bluuebunny/crossref_metadata_2025_split huggingface dataset:
Persistent memory despite rapid contraction of circulating T Cell responses to SARS-CoV-2 mRNA vaccination
Authors: Taus Ellie , Hofmann Christian , Ibarrondo F. Javier , Gong Laura S. , Hausner Mary Ann , Fulcher Jennifer A. , Krogstad Paul , Kitchen Scott G. , Ferbas Kathie G. , Tobin Nicole H. , Rimoin Anne W. , Aldrovandi Grace M. , Yang Otto O. 
Published: February 2023

IntroductionWhile antibodies raised by SARS-CoV-2 mRNA vaccines have had compromised efficacy to prevent breakthrough infections due to both limited durability and spike sequence variation, the vaccines have remained highly protective against severe illness. This protection is mediated through cellular immunity, particularly CD8+ T cells, and lasts at least a few months. Although several studies have documented rapidly waning levels of vaccine-elicited antibodies, the kinetics of T cell responses have not been well defined.MethodsInterferon (IFN)-γ enzyme-linked immunosorbent spot (ELISpot) assay and intracellular cytokine staining (ICS) were utilized to assess cellular immune responses (in isolated CD8+ T cells or whole peripheral blood mononuclear cells, PBMCs) to pooled peptides spanning spike. ELISA was performed to quantitate serum antibodies against the spike receptor binding domain (RBD). ResultsIn two persons receiving primary vaccination, tightly serially evaluated frequencies of anti-spike CD8+ T cells using ELISpot assays revealed strikingly short-lived responses, peaking after about 10 days and becoming undetectable by about 20 days after each dose. This pattern was also observed in cross-sectional analyses of persons after the first and second doses during primary vaccination with mRNA vaccines. In contrast, cross-sectional analysis of COVID-19-recovered persons using the same assay showed persisting responses in most persons through 45 days after symptom onset. Cross-sectional analysis using IFN-γ ICS of PBMCs from persons 13 to 235 days after mRNA vaccination also demonstrated undetectable CD8+ T cells against spike soon after vaccination, and extended the observation to include CD4+ T cells. However, ICS analyses of the same PBMCs after culturing with the mRNA-1273 vaccine in vitro showed CD4+ and CD8+ T cell responses that were readily detectable in most persons out to 235 days after vaccination.DiscussionOverall, we find that detection of spike-targeted responses from mRNA vaccines using typical IFN-γ assays is remarkably transient, which may be a function of the mRNA vaccine platform and an intrinsic property of the spike protein as an immune target. However, robust memory, as demonstrated by capacity for rapid expansion of T cells responding to spike, is maintained at least several months after vaccination. This is consistent with the clinical observation of vaccine protection from severe illness lasting months. The level of such memory responsiveness required for clinical protection remains to be defined.
Association between inflammatory cytokines and symptoms of major depressive disorder in adults
Authors: Min Xue , Wang Genwei , Cui Yalian , Meng Peipei , Hu Xiaodong , Liu Sha , Wang Yanfang 
Published: February 2023

ObjectiveThis study investigated the association between inflammatory cytokines and major depressive disorder.MethodsPlasma biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). Statistical analysis of baseline biomarkers in the major depression disorder (MDD) group and healthy controls (HC) group, and differences in biomarkers before and after treatment. Spearman analysis was performed to correlate baseline and after treatment MDD biomarkers with the 17-item Hamilton Depression Rating Scale (HAMD-17) total scores. Receiver operator characteristic (ROC) curves were analyzed for the effect of biomarkers on MDD and HC classification and diagnosis.ResultsTumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were significantly higher in the MDD group than in the HC group, while high mobility group protein 1 (HMGB1) levels were significantly lower in the MDD group. The AUCs for HMGB1, TNF-α, and IL-6 were 0.375, 0.733, and 0.783, respectively, according to the ROC curves. MDD patients with brain-derived neurotrophic factor precursor (proBDNF) levels were positively correlated with total HAMD-17 scores. The levels of proBDNF levels were positively correlated with the total HAMD-17 score in male MDD patients, and brain-derived neurotrophic factor (BDNF) and interleukin 18 (IL-18) levels were negatively correlated with the total HAMD-17 score in female MDD patients.ConclusionInflammatory cytokines are associated with the severity of MDD, and TNF-α and IL-6 have the potential as objective biomarkers to aid in the diagnosis of MDD.
Alterations in the immune system persist after one year of convalescence in severe COVID-19 patients
Authors: Abarca-Zabalía Judith , González-Jiménez Adela , Calle-Rubio Myriam , López-Pastor Andrea R. , Fariña Tomás , Ramos-Acosta Carlos , Anguita Eduardo , Urcelay Elena , Espino-Paisán Laura 
Published: February 2023

IntroductionSevere COVID-19 originates a myriad of alterations in the immune system during active disease, especially in the T and NK cell compartments, but several studies in the last year have unveiled some alterations that persist in convalescence. Although most of the studies follow the participants for a short recovery time, studies following patients up to three or six months still find alterations. We aimed at evaluating changes in the NK, T and B cell compartments after severe COVID-19 in participants with a median recovery time of eleven months.MethodsEighteen convalescent of severe COVID-19 (CSC), 14 convalescent of mild COVID-19 (CMC) and nine controls were recruited. NKG2A, NKG2C, NKG2D and the activating receptor NKp44 were evaluated in NKbright, NKdim and NKT subpopulations. In addition, CD3 and CD19 were measured and a basic biochemistry with IL-6 levels was obtained.ResultsCSC participants showed lower NKbright/NKdim ratio, higher NKp44 expression in NKbright subpopulations, higher levels of serum IL-6, lower levels of NKG2A+ T lymphocytes and a trend to a lower expression of CD19 in B lymphocytes compared to controls. CMC participants showed no significant alterations in the immune system compared to controls.ConclusionsThese results are concordant with previous studies, which find alterations in CSC weeks or months after resolution of the symptoms, and point to the possibility of these alterations lasting one year or more after COVID-19 resolution.
Recent advances in addressing the market failure of new antimicrobials: Learnings from NICE's subscription-style payment model
Authors: Schurer Marieke , Patel Renu , van Keep Marjolijn , Horgan Jake , Matthijsse Suzette , Madin-Warburton Matthew 
Published: February 2023

BackgroundAntimicrobial resistance (AMR) is a growing threat to global health. With pathogenic bacteria inevitably becoming more resistant to existing antimicrobials, mortality and costs due to AMR will significantly increase over the next few decades if adequate action is not taken. A major challenge in addressing AMR is the lack of financial incentives for manufacturers to invest in developing new antimicrobials. This is partly because current approaches in health technology assessment (HTA) and standard modeling methods fail to capture the full value of antimicrobials.AimWe explore recent reimbursement and payment frameworks, particularly pull incentives, aimed to address the market failures in antimicrobials. We focus on the “subscription-style” payment model recently used in the UK and discuss the learnings for other European countries.MethodsA pragmatic literature review was conducted to identify recent initiatives and frameworks between 2012 and 2021, across seven European markets. The National Institute for Health and Care Excellence (NICE) technology appraisals for cefiderocol and for ceftazidime with avibactam were reviewed to evaluate how the new UK model has been applied in practice and identify the key challenges.ConclusionThe UK and Sweden are the first European countries to pilot the feasibility of implementing pull incentives through fully and partially delinked payment models, respectively. The NICE appraisals highlighted the complexity and large areas of uncertainty of modeling antimicrobials. If HTA and value-based pricing are part of the future in tackling the market failure in AMR, European-level efforts may be needed to overcome some of the key challenges.
Olfactory function changes and the predictive performance of the Chinese Smell Identification Test in patients with mild cognitive impairment and Alzheimer's disease
Authors: Mi Yan , Ma Xiaojuan , Du Shan , Du Chengxue , Li Xiaobo , Tan Huihui , Zhang Jie , Zhang Qi , Shi Wenzhen , Zhang Gejuan , Tian Ye 
Published: February 2023

ObjectivesOlfactory disorder is one of the sensory features that reflects a decline in cognitive function. However, olfactory changes and the discernibility of smell testing in the aging population have yet to be fully elucidated. Therefore, this study aimed to examine the effectiveness of the Chinese Smell Identification Test (CSIT) in distinguishing individuals with cognitive decline from those with normal aging and to determine whether the patients with MCI and AD show changes in their olfactory identification abilities.MethodsThis cross-sectional study included eligible participants aged over 50 years between October 2019 and December 2021. The participants were divided into three groups: individuals with mild cognitive impairment (MCI), individuals with Alzheimer's disease (AD), and cognitively normal controls (NCs). All participants were assessed using neuropsychiatric scales, the Activity of Daily Living scale, and the 16-odor cognitive state test (CSIT) test. The test scores and the severity of olfactory impairment were also recorded for each participant.ResultsIn total, 366 eligible participants were recruited, including 188 participants with MCI, 42 patients with AD, and 136 NCs. Patients with MCI achieved a mean CSIT score of 13.06 ± 2.05, while patients with AD achieved a mean score of 11.38 ± 3.25. These scores were significantly lower than those of the NC group (14.6 ± 1.57; P &lt; 0.001). An analysis showed that 19.9% of NCs exhibited mild olfactory impairment, while 52.7% of patients with MCI and 69% of patients with AD exhibited mild to severe olfactory impairment. The CSIT score was positively correlated with the MoCA and MMSE scores. The CIST score and the severity of olfactory impairment were identified as robust indicators for MCI and AD, even after adjusting for age, gender, and level of education. Age and educational level were identified as two important confounding factors that influence cognitive function. However, no significant interactive effects were observed between these confounders and CIST scores in determining the risk of MCI. The area under the ROC curve (AUC) generated from the ROC analysis was 0.738 and 0.813 in distinguishing patients with MCI and patients with AD from NCs based on the CIST scores, respectively. The optimal cutoff for distinguishing MCI from NCs was 13, and for distinguishing AD from NCs was 11. The AUC for distinguishing AD from MCI was 0.62.ConclusionsThe olfactory identification function is frequently affected in patients with MCI and patients with AD. CSIT is a beneficial tool for the early screening of cognitive impairment among elderly patients with cognitive or memory issues.
Efficacy and safety of a biomarker-driven cetuximab-based treatment regimen over 3 treatment lines in mCRC patients with RAS/BRAF wild type tumors at start of first line: The CAPRI 2 GOIM trial
Authors: Martini Giulia , Ciardiello Davide , Napolitano Stefania , Martinelli Erika , Troiani Teresa , Latiano Tiziana Pia , Avallone Antonio , Normanno Nicola , Di Maio Massimo , Maiello Evaristo , Ciardiello Fortunato 
Published: February 2023

BackgroundMonoclonal antibodies targeting EGFR such as cetuximab or panitumumab represent a major step forward in the treatment of RAS wild type (WT) metastatic colorectal cancer (mCRC). Unfortunately, primary and acquired resistance mechanisms occur, with a huge percentage of patients succumbing to the disease. In the last years, RAS mutation has been identified as the main molecular driver that determine resistance to anti-EGFR monoclonal antibodies. Liquid biopsy analysis allows to a dynamic and longitudinal assessment of mutational status during mCRC disease and has provided important information on the use of anti-EGFR drugs beyond progression or as rechallenge strategy in patients with RAS WT tumors.MethodsThe phase II CAPRI 2 GOIM trial investigates the efficacy and safety of a bio-marker-driven cetuximab-based treatment regimen over 3 treatment lines in mCRC patients with RAS/BRAF WT tumors at start of first line.DiscussionThe aim of the study is to identify patients with RAS/BRAF WT tumors defined as “addicted” to an-anti EGFR based treatment along three lines of therapy. Moreover, the trial will evaluate the activity of cetuximab re-introduction in combination with irinotecan as 3rd line therapy as rechallenge for patients that will be treated in second line with FOLFOX plus bevacizumab, having a RAS/BRAF mutant disease at progression after FOLFIRI plus cetuximab first line. A novel characteristic of this program is that the therapeutic algorithm will be defined at each treatment decision (first line, second line and third line) in a prospective fashion in each patient by a liquid biopsy assessment of RAS/BRAF status by a comprehensive 324 genes Foundation One Liquid assay (Foundation/Roche).Trial registrationEudraCT Number: 2020-003008-15, ClinicalTrials.gov identifier: NCT05312398.
Burnout syndrome, doctor-patient relationship and family support of pediatric medical staff during a COVID-19 Local outbreak in Shanghai China: A cross-sectional survey study
Authors: Lyu Baiyu , Xu Meijia , Lu Lijuan , Zhang Xiaoying 
Published: February 2023

ObjectivesTo explore burnout syndrome (BOS) incidence, doctor-patient relationship, and family support on pediatric medical staff in Shanghai comprehensive hospitals during a COVID-19 local outbreak.MethodsA cross-sectional survey of pediatric medical staff from 7 comprehensive hospitals across Shanghai was conducted from March to July 2022. The survey included BOS, doctor-patient relationships, family support, and the related factors of COVID-19. The T-test, variance, the LSD-t test, Pearson's r correlation coefficient, and multiple regression analyses examined the data.ResultsUsing Maslach Burnout Inventory-General Survey (MBI-GS), 81.67% of pediatric medical staff had moderate BOS, and 13.75% were severe. The difficult doctor-patient relationship was positively correlated with emotional exhaustion(EE), cynicism(Cy), and negatively with personal accomplishment(PA). When medical staff need help, the greater the support provided by the family, the lower the EE and CY, and the higher the PA.Conclusion“In our study, the pediatric medical staff in Shanghai comprehensive hospitals had significant BOS during a COVID-19 local outbreak.” We provided the potential steps that can be taken to reduce the increasing rate of BOS in pandemics. These measures include increased job satisfaction, psychological support, maintaining good health, increased salary, lower intent to leave the profession, regularly carrying out COVID-19 prevention training, improving doctor-patient relations, and strengthening family support.
Factors influencing plasma concentration of voriconazole and voriconazole- N-oxide in younger adult and elderly patients
Authors: Cheng Lin , Liang Zaiming , Liu Fang , Lin Ling , Zhang Jiao , Xie Linli , Yu Mingjie , Sun Fengjun 
Published: February 2023

Background: Voriconazole (VCZ) metabolism is influenced by many factors. Identifying independent influencing factors helps optimize VCZ dosing regimens and maintain its trough concentration (C0) in the therapeutic window.Methods: We conducted a prospective study investigating independent factors influencing VCZ C0 and the VCZ C0 to VCZ N-oxide concentration ratio (C0/CN) in younger adults and elderly patients. A stepwise multivariate linear regression model, including the IL-6 inflammatory marker, was used. The receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive effect of the indicator.Results: A total of 463 VCZ C0 were analyzed from 304 patients. In younger adult patients, the independent factors that influenced VCZ C0 were the levels of total bile acid (TBA) and glutamic-pyruvic transaminase (ALT) and the use of proton-pump inhibitors. The independent factors influencing VCZ C0/CN were IL-6, age, direct bilirubin, and TBA. The TBA level was positively associated with VCZ C0 (ρ = 0.176, p = 0.019). VCZ C0 increased significantly when the TBA levels were higher than 10 μmol/L (p = 0.027). ROC curve analysis indicated that when the TBA level ≥4.05 μmol/L, the incidence of a VCZ C0 greater than 5 μg/ml (95% CI = 0.54–0.74) (p = 0.007) increased. In elderly patients, the influencing factors of VCZ C0 were DBIL, albumin, and estimated glomerular filtration rate (eGFR). The independent factors that affected VCZ C0/CN were eGFR, ALT, γ-glutamyl transferase, TBA, and platelet count. TBA levels showed a positive association with VCZ C0 (ρ = 0.204, p = 0.006) and C0/CN (ρ = 0.342, p &lt; 0.001). VCZ C0/CN increased significantly when TBA levels were greater than 10 μmol/L (p = 0.025). ROC curve analysis indicated that when the TBA level ≥14.55 μmol/L, the incidence of a VCZ C0 greater than 5 μg/ml (95% CI = 0.52–0.71) (p = 0.048) increased.Conclusion: TBA level may serve as a novel marker for VCZ metabolism. eGFR and platelet count should also be considered when using VCZ, especially in elderly patients.
Positive allosteric GABAA receptor modulation counteracts lipotoxicity-induced gene expression changes in hepatocytes in vitro
Authors: Rohbeck Elisabeth , Niersmann Corinna , Köhrer Karl , Wachtmeister Thorsten , Roden Michael , Eckel Jürgen , Romacho Tania 
Published: February 2023

Introduction: We have previously shown that the novel positive allosteric modulator of the GABAA receptor, HK4, exerts hepatoprotective effects against lipotoxicity-induced apoptosis, DNA damage, inflammation and ER stress in vitro. This might be mediated by downregulated phosphorylation of the transcription factors NF-κB and STAT3. The current study aimed to investigate the effect of HK4 on lipotoxicity-induced hepatocyte injury at the transcriptional level.Methods: HepG2 cells were treated with palmitate (200 μM) in the presence or absence of HK4 (10 μM) for 7 h. Total RNA was isolated and the expression profiles of mRNAs were assessed. Differentially expressed genes were identified and subjected to the DAVID database and Ingenuity Pathway Analysis software for functional and pathway analysis, all under appropriate statistical testing.Results: Transcriptomic analysis showed substantial modifications in gene expression in response to palmitate as lipotoxic stimulus with 1,457 differentially expressed genes affecting lipid metabolism, oxidative phosphorylation, apoptosis, oxidative and ER stress among others. HK4 preincubation resulted in the prevention of palmitate-induced dysregulation by restoring initial gene expression pattern of untreated hepatocytes comprising 456 genes. Out of the 456 genes, 342 genes were upregulated and 114 downregulated by HK4. Enriched pathways analysis of those genes by Ingenuity Pathway Analysis, pointed towards oxidative phosphorylation, mitochondrial dysregulation, protein ubiquitination, apoptosis, and cell cycle regulation as affected pathways. These pathways are regulated by the key upstream regulators TP53, KDM5B, DDX5, CAB39 L and SYVN1, which orchestrate the metabolic and oxidative stress responses including modulation of DNA repair and degradation of ER stress-induced misfolded proteins in the presence or absence of HK4.Discussion: We conclude that HK4 specifically targets mitochondrial respiration, protein ubiquitination, apoptosis and cell cycle. This not only helps to counteract lipotoxic hepatocellular injury through modification of gene expression, but - by targeting transcription factors responsible for DNA repair, cell cycle progression and ER stress - might even prevent lipotoxic mechanisms. These findings suggest that HK4 has a great potential for the treatment of non-alcoholic fatty liver disease (NAFLD).
Prevalence of psychosocial work factors and stress and their associations with the physical and mental health of hospital physicians: A cross-sectional study in Lithuania
Authors: Zutautiene Rasa , Kaliniene Gintare , Ustinaviciene Ruta , Radisauskas Ricardas 
Published: February 2023

BackgroundA negative psychosocial work environment causes stress to the physicians of healthcare institutions, which affect their physical and mental health. This study aimed to evaluate the prevalence of psychosocial work factors and stress and their associations with the physical and mental health of hospital physicians in the Kaunas region of Lithuania.Materials and methodsA cross-sectional study was performed. It was based on a questionnaire survey, which contained the Job Content Questionnaire (JCQ), three scales of Copenhagen Psychosocial Questionnaire (COPSOQ), and Medical Outcomes Study Short Form-36 (SF-36) health survey. The study was carried out in 2018. A total of 647 physicians completed the survey. Multivariate logistic regression models were performed by using the stepwise method. In the models potentially, confounding factors such as age and gender were controlled. In our study, the dependent variables were stress dimensions, and the independent variables were psychosocial work factors.ResultsThe analysis showed that a quarter of surveyed physicians were classified as having low job skill discretion and decision-making authority, and the support of supervisors was weak. Approximately one-third of the respondents had low decision latitude, low co-worker support, and high job demands, and felt insecure at work. Job insecurity and gender were found to be the strongest independent variables for general and cognitive stress. The support of the supervisor was found as a significant factor in the case of somatic stress. Better evaluation of mental health was related to job skill discretion and co-workers' and supervisors' support, but it did not affect physical health.ConclusionThe confirmed associations suggest that looking at work organization factors, reducing exposure to stress, and increasing perception of the psychosocial environment can be linked to better subjective health evaluation.