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20 p.-9 fig.-2 tab., Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. The 5-year survival rate of CRC patients depends on the stage at diagnosis, being higher than 80% when CRC is diagnosed in the early stages but lower than 10% when CRC is diagnosed in advanced stages. Autoantibodies against specific CRC autoantigens (tumor-associated antigens (TAAs)) in the sera of patients have been widely demonstrated to aid in early diagnosis. Thus, we herein aim to identify autoantigens target of autoantibodies specific to CRC that possess a significant ability to discriminate between CRC patients and healthy individuals by means of liquid biopsy. To that end, we examined the protein content of the exosomes released by five CRC cell lines and tissue samples from CRC patients by means of immunoprecipitation coupled with mass spectrometry analysis. A total of 103 proteins were identified as potential autoantigens specific to CRC. After bioinformatics and meta-analysis, we selected 15 proteins that are more likely to be actual CRC autoantigens in order to evaluate their role in CRC prognosis by Western blot (WB) and immunohistochemistry (IHC). We found dysregulation at the protein level for 11 of these proteins in both tissue and plasma exosome samples from patients, along with an association of nine of these proteins with CRC prognosis. After validation, all but one showed a statistically significant high diagnostic ability to distinguish CRC patients and individuals with premalignant lesions from healthy individuals, either by luminescence Halotag-based beads, or by a multiplexed biosensing platform involving the use of magnetic microcarriers as solid support modified with covalently immobilized Halotag fusion proteins constructed for CRC detection. Taken together, our results highlight the usefulness of the approach defined here to identify the TAAs specific to chronic diseases; they also demonstrate that the measurement of autoantibody levels in plasma against the TAAs identified here could be integrated into a point-of-care (POC) device for CRC detection with high diagnostic ability., This work was supported by the financial support of the PI17CIII/00045 and PI20CIII/00019 grants from the AES-ISCIII program to R.B. The financial support of the PID2019-103899RB-I00 (Ministerio de Ciencia e Innovación) Research Project and the TRANSNANOAVANSENS-CM Program from the Comunidad de Madrid (S2018/NMT-4349) to S.C. are gratefully acknowledged. G.D. acknowledges the financial support of PI15/00246 grant of the FIS and Cátedra UAM-Roche en Medicina de Innovación. The FPU predoctoral contract to A.M-C. is supported by the Spanish Ministerio de Educación, Cultura y Deporte. G.S-F. is recipient of a predoctoral contract (1193818N) supported by The Flanders Research Foundation (FWO). M.A-N. was supported by a contract of the Programa Operativo de Empleo Juvenily la Iniciativa de Empleo Juvenil (YEI) with the participation of the Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid y del Fondo Social Europeo. The predoctoral contract from the Spanish Ministerio de Economía y Competitividad (BES-2016-076606, E.P.) and Talento-Contract from Comunidad de Madrid (2019-T2/IND-15965, R.M.T-R.) are also gratefully acknowledged.

Background The majority of fetal structural defects can be detected in the second trimester, thus this is the main time for screening for structural defects. 3D imaging of the fetal brain does not create a common part of this screening. Methods This prospective observational study was conducted at the Fetal Medicine Center of The Gynecological-Obstetrical Department of the University Hospital Olomouc in years 2017- 2020. The study sample was 451 consecutively scanned morphologically normal fetuses attending for routine second trimester anatomical survey at 20-22 weeks of pregnancy. A transabdominal 3D ultrasound volume acquisition of fetal brain was obtained from an axial and sagittal plane using skull sutures as an acoustic window. Results Both the corpus callosum (CC) and the vermis (VC) were detected in 51.7% of examinations in the sagittal plane, and in 31.7% in the axial plane. In 61.9% of the examinations, there was at least partial detection in both planes. Maternal BMI was found to be the only significant predictor of the quality of imaging in both planes. Conclusion 3D acquisition of fetal brain images in the sagittal plane followed by manipulation of acquired volume was valuable in assessment of corpus callosum and cerebellar vermis. This allows reconstruction of the sagittal plane that can be difficult to obtain in 2D imaging.

Purpose: Aim was to analyze demographic and tumor characteristics, treatment, and survival of patients with lung cancer younger than 40 years of age (U40) compared to older subgroups (41–70 and >70...

The treatment of coronary artery disease (CAD), which is defined by stable anatomical atherosclerotic and functional alterations of epicardial vessels or microcirculation, focuses on managing intermittent angina symptoms and preventing major adverse cardiovascular events with optimal medical therapy. When patients with known CAD present with angina and no acute coronary syndrome, they have historically been evaluated with a variety of noninvasive stress tests that utilize electrocardiography, radionuclide scintigraphy, echocardiography, or magnetic resonance imaging for determining the presence and extent of inducible myocardial ischemia. Patient event-free survival, however, is largely driven by the coronary atherosclerotic disease burden, which is not directly assessed by functional testing. Direct evaluation of coronary atherosclerotic disease by coronary computed tomography angiography (coronary CTA) has emerged as the first line noninvasive imaging modality as it improves diagnostic accuracy and positively influences clinical management. Compared to functional assessment of CAD, coronary CTA-guided management results in improved patient outcomes by facilitating prevention of myocardial infarction. Other strengths of coronary CTA include detailed atherosclerotic plaque characterization and the ability to assess functional significance of specific lesions, which may further improve risk assessment and prognosis and lead to more appropriate referrals for additional testing, such as invasive coronary angiography.

Multiple myeloma (MM) measurable residual disease (MRD) persisting after treatment is an adverse prognostic factor for progression free survival (PFS) and overall survival.1Genomic mutations occurred in the remaining clonal aberrant plasma cells (A-PCs) are linked to the development of drug resistance and disease relapse.2 Thus, personalised treatment based on the genomic profile of MRD could be highly beneficial and ultimately increase patients’ survival. However, while large-scale sequencing studies have characterised the genome of many malignancies including MM,3–8 the genomic mutations present in MM MRD are at the beginning of investigation.9 Here, we set up an exome sequencing analysis to identify genomic mutations characteristic for MM MRD and explore if they could mediate drug response, resistance or disease progression.

The incidence of cutaneous malignant melanoma is increasing worldwide. While the treatment of initial stages of the disease is simple, the advanced disease frequently remains fatal despite novel therapeutic options . This requires identification of novel therapeutic targets in melanoma. Similarly to other types of tumours, the cancer microenvironment plays a prominent role and determines the biological properties of melanoma. Importantly, melanoma cell-produced exosomes represent an important tool of intercellular communication within this cancer ecosystem. We have focused on potential differences in the activity of exosomes produced by melanoma cells towards melanoma-associated fibroblasts and normal dermal fibroblasts. Cancer-associated fibroblasts were activated by the melanoma cell-produced exosomes significantly more than their normal counterparts, as assessed by increased transcription of genes for inflammation-supporting cytokines and chemokines, namely IL-6 or IL-8. We have observed that the response is dependent on the duration of the stimulus via exosomes and also on the quantity of exosomes. Our study demonstrates that melanoma-produced exosomes significantly stimulate the tumour-promoting proinflammatory activity of cancer-associated fibroblasts. This may represent a potential new target of oncologic therapy .

Background/aim LUCAS is a clinical lung cancer registry (ClinicalTrials.gov identifier is NCT04228237), prospectively collecting data from newly diagnosed lung cancer patients in seven pneumooncology centers in the Czech Republic, since June 1, 2018. The aim of the study was to assess the stage of the disease at the time of diagnosis, percentage of morphological types, survival, percentage of driving mutations, eligibility for radical surgery, and percentage of patients who undergo radical surgery, in the non-smoking population in comparison with smokers and former smokers. Patients and methods The total number of patients in the registry at the time of the analysis was 2,743. Only 2,439 patients with complete records (smoking status, stage, and type of tumor) were included in this study. Results The analysis indicated that non-smokers are diagnosed at a later stage of the disease but they have a better survival rate than smokers. Fewer smokers with stage III disease who are eligible for radical surgery will undergo surgery compared to non-smokers with the same clinical stage. Driving mutations are more common in non-smokers, even after adjustment for the more frequent occurrence of adenocarcinoma in the group of non-smokers. Conclusion The data from LUCAS registry are consistent with already known facts, suggesting that the LUCAS registry is a useful clinical tool.

Background/aim Per literature, patients with epidermal growth factor receptor (EGFR) exon-20 insertions respond poorly to tyrosine kinase inhibitors (TKIs). This study analyzed real-world data to examine the prognostic and predictive value of these mutations. Patients and methods We conducted a retrospective cohort study using Czech TULUNG Registry data, with data on multiple mutation types, collected in 2011-2020. Results We analyzed 554 (95.85%) patients with EGFR exon-19 deletions or exon-21 L858R substitutions and 24 (4.15%) patients with exon-20 insertions who received first-line high-value therapies. We summarized clinical characteristics and outcomes in all patients and by cohort. The risk of progression was statistically significantly higher (86%) in the exon-20 insertion cohort compared to the cohort with other mutations. Although not statistically significant, the risk of death was 44% higher in patients with exon-20 insertions. Conclusion Advanced NSCLC patients with rare EGFR exon-20 insertions have a high risk of progression.

In Western societies, human existence and illness are mostly constructed from the perspective of mind-body dualism: body and mind are considered to function independently, and the body/the physical as primary and more real. Research shows, however, that mind-body dualism is no longer tenable, especially in healthcare contexts. This led to the rise the biopsychosocial model, in which bodily experiences, including illness, are seen an interplay of the physical and the psychological, and the social. This model is the current gold standard for treating chronic pain. As these perspectives on the body and illness are potentially conflicting, and discursively constructed, this paper examines whether they are a source of misalignment in interactions between chronic pain patients and their doctors in a pain clinic. The analysis shows these perspectives indeed lead to misalignment, for instance when discussing the relevance of psychotherapy, and lead to intricate uses of argumentative resources to account for the differing perspectives on (the treatment of) pain.

BACKGROUND Despite the high prevalence of depression and anxiety in chronic pain conditions, current knowledge concerning emotional distress among painful diabetic polyneuropathy (pDSPN) and other diabetes mellitus (DM) sufferers is limited. METHODS This observational multicentre cohort study employed the Hospital Anxiety and Depression Scale, the Beck Depression Inventory II and the State-Trait Anxiety Inventory to assess symptoms of depression and anxiety in several groups with diabetes, as well as in a control group. The study cohort included 347 pDSPN patients aged 63.4 years (median), 55.9% males; 311 pain-free diabetic polyneuropathy (nDSPN) patients aged 63.7 years, 57.9% males; 50 diabetes mellitus (DM) patients without polyneuropathy aged 61.5 years, 44.0% males; and 71 healthy controls (HC) aged 63.0 years, 42.3% males. The roles played in emotional distress were explored in terms of the biological, the clinical (diabetes-, neuropathy- and pain-related), the socio-economic and the cognitive factors (catastrophizing). RESULTS The study disclosed a significantly higher prevalence of the symptoms of depression and anxiety not only in pDSPN (46.7% and 60.7%, respectively), but also in patients with nDSPN (24.4% and 44.4%) and DM without polyneuropathy (22.0% and 30.0%) compared with HCs (7.0% and 14.1%, p

Background Human papillomavirus (HPV) has been shown to adversely affect human reproduction. We aimed to evaluate the prevalence of human papillomavirus (HPV) infection in men and its correlation with semen parameters and reproductive outcomes. Methods Semen samples and penile swabs were collected from potential sperm donors (SD, n = 97) and male partners of infertile couples (IM, n = 328). The presence of HPV DNA in semen samples and penile swabs was analyzed. Associations between hrHPV positive status and fertility outcomes as well as socio-behavioral and health characteristics were evaluated using the R software package. Results High-risk HPV (hrHPV) genotypes were detected in 28.9% of SD and 35.1% of IM (P = 0.312). Penile swabs were more frequently positive for hrHPV genotypes than semen samples in both IM (32.3% vs. 11.9%, P P = 0.006). Men with hrHPV positive semen samples had lower semen volume (median volume 2.5 ml vs. 3 ml, P = 0.009), sperm concentration (median concentration 16 × 106/ml vs. 31 × 106/ml, P = 0.009) and total sperm count (median count 46 × 106 vs. 82 × 106, P = 0.009) than men with hrHPV negative samples. No association was identified between penile hrHPV status and semen parameters. Conclusions Our findings indicate that penile HPV infection is common in both potential sperm donors and men from infertile couples. Although HPV positivity is higher in penile swabs, only HPV infection in semen samples affects sperm parameters. However, there was no association between hrHPV positivity in semen and fertility outcomes including abortion rate.

The study aims to evaluate the monitoring of risk factors of cardiovascular diseases in the young population, which significantly contribute to the origin and development of cardiovascular diseases, such as peripheral artery diseases, atherosclerosis, stroke, and others. We focused on a group of young adult men (n = 110) in the age range of 30 to 50 years, which we selected from the database of 800 patients hospitalized in the Cardio Center in Nitra during 2010 – 2020. When evaluating the influence of meat products consumption frequency on biochemical parameters and BMI, we recorded a statistically significant effect at the level of p

Background. Overweight and obesity are defined as abnormal or excessive fat accumulation that may impair health. Obesity is associated with many chronic diseases, including cardiovascular disease and diabetes, and recently the role of overweight and obesity in lung disease has received new interest. Chronic obstructive lung disease is the third-leading cause of death globally, and both obesity and diet appear to play roles in its pathophysiology. Cross-sectional studies have demonstrated an inverse association between obesity and the prevalence of chronic obstructive pulmonary disease (COPD). Objective. This study aims to evaluate the relationship between smoking, lipid profile and obesity (body composition changes) in a selected groups of population (30 non-smokers, 30 smokers and 60 COPD patients). Material and Methods. We evaluated fat mass, fat free mass, body mass index and lipid profile in a group of 120 randomly selected probands (60 COPD patients; 30 smokers without COPD; 30 non-smokers without COPD) to identify possible negative relationships of smoking to body composition. To the measurement of fat mass (FM) and fat free mass (FFM) was used a device Bodystat Quadscan 4000 (Bodystat Ltd, British Isles). The device works by using four-frequency bioelectrical impedance analysis. Laboratory parameters as total cholesterol (T-C), high-density cholesterol (HDL-C), low-density cholesterol (LDL-C) and triacylglycerols (TG) were investigated by automated clinical chemistry analyzer LISA 200th. The measured values were statistically processed and evaluated in a statistical program STATISTICA Cz. Version 7.1. (Kruskall-Wallis test). Results. A comparison of the mean fat mass we found statistically highly significant differences between the group of COPD patients and non-smokers (P

Revathy Munuswamy,1,* Jana De Brandt,2,* Chris Burtin,2 Wim Derave,3 Joseph Aumann,4 Martijn A Spruit,5,6,* Luc Michiels1,* 1Faculty of Medicine and Life Sciences, Biomedical Research Institute BIOMED, Hasselt University, Hasselt, Belgium; 2Faculty of Rehabilitation Sciences, Rehabilitation Research Center REVAL, Biomedical Research Institute BIOMED, Hasselt University, Hasselt, Belgium; 3Department of Movement and Sports Sciences, Ghent University, Ghent, Belgium; 4Department of Pneumology, Jessa Hospital, Hasselt, Belgium; 5Department of Research and Development, CIRO, Horn, the Netherlands; 6Department of Respiratory Medicine, Maastricht University Medical Centre, Faculty of Health, Medicine and Life Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, the Netherlands*These authors contributed equally to this workCorrespondence: Luc Michiels Email luc.michiels@uhasselt.beAbstract: Chronic low-grade systemic inflammation is frequently observed in patients with chronic obstructive pulmonary disease (COPD), e.g., elevated pentameric CRP (pCRP). However, pCRP can dissociate to form monomeric CRP (mCRP) which exhibits a clear pro-inflammatory behaviour in contrast to the more anti-inflammatory properties of pCRP. Therefore, mCRP may be an informative biomarker to demonstrate chronic low-grade systemic inflammation. This was confirmed by analysing serum samples from 38 patients with COPD and 18 non-COPD control persons (NCCP). mCRP was significantly elevated in patients with COPD vs. NCCP, indicating that mCRP might be considered as a new sensitive marker of chronic low-grade systemic inflammation.Keywords: COPD, low-grade systemic inflammation, pCRP, mCRP

BACKGROUND Few studies have compared the features of thyroid cancer among races and ethnicities. We hypothesized that race and ethnicity may influence the frequency and features of thyroid malignancy in thyroid nodules. METHOD This was a retrospective chart review of patients between 2013 and 2020 who underwent thyroidectomy. RESULTS In the analysis of 2737 patients, thyroid cancer was less prevalent among Blacks (24.0% vs Whites 52.1%, Hispanics 58.7%, Asians 71.7%, and Others 57.9%, p

Introduction: Thyroid hormones affect the cardiovascular system, but the precise mechanisms of their effects on the development of atherosclerosis are not entirely clear. The relationship between subclinical hypothyroidism, dyslipidemia and carotid atherosclerosis has been widely investigated, but the findings were controversial. The aim of the present study was to determine whether female subjects with subclinical hypothyroidism (SHypo) have increased carotid intima-media thickness (IMT) compared with euthyroid subjects, as well as to examine the association of SHypo, carotid atherosclerosis and dyslipidemia. Methods: This research included 100 women aged 30 to 70 years who were divided into two groups: the SHypo group including subjects with signs of subclinical hypothyroidism and the control group of euthyroid subjects. Carotid IMT thickness using B mode ultrasound was determined and its correlation with serum concentrations of fT4, TSH, CRP, and lipid profile including small dense LDL (sdLDL) was analysed. Results: Subjects with SHypo had significantly increased carotid IMT (IMT ≥ 75th centile) in all three measured segments of the right (p p = 0.001) carotid artery compared to the control group, with a significantly more frequent appearance of plaque (25% vs. 9%; p = 0.05). Significant positive correlations were found between higher TSH and higher IMT values. Increased age, LDL cholesterol, and TSH predicted thickening of the carotid artery IMT. Conclusions: It is important to screen people showing early, subclinical signs of thyroid gland dysfunction due to its impact on carotid atherosclerosis development.

An abdominal aortic aneurysm (AAA) is a permanent dilatation of the abdominal aorta, usually accompanied by thrombus formation. The current clinical imaging modalities cannot reliably visualize the thrombus composition. Remodeling of the extracellular matrix (ECM) during AAA development leads to stiffness changes, providing a potential imaging marker. 14 apolipoprotein E-deficient mice underwent surgery for angiotensin II-loaded osmotic minipump implantation. 4 weeks post-op, 5 animals developed an AAA. The aneurysm was imaged ex vivo by microscopic multifrequency magnetic resonance elastography (µMMRE) with an in-plane resolution of 40 microns. Experiments were performed on a 7-Tesla preclinical magnetic resonance imaging scanner with drive frequencies between 1000 Hz and 1400 Hz. Shear wave speed (SWS) maps indicating stiffness were computed based on tomoelastography multifrequency inversion. As control, the aortas of 5 C57BL/6J mice were examined with the same imaging protocol. The regional variation of SWS in the thrombus ranging from 0.44±0.07 to 1.20±0.31 m/s was correlated fairly strong with regional histology-quantified ECM accumulation (R2=0.79). Our results suggest that stiffness changes in aneurysmal thrombus reflect ECM remodeling, which is critical for AAA risk assessment. In the future, µMMRE could be used for a mechanics-based clinical characterization of AAAs in patients. STATEMENT OF SIGNIFICANCE: : To our knowledge, this is the first study mapping the stiffness of abdominal aortic aneurysms with microscopic resolution of 40 µm. Our work revealed that stiffness critically changes due to extracellular matrix (ECM) remodeling in the aneurysmal thrombus. We were able to image various levels of ECM remodeling in the aneurysm reflected in distinct shear wave speed patterns with a strong correlation to regional histology-quantified ECM accumulation. The generated results are significant for the application of microscopic multifrequency magnetic resonance elastography for quantification of pathological remodeling of the ECM and may be of great interest for detailed characterization of AAAs in patients.

Background: The association between heart rate (HR) and pulmonary embolism (PE) outcomes has not been well studied. Furthermore, optimal cutoffs to identify low-risk and intermediate- to high-risk patients are not well known. Research Question: Does an association exist between baseline HR and PE outcome across the continuum of HR values? Study Design and Methods: The current study included 44,331 consecutive nonhypotensive patients with symptomatic PE from the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001 and 2021. Outcomes included 30-day all-cause and PE-specific mortality. We used hierarchical logistic regression to assess the association between admission HR and outcomes. Results: A positive relationship was found between admission HR and 30-day all-cause and PE-related mortality. Considering an HR of 80 to 99 beats/min as a reference, patients in the higher HR strata showed higher rates of all-cause death (adjusted OR, 1.5 for HR of 100-109 beats/min; adjusted OR, 1.7 for HR of 110-119 beats/min; adjusted OR, 1.9 for HR of 120-139 beats/min; and adjusted OR, 2.4 for HR of ≥ 140 beats/min). Patients in the lower strata of HR showed significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR, 0.6 for HR of 60-79 beats/min; and adjusted OR, 0.5 for HR of < 60 beats/min). The findings for 30-day PE-related mortality were similar. For identification of low-risk patients, a cutoff value of 80 beats/min (vs 110 beats/min) increased the sensitivity of the simplified Pulmonary Embolism Severity Index (sPESI) from 93.4% to 98.8%. For identification of intermediate- to high-risk patients, a cutoff value of 140 beats/min (vs 110 beats/min) increased the specificity of the Bova score from 93.2% to 98.0%. Interpretation: In nonhypotensive patients with acute symptomatic PE, a high HR portends an increased risk of all-cause and PE-related mortality. Modifying the HR cutoff in the sPESI and the Bova score improves prognostication of patients with PE.

Rationale: Prior work suggests that Black persons have more severe obstructive sleep apnea (OSA) upon clinical presentation. However, the extent to which this may reflect differences in symptoms or...

PET/computed tomography and PET/MR imaging are used to evaluate the post-treatment neck. Although 18F-FDG is helpful in the staging and treatment response assessment of head and neck cancer, recently developed PET radiotracers targeting specific surface markers are promising for applications of diagnostic problem solving and improved extent delineation. Diffusion-weighted MR imaging is helpful in the differential diagnosis of head and neck neoplasms, and improves the sensitivity and specificity for the detection of certain pathologies. Following standardized imaging parameters for PET/computed tomography and diffusion-weighted imaging in PET/MR imaging improves diagnostic accuracy and allows for future research data mining.

Aims Patients on chronic haemodialysis have a wide range of changes in cardiac function and structure, including left ventricular hypertrophy, dilation and diastolic dysfunction or pulmonary hypertension. All these changes were linked to increased mortality in previous studies. High-flow arteriovenous fistulas (AVF) are supposed to be a factor contributing to their development. This study investigated the early effect of surgical AVF blood flow (Qa) reduction on these changes in patients with or without heart failure changes. Methods and results Forty-two patients in chronic haemodialysis programme with high-flow AVF (Qa over 1500 mL/min), indicated for surgery for ≥1 of the following indications: 1.manifest heart failure; 2.hand ischemia; 3.advanced structural heart changes detected by echocardiography. The patients underwent echocardiography on selection visit, before blood flow reducing surgery and six weeks thereafter. The Qa reduction led to decrease of left ventricular mass (p = 0.02), end-diastolic volume (p = 0.008), end-diastolic diameter (p = 0.003) and left atrial volume (p = 0.0006). Diastolic function improved. Similarly, right ventricular diameter and right atrial volume decreased (p = 0.000001 and 0.00009, respectively) together with the decrease of estimated pulmonary artery systolic pressure. 81% of patients suffered from pulmonary hypertension prior to surgery, only 36% thereafter. Conclusion The surgical restriction of the hyperkinetic circulation leads to several improvements of heart structure and function, which was linked to higher mortality in other studies. The beneficial effect of Qa reduction is present even in patients without symptoms of heart failure. The contribution of AVF must be considered with structural or functional heart changes.

© 2020, The Author(s), under exclusive licence to Springer Nature Limited.Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Glucagon is actually used in the treatment of severe hypoglycemia. Due to technological difficulties with stability in solution, glucagon in currently available preparations was contained in a form of powder, which needs to be first dissolved in the water before application. This particular administration of glucagon was associated with a certain delay and several mistakes that decreased real amount of glucagon injected in the body. Currently two new formulas of glucagon appeared on the market - first as a stable liquid solution, second as a powder for nasal administration. This article summarizes currently available information about these preparations.

Background Data about the genotype-specific human papillomavirus (HPV) prevalence in the Czech Republic is limited. We aimed to evaluate the prevalence and concordance of genotype-specific HPV infection detected in semen samples, penile swabs and cervical swabs from non-vaccinated heterosexual couples without HPV-associated disease. Methods Semen samples and penile swabs were collected from male partners and cervical swabs were collected from female partners of heterosexual couples treated for infertility (n = 195). Presence of HPV DNA in semen samples and cervical swabs was analyzed using the cobas® HPV Test and PapilloCheck®. Only the PapilloCheck® test was used to detect HPV in penile swabs. The genotype-specific prevalence and concordance of HPV infection not targeted by vaccine were evaluated using Fisher exact test. Results Both partners were infected with any HPV type in 13.8% (27/195) of couples and, of these couples, 55.6% (15/27) harbored at least one mutual genotype. High-risk HPV (hrHPV) genotypes were detected in 12.3% (24/195) of semen samples, 31.3% (61/195) of penile swabs, and 19.5% (38/195) of cervical swabs (P P P = 0.055). Conclusions This study showed that the detection of HPV infection differ by anatomic site and gender. Regardless the anatomic site, high prevalence of HPV genital infection was found in both Czech men and women.

Background/Aim: We investigated efficacy differences for afatinib versus gefitinib in non-small-cell lung cancer (NSCLC) according to epidermal growth factor receptor (EGFR) mutations. Patients and Methods: We retrospectively analysed data for 343 patients with NSCLC with performance status 1 having EGFR mutations treated with gefitinib or afatinib. Overall response rate (ORR) was tested by Fisher & rsquo;s exact test. Overall (OS) and progression free (PFS) survival were estimated by Kaplan & ndash;Meier method. Results: ORR did not differ in any group or subgroup. Among all patients, we observed significantly longer PFS for those treated with afatinib vs. gefitinib (median 13.4 vs. 9.5 months, p=0.026), but only a nonsignificant trend was observed for OS. We showed nonsignificant trends of better PFS and OS using afatinib for exon 19 deletion and L858R subgroups. We observed no significant PFS differences for other EGFR mutations but a nonsignificant trend towards better OS for those treated with afatinib. Conclusion: Afatinib led to longer PFS for patients with common EGFR mutations but not for those with rare mutations.

Rose bengal and erythrosin B are xanthene dyes mainly known and used as antimicrobial agents, but due to their photodynamic activity they are also potential photosensitizers for cancer photodynamic therapy. The aim of this work is to study a photodynamic efficacy of rose bengal and erythrosin B against human skin melanoma and mouse fibroblast cell lines, compare them with each other and find out their photodynamic properties induced by light emitting diodes with total light dose of 5 J/cm2. To fully identify and understand photodynamic properties of both potentially effective photosensitizers, a set of complex in vitro tests such as cell cytotoxic assay, measurement of reactive oxygen species production, mitochondrial membrane potential change assay, mode of cell death determination or comet assay were made. Although both photosensitizers proved to have similar properties such as increasing production of reactive oxygen species with the higher concentration, predominance of necrotic mode of death or genotoxicity, the more effective photosensitizer was rose bengal because its EC50 was over 20 times lower for both cell lines than in case of erythrosin B.

Introduction It is unclear whether adiposity leads to changes in movement behaviors, and there is a lack of compositional analyses of longitudinal data which focus on these associations. Using a compositional approach, this study aimed to examine the associations between baseline adiposity and 7-year changes in physical activity (PA) and sedentary behavior (SB) among elderly women. We also explored the longitudinal associations between change in adiposity and change in movement-behavior composition. Methods This longitudinal study included 176 older women (mean baseline age 62.8 (4.1) years) from Central Europe. Movement behavior was assessed by accelerometers and adiposity was measured by bioelectrical impedance analysis at baseline and follow-up. A set of multivariate least-squares regression analyses was used to examine the associations of baseline adiposity and longitudinal changes in adiposity as explanatory variables with longitudinal changes in a 3-part movement-behavior composition consisting of SB, light PA (LPA) and moderate-to-vigorous PA (MVPA) as outcome variables. Results No significant associations were found between baseline adiposity and longitudinal changes in the movement-behavior composition (p > 0.05). We found significant associations of changes in body mass index (BMI) and fat mass percentage (FM%) with changes in the movement-behavior composition. An increase in BMI was associated with an increase of SB at the expense of LPA and MVPA (β = 0.042, p = 0.009) and with a decrease of MVPA in favor of SB and LPA (β = − 0.059, p = 0.037). An increase in FM% was significantly associated only with an increase of SB at the expense of LPA and MVPA (β = 0.019, p = 0.031). Conclusions This study did not support the assumption that baseline adiposity is associated with longitudinal changes in movement behaviors among elderly women, but we found evidence for change-to-change associations, suggesting that a 7-year increase in adiposity is associated with a concurrent increase of SB at the expense of LPA and MVPA and with a concurrent decrease of MVPA in favor of LPA and SB. Public health interventions are needed to simultaneously prevent weight gain and promote physically active lifestyle among elderly women.

Aging of the immune system, or immunosenescence, alters the viral immune response in the elderly, especially when frailty exists. Research findings have demonstrated an imbalance in pro- and anti-inflammatory mechanisms, reduced production and diversification of T lymphocytes, and an alteration in immunovigilance and antibody synthesis. In this context, nutrition has a role in combating sarcopenia and frailty. Some food components that contribute to immune-competence are protein, vitamin D, n-3 fatty acids, antioxidant vitamins (vitamins C and E), zinc, selenium and iron. In times of a pandemic, nutritional recommendations for immune-competence in the elderly should be based on clinical studies. In this article, immunosenescence and its relationship to nutrition are addressed, including interventions studied in the context of the COVID-19 pandemic.

Background Acute pancreatitis (AP) is one of the most common causes of gastrointestinal-related hospitalizations in the United States. Severe AP (SAP) is associated with a mortality rate of nearly 30% and is distinguished from milder forms of AP. Risk stratification to identify SAP cases needing inpatient treatment is an important aspect of AP diagnosis. Methods We developed machine learning algorithms to predict which patients presenting with AP would require treatment for SAP. Three models were developed using logistic regression, neural networks, and XGBoost. Models were assessed in terms of area under the receiver operating characteristic (AUROC) and compared to the Harmless Acute Pancreatitis Score (HAPS) and Bedside Index for Severity in Acute Pancreatitis (BISAP) scores for AP risk stratification. Results 61,894 patients were used to train and test the machine learning models. With an AUROC value of 0.921, the model developed using XGBoost outperformed the logistic regression and neural network-based models. The XGBoost model also achieved a higher AUROC than both HAPS and BISAP for identifying patients who would be diagnosed with SAP. Conclusions Machine learning may be able to improve the accuracy of AP risk stratification methods and allow for more timely treatment and initiation of interventions.

Candida and other fungal species play an increasing role in nosocomial infections, including cholangitis and cholangiosepsis. Early diagnosis and prompt treatment are essential in successful patient outcomes. Fluconazole is an antifungal of choice in fluconazole-sensitive Candida infections. Little information is known about the fluconazole biliary excretion. Decreased tissue penetration may be one of the possible causes of treatment failure. Due to favorable pharmacokinetics, therapeutic drug monitoring of this antifungal has not been recommended routinely. In the presented case we report the successful therapeutic drug monitoring-guided fluconazole treatment in a patient with cholangitis and cholangiosepsis caused by fluconazole-sensitive Candida spp.

Background/Purpose Previous studies have shown that a patent, watertight esophageal anastomosis can be accomplished safely using specially-shaped magnets in piglets. However, it is unclear whether such a magnetic esophageal compression anastomosis (MECA) remains patent in the long-term. The purpose of this study was to evaluate the long-term outcome of MECA in an experimental pig model over an observation period of 2 months. Methods Ten piglets underwent creation of an MECA with custom-made 8 mm magnets and a U-shaped esophageal bypass loop to allow peroral nutrition at eight weeks of life. Two weeks later, the bypass loop was closed surgically, requiring the pigs to swallow via the newly created magnetic compression anastomosis. The pigs were fed soft chow for 2 months. They were monitored for weight gain and signs of dysphagia. At the endpoint of two months, esophagoscopy and contrast esophagography was performed. After removal of the esophagus, the tissues were macroscopiocally and histologically assessed. Results Six piglets survived until the endpoint. In two pigs, closure of the bypass loop failed, these demonstrated mean weight gain of 792 gs/day [95% Confidence interval 575 to 1009 gs/day]. Weight gain in four pigs that exclusively fed via the magnetic anastomosis averaged 577 gs/day [95% confidence interval 434 to 719 gs/day (p = 0.18)]. There were no signs of dysphagia. All magnets passed with the stool within 16 days. After 2 months, a well-formed magnetic compression anastomosis was visible and easily negotiated with a 6.5 mm endoscope. Esophogram and macroscopic findings confirmed patentency of the esophageal anastomoses. Histopathology showed a circular anastomosis lined with contiguous epithelium. Conclusion MECA creates a long-term functional and patent anastomosis in pigs. This concept may facilitate minimally-invasive esophageal atresia repair by obviating a technically challenging and time-consuming hand-sewn anastomosis.

Purpose To evaluate the diagnostic accuracy of computed tomography angiography (CTA) acquired with shuttle technique (CTAs) and helical CTA (CTAh) for vasospasm, using digital subtraction angiography (DSA) obtained within 24 h as reference standard. Methods Thirty-six patients with suspected vasospasm in the setting of aneurysmal subarachnoid hemorrhage (ASAH, 30/36) or acute inflammatory/infectious conditions (6/36) who underwent CTAs (17/36) or CTAh (19/36) followed by DSA within 24 h were identified retrospectively. Presence of vasospasm in the proximal cerebral arterial segments was assessed qualitatively and semi-quantitatively on CTA and subsequent DSA. Sensitivity, specificity, and receiver operating characteristic (ROC) curves were calculated. Inter-rater variability was assessed using Cohen's kappa. Results On CTAs, 35% of patients had low and 65% had high vasospasm burden. On CTAh, 37% had low and 63% had high vasospasm burden. ROC analysis demonstrated an AUC of 0.87 for CTAs (95%CI 0.67–1.00, p = 0.015) and 0.88 for CTAh (0.72–1.00, p = 0.028). Cohen's kappa was 0.843 (95%CI 0.548–1.000). Thresholding with Youden's J index, CTAs had a sensitivity of 85.71% (95%CI 48.69 to 99.27) and specificity of 66.67% (35.42 to 87.94). CTAh had sensitivity of 100% (56.55 to 100.00) and specificity of 78.57% (52.41 to 92.43). Conclusion CTAs and CTAh yielded similar sensitivity, specificity, and AUC values on ROC analysis for the detection of vasospasm using DSA as reference standard. Our findings suggest that CTAs is a promising alternative to CTAh especially in patients requiring serial imaging, given its potential advantages of decreased radiation exposure, contrast dose, and cost-effectiveness.

Expression of inhibitory designer receptors exclusively activated by designer drugs (DREADDs) on excitatory hippocampal neurons in the hippocampus represents a potential new therapeutic strategy for drug-resistant epilepsy. To overcome the limitations of the commonly used DREADD agonist clozapine, we investigated the efficacy of the novel DREADD ligand JHU37160 in chemogenetic seizure suppression in the intrahippocampal kainic acid (IHKA) mouse model for temporal lobe epilepsy (TLE). In addition, seizure-suppressing effects of chemogenetics were compared to the commonly used anti-epileptic drug (AED), levetiracetam (LEV). Therefore, an adeno-associated viral vector was injected in the sclerotic hippocampus of IHKA mice to induce expression of a tagged inhibitory DREADD hM4Di or only a tag (control) specifically in excitatory neurons using the CamKIIα promoter. Subsequently, animals were treated with LEV (800 mg/kg), clozapine (0.1 mg/kg), and DREADD ligand JHU37160 (0.1 mg/kg) and the effect on spontaneous seizures was investigated. Clozapine and JHU37160-mediated chemogenetic treatment both suppressed seizures in DREADD-expressing IHKA mice. Clozapine treatment suppressed seizures up to 34 h after treatment, and JHU37160 effects lasted for 26 h after injection. Moreover, both compounds reduced the length of seizures that did occur after treatment up to 28 h and 18 h after clozapine and JHU37160, respectively. No seizure-suppressing effects were found in control animals using these ligands. Chemogenetic seizure treatment suppressed seizures during the first 30 min after injection, and seizures remained suppressed during 8 h following treatment. Chemogenetics thus outperformed effects of levetiracetam (p

The significant growth in traffic density in Slovakia, combined with the country’s economic change, has resulted in new environmental noise issues, particularly in road traffic noise. The objective of this study was to assess and evaluate the impact of environmental noise on the psychosocial well-being of young healthy individuals in the two main Slovak cities of Bratislava and Kosice. To assess noise annoyance, interference with activities, and sleep disturbance, the ICBEN (The International Commission on the Biological Effects of Noise) anonymous validated “Noise annoyance questionnaire” was applied; noise levels were objectified by direct measurements using a sound level analyzer with a frequency analysis module. Young individuals between the ages of 20 and 30 were interviewed in Bratislava (533 respondents, 155 males) and Kosice (355 respondents, 111 males). The majority of the respondents in both cities were exposed to medium levels of road traffic noise LAeq ≥ 60 dB. In Bratislava, 27.82 % of respondents resided in the higher noise exposure category LAeq ≥ 70 dB, while in Kosice, 39.9 % resided in the lower noise exposure category LAeq < 50 dB. Road traffic noise annoys respondents in the higher noise exposure category in Bratislava 63.51 %, and even in the lower noise exposure category in Kosice, it interferes with reading and mental work, sleep and falling asleep 46.51 %. The study has identified traffic noise as an environmental issue in large cities, emphasizing the need for vulnerable individuals to be protected, particularly at night.

Objectives This study sought to comprehensively determine the procedural safety and midterm efficacy of hybrid ablations. Background Hybrid ablation of atrial fibrillation (AF) (thoracoscopic ablation followed by catheter ablation) has been used for patients with nonparoxysmal AF; however, accurate data regarding efficacy and safety are still limited. Methods Patients with nonparoxysmal AF underwent thoracoscopic, off-pump ablation using the COBRA Fusion radiofrequency system (Estech) followed by a catheter ablation 3 months afterward. The safety of the procedure was assessed using sequential brain magnetic resonance and neuropsychological examinations at baseline (1 day before), postoperatively (2-4 days for brain magnetic resonance imaging or 1 month for neuropsychological examination), and at 9 months after the surgical procedure. Implantable loop recorders were used to detect arrhythmia recurrence. Arrhythmia-free survival (the primary efficacy endpoint) was defined as no episodes of AF or atrial tachycardia while off antiarrhythmic drugs, redo ablations or cardioversions. Results Fifty-nine patients (age: 62.5 ± 10.5 years) were enrolled, 37 (62.7%) were men, and the mean follow-up was 30.3 ± 10.8 months. Thoracoscopic ablation was successfully performed in 55 (93.2%) patients. On baseline magnetic resonance imaging, chronic ischemic brain lesions were present in 60% of patients. New ischemic lesions on postoperative magnetic resonance imaging were present in 44.4%. Major postoperative cognitive dysfunction was present in 27.0% and 17.6% at 1 and 9 months postoperatively, respectively. The probability of arrhythmia-free survival was 54.0% (95% CI: 41.3-66.8) at 1 year and 43.8% (95% CI: 30.7–57.0) at 2 years. Conclusions The thoracoscopic ablation is associated with a high risk of silent cerebral ischemia. The midterm efficacy of hybrid ablations is moderate.

Purpose of review This review serves as a summary of healthcare maintenance items that should be addressed when managing patients with inflammatory bowel disease (IBD). This manuscript discusses vaccine-preventable illnesses, cancer prevention recommendations, and other screenings that are important to gastroenterologists and primary care physicians caring for patients with IBD. Recent findings Patients with IBD often require immunomodulator agents and/or biologics to induce and maintain disease remission which can increase the risk of developing several infections. Also, subsets of patients with IBD are at an increased risk for a number of malignancies including colon, cervical, and skin cancers. Summary Staying up-to-date with health care maintenance of patients with IBD is critical, especially given their increased risk for vaccine-preventable infections as well as comorbidities such as cancers, bone health, and mood disorders. Gastroenterologists and primary care physicians should familiarize themselves with the required screenings and vaccines that are recommended for adult patients with IBD, particularly those who are immunosuppressed.

Penttinen type of premature aging syndrome is an extremely rare progeroid disorder, caused by activating variants in the receptor tyrosine kinase domain of the PDGFRB gene. Only eight individuals have been previously reported worldwide, with a consistent phenotype of prematurely aged appearance, lipoatrophy, hypertrophic skin lesions, proptosis, malar hypoplasia, and marked acro-osteolysis. We report the first patient of Penttinen syndrome from India, with novel radiographic findings of terminal phalangeal tufting, thereby expanding the phenotypic spectrum of Penttinen syndrome.

Background Colorectal cancer (CRC) is an ideal disease for screening due to known and detectable precursor lesions and slow progression from benign adenoma to invasive cancer. The introduction of organized population-based screening programs reduces the burden of colorectal cancer and increases the quality of the screening process with a more favorable harm to benefit ratio compared to opportunistic screening. Methods The study used the microsimulation screening analysis-colon simulation model for the estimation of the effect of various factors on cancer incidence and mortality. The model simulated the Slovakian population from 2018 to 2050. Study includes the analysis of two screening strategies the fecal immunochemical test (FIT) every 2 years and annual FIT. Cost-effectiveness parameters were evaluated comparing each simulated screening scenario with no screening. Results Compared to no screening, the biennial FIT would detect 29 600 CRC cases and annual FIT 37 800 CRC cases. Mortality due to CRC showed benefits for both strategies with 17,38% reduction in biennial FIT and 24,67% reduction in annual FIT approach. Both screening programs were more costly as well as more effective compared to no screening. The ICER for biennial FIT strategy was 1776 EUR per 1 QALY and for the annual FIT 3991 EUR per 1 QALY. Conclusions In summary, this is the first cost-effectiveness analysis focusing on multiple national CRC screening strategies in Slovakia. Both strategies demonstrated cost-effectiveness compared to no screening. However, for optimal population-based programmatic screening strategy, the policymakers should also consider human resources availability, acceptability of screening test among the population or additional resources including the screening funding.

Purpose: Gliomas are intrinsic brain tumors with a high degree of constitutive and acquired resistance to standard therapeutic modalities such as radiotherapy and alkylating chemotherapy. Glioma subtypes are recognized by characteristic mutations. Some of these characteristic mutations have shown to generate immunogenic neoepitopes suitable for targeted immunotherapy. Experimental Design: Using peptide-based ELISpot assays, we screened for potential recurrent glioma neoepitopes in MHC-humanized mice. Following vaccination, droplet-based single-cell T-cell receptor (TCR) sequencing from established T-cell lines was applied for neoepitope-specific TCR discovery. Efficacy of intraventricular TCR-transgenic T-cell therapy was assessed in a newly developed glioma model in MHC-humanized mice induced by CRISPR-based delivery of tumor suppressor–targeting guide RNAs. Results: We identify recurrent capicua transcriptional repressor (CIC) inactivating hotspot mutations at position 215 CICR215W/Q as immunogenic MHC class II (MHCII)-restricted neoepitopes. Vaccination of MHC-humanized mice resulted in the generation of robust MHCII-restricted mutation-specific T-cell responses against CICR215W/Q. Adoptive intraventricular transfer of CICR215W-specific TCR-transgenic T cells exert antitumor responses against CICR215W-expressing syngeneic gliomas. Conclusions: The integration of immunocompetent MHC-humanized orthotopic glioma models in the discovery of shared immunogenic glioma neoepitopes facilitates the identification and preclinical testing of human leukocyte antigen (HLA)-restricted neoepitope-specific TCRs for locoregional TCR-transgenic T-cell adoptive therapy.

Background Hepatocellular carcinoma (HCC) is a major contributor to the worldwide cancer burden. Recent studies on HCC have demonstrated dramatic alterations in expression of several cytochrome P450 (CYP) family members that play a crucial role in biotransformation of many drugs and other xenobiotics; however, the mechanisms responsible for their deregulation remain unclear. Methods We investigated a potential involvement of miRNAs in downregulation of expression of CYPs observed in HCC tumors. We compared miRNA expression profiles (TaqMan Array Human MicroRNA v3.0 TLDA qPCR) between HCC human patient tumors with strong (CYP-) and weak/no (CYP+) downregulation of drug-metabolizing CYPs. The role of significantly deregulated miRNAs in modulation of expression of the CYPs and associated xenobiotic receptors was then investigated in human liver HepaRG cells transfected with relevant miRNA mimics or inhibitors. Results We identified five differentially expressed miRNAs in CYP- versus CYP+ tumors, namely miR-29c, miR-125b1, miR-505, miR-653 and miR-675. The two most-upregulated miRNAs found in CYP- tumor samples, miR-29c and miR-653, were found to act as efficient suppressors of CYP1A2 or AHR expression. Conclusions Our results revealed a novel role of miR-653 and miR-29c in regulation of expresion of CYPs involved in crucial biotransformation processes in liver, which are often deregulated during liver cancer progression.

Purpose 68 Ga-fibroblast-activation protein inhibitor (FAPI) positron emission tomography (PET) is a novel technique targeting FAP-alpha. This protein is expressed by activated fibroblasts which are the main contributors to tissue remodeling. The aim of this proof-of-concept study was to assess 68 Ga-FAPI uptake in the pulmonary vein (PV) region of the left atrium after pulmonary vein isolation (PVI) with cryoballoon ablation (CBA) and radiofrequency (RFA) as a surrogate for thermal damage. Methods Twelve PVI patients (5 RFA, 7 CBA) underwent 68 Ga-FAPI-PET 20.5 ± 12.8 days after PVI. Five patients without atrial fibrillation or previous ablation served as controls. Standardized uptake values of localized tracer uptake were calculated. Results Focal FAPI uptake around the PVs was observed in 10/12 (83.3%) PVI patients, no uptake was observed in 2 PVI patients and all controls. Patients after PVI had higher FAPI uptake in PVs compared to controls (SUVmax: 4.3 ± 2.2 vs. 1.6 ± 0.2, p peak: 2.9 ± 1.4 vs. 1.3 ± 0.2, p peak) in CBA compared to RFA patients (4.4 ± 1.5 vs. 2.5 ± 0.8, p = 0.02). Conclusion We demonstrate in-vivo visualization of 68 Ga-FAPI uptake as a surrogate for fibroblast activation after PVI. CBA seems to cause more pronounced fibroblast activation following tissue injury than RFA. Future studies are warranted to assess if this modality can contribute to a better understanding of the mechanisms of AF recurrence after PVI by lesion creation and gap assessment.

Many patients with coronavirus disease 2019 in intensive care units suffer from cytokine storm. Although anti-inflammatory therapies are available to treat the problem, very often, these treatments cause immunosuppression. Because angiotensin-converting enzyme 2 (ACE2) on host cells serves as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to delineate a SARS-CoV-2–specific anti-inflammatory molecule, we designed a hexapeptide corresponding to the spike S1–interacting domain of ACE2 receptor (SPIDAR) that inhibited the expression of proinflammatory molecules in human A549 lung cells induced by pseudotyped SARS-CoV-2, but not vesicular stomatitis virus. Accordingly, wild-type (wt), but not mutated (m), SPIDAR inhibited SARS-CoV-2 spike S1–induced activation of NF-κB and expression of IL-6 and IL-1β in human lung cells. However, wtSPIDAR remained unable to reduce activation of NF-κB and expression of proinflammatory molecules in lungs cells induced by TNF-α, HIV-1 Tat, and viral dsRNA mimic polyinosinic-polycytidylic acid, indicating the specificity of the effect. The wtSPIDAR, but not mutated SPIDAR, also hindered the association between ACE2 and spike S1 of SARS-CoV-2 and inhibited the entry of pseudotyped SARS-CoV-2, but not vesicular stomatitis virus, into human ACE2-expressing human embryonic kidney 293 cells. Moreover, intranasal treatment with wtSPIDAR, but not mutated SPIDAR, inhibited lung activation of NF-κB, protected lungs, reduced fever, improved heart function, and enhanced locomotor activities in SARS-CoV-2 spike S1–intoxicated mice. Therefore, selective targeting of SARS-CoV-2 spike S1-to-ACE2 interaction by wtSPIDAR may be beneficial for coronavirus disease 2019.

BACKGROUND AND AIMS: Studies examining kidney failure patients with COVID-19 reported higher mortality in hemodialysis patients than in kidney transplant recipients. However, hemodialysis patients are often older and have more comorbidities. This study investigated the association of type of kidney replacement therapy with COVID-19 severity adjusting for differences in characteristics. METHOD: Data were retrieved from the European Renal Association COVID-19 Database (ERACODA), which includes kidney replacement therapy patients diagnosed with COVID-19 from all over Europe. We included all kidney transplant recipients and hemodialysis patients who presented between February 1st and December 1st 2020 and had complete information reason for COVID-19 screening and vital status at day 28. The diagnosis of COVID-19 was made based on a PCR of a nasal or pharyngeal swab specimens and/or COVID-19 compatible findings on a lung CT scan. The association of kidney transplantation or hemodialysis with 28-day mortality was examined using Cox proportional-hazards regression models adjusted for age, sex, frailty and comorbidities. Additionally, this association was investigated in the subsets of patients that were screened because of symptoms or have had routine screening. RESULTS: A total of 1,670 patients (496 functional kidney transplant recipients and 1,174 hemodialysis patients) were examined. 16.9% of kidney transplant recipients and 23.9% of hemodialysis patients died within 28 days of presentation. In an unadjusted model, the risk of 28-day mortality was 33% lower in kidney transplant recipients compared with hemodialysis patients (hazard ratio (HR): 0.67, 95% CI: 0.52, 0.85). However, in an age, sex and frailty adjusted model, the risk of 28-day mortality was 29% higher in kidney transplant recipients (HR=1.29, 95% CI: 1.00, 1.68), whereas in a fully adjusted model the risk was even 43% higher (HR=1.43, 95% CI: 1.06, 1.93). This association in patients who were screened because of symptoms (n=1,145) was similar (fully adjusted model HR=1.46, 95% CI: 1.05, 2.04). Results were similar when other endpoints were studied (e.g. risk for hospitalization, ICU admission or mortality beyond 28 days) as well as across subgroups. Only age was found to interact significantly, suggesting that the increased mortality risk associated with kidney transplantation was especially present in elderly subjects. CONCLUSION: In this study, kidney transplant recipients had a greater risk of a more severe course of COVID-19 compared with hemodialysis patients when adjusted for age, sex and comorbidities.

The amount and distribution of fat and overweight in the human body are critical when determining the risk for different illnesses. Different disorders have a close connection to abnormal fat distribution and overweight. Obesity develops when a person's weight is out of proportion to their body fat. As a result, obesity rates have lately risen in both West Bengal and India. Overeating, a sedentary lifestyle, and a lack of physical exercise are the most evident causes of obesity and overweight. Excess fat and overweight are produced as a consequence, putting people of West Bengal at greater risk for health problems. The study's goals are to understand better and record the prevalence of obesity and overweight in the West Bengal's population

Endocrine and paracrine fibroblast growth factor 23 (FGF23) is a protein predominantly produced by bone cells with strong impact on phosphate and vitamin D metabolism by targeting the kidney. Plasma FGF23 concentration early rises in kidney and cardiovascular diseases correlating with progression and outcome. Lactic acid is generated in anaerobic glycolysis. Lactic acidosis is the consequence of various physiological and pathological conditions and may be fatal. Since FGF23 production is stimulated by inflammation and lactic acid induces pro-inflammatory signaling, we investigated whether and how lactic acid influences FGF23. Experiments were performed in UMR106 osteoblast-like cells, Fgf23 mRNA levels estimated from quantitative real-time polymerase chain reaction, and FGF23 protein determined by enzyme-linked immunosorbent assay. Lactic acid dose-dependently induced Fgf23 gene expression and up-regulated FGF23 synthesis. Also, Na+-lactate as well as formic acid and acetic acid up-regulated Fgf23. The lactic acid effect was significantly attenuated by nuclear factor kappa-light-chain enhancer of activated B-cells (NFκB) inhibitors wogonin and withaferin A. Lactic acid induces FGF23 production, an effect at least in part mediated by NFκB. Lactic acidosis may, therefore, be paralleled by a surge in plasma FGF23.

ZusammenfassungDie Riesenzellarteriitis (RZA) ist in der Altersgruppe der über 50-Jährigen die häufigste idiopathische systemische Vaskulitis. Die Erkrankung bedarf einer zeitnahen Diagnostik und Therapie, um schwere Komplikationen wie eine Erblindung oder einen Schlaganfall zu vermeiden. Die Rezidivneigung erfordert eine mehrjährige, zum Teil lebenslange Glukokortikoid(GC)-Therapie, was das Risiko GC-induzierter Langzeitnebenwirkungen erhöht. Daher wird bei der Mehrzahl der Patienten eine additive GC-einsparende Therapie empfohlen. Hierzu steht der Anti-IL-6-Rezeptor-Antikörper Tocilizumab in subkutaner Applikation als zugelassene Substanz zur Verfügung, alternativ kann Methotrexat (MTX) eingesetzt werden (off-label).

Objective: Rheumatoid arthritis (RA) is characterized by systemic inflammation and the presence of anti-citrullinated protein antibodies (ACPAs), which contain remarkably high levels of Fab glycosylation. Anti-hinge antibodies (AHAs) recognize immunoglobulin G (IgG) hinge neoepitopes exposed following cleavage by inflammation-associated proteases, and are also frequently observed in RA, and at higher levels compared to healthy controls (HCs). Here, we investigated AHA specificity and levels of Fab glycosylation as potential immunological markers for RA. Method: AHA serum levels, specificity, and Fab glycosylation were determined for the IgG1/4-hinge cleaved by matrix metalloproteinase-3, cathepsin G, pepsin, or IdeS, using enzyme-linked immunosorbent assay and lectin affinity chromatography, in patients with early active RA (n = 69) and HCs (n = 97). Results: AHA reactivity was detected for all hinge neoepitopes in both RA patients and HCs. Reactivity against CatG-IgG1-F(ab´)2s and pepsin-IgG4-F(ab´)2s was more prevalent in RA. Moreover, all AHA responses showed increased Fab glycosylation levels in both RA patients and HCs. Conclusions: AHA responses are characterized by elevated levels of Fab glycosylation and highly specific neoepitope recognition, not just in RA patients but also in HCs. These results suggest that extensive Fab glycosylation may develop in response to an inflammatory proteolytic microenvironment, but is not restricted to RA.

OBJECTIVES: The purpose of this study was to develop a risk prediction model for patients with nonobstructive CAD. BACKGROUND: Among stable chest pain patients, most cardiovascular (CV) events occur in those with nonobstructive coronary artery disease (CAD). Thus, developing tailored risk prediction approaches in this group of patients, including CV risk factors and CAD characteristics, is needed. METHODS: In Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) computed tomographic angiography patients, a core laboratory assessed prevalence of CAD (nonobstructive 1% to 49% left main or 1% to 69% stenosis any coronary artery), degree of stenosis (minimal: 1% to 29%; mild: 30% to 49%; or moderate: 50% to 69%), high-risk plaque (HRP) features (positive remodeling, low-attenuation plaque, and napkin-ring sign), segment involvement score (SIS), and coronary artery calcium (CAC). The primary end point was an adjudicated composite of unstable angina pectoris, nonfatal myocardial infarction, and death. Cox regression analysis determined independent predictors in nonobstructive CAD. RESULTS: Of 2,890 patients (age 61.7 years, 46% women) with any CAD, 90.4% (n = 2,614) had nonobstructive CAD (mean age 61.6 yrs, 46% women, atherosclerotic cardiovascular disease [ASCVD] risk 16.2%). Composite events were independently predicted by ASCVD risk (hazard ratio [HR]: 1.03; p = 0.001), degree of stenosis (30% to 69%; HR: 1.91; p = 0.011), and presence of ≥2 HRP features (HR: 2.40; p = 0.008). Addition of ≥2 HRP features to: 1) ASCVD and CAC; 2) ASCVD and SIS; or 3) ASCVD and degree of stenosis resulted in a statistically significant improvement in model fit (p = 0.0036; p = 0.0176; and p = 0.0318; respectively). Patients with ASCVD ≥7.5%, any HRP, and mild/moderate stenosis had significantly higher event rates than those who did not meet those criteria (3.0% vs. 6.2%; p = 0.007). CONCLUSIONS: Advanced coronary plaque features have incremental value over total plaque burden for the discrimination of clinical events in low-risk stable chest pain patients with nonobstructive CAD. This may be a first step to improve prevention in this cohort with the highest absolute risk for CV events.

Background Germ cell tumors represent highly curable disease even in metastatic stage. However, poor-risk patients with an unfavorable serum tumor marker (STM) decline after the first cycle of chemotherapy represent a subgroup with dismal prognosis, with approximately 50% cure rate using bleomycin, etoposide, and cisplatin (BEP). Objective The aim of this study was to determine the efficacy and safety of paclitaxel, ifosfamide, and cisplatin (TIP) in this patient population. Design, setting, and participants This was an open-labeled, nonrandomized, single-center phase II trial to study the efficacy and toxicity of TIP in the first-line treatment of germ cell tumor patients with an unfavorable decline of STMs. Nineteen patients with a poor prognosis according to the International Germ Cell Cancer Collaboration Group classification and an unfavorable STM decline after the first cycle of chemotherapy were included in this phase II study (NCT02414685). The treatment regimen consisted of paclitaxel 250 mg/m2 on day 1, ifosfamide 1200 mg/m2 on days 1–5, and cisplatin 20 mg/m2 on days 1–5, totally for four cycles. Outcome measurements and statistical analysis The primary endpoint was complete response (CR) rate. An optimal Simon two-stage design was used with a type I error of 5% and study power of 80%. If fewer than six CRs to study therapy have been observed among the first 19 patients, the study was to be terminated. Results and limitations A CR was achieved in four (21.1%) patients; therefore, the study was terminated in the first stage. A favorable response rate (CR or partial remission with negative tumor markers) was observed in 14 (78.9%) patients. At a median follow-up period of 35.2 mo (range, 5.6–62.1 mo), ten (52.6%) patients experienced disease progression and eight patients (42.1%) died. The 2-yr progression-free and overall survival was 41.2% (95% confidence interval [CI] 16.8–65.7) and 72.7% (95% CI 48.9–96.4), respectively. TIP was well tolerated, and no unexpected toxicity was observed. No informative biomarkers, including miR-371a-3p was identified. Conclusions Treatment modification from the BEP to the TIP regimen in patients with an unfavorable STM decline after the first cycle of chemotherapy was not associated with improved outcome, and four cycles of BEP remain the standard treatment option in this patient population. Patient summary Poor-risk patients with an unfavorable serum tumor marker decline after the first cycle of chemotherapy represent a subgroup with dismal prognosis, with an approximately 50% cure rate using bleomycin, etoposide, and cisplatin (BEP). Treatment modification from the BEP regimen to the paclitaxel, ifosfamide, and cisplatin regimen in patients with an unfavorable serum tumor marker decline after the first cycle of chemotherapy was not associated with improved outcome, and four cycles of BEP remain the standard treatment option in this patient population., Take Home Message Poor-risk patients with an unfavorable serum tumor marker (STM) decline after the first cycle of chemotherapy represent a subgroup with dismal prognosis, with approximately 50% cure rate using bleomycin, etoposide, and cisplatin (BEP). The aim of this study was to determine the efficacy and safety of paclitaxel, ifosfamide, and cisplatin (TIP) in this patient population. Treatment modification from the BEP to the TIP regimen in this patient population was not associated with an improved outcome, and four cycles of BEP remain the standard treatment option in this group of patients.

Most head and neck paragangliomas (PGLs) are biochemically silent and often present with recurrence and metastases in association with hereditary syndromes. Whole-body functional imaging is increasingly used to detect tumor extent and guide treatment planning of PGLs. [68Ga]-DOTATATE, which targets somatostatin receptor 2 (SSTR2) overexpression, has emerged as a sensitive functional imaging modality in PGLs. We present a patient with metastatic glomus caroticum PGL in whom [68Ga]-DOTATATE PET/MRI provided a more accurate characterization of metastatic extent, as compared to gadolinium-enhanced MRI of the neck and whole body [18F]-FDG PET/CT. We then review the current literature and discuss the imaging implications of [68Ga]-DOTATATE PET/MRI in PGLs.