tool for Improving Nitrogen Management
Authors: Galindo Fernando Shintate , Pagliari Paulo Humberto , Fernandes Guilherme Carlos , Rodrigues Willian Lima , Boleta Eduardo Henrique Marcandalli , Jalal Arshad , Céu Elaine Garcia Oliveira , Lima Bruno Horschut de , Lavres José , Teixeira Filho Marcelo Carvalho Minhoto
Published: February 2022

Sustainable intensification of cropping systems requires to increase productivity and nutrients use efficiency while reducing negative impacts of agricultural management practices on ecosystem and environment. Plant growth-promoting rhizobacteria (PGPR) inoculations are considered one of the most promising and safe strategy to alleviate environmental alterations in context of climatic extremes to improve plant nutrition while reducing dependency of nitrogen (N) fertilizer application. This study investigated the interactive effects of N levels and inoculation with A. brasilense on plant biomass, grain yield, agronomic efficiency (AE) of applied N, apparent N-fertilizer recovery (AFR) and N content in plant targeting economic feasibility of wheat production system. The field trial tested 4 N application levels applied in side-dressing (control, low, average and high; named 0, 50, 100 and 200 kg N ha−1) and two inoculations (without and with A. brasilense seed inoculation). The results exhibited that inoculation with A. brasilense enhanced AE, AFR and N uptake in wheat plants with increased root and shoot N accumulation and grain N accumulation under average and high N application levels. In addition, inoculation increased root and shoot biomass, leading to a yield increase of 10.3% compared with non-inoculated plants. Wheat plant inoculation associated with application of the average N level provided the greatest profitability. Furthermore, results showed that reducing N fertilization from 100 to 50 kg N ha−1 along A. brasilense inoculation led to an increase in operating profit of 10.5%. In view of low economic cost, ease of application, and high probability of a positive response by wheat crops, even associated with different N application levels, the inoculation with A. brasilense prone to be a key sustainable management practice to improve wheat production under tropical conditions. This practice has the potential to increase wheat grain yield, N use and uptake, and overall farm profitability.
Reconstructing Macroevolutionary Patterns in Avian MHC Architecture With Genomic Data
Authors: He Ke , Liang Chun-hong , Zhu Ying , Dunn Peter , Zhao Ayong , Minias Piotr
Published: February 2022

The Major Histocompatibility Complex (MHC) is a hyper-polymorphic genomic region, which forms a part of the vertebrate adaptive immune system and is crucial for intra- and extra-cellular pathogen recognition (MHC-I and MHC-IIA/B, respectively). Although recent advancements in high-throughput sequencing methods sparked research on the MHC in non-model species, the evolutionary history of MHC gene structure is still poorly understood in birds. Here, to explore macroevolutionary patterns in the avian MHC architecture, we retrieved contigs with antigen-presenting MHC and MHC-related genes from available genomes based on third-generation sequencing. We identified: 1) an ancestral avian MHC architecture with compact size and tight linkage between MHC-I, MHC-IIA/IIB and MHC-related genes; 2) three major patterns of MHC-IIA/IIB unit organization in different avian lineages; and 3) lineage-specific gene translocation events (e.g., separation of the antigen-processing TAP genes from the MHC-I region in passerines), and 4) the presence of a single MHC-IIA gene copy in most taxa, showing evidence of strong purifying selection (low dN/dS ratio and low number of positively selected sites). Our study reveals long-term macroevolutionary patterns in the avian MHC architecture and provides the first evidence of important transitions in the genomic arrangement of the MHC region over the last 100 million years of bird evolution.
Anti-Tumor Potency of Short-Term Interleukin-15 Dendritic Cells Is Potentiated by In Situ Silencing of Programmed-Death Ligands
Authors: Versteven Maarten , Flumens Donovan , Campillo-Davó Diana , De Reu Hans , Van Bruggen Laura , Peeters Stefanie , Van Tendeloo Viggo , Berneman Zwi , Dolstra Harry , Anguille Sébastien , Hobo Willemijn , Smits Evelien , Lion Eva
Published: February 2022

Dendritic cell (DC) vaccines have proven to be a valuable tool in cancer immune therapy. With several DC vaccines being currently tested in clinical trials, knowledge about their therapeutic value has been significantly increased in the past decade. Despite their established safety, it has become clear that objective clinical responses are not yet robust enough, requiring further optimization. Improvements of this advanced therapy medicinal product encompass, among others, regulating their immune stimulating capacity by in situ gene engineering, in addition to their implementation in combination therapy regimens. Previously, we have reported on a superior monocyte-derived DC preparation, including interleukin-15, pro-inflammatory cytokines and immunological danger signals in the culture process. These so-called IL-15 DCs have already proven to exhibit several favorable properties as cancer vaccine. Evolving research into mechanisms that could further modulate the immune response towards cancer, points to programmed death-1 as an important player that dampens anti-tumor immunity. Aiming at leveraging the immunogenicity of DC vaccines, we hypothesized that additional implementation of the inhibitory immune checkpoint molecules programmed death-ligand (PD-L)1 and PD-L2 in IL-15 DC vaccines would exhibit superior stimulatory potential. In this paper, we successfully implemented PD-L silencing at the monocyte stage in the 3-day IL-15 DC culture protocol resulting in substantial downregulation of both PD-L1 and PD-L2 to levels below 30%. Additionally, we validated that these DCs retain their specific characteristics, both at the level of phenotype and interferon gamma secretion. Evaluating their functional characteristics, we demonstrate that PD-L silencing does not affect the capacity to induce allogeneic proliferation. Ultimately designed to induce a durable tumor antigen-specific immune response, PD-L silenced IL-15 DCs were capable of surpassing PD-1-mediated inhibition by antigen-specific T cells. Further corroborating the superior potency of short-term IL-15 DCs, the combination of immune stimulatory components during DC differentiation and maturation with in situ checkpoint inhibition supports further clinical translation.
Evidence for an Adult-Like Type 1-Immunity Phenotype of Vδ1, Vδ2 and Vδ3 T Cells in Ghanaian Children With Repeated Exposure to Malaria
Authors: León-Lara Ximena , Yang Tao , Fichtner Alina Suzann , Bruni Elena , von Kaisenberg Constantin , Eiz-Vesper Britta , Dodoo Daniel , Adu Bright , Ravens Sarina
Published: February 2022

Effector capabilities of γδ T cells are evident inPlasmodiuminfection in young and adult individuals, while children are the most vulnerable groups affected by malaria. Here, we aimed to investigate the age-dependent phenotypic composition of Vδ1+, Vδ2+, and Vδ3+T cells in children living in endemic malaria areas and how this differs between children that will develop symptomatic and asymptomaticPlasmodium falciparuminfections. Flow cytometric profiling of naïve and effector peripheral blood γδ T cells was performed in 6 neonates, 10 adults, and 52 children. The study population of young children, living in the same malaria endemic region of Ghana, was monitored for symptomaticvsasymptomatic malaria development for up to 42 weeks after peripheral blood sampling at baseline. For the Vδ2+T cell population, there was evidence for an established type 1 effector phenotype, characterized by CD94 and CD16 expression, as early as 1 year of life. This was similar among children diagnosed with symptomatic or asymptomatic malaria. In contrast, the proportion of type 2- and type 3-like Vδ2 T cells declined during early childhood. Furthermore, for Vδ1+and Vδ3+T cells, similar phenotypes of naïve (CD27+) and type 1 effector (CD16+) cells were observed, while the proportion of CD16+Vδ1+T cells was highest in children with asymptomatic malaria. In summary, we give evidence for an established adult-like γδ T cell compartment in early childhood with similar biology of Vδ1+and Vδ3+T cells. Moreover, the data supports the idea that type 1 effector Vδ1+T cells mediate the acquisition of and can potentially serve as biomarker for natural immunity toP. falciparuminfections in young individuals from malaria-endemic settings.
Neurogenesis and Viral Infection
Authors: Ihunwo Amadi Ogonda , Perego Jessica , Martino Gianvito , Vicenzi Elisa , Panina-Bordignon Paola
Published: February 2022

Neural stem cells (NSCs) are multipotent stem cells that reside in the fetal and adult mammalian brain, which can self-renew and differentiate into neurons and supporting cells. Intrinsic and extrinsic cues, from cells in the local niche and from distant sites, stringently orchestrates the self-renewal and differentiation competence of NSCs. Ample evidence supports the important role of NSCs in neuroplasticity, aging, disease, and repair of the nervous system. Indeed, activation of NSCs or their transplantation into injured areas of the central nervous system can lead to regeneration in animal models. Viral invasion of NSCs can negatively affect neurogenesis and synaptogenesis, with consequent cell death, impairment of cell cycle progression, early differentiation, which cause neural progenitors depletion in the cortical layer of the brain. Herein, we will review the current understanding of Zika virus (ZIKV) infection of the fetal brain and the NSCs, which are the preferential population targeted by ZIKV. Furthermore, the potential neurotropic properties of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may cause direct neurological damage, will be discussed.
A Pan-Cancer Analysis of the Oncogenic Role of Cell Division Cycle-Associated Protein 4 (CDCA4) in Human Tumors
Authors: Fang Hui , Sheng Shuyan , Chen Bangjie , Wang Jianpeng , Mao Deshen , Han Yanxun , Liu Yuchen , Wang Xinyi , Gui Siyu , Zhang Tongyuan , Zhang Lizhi , Li Conghan , Hu Xinyang , Deng Wanyu , Liu Xin , Xu Honghai , Xu Wentao , Wang Xingyu , Liu Rongqiang , Kong Weihao
Published: February 2022

Purpose

To unravel the oncogenic role of CDCA4 in different cancers from the perspective of tumor immunity.

Methods

Raw data on CDCA4 expression in tumor samples and paracancerous samples were obtained from TCGA and GTEX databases. In addition, we investigated pathological stages and the survival analysis of CDCA4 in pan-cancer across Gene Expression Profiling Interactive Analysis (GEPIA) database. Cox Proportional Hazards Model shows that high CDCA4 levels are associated with several vital indicators in oncology. On the one hand, we explored the correlation between CADA4 expression and tumor immune infiltration by the TIMER tool; On the other hand, we utilized the methods of CIBERSORT and ESTIMATE computational to evaluate the proportion of tumor infiltrating immune cells (TIIC) and the amounts of stromal and immune components based on TCGA database. The use of antineoplastic drugs and the expression of CDCA4 also showed a high correlation via linear regression. Protein–Protein Interaction analysis was performed in the GeneMANIA database, and enrichment analysis was performed and predicted signaling pathways were identified by using Gene Ontology and Kyoto Encyclopedia of Genes. The correlation between CDCA4 expression with Copy number variations (CNV) and methylation is detailed, respectively. Molecular biology experiments including Western blotting, flow cytometry, EDU staining, Transwell and Wound Healing assay to validate the cancer promoting role of CDCA4 in hepatocellular carcinoma (HCC).

Results

Most tumors highly expressed CDCA4. Elevated CDCA4 expression was associated with poor OS and DFS. There was a significant correlation between CDCA4 expression and TITCs. Moreover, markers of TIICs exhibited distinct patterns of CDCA4 associated immune infiltration. In addition, we pay attention to the association between the expression of CDCA4 and the use of the anti-tumor drugs. CDCA4 is related to biological progress (BP), cellular component (CC) and molecular function (MF). Dopaminergic Synapse, AMPK, Sphingolipid, Chagas Disease, mRNA Surveillance were significantly enriched pathways in positive and negative correlation genes with CDCA4. CNV is thought to be a positive correlation with CDCA4 expression. Conversely, methylation is negative correlation with CDCA4 expression. Molecular biology experiments confirm a cancer promoting role for CDCA4 in HCC

Conclusion

CDCA4 may serve as a biomarker for cancer immunologic infiltration and poor prognosis, providing a new way of thinking for cancer treatment.
Secreted Autotransporter Toxin (Sat) Mediates Innate Immune System Evasion
Authors: Freire Claudia A. , Silva Rosa M. , Ruiz Rita C. , Pimenta Daniel C. , Bryant Jack A. , Henderson Ian R. , Barbosa Angela S. , Elias Waldir P.
Published: February 2022

Several strategies are used by Escherichia coli to evade the host innate immune system in the blood, such as the cleavage of complement system proteins by secreted proteases. Members of the Serine Proteases Autotransporters of Enterobacteriaceae (SPATE) family have been described as presenting proteolytic effects against complement proteins. Among the SPATE-encoding genes sat (secreted autotransporter toxin) has been detected in high frequencies among strains of E. coli isolated from bacteremia. Sat has been characterized for its cytotoxic action, but the possible immunomodulatory effects of Sat have not been investigated. Therefore, this study aimed to evaluate the proteolytic effects of Sat on complement proteins and the role in pathogenesis of BSI caused by extraintestinal E. coli (ExPEC). E. coli EC071 was selected as a Sat-producing ExPEC strain. Whole-genome sequencing showed that sat sequences of EC071 and uropathogenic E. coli CFT073 present 99% identity. EC071 was shown to be resistant to the bactericidal activity of normal human serum (NHS). Purified native Sat was used in proteolytic assays with proteins of the complement system and, except for C1q, all tested substrates were cleaved by Sat in a dose and time-dependent manner. Moreover, E. coli DH5α survived in NHS pre-incubated with Sat. EC071-derivative strains harboring sat knockout and in trans complementations producing either active or non-active Sat were tested in a murine sepsis model. Lethality was reduced by 50% when mice were inoculated with the sat mutant strain. The complemented strain producing active Sat partially restored the effect caused by the wild-type strain. The results presented in this study show that Sat presents immunomodulatory effects by cleaving several proteins of the three complement system pathways. Therefore, Sat plays an important role in the establishment of bloodstream infections and sepsis.
Safeguarding Seafood Security, Marine Biodiversity and Threatened Species: Can We Have Our Fish and Eat It too?
Authors: Jefferson Tamlin , Palomares Maria L. D. , Lundquist Carolyn J.
Published: February 2022

The ocean contains an abundance of biodiversity that is vital to global food security. However, marine biodiversity is declining. Marine protected areas and marine reserves have been used to protect biodiversity, conserve threatened species and rebuild exploited species, but are perceived as restrictive to fishing, which has slowed progress towards ocean protection targets. Here, we perform a spatial prioritisation of the ocean to protect biodiversity, threatened species and food security. Food security was quantified using catch in tonnes per km2, per 0.5-degree cell of the ocean, using data from the Sea Around Us, a global database of industrial, artisanal, subsistence, and recreational fishing catches. Using Representative Biodiversity Areas [RBAs (the top 30% of the ocean based on holistic measures of biodiversity)], maps of 974 threatened species, and catch data for 2,170 exploited species, we find that these multiple, competing objectives are achievable with minimal compromise. Protecting 30% of the ocean using a multi-objective solution could protect 89% of RBAs, 89% of threatened species and maintain access to fishing grounds that provide 89% of global catch. Even when prioritising food security above conservation objectives we find significant protection for biodiversity and threatened species (85% RBAs, 73% threatened species). We highlight four exploited species for improved management, as they are consistently caught in areas of high conservation importance (skipjack tuna,Katsuwonus pelamis; yellowfin tuna,Thunnus albacares; Atlantic cod,Gadus morhua; Chilean jack mackerel,Trachurus murphyi). We show that a globally coordinated approach to marine conservation and food security is necessary, as regional scale strategies are shown to be less efficient and may result in conflict between food security and conservation objectives. Our results add support for calls to protect 30% of the ocean by 2030, and show where protection would best protect food security and conserve biodiversity and threatened species.
Retinal Nerve and Vascular Changes in Prediabetes
Authors: Peng Rui Ping , Zhu Zi Qian , Shen Hong Yi , Lin Hong Mei , Zhong Lei , Song Si Qi , Liu Tian , Ling Shi Qi
Published: February 2022

Objective

This study aimed to observe vascular and neuroretinal alterations in people with prediabetes [impaired fasting glucose (IFG) and impaired glucose tolerance (IGT)] and normal glucose metabolism.

Methods

A total of 21 patients with prediabetes (42 eyes) and 20 healthy controls (40 eyes) participated in our study. All patients underwent a complete eye examination [including fundus fluorescein angiography (FFA) and optical coherence tomography (OCT)] and a related general examination (complete biochemical analysis, routine blood tests, and glycosylated hemoglobin).

Results

On FFA, no patients in either group showed any microvascular alterations. The total peripapillary retinal nerve fiber layer (pRNFL) in the prediabetic group was significantly thinner than that in the healthy control group (p < 0.0001). Only the temporal pRNFL thickness was significantly less in patients with prediabetes compared to the normal people. There was no significant difference in the thickness of retina in the range of 1 mm diameter of macular fovea (p = 0.286), but in the prediabetic group, the macular retinal thickness within the diameter of 6 mm in nasal side (p < 0.0001), superior side (p < 0.0001), temporal side (p = 0.008), and inferior side (p = 0.001) were lower than that in the control group.

Conclusion

In the prediabetic group, there was no microvascular alterations, but the total pRNFL and the temporal pRNFL was significantly thinner, and the macular retinal thickness within the diameter of 6 mm in the nasal, temporal, and inferior side were lower than that in the healthy control group. These data confirm neuroretinal alterations in prediabetes prior to microvascular injury.
Sleep Quality Is Associated With Severe Meibomian Gland Disruption in Dry Eye
Authors: Zhu Yirui , Huang Xiaodan , Lin Lin , Di Mengshu , Chen Ruida , Fang Fei , Jin Xiuming
Published: February 2022

Purpose

To investigate the association between sleep quality and meibomian gland dropout characteristics in dry eye patients.

Methods

This cross-sectional study involved 172 dry eye patients with no history of conditions or factors that could confound dry eye disease (DED) and/or meibomian gland dropout. Participants underwent a comprehensive anterior eye assessment. The validated Athens Insomnia Scale (AIS) and Pittsburgh Sleep Quality Index (PSQI) were used to assess sleep quality. The measured outcomes were dry eye symptoms via the Ocular Surface Disease Index (OSDI), tear breakup time (TBUT), corneal fluorescein staining, meibomian gland function, and extent of meibomian gland dropout.

Results

Of the dry eye participants, 34.9% had severe meibomian gland dropout (SMD) and 41.3% of the subjects had poor sleep quality. Patients with poor sleep quality had greater Meibomian gland dropout while the sleep AIS and PSQI scores were significantly correlated with Meibomian gland dropout (r = 0.495, p < 0.001; r = 0.24, p = 0.002; respectively). SMD patients had worse scores on all components of the PSQI (all p < 0.001, corrected for age and sex). Use of sleep medication, poor habitual sleep efficiency, and sleep disturbance were particularly prevalent in SMD patients as compared to Non-severe meibomian gland dropout (NSMD) patients. Multivariate logistic regression analysis revealed that sleep quality was eventually associated with female gender (p = 0.042), OSDI (p = 0.004), TBUT (p = 0.036), and Meibomian gland dropout score (p < 0.001).

Conclusion

It was found that greater meibomian gland dropout in poor sleep quality individuals is especially related to use of sleep medication, poor habitual sleep efficiency, and sleep disturbance. This finding suggests a need for long-term studies of anterior eye health in people with poor sleep quality.
The Association Between White Blood Cell Count and Insulin Resistance in Community-Dwelling Middle-Aged and Older Populations in Taiwan: A Community-Based Cross-Sectional Study
Authors: Chen Jau-Yuan , Chen Yun-Hung , Lee Yu-Chien , Tsou Meng-Ting
Published: February 2022

Background

Insulin resistance (IR) is a major pathophysiological factor in the development and progression of diabetes mellitus (DM). DM is highly prevalent in Taiwan and has become one of the most common health problems in family medicine and primary care. We aimed to use white blood cell count (WBC), a common physiological parameter, to develop a simple clinical prediction rule for IR in the middle-aged and old Taiwanese population.

Methods

In this cross-sectional community-based study, the participants completed a questionnaire comprising personal and medical history data and underwent anthropometric measurements and blood sampling. IR was defined as a HOMA-IR index ≥2. Independent t-test, Mann–Whitney U test, chi-square test, Pearson's correlation test, multivariate binary logistic regression, and receiver operating characteristic curves were used to evaluate the association between the WBC count and IR.

Results

A total of 398 community-dwelling middle-aged and older persons (34.9% men) with a mean age of 64.43 ± 8.45 years were enrolled for the analysis. A significant association was identified between the WBC counts and IR, with a Pearson's correlation coefficient of 0.37 (p-value <0.001). Multivariate logistic regression revealed that WBC count (OR = 1.50; 95% CI = 1.25–1.81) was an independent risk factor for IR after adjusting for confounding variables. The area under the receiver operating characteristic curve for WBC count was 0.67, and the optimal threshold value was 5.65 1,000/uL.

Conclusion

A high WBC count is positively related to an increased risk of IR among middle-aged and older people in Taiwan.
Orphan Drug Prices and Epidemiology of Rare Diseases: A Cross-Sectional Study in Italy in the Years 2014–2019
Authors: Villa Federico , Di Filippo Aurora , Pierantozzi Andrea , Genazzani Armando , Addis Antonio , Trifirò Gianluca , Cangini Agnese , Tafuri Giovanni , Settesoldi Daniela , Trotta Francesco
Published: February 2022

Introduction

It is well acknowledged that the price of orphan drugs is normally higher than that resulting from the value-based pricing. A correlation between the cost of therapy for orphan drugs and the epidemiology (prevalence and incidence) of the related rare disease can be hypothesized.

Methods

This analysis includes all approved orphan drugs by European Medicines Agency whose reimbursement was granted for the first therapeutic indication in the years 2014–2019 in Italy. Regression and correlation analyses were performed to analyze the possible correlations between the logarithm of the annual therapy cost and the epidemiology of the rare diseases, between orphan drugs consumption and epidemiology of related rare disease and between therapy cost and the consumption.

Results

The regression analysis between the annual cost of therapy estimated on the published ex-factory price and the prevalence showed a slightly decreasing, not statistically significant, trend (coefficient: −0.10, p-value: 0.41). The results were similar when using the price resulting from the application of Managed Entry Agreements (coefficient: −0.11, p-value: 0.40). The regression analysis between sales volume and prevalence showed a positive slope without an acceptable level of significance (p-value: 0.04). The correlation analysis between the therapy cost and the sales volume highlighted again an absence of significant association, similarly if considering only ATC L orphan drugs, or the incidence.

Discussion

The definition of the price of an orphan drug seems not to depend on the rarity of the disease, and sales volumes do not correlate with the epidemiology of the rare disease and with the annual cost of therapy.
CCL5 as a Prognostic Marker for Survival and an Indicator for Immune Checkpoint Therapies in Small Cell Lung Cancer
Authors: Tang Yichun , Hu Yueyang , Niu Yuchun , Sun Lei , Guo Linlang
Published: February 2022

The standard treatment for small cell lung cancer (SCLC) has not changed in decades. Recently, important advances have been made in immunotherapy. However, analysis of these trials suggests that only a small proportion of patients benefit from immune checkpoint blockade (ICB). Identifying these patients is a clinical challenge. In this study, we applied the ESTIMATE calculation to calculate immune scores in 159 cases of SCLC from two published cohorts. COX regression analysis was used to analyze the differentially expressed genes (DEGs) with high and low immune score. We found that CCL5 expression was positively correlated with survival in SCLC patients. In addition, we verified the effect of CCL5 on survival and response to treatment in another cohort that received immunotherapy. Meanwhile, Gene set enrichment analysis (GSEA) showed that genes with high expression of CCL5 were mainly enriched in immune-related activities. The result of Tumor Immune Dysfunction and Exclusion (TIDE) demonstrated that CCL5 was a potential biomarker to predict response to ICB for SCLC, which is correspondent with the result in verified cohort. These results suggest that CCL5 may be the reason for TME to maintain its immune dominance, making it a favorable factor for ICB. Therefore, CCL5 levels may help to outline the prognosis of patients with SCLC.
Daily Step Counts in Patients With Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Observational Studies
Authors: Zhang Fan , Ren Yibo , Wang Hui , Bai Yan , Huang Liuyan
Published: February 2022

Background

Physical inactivity is an essential factor in the prognosis of patients with chronic kidney disease (CKD). Daily step count is a straightforward measure to assess physical activity levels. Understanding the step counts among different CKD stages is essential to change sedentary behavior.

Objectives

This systematic review and meta-analysis aimed to investigate the daily step counts in patients with CKD at a different stage.

Design

A systematic review and meta-analysis.

Data Sources

The literature search was performed in PubMed, Embase, and Web of Science from inception to November 3rd, 2021.

Review Methods

Observational studies (cross-sectional, case-control, or cohort studies) reported specific values of step counts in CKD patients by the wearable device were included. A random-effects model was used to pool the data. Subgroup analysis explored differences in outcomes by stage of CKD. Heterogeneity between studies was assessed using the χ2 test of Cochrane's Q statistic. A contour-enhanced funnel plot was conducted to investigate publication bias. Univariate and multivariate meta-regression was conducted to examine possible sources of heterogeneity.

Results

Twenty-eight articles were identified and used for quantitative analysis. The result showed that the daily step count in patients with CKD was 4642.47 (95% CI: 4274.18–5010.76), and significantly lower than the healthy population. Subgroup analysis revealed that the step counts decreased before dialysis, dropped to a freezing point at the hemodialysis phase, and increased after kidney transplantation. Meta-regression analysis showed that daily step counts were relatively higher in the Americas or younger than 60 or kidney transplant recipients.

Conclusion

The status of daily step counts in patients with CKD decreases with CKD severity and increases after kidney transplantation. Although studies have begun to focus on strategies to improve step counts in patients with CKD, future studies should focus more on step counts in pre-dialysis patients and changing their physically inactive lifestyle early to alleviate deteriorating renal function.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=291551, identifier: CRD42021291551.
Bacterioplankton Zonation Does Exist in High Elevation, Polymictic Lakes
Authors: Aguilar Pablo , Vila Irma , Sommaruga Ruben
Published: February 2022

The assessment of distribution patterns or zonation of planktonic microbes along the water column is a crucial step to interpret their function in the ecosystem. In lakes without seasonal thermal stratification or polymictic systems such as high elevation tropical lakes, planktonic bacterial taxa are probably homogeneously distributed in the water column in contrast to what is known for thermally stratified lakes. However, we know little about bacterial distribution patterns in polymictic lakes and their relation to environmental gradients other than temperature. Here we assessed the diversity, microdiversity, and bacterial community composition at different discrete depths in three high elevation lakes (4,400–4,550 m above sea level) from the Andean plateau to test whether bacterial zonation patterns exist along the water column. For this objective, we analyzed bulk DNA and the putatively active fraction (cDNA) of the 16S rRNA gene. Although a clear gradient of temperature and oxygen was not detected along the water column, a significant vertical spatial zonation of the bacterial communities was present in two out of the three lakes, with microdiversity contributing to such pattern. Our results provide a reference for understanding how changing environmental conditions could affect high elevation aquatic ecosystems, particularly when warming is amplified with elevation, accelerating changes in hydrological regimes and biodiversity. Finally, our results highlight the importance of incorporating the whole water column in ecological studies of aquatic ecosystems lacking temporal or permanent thermal stratification.
Contribution of the Mitochondrial Carbonic Anhydrase (MoCA1) to Conidiogenesis and Pathogenesis in Magnaporthe oryzae
Authors: Dang Yuejia , Wei Yi , Batool Wajjiha , Sun Xicen , Li Xiaoqian , Zhang Shi-Hong
Published: February 2022

The interconversion of CO2 and HCO3− catalyzed by carbonic anhydrases (CAs) is a fundamental biochemical process in organisms. During mammalian–pathogen interaction, both host and pathogen CAs play vital roles in resistance and pathogenesis; during planta–pathogen interaction, however, plant CAs function in host resistance but whether pathogen CAs are involved in pathogenesis is unknown. Here, we biologically characterized the Magnaporthe oryzae CA (MoCA1). Through detecting the DsRED-tagged proteins, we observed the fusion MoCA1 in the mitochondria of M. oryzae. Together with the measurement of CA activity, we confirmed that MoCA1 is a mitochondrial zinc-binding CA. MoCA1 expression, upregulated with H2O2 or NaHCO3 treatment, also showed a drastic upregulation during conidiogenesis and pathogenesis. When MoCA1 was deleted, the mutant ΔMoCA1 was defective in conidiophore development and pathogenicity. 3,3′-Diaminobenzidine (DAB) staining indicated that more H2O2 accumulated in ΔMoCA1; accordingly, ATPase genes were downregulated and ATP content decreased in ΔMoCA1. Summarily, our data proved the involvement of the mitochondrial MoCA1 in conidiogenesis and pathogenesis in the rice blast fungus. Considering the previously reported HCO3− transporter MoAE4, we propose that MoCA1 in cooperation with MoAE4 constitutes a HCO3− homeostasis-mediated disease pathway, in which MoCA1 and MoAE4 can be a drug target for disease control.
Emerging Electroencephalographic Biomarkers to Improve Preclinical to Clinical Translation in Alzheimer’s Disease
Authors: Cope Zackary A. , Murai Takeshi , Sukoff Rizzo Stacey J.
Published: February 2022

Continually emerging data indicate that sub-clinical, non-convulsive epileptiform activity is not only prevalent in Alzheimer’s disease (AD) but is detectable early in the course of the disease and predicts cognitive decline in both humans and animal models. Epileptiform activity and other electroencephalographic (EEG) measures may hold powerful, untapped potential to improve the translational validity of AD-related biomarkers in model animals ranging from mice, to rats, and non-human primates. In this review, we will focus on studies of epileptiform activity, EEG slowing, and theta-gamma coupling in preclinical models, with particular focus on its role in cognitive decline and relevance to AD. Here, each biomarker is described in the context of the contemporary literature and recent findings in AD relevant animal models are discussed.
Age-Related Hearing Loss: Sensory and Neural Etiology and Their Interdependence
Authors: Elliott Karen L. , Fritzsch Bernd , Yamoah Ebenezer N. , Zine Azel
Published: February 2022

Age-related hearing loss (ARHL) is a common, increasing problem for older adults, affecting about 1 billion people by 2050. We aim to correlate the different reductions of hearing from cochlear hair cells (HCs), spiral ganglion neurons (SGNs), cochlear nuclei (CN), and superior olivary complex (SOC) with the analysis of various reasons for each one on the sensory deficit profiles. Outer HCs show a progressive loss in a basal-to-apical gradient, and inner HCs show a loss in a apex-to-base progression that results in ARHL at high frequencies after 70 years of age. In early neonates, SGNs innervation of cochlear HCs is maintained. Loss of SGNs results in a considerable decrease (~50% or more) of cochlear nuclei in neonates, though the loss is milder in older mice and humans. The dorsal cochlear nuclei (fusiform neurons) project directly to the inferior colliculi while most anterior cochlear nuclei reach the SOC. Reducing the number of neurons in the medial nucleus of the trapezoid body (MNTB) affects the interactions with the lateral superior olive to fine-tune ipsi- and contralateral projections that may remain normal in mice, possibly humans. The inferior colliculi receive direct cochlear fibers and second-order fibers from the superior olivary complex. Loss of the second-order fibers leads to hearing loss in mice and humans. Although ARHL may arise from many complex causes, HC degeneration remains the more significant problem of hearing restoration that would replace the cochlear implant. The review presents recent findings of older humans and mice with hearing loss.
A Role for Serotonin in Modulating Opposing Drive and Brake Circuits of Impulsivity
Authors: Desrochers Stephanie S. , Spring Mitchell G. , Nautiyal Katherine M.
Published: February 2022

Impulsivity generally refers to a deficit in inhibition, with a focus on understanding the neural circuits which constitute the “brake” on actions and gratification. It is likely that increased impulsivity can arise not only from reduced inhibition, but also from a heightened or exaggerated excitatory “drive.” For example, an action which has more vigor, or is fueled by either increased incentive salience or a stronger action-outcome association, may be harder to inhibit. From this perspective, this review focuses on impulse control as a competition over behavioral output between an initially learned response-reward outcome association, and a subsequently acquired opposing inhibitory association. Our goal is to present a synthesis of research from humans and animal models that supports this dual-systems approach to understanding the behavioral and neural substrates that contribute to impulsivity, with a focus on the neuromodulatory role of serotonin. We review evidence for the role of serotonin signaling in mediating the balance of the “drive” and “brake” circuits. Additionally, we consider parallels of these competing instrumental systems in impulsivity within classical conditioning processes (e.g., extinction) in order to point us to potential behavioral and neural mechanisms that may modulate the competing instrumental associations. Finally, we consider how the balance of these competing associations might contribute to, or be extracted from, our experimental assessments of impulsivity. A careful understanding of the underlying behavioral and circuit level contributions to impulsivity is important for understanding the pathogenesis of increased impulsivity present in a number of psychiatric disorders. Pathological levels of impulsivity in such disorders are likely subserved by deficits in the balance of motivational and inhibitory processes.
The Frailty Puzzle: Searching for Immortality or for Knowledge Survival?
Authors: Govoni Stefano , Fagiani Francesca , Lanni Cristina , Allegri Nicola
Published: February 2022

What is the value of assessing the biological age and frailty and predicting residual lifespan and health status? The benefit is obvious if we have means to alter the pace of aging and the development of frailty. So far, limited but increasing examples of interventions altering the predicted status indicate that, at least in some cases, this is possible through interventions spanning from the economic-social through drug treatments. Thus, why searching for biological markers, when some clinical and socio-economic indicators do already provide sufficiently accurate predictions? Indeed, the search of frailty biomarkers and of their biological clocks helps to build up a mechanistic frame that may orientate the design of interventions and the time window of their efficacy. Among the candidate biomarkers identified, several studies converge to indicate epigenetic clocks as a promising sensitive biomarker of the aging process. Moreover, it will help to establish the relationship between personal aging and health trajectories and to individuate the check points beyond which biological changes are irreversible.
Precise Mapping of Otp Expressing Cells Across Different Pallial Regions Throughout Ontogenesis Using Otp-Specific Reporter Transgenic Mice
Authors: Morales Lorena , González-Alonso Alba , Desfilis Ester , Medina Loreta
Published: February 2022

Taking advantage of two Otp-specific reporter lines of transgenic mice (Otp-eGFP and Otp-Cre; Rpl22-HA), we identify and describe different Otp cell populations across various pallial regions, including the pallial amygdala, the piriform cortex, the mesocortex, the neocortex, and the hippocampal complex. Some of these populations can be followed throughout development, suggesting migration from external sources (for example, those of the pallial amygdala and at least some of the cingulate cortex). Other cells become visible during postnatal development (some of those in the neocortex and hippocampal formation) or in adulthood (those of the parahippocampal lobe), and seem to be produced locally. We discuss the possible role of Otp in these different populations during different moments of ontogenesis. We also analyze the connectivity patterns of some of these cells and discuss their functional implications. For example, our data suggest that Otp cells of the pallial amygdala might be engaged in networks with other Otp cells of the medial amygdala with the same embryonic origin, and may regulate specific aspects of social behavior. Regarding Otp cells in the parahippocampal lobe, they seem to be projection neurons and may regulate hippocampal function during spatial navigation and memory formation. The two reporter transgenic mice employed here provide very powerful tools for high precision studies on these different Otp cells of the pallium, but careful attention should be paid to the age and to differences between lines.