Chimeric antigen receptor (CAR) T cell therapy holds enormous potential for the treatment of hematologic malignancies. Despite its benefits, it is still used as a second line of therapy, mainly ...because of its severe side effects and patient unresponsiveness. Numerous researchers worldwide have attempted to identify effective predictive biomarkers for early prediction of treatment outcomes and adverse effects in CAR T cell therapy, albeit so far only with limited success. This review provides a comprehensive overview of the current state of predictive biomarkers. Although existing predictive metrics correlate to some extent with treatment outcomes, they fail to encapsulate the complexity of the immune system dynamics. The aim of this review is to identify six major groups of predictive biomarkers and propose their use in developing improved and efficient prediction models. These groups include changes in mitochondrial dynamics, endothelial activation, central nervous system impairment, immune system markers, extracellular vesicles, and the inhibitory tumor microenvironment. A comprehensive understanding of the multiple factors that influence therapeutic efficacy has the potential to significantly improve the course of CAR T cell therapy and patient care, thereby making this advanced immunotherapy more appealing and the course of therapy more convenient and favorable for patients.
The immune system has a known role in the aetiology, progression and final treatment outcome of oral squamous cell cancers. The aim of this study was to evaluate the influence of radical surgery and ...radiotherapy on advanced oral squamous cell carcinoma blood counts, lymphocyte subsets and levels of acute inflammatory response markers.
Blood samples were obtained from 56 patients 5 days before and 10 days after surgery, 30 days and 1 year after radiotherapy. The whole blood count, lymphocyte subsets and inflammatory response markers (C-reactive protein, erythrocyte sedimentation rate, leukocyte count, expression of index CD64 and index CD163 on neutrophils and monocytes) were measured, statistically analysed and correlated with clinical treatment outcomes.
The post-operative period was characterised by the onset of anaemia, thrombocytosis, lymphopenia with reduced B lymphocyte, T helper cell and NK cell counts, and a rise in acute phase reactants. Immediately after radiotherapy, the anaemia improved, the lymphopenia worsened, and thrombocyte levels returned to pre-treatment values. There was a drop in counts across the T and B cell lines, including a reduction in B lymphocytes, naïve and memory T cells with reduced CD4+ and CD8+ counts and a decreased CD4/CD8 ratio. One year after radiotherapy all the lymphocyte subsets remained depressed, the only exception being NK cells, whose levels returned to pre-treatment values.
We concluded that surgery resulted in a stronger acute phase response than radiotherapy, while radiotherapy caused a long-lasting reduction in lymphocyte counts. There was no correlation between any of the pre-treatment parameters and the clinical outcome.
The COVID-19 pandemic caused a massive healthcare crisis. To investigate what makes healthcare system resilient and physicians better at coping during a crisis situation, our study investigated the ...role risk exposure, such as working at COVID-19 entry points, sleep, and perceived work safety played in reducing negative psychological functioning at work, as well as their effects on adverse and potentially fatal incidences of compromised safety and medical errors.
Our study included a representative sample of 1,189 physicians, from all 12 Slovenian regions and all medical occupations, as registered by the Medical Chamber of Slovenia. For the purposes of this study, a Questionnaire of Sleep and Psychological Functioning at Work was developed in the form of an online retrospective self-report. Additionally, our study included items assessing physicians perceived work safety and frequency of negative outcomes (compromised safety and medical errors) during the first month of the Covid-19 epidemic.
Physicians working at COVID-19 entry points were more likely to experience night awakening, slept less than 5 h per night, experience nightmares, and had lower levels of psychological functioning in comparison to other physicians. Both hypothesized models showed adequate fit. A higher score on the sleep scale (sleep quantity, sleep quality, and shorter sleep latency) has been shown to predict lower levels of negative psychological functioning at work and, indirectly, reduced incidences of compromised safety and medical errors. Contrary to our expectations, no significant direct effect of sleep on compromised safety and medical errors was found. When perceived work safety was added into the model, the model showed improved fit, with perceived work safety predicting better sleep, less negative psychological functioning at work, and less compromised safety.
Sleep and safety both play an important role in reducing negative psychological functioning at work and, by doing so, decreasing the negative and potentially fatal incidents during the pandemic, such as compromised safety and medical errors. Further, research is needed to see how medical guidelines can be updated to ensure physicians sleep and that their safety is protected.
To evaluate whether DNA fragmentation and/or mitochondrial membrane potential (MMP) predict natural conception better than standard sperm parameters.
Prospective cross-sectional study.
University ...medical center.
Eighty-five infertile and 51 fertile men.
Assessment of sperm DNA fragmentation, MMP, and standard semen parameters over a 6- to 12-month observation period.
Comparison between the results of DNA fragmentation, MMP, and standard sperm parameters alone or combined and achievement of natural conception.
Twenty-six of the 85 (31%) men from infertile couples conceived naturally. The median values of DNA fragmentation and MMP in the men who conceived within the observation period were similar to those in the fertile controls. Optimal threshold values of DNA fragmentation and MMP were 25% as determined by receiver operating characteristic analysis (area under the curve AUC, 0.70; 95% confidence interval (CI) 0.58-0.82) and 62.5% (AUC, 0.68, 95% CI 0.56-0.80), respectively. The men in the infertile group with values of DNA fragmentation ≤25% and with MMP values ≥62.5% had significantly higher odds for conception (odds ratio OR, 5.22; 95% CI 1.82-14.93 and OR, 4.67; 95% CI 1.74-12.5, respectively). Normal semen analysis alone had no predictive value for natural conception (OR, 1.84; 95% CI 0.67-5.07). Both sperm function tests combined had significant odds for natural conception (OR, 8.24; 95% CI 2.91-23.33), with a probability of 0.607 (60.7%) for both normal values and 0.158 (15.8%) for abnormal values.
Sperm DNA fragmentation and MMP combined may be superior to standard semen parameters for the prediction of natural conception.
The aim of the study was to address the working population with an occupational stress prevention program using mHealth solution and encourage them for healthy lifestyle choices.
Seventeen ...participants were randomized from the corporate setting. A 24alife app with a good compliance program was selected. Test battery has been designed to test the physical readiness, psychological evaluation and biological blood markers for stress. Participants were followed up after 30, 60 and 90 days, respectively, within the intervention period. Weight of participants was tracked three times per month. Univariate analysis compared the continuous variables by One-Way Repeated-Measures ANOVA test when the data were normally distributed, or Wilcoxon rank sum test for abnormal distribution of variables.
Participants used the app with a compliance rate of 94.1%. The psychological evaluation revealed higher motivation for work, lower burnout scores and participants gave subjective responses of better general wellbeing. Some of the participants lost up to four kg of body mass. Physical readiness has also improved.
Results of mHealth projects on corporate could include primary health care institutions and health ministry to extend the existing system to patients' pockets where they can monitor their disease and increase the ability of self-care.
Group B Streptococcus (GBS) is the leading cause of invasive neonatal disease in the industrialized world. We aimed to genomically and phenotypically characterise invasive GBS isolates in Slovenia ...from 2001 to 2018 and contemporary colonising GBS isolates from screening cultures in 2018.
GBS isolates from 101 patients (invasive isolates) and 70 pregnant women (colonising isolates) were analysed. Basic clinical characteristics of the patients were collected from medical records. Antimicrobial susceptibility and phenotypic capsular serotype were determined. Whole-genome sequencing was performed to assign multilocus sequence types (STs), clonal complexes (CCs), pathogenicity/virulence factors, including capsular genotypes, and genome-based phylogeny.
Among invasive neonatal disease patients, 42.6% (n = 43) were females, 41.5% (n = 39/94) were from preterm deliveries (< 37 weeks gestation), and 41.6% (n = 42) had early-onset disease (EOD). All isolates were susceptible to benzylpenicillin with low minimum inhibitory concentrations (MICs; ≤0.125 mg/L). Overall, 7 serotypes were identified (Ia, Ib, II-V and VIII); serotype III being the most prevalent (59.6%). Twenty-eight MLST STs were detected that clustered into 6 CCs. CC-17 was the most common CC overall (53.2%), as well as among invasive (67.3%) and non-invasive (32.9%) isolates (p < 0.001). CC-17 was more common among patients with late-onset disease (LOD) (81.4%) compared to EOD (47.6%) (p < 0.001). The prevalence of other CCs was 12.9% (CC-23), 11.1% (CC-12), 10.5% (CC-1), 8.2% (CC-19), and 1.8% (CC-498). Of all isolates, 2.3% were singletons.
A high prevalence of hypervirulent CC-17 isolates, with low genomic diversity and characteristic profile of pathogenicity/virulence factors, was detected among invasive neonatal and colonising GBS isolates from pregnant women in Slovenia. This is the first genomic characterisation of GBS isolates in Slovenia and provides valuable microbiological and genomic baseline data regarding the invasive and colonising GBS population nationally. Continuous genomic surveillance of GBS infections is crucial to analyse the impact of IND prevention strategies on the population structure of GBS locally, nationally, and internationally.
There is insufficient knowledge about how aerobic exercise impacts the disease process of multiple sclerosis, which is characterized by accumulation of white matter lesions and accelerated brain ...atrophy.
To examine the effect of aerobic exercise on neuroinflammation and neurodegeneration by magnetic resonance imaging and clinical measures of disease activity and progression in persons with multiple sclerosis.
An exploratory 12-week randomized control trial including an intervention group (n = 14, 12 weeks of aerobic exercise twice weekly) and a control group (n = 14, continuation of usual lifestyle). Primary outcomes were magnetic resonance imaging measures (lesion load, brain structure volume change), while secondary outcomes included disability measures, blood cytokine levels, cognitive tests and patient-reported outcomes.
The effects of aerobic exercise on whole brain and grey matter atrophy were minor. Surprisingly, the observed effect on volume (atrophy) in selected brain substructures was heterogeneous. Putaminal and posterior cingulate volumes decreased, parahippocampal gyrus volume increased, thalamus and amygdala volume remained the same, and active lesion load and count decreased. However, apart from weak improvements in walking speed and brain-derived neurotrophic factor levels, there was no effect of aerobic exercise on other clinical, cognitive or patient-reported outcomes.
These results suggest that aerobic exercise in persons with multiple sclerosis has a positive effect on the volume of some of the substructures of the brain, possibly indicating a slowing of the neurodegenerative process in these regions, but a negative impact on the volume of some other substructures, with unclear implications. Further research is needed to determine whether the slight decrease in active lesion volume and count implies an anti-inflammatory effect of aerobic exercise, and the exact significance of the heterogeneous results of volumetric assessments.
(Group B
, GBS), a Gram-positive commensal in healthy adults, remains a major cause of neonatal infections, usually manifesting as sepsis, meningitis, or pneumonia. Intrapartum antibiotic prophylaxis ...has greatly reduced the incidence of early-onset disease. However, given the lack of effective measures to prevent the risk of late-onset disease and invasive infections in immunocompromised individuals, more studies investigating the GBS-associated pathogenesis and the interplay between bacteria and host immune system are needed.
Here, we examined the impact of 12 previously genotyped GBS isolates belonging to different serotypes and sequence types on the immune response of THP-1 macrophages.
Flow cytometry analysis showed isolate-specific differences in phagocytic uptake, ranging from 10% for isolates of serotype Ib, which possess the virulence factor protein β, to over 70% for isolates of serotype III. Different isolates also induced differential expression of co-stimulatory molecules and scavenger receptors with colonizing isolates inducing higher expression levels of CD80 and CD86 compared to invasive isolates. In addition, real-time measurements of metabolism revealed that macrophages enhanced both glycolysis and mitochondrial respiration after GBS infection, with isolates of serotype III being the most potent activators of glycolysis and glycolytic ATP production. Macrophages also showed differential resistance to GBS-mediated cell cytotoxicity as measured by LDH release and real-time microscopy. The differences were evident both between serotypes and between isolates obtained from different specimens (colonizing or invasive isolates) demonstrating the higher cytotoxicity of vaginal compared with blood isolates.
Thus, the data suggest that GBS isolates differ in their potential to become invasive or remain colonizing. In addition, colonizing isolates appear to be more cytotoxic, whereas invasive isolates appear to exploit macrophages to their advantage, avoiding the immune recognition and antibiotics.
Background
Data on alterations in peripheral blood lymphocyte (PBL) subtypes in dogs with myxomatous mitral valve disease (MMVD) is lacking.
Objectives
To investigate PBL subtypes and their ...correlation with parameters of inflammation and MMVD progression markers in dogs with different stages of MMVD.
Animals
Seventy‐eight client‐owned dogs: 65 with MMVD (American College of Veterinary Internal Medicine ACVIM classification stages B2, C, and D) and 13 healthy controls.
Methods
Prospective cross‐sectional study. Complete cardiac assessment, flow cytometry (T lymphocytes CD3+, their subtypes CD3+CD4+, CD3+CD8+, CD3+CD4+CD8+, CD3+CD4−CD8−, and B lymphocytes CD45+CD21+) and measurement of N‐terminal pro B‐type natriuretic peptide, cardiac troponin I, and C‐reactive protein concentrations were performed.
Results
The percentage of CD3+CD4+ lymphocytes was significantly lower in stable ACVIM C patients (P = .01) and unstable ACVIM C and D patients (P = .003), the percentage of CD3+CD8+ lymphocytes was significantly higher in stable ACVIM C patients (P = .01) and unstable ACVIM C and D patients (P = .01), CD3+CD8+ lymphocyte concentration was significantly higher in unstable ACVIM C and D patients (P = .05), and the CD3+CD4+/CD3+CD8+ ratio was significantly lower in stable ACVIM C patients (P = .01) and unstable ACVIM C and D patients (P = .01) compared with healthy controls.
Conclusions and Clinical Importance
The percentages of CD3+CD4+ and CD3+CD8+ PBL and CD4+/CD8+ ratio were altered in MMVD dogs with congestive heart failure (ACVIM C, D), but not in ACVIM B2, suggesting involvement of these PBL subtypes in the pathogenesis of congestive heart failure in dogs with MMVD.
Aicardi-Goutières syndrome (AGS) is a genetically determined early-onset progressive encephalopathy caused by mutations leading to overexpression of type I interferon (IFN) and resulting in various ...clinical phenotypes. A gain-of-function (GOF) mutation in the
gene is associated with robust production of type I IFN and activation of the Janus kinase (JAK) signal transducer and activator of the transcription (STAT) pathway, which can cause AGS type 7. We detail the clinical case of an infant who initially presented with
pneumonia (PCP), had recurrent respiratory infections, and was later treated with a JAK inhibitor, baricitinib, because of a genetically confirmed GOF mutation in the
gene. This spectrum of
GOF mutations with overlapping features of hyperinflammation and severe opportunistic infection, which mimics combined immunodeficiency (CID), has not been described before. In this case, therapy with baricitinib effectively blocked IFN-α activation and reduced STAT1 signaling but had no effect on the progression of the neurological disease.
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