Recent advances on CAR-T signaling pave the way for prolonged persistence and new modalities in clinic.

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies. The importance of the receptor costimulatory domain for long-term CAR-T cell engraftment and therapeutic efficacy was demonstrated with second-generation CAR-T cells. Fifth generation CAR-T cells are currently in preclinical trials. At the same time, the processes that orchestrate the activation and differentiation of CAR-T cells into a specific phenotype that predisposes them to long-term persistence are not fully understood. This review highlights ongoing research aimed at elucidating the role of CAR domains and T-cell signaling molecules involved in these processes.

Antithrombotic Usage, Including Three-Year Outcomes With Dabigatran and Vitamin K Antagonists for Atrial Fibrillation, in Eastern Europe: A Descriptive Analysis From Phase 3 of the GLORIA-AF Registry.

BACKGROUND: Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is a prospective registry of outcomes from patients with newly diagnosed AF at risk of stroke. In the propensity score (PS)-matched global population of phase 3 GLORIA-AF, at 3 years, dabigatran-treated patients experienced reduced risk for major bleeding, and similar risk for stroke and myocardial infarction, compared with vitamin K antagonist (VKA)-treated patients. STUDY QUESTION: Do patients in Eastern Europe benefit from treatment with dabigatran versus VKA? STUDY DESIGN: Descriptive analysis, without PS matching. To contextualize the Eastern Europe results of GLORIA-AF phase 3, we also descriptively analyzed the global population without PS matching. Consecutive patients with newly diagnosed AF and CHA2DS2-VASc-score ≥1 were enrolled until December 2016 in 38 countries (9 in Eastern Europe). MEASURES AND OUTCOMES: Three-year outcomes with dabigatran and VKA. RESULTS: In Eastern Europe, 1341 patients were eligible (6% of patients globally), and incidence rates (per 100 patient-years) for the following outcomes were numerically lower with dabigatran (N = 498) versus VKA (N = 466): major bleeding (0.26 vs. 0.90), all-cause death (2.04 vs. 3.50), and a composite of stroke, systemic embolism, myocardial infarction, life-threatening bleeding, and vascular death (1.37 vs. 1.92); stroke was comparable (0.51 vs. 0.50). All incidence rates were numerically lower in Eastern Europe versus the global population for both treatments. Chronic concomitant use of high bleeding risk medications (eg, nonsteroidal anti-inflammatories) was lower in Eastern Europe (dabigatran 3.8%, VKA 9.3%) than globally (dabigatran 14.8%, VKA 20.6%) and persistence with dabigatran was higher in Eastern Europe (76%) than globally (64%). CONCLUSIONS: Dabigatran was associated with numerically reduced major bleeding, all-cause death, and cardiovascular (CV) composite, with comparable risk of stroke versus VKA, in Eastern Europe. Limitations of this descriptive analysis include few CV events (n = 11 for stroke, in the dabigatran and VKA groups combined) and a lack of statistical analysis and PS matching, which precludes definitive conclusions; however, the CV outcomes in Eastern Europe were consistent with the beneficial impact of dabigatran versus VKA in the statistically analyzed global population with PS matching.

Analysis of Prevalence and Clinical Features of Aortic Stenosis in Patients with and without Bicuspid Aortic Valve Using Machine Learning Methods.

Aortic stenosis (AS) is the most commonly diagnosed valvular heart disease, and its prevalence increases with the aging of the general population. However, AS is often diagnosed at a severe stage, necessitating surgical treatment, due to its long asymptomatic period. The objective of this study was to analyze the frequency of AS in a population of cardiovascular patients using echocardiography (ECHO) and to identify clinical factors and features associated with these patient groups. We utilized machine learning methods to analyze 84,851 echocardiograms performed between 2010 and 2018 at the National Medical Research Center named after V.A. Almazov. The primary indications for ECHO were coronary artery disease (CAD) and hypertension (HP), accounting for 33.5% and 14.2% of the cases, respectively. The frequency of AS was found to be 13.26% among the patients (n = 11,252). Within our study, 1544 patients had a bicuspid aortic valve (BAV), while 83,316 patients had a tricuspid aortic valve (TAV). BAV patients were observed to be younger compared to TAV patients. AS was more prevalent in the BAV group (59%) compared to the TAV group (12%), with a p-value of <0.0001. By employing a machine learning algorithm, we randomly identified significant features present in AS patients, including age, hypertension (HP), aortic regurgitation (AR), ascending aortic dilatation (AscAD), and BAV. These findings could serve as additional indications for earlier observation and more frequent ECHO in specific patient groups for the earlier detection of developing AS.

Tissue and Circulating MicroRNAs 378 and 142 as Biomarkers of Obesity and Its Treatment Response.

Promising approaches to the treatment of obesity include increasing energy expenditure and slowing down fibrogenesis of adipose tissue. The neurotransmitter reuptake inhibitor sibutramine affects appetite and activates lipolysis in a catecholaminergic way. MicroRNAs (miRs) are considered as biomarkers of molecular genetic mechanisms underlying various processes. The profile of a number of miRs is altered in obesity, both in the circulation and in adipose tissue. The aim of this study was to assess the expression levels of miRs (hsa-miR-378a-3p, hsa-miR-142-3p) by real-time polymerase chain reaction in subcutaneous adipose tissue (SAT) and in plasma in patients with different degrees and duration of obesity and during sibutramine therapy. This study included 51 obese patients and 10 healthy subjects with normal weight who formed a control group. The study found that, before treatment, obese patients had no significant difference in the expression level of miR-378 in SAT and plasma compared to the control group, while the expression of miR-142 was significantly decreased in SAT and increased in plasma. A significant elevation in miR-378 expression level was noted in patients with first-degree obesity and duration of less than 10 years, and the decline in miR-142 increased with the duration of obesity. These data indicate a maximal increase in the expression of the adipogenesis inducer miR-378 in the early stages of obesity, a progressive decrease in the expression of the fibrogenesis inhibitor miR-142 in SAT with growth of duration of obesity and the likely presence of antifibrogenic effects of sibutramine realized through miR-142 activation.

Transgenerational and intergenerational effects of early childhood famine exposure in the cohort of offspring of Leningrad Siege survivors.

Famine exposure during early life development can affect disease risk in late-life period, yet, transmission of phenotypic features from famine-exposed individuals to the next generations has not been well characterized. The purpose of our case-control study was to investigate the association of parental starvation in the perinatal period and the period of early childhood with the phenotypic features observed in two generations of descendants of Leningrad siege survivors. We examined 54 children and 30 grandchildren of 58 besieged Leningrad residents who suffered from starvation in early childhood and prenatal age during the Second World War. Controls from the population-based national epidemiological ESSE-RF study (n = 175) were matched on sex, age and body mass index (BMI). Phenotypes of controls and descendants (both generations, children and grandchildren separately) were compared, taking into account multiple testing. Comparison of two generations descendants with corresponding control groups revealed significantly higher creatinine and lower glomerular filtration rate (GFR), both in meta-analysis and in independent analyses. The mean values of GFR for all groups were within the normal range (GFR less than 60 mL/min/1.73 m2 was recorded in 2 controls and no one in DLSS). Additionally, independent of the creatinine level, differences in the eating pattern were detected: insufficient fish and excessive red meat consumption were significantly more frequent in the children of the Leningrad siege survivors compared with controls. Blood pressure, blood lipids and glucose did not differ between the groups. Parental famine exposure in early childhood may contribute to a decrease in kidney filtration capacity and altered eating pattern in the offspring of famine-exposed individuals.

Trial protocol for the study of recommendation system DiaCompanion with personalized dietary recommendations for women with gestational diabetes mellitus (DiaCompanion I).

Background: Gestational diabetes mellitus (GDM) is a common complication of pregnancy associated with serious adverse outcomes for mothers and their offspring. Achieving glycaemic targets is the mainstream in the treatment of GDM in order to improve pregnancy outcomes. As GDM is usually diagnosed in the third trimester of pregnancy, the time frame for the intervention is very narrow. Women need to get new knowledge and change their diet very quickly. Usually, these patients require additional frequent visits to healthcare professionals. Recommender systems based on artificial intelligence could partially substitute healthcare professionals in the process of educating and controlling women with GDM, thus reducing the burden on the women and healthcare systems. We have developed a mobile-based personalized recommendation system DiaCompanion I with data-driven real time personal recommendations focused primarily on postprandial glycaemic response prediction. The study aims to clarify the effect of using DiaCompanion I on glycaemic levels and pregnancy outcomes in women with GDM. Methods: Women with GDM are randomized to 2 treatment groups: utilizing and not utilizing DiaCompanion I. The app provides women in the intervention group the resulting data-driven prognosis of 1-hour postprandial glucose level every time they input their meal data. Based on the predicted glucose level, they can adjust their current meal so that the predicted glucose level falls within the recommended range below 7 mmol/L. The app also provides reminders and recommendations on diet and lifestyle to the participants of the intervention group. All the participants are required to perform 6 blood glucose measurements a day. Capillary glucose values are retrieved from the glucose meter and if not available, from the woman's diary. Additionally, data on glycaemic levels during the study and consumption of major macro- and micronutrients will be collected using the mobile app with electronic report forms in the intervention group. Women from the control group receive standard care without the mobile app. All participants are prescribed with insulin therapy if needed and modifications in their lifestyle. A total of 216 women will be recruited. The primary outcome is the percentage of postprandial capillary glucose values above target (>7.0 mmol/L). Secondary outcomes include the percentage of patients requiring insulin therapy during pregnancy, maternal and neonatal outcomes, glycaemic control using glycated hemoglobin (HbA1c), continuous glucose monitoring data and other blood glucose metrics, the number of patient visits to endocrinologists and acceptance/satisfaction of the two strategies assessed using a questionnaire. Discussion: We believe that the approach including DiaCompanion I will be more effective in patients with GDM for improving glycaemic levels and pregnancy outcomes. We also expect that the use of the app will help reduce the number of clinic visits. Trial registration number: ClinicalTrials.gov, Identifier NCT05179798.

Device-based neuromodulation for cardiovascular diseases and patient' s age.

The autonomic nervous system plays an important role in the pathogenesis of cardiovascular diseases. With aging, autonomic activity changes, and this impacts the physiological reactions to internal and external signals. Both sympathetic and parasympathetic responses seem to decline, reflecting functional and structural changes in nervous regulation. Although some investigators suggested that both the sympathetic and parasympathetic activities were suppressed, others found that only the parasympathetic activity was suppressed while the sympathetic activity increased. In addition, cardiac innervation progressively diminishes with aging. Therefore, one may suggest that neuromodulation interventions may have different effects, and older age groups can express an attenuated response. This article aims to discuss the effect of device-based neuromodulation in different cardiovascular diseases, depending on the patient's age. Thus, we cover renal denervation, pulmonary artery denervation, baroreceptor activation therapy, vagus nerve stimulation, spinal cord stimulation, ganglionated plexi ablation for the management of arterial and pulmonary hypertension, heart failure, angina and arrhythmias. The results of many clinical studies appeared to be unconvincing. In view of the low rate of positive findings in clinical studies incorporating neuromodulation approaches, we suggest the underestimation of advanced age as a potential contributing factor to poorer response. Analysis of outcomes between different age groups in clinical trials may shed more light on the true effects of neuromodulation when neutral/ambiguous results are obtained.

The Ratio of Diastolic and Systolic Arterial Pressure is Associated with Pulse Pressure.

Pulse pressure (PP) is defined as the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP). The metric PP is not unique, as numerous combinations of SBP and DBP yield the same value for PP. Therefore, we introduced the PP companion (PPC) which is calculated using the Pythagorean theorem. Only the combination of PP and PPC offers unique characterization. Interestingly, PPCwas found to be associated with mean arterial pressure (MAP). Another mathematical construct frequently used in hemodynamic studies refers to the ratio of DBP and SBP, or DBP/SBP, denoted as Prat. As Prat and PP share the same companion (C), we investigated the association between PratC and MAP, as well as the connection between PP and Prat. Various patient cohorts were included: A) 52 heart failure patients (16 women), B) 88 patients (11 women) with acute cardiac syndromes, C) 257 patients (68 men) diagnosed with atherosclerosis or any of various types of autoimmune disease, and D) 106 hypertensives (51 men). Linear regression analysis resulted in the following correlations: A: R (PratC, MAP) = 0.94, R (PP, Prat) = -0.91 B: R (PratC, MAP) = 0.98, R (PP, Prat) = -0.85 C: R (PratC, MAP) = 0.97, R (PP, Prat) = -0.86 D: R (PratC, MAP) = 0.92, R (PP, Prat) = -0.82 We conclude that Prat carries no substantial incremental value beyond PP, while both Prat and PP are incomplete metrics, requiring simultaneous consideration of MAP. Clinical Relevance- Various ratio-based metrics have been introduced in hemodynamic studies without paying attention to missing components or even redundant candidates. Here we present a uniform method to provide comprehensive insight.

Cytokine Storm Signature in Patients with Moderate and Severe COVID-19.

Hypercytokinemia, found in SARS-CoV-2 infection, contributes to multiple organ dysfunctions with acute respiratory distress syndrome, shock etc. The aim of this study was to describe cytokine storm signatures in patients with acute COVID-19 and to investigate their influence on severity of the infection. Plasma levels of 47 cytokines were investigated in 73 patients with moderate and severe COVID-19 (41 and 32, respectively) and 11 healthy donors (HD). The most elevated levels comparing patients and the HD were observed for seven pro-inflammatory cytokines (IL-6, IL-8, IL-15, IL-18, IL-27, IFNγ, TNFα), three chemokines (GROα, IP-10, MIG), two anti-inflammatory cytokines (IL-1RA, IL-10), and two growth factors (G-CSF, M-CSF). The patients with severe disease had significantly higher levels of FGF-2/FGF-basic, IL-1ß, and IL-7 compared to the HD. The two groups of patients differed from each other only based on the levels of EGF, eotaxin, and IL-12 p40. Pneumonia lung injury, characterized by computer tomography, positively correlated with levels of EGF, IP-10, MCP-3 levels and negatively with IL-12 p40. Pro-inflammatory factors including IL-6, TNFα, and IP-10 negatively correlated with the frequency of the circulating T-helper17-like cells (Th17-like) and follicular Th cells that are crucial to develop SARS-CoV-2-specific plasma cells and memory B cells. Obtained data on the cytokine levels illustrate their influence on progression and severity of COVID-19.

Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial.

AIMS: To investigate the impact of patiromer on the serum potassium level and its ability to enable specified target doses of renin-angiotensin-aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of the RAASi therapy [≥50% recommended dose of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist (MRA) spironolactone or eplerenone]. Specified target doses of the RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in the adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13-43) weeks, the adjusted mean change in potassium was +0.03 mmol/l in the patiromer group and +0.13 mmol/l in the placebo group [difference in the adjusted mean change between patiromer and placebo: -0.10 mmol/l (95% confidence interval, CI -0.13, 0.07); P < 0.001]. Risk of hyperkalemia >5.5 mmol/l [hazard ratio (HR) 0.63; 95% CI 0.45, 0.87; P = 0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P = 0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P < 0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P < 0.001) and total RAASi use score (win ratio 1.25, P = 0.048) favored the patiromer arm. Adverse events were similar between groups. CONCLUSION: Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066).

Effect of Cholecalciferol Supplementation on the Clinical Features and Inflammatory Markers in Hospitalized COVID-19 Patients: A Randomized, Open-Label, Single-Center Study.

Recent studies showed that a low 25-hydroxyvitamin D (25(OH)D) level was associated with a higher risk of morbidity and severe course of COVID-19. Our study aimed to evaluate the effects of cholecalciferol supplementation on the clinical features and inflammatory markers in patients with COVID-19. A serum 25(OH)D level was determined in 311 COVID-19 patients. Among them, 129 patients were then randomized into two groups with similar concomitant medication. Group I (n = 56) received a bolus of cholecalciferol at a dose of 50,000 IU on the first and the eighth days of hospitalization. Patients from Group II (n = 54) did not receive the supplementation. We found significant differences between groups with the preferential increase in serum 25(OH)D level and Δ 25(OH)D in Group I on the ninth day of hospitalization (p < 0.001). The serum 25(OH)D level on the ninth day was negatively associated with the number of bed days (r = −0.23, p = 0.006); we did not observe other clinical benefits in patients receiving an oral bolus of cholecalciferol. Moreover, in Group I, neutrophil and lymphocyte counts were significantly higher (p = 0.04; p = 0.02), while the C-reactive protein level was significantly lower on the ninth day of hospitalization (p = 0.02). Patients with supplementation of 100,000 IU of cholecalciferol, compared to those without supplementation, showed a decrease in the frequencies of CD38++CD27 transitional and CD27−CD38+ mature naive B cells (p = 0.006 and p = 0.02) and an increase in the level of CD27−CD38− DN B cells (p = 0.02). Thus, the rise in serum 25(OH)D level caused by vitamin D supplementation in vitamin D insufficient and deficient patients may positively affect immune status and hence the course of COVID-19.

Case Report: Supernormal Vascular Aging in Leningrad Siege Survivors.

Age-related changes in the vascular system play an important role in the biological age and lifespan of a person and maybe affected from an early age onward. One of the indicators of changes in the vascular system is arterial wall stiffness and its main measure, i.e., carotid-femoral pulse wave velocity (cfPWV). We examined arterial wall stiffness in a sample of 305 Leningrad Siege survivors to assess how hunger and stressful conditions during fetal development and early childhood affected the state of the cardiovascular system at a later age and what factors may neutralize the negative impact sustained in early childhood. Here, we presented an evaluation of two unique patients with supernormal vascular aging (SUPERNOVA) phenotype from this cohort and described the details of congruence between hereditary resistance and practiced lifestyle yielding slower biological aging rate.

Application of Machine Learning Methods to Analyze Occurrence and Clinical Features of Ascending Aortic Dilatation in Patients with and without Bicuspid Aortic Valve.

Aortic aneurysm (AA) rapture is one of the leading causes of death worldwide. Unfortunately, the diagnosis of AA is often verified after the onset of complications, in most cases after aortic rupture. The aim of this study was to evaluate the frequency of ascending aortic aneurysm (AscAA) and aortic dilatation (AD) in patients with cardiovascular diseases undergoing echocardiography, and to identify the main risk factors depending on the morphology of the aortic valve. We processed 84,851 echocardiographic (ECHO) records of 13,050 patients with aortic dilatation (AD) in the Almazov National Medical Research Centre from 2010 to 2018, using machine learning methodologies. Despite a high prevalence of AD, the main reason for the performed ECHO was coronary artery disease (CAD) and hypertension (HP) in 33.5% and 14.2% of the patient groups, respectively. The prevalence of ascending AD (>40 mm) was 15.4% (13,050 patients; 78.3% (10,212 patients) in men and 21.7% (2838 patients) in women). Only 1.6% (n = 212) of the 13,050 patients with AD knew about AD before undergoing ECHO in our center. Among all the patients who underwent ECHO, we identified 1544 (1.8%) with bicuspid aortic valve (BAV) and 635 with BAV had AD (only 4.8% of all AD patients). According to the results of the random forest feature importance analysis, we identified the eight main factors of AD: age, male sex, vmax aortic valve (AV), aortic stenosis (AS), blood pressure, aortic regurgitation (AR), diabetes mellitus, and heart failure (HF). The known factors of AD-like HP, CAD, hyperlipidemia, BAV, and obesity, were also AD risk factors, but were not as important. Our study showed a high frequency of AscAA and dilation. Standard risk factors of AscAA such as HP, hyperlipidemia, or obesity are significantly more common in patients with AD, but the main factors in the formation of AD are age, male sex, vmax AV, blood pressure, AS, AR, HF, and diabetes mellitus. In males with BAV, AD incidence did not differ significantly, but the presence of congenital heart disease was one of the 12 main risk factors for the formation of AD and association with more significant aortic dilatation in AscAA groups.

Relationship between the Levels of lncRNA H19 in Plasma and Different Adipose Tissue Depots with Patients' Response to Bariatric Surgery.

Bariatric surgery represents a widespread approach to treating morbid obesity. The search for biomarkers to identify patients to whom this type of treatment will be most effective is needed. Our aim was to characterize the relationship of levels of lncRNA H19 in plasma and different adipose tissue depots with patients' response to bariatric surgery. The study includes control subjects, patients with obesity and patients with obesity accompanied by impaired carbohydrate metabolism (ICM). Quantitative analysis of lncRNA H19 levels has been performed using qPCR in plasma and subcutaneous (SAT) and visceral adipose tissue (VAT). Patients with obesity without ICM have higher levels of lncRNA H19 in VAT compared to SAT, and higher levels of lncRNA H19 in SAT compared to SAT of control individuals. One year after the intervention, levels of lncRNA H19 decreased in SAT of patients with obesity without ICM. The preoperative level of lncRNA H19 in VAT demonstrates a positive correlation with excess weight loss and a negative correlation with initial BMI. In conclusion, ICM affects expression of lncRNA H19 in SAT of patients with obesity. The preoperative level of lncRNA H19 in VAT can be used to predict excess weight loss in patients with obesity after bariatric surgery.

Vitamin D Intake May Reduce SARS-CoV-2 Infection Morbidity in Health Care Workers.

In the last 2 years, observational studies have shown that a low 25-hydroxyvitamin D (25(OH)D) level affected the severity of infection with the novel coronavirus (COVID-19). This study aimed to analyze the potential effect of vitamin D supplementation in reducing SARS-CoV-2 infection morbidity and severity in health care workers. Of 128 health care workers, 91 (consisting of 38 medical doctors (42%), 38 nurses (42%), and 15 medical attendants (16%)) were randomized into two groups receiving vitamin D supplementation. Participants of group I (n = 45) received water-soluble cholecalciferol at a dose of 50,000 IU/week for 2 consecutive weeks, followed by 5000 IU/day for the rest of the study. Participants of group II (n = 46) received water-soluble cholecalciferol at a dose of 2000 IU/day. For both groups, treatment lasted 3 months. Baseline serum 25(OH)D level in health care workers varied from 3.0 to 65.1 ng/mL (median, 17.7 (interquartile range, 12.2; 24.7) ng/mL). Vitamin D deficiency, insufficiency, and normal vitamin D status were diagnosed in 60%, 30%, and 10%, respectively. Only 78 subjects completed the study. Vitamin D supplementation was associated with an increase in serum 25(OH)D level, but only intake of 5000 IU/day was accompanied by normalization of serum 25(OH)D level, which occurred in 53% of cases. Neither vitamin D intake nor vitamin D deficiency/insufficiency were associated with a decrease in SARS-CoV-2 morbidity (odds ratio = 2.27; 95% confidence interval, 0.72 to 7.12). However, subjects receiving high-dose vitamin D had only asymptomatic SARS-CoV-2 in 10 (26%) cases; at the same time, participants who received 2000 IU/day showed twice as many SARS-CoV-2 cases, with mild clinical features in half of them.

Vitamin D Status and Immune Response in Hospitalized Patients with Moderate and Severe COVID-19.

A low 25-hydroxyvitamin D (25(OH)D) level is considered as an independent risk factor for COVID-19 severity. However, the association between vitamin D status and outcomes in COVID-19 is controversial. In the present study we investigate the association between the serum 25(OH)D level, immune response, and clinical disease course in patients with COVID-19. A total of 311 patients hospitalized with COVID-19 were enrolled. For patients with a vitamin D deficiency/insufficiency, the prevalence of severe COVID-19 was higher than in those with a normal 25(OH)D level (p < 0.001). The threshold of 25(OH)D level associated with mortality was 11.4 ng/mL (p = 0.003, ROC analysis). The frequency of CD3+CD4+ T helper (Th) cells was decreased in patients with 25(OH)D level ≤ 11.4 ng/mL, compared to healthy controls (HCs). There were no differences in the frequency of naive, central memory (CM), effector memory (EM), and terminally differentiated effector memory Th cells in patients with COVID-19 compared to HCs. The frequency of T-follicular helpers was decreased both in patients with 25(OH)D level > 11.4 ng/mL (p < 0.001) and 25(OH)D level ≤ 11.4 ng/mL (p = 0.003) compared to HCs. Patients with 25(OH)D level > 11.4 ng/mL had an increased frequency of Th2 CM (p = 0.010) and decreased Th17 CM (p < 0.001). While the frequency of Th2 EM was significantly increased, the frequency of Th17 EM was significantly decreased in both groups compared to HCs. Thus, 25(OH)D level is an independent risk factor for the disease severity and mortality in patients with COVID-19. We demonstrate that the serum 25(OH)D level ≤ 11.4 ng/mL is associated with the stimulation of Th2 and the downregulation of Th17 cell polarization of the adaptive immunity in patients with COVID-19.

Bromhexine Hydrochloride Prophylaxis of COVID-19 for Medical Personnel: A Randomized Open-Label Study.

BACKGROUND: Bromhexine hydrochloride has been suggested as a TMPRSS2 protease blocker that precludes the penetration of SARS-CoV-2 into cells. We aimed to assess the preventive potential of regular bromhexine hydrochloride intake for COVID-19 risk reduction in medical staff actively involved in the evaluation and treatment of patients with confirmed or suspected SARS-CoV-2 infection. METHODS: In a single-centre randomized open-label study, medical staff managing patients with suspected and confirmed COVID-19 were enrolled and followed up for 8 weeks. The study began at the initiation of COVID-19 management in the clinic. The study was prematurely terminated after the enrollment of 50 participants without a history of SARS-CoV-2 infection: 25 were assigned to bromhexine hydrochloride treatment (8 mg 3 times per day), and 25 were controls. The composite primary endpoint was a positive nasopharyngeal swab polymerase chain reaction (PCR) test for SARS-CoV-2 or signs of clinical infection within 28 days and at week 8. Secondary endpoints included time from the first contact with a person with COVID-19 to the appearance of respiratory infection symptoms; the number of days before a first positive SARS-CoV-2 test; the number of asymptomatic participants with a positive nasopharyngeal swab test; the number of symptomatic COVID-19 cases; and adverse events. RESULTS: The rate of the combined primary endpoint did not differ significantly between the active treatment group (2/25 [8%]) and control group (7/25 [28%]); P=0.07. A fewer number of participants developed symptomatic COVID-19 in the treatment group compared to controls (0/25 vs. 5/25; P=0.02). CONCLUSION: Although the study was underpowered, it showed that Bromhexine hydrochloride prophylaxis was associated with a reduced rate of symptomatic COVID-19. The prophylactic treatment was not associated with a lower combined primary endpoint rate, a positive swab PCR test, or COVID-19 (ClinicalTrials.gov number, NCT04405999).

Hyperleptinemia results in systemic inflammation and the exacerbation of ischemia-reperfusion myocardial injury.

AIM: Hyperleptinemia potentiates the effects of many atherogenic factors, such as inflammation, platelet aggregation, migration, hypertrophy, proliferation of vascular smooth muscle cells, and endothelial cell dysfunction. The present study analysed the effects of long-term hyperleptinemia in an in vivo myocardial ischemia-reperfusion model to demonstrate whether the in vivo deleterious effect also affects cardiac structure and function. MAIN METHODS: Rats were subcutaneously administered leptin for 8 days to estimate the involvement of the JAK/STAT pathway. Data from 58 male Wistar rats were included in the final analysis. Myocardial infarction (MI) was modelled by the 30-minute ligation of the main left coronary artery followed by 120-minute reperfusion. Hemodynamic measurements, electrocardiography monitoring, echocardiography, myocardial infarct size and area at risk, blood biochemical parameters, leptin, IL-6, TNF-alpha, FGF-21, and cardiomyocyte morphology were measured. The expression of JAK2, p-JAK2, STAT3, p-STAT3 was assessed by Western Blot analysis. Statistical analyses were performed using IBM SPSS Statistics v.26. KEY FINDINGS: Eight-day hyperleptinemia in rats leads to an increase in blood pressure and heart rate, myocardial hypertrophy, impaired LV function, the frequency of ischemic arrhythmias, dyslipidemia, systemic inflammation, and the size of induced myocardial infarction. Significance: The blockade of the JAK/STAT signalling pathway effectively reverses the negative effects of leptin, including increased blood pressure and total cholesterol.

Integrative Analysis of Multi-Omics and Genetic Approaches-A New Level in Atherosclerotic Cardiovascular Risk Prediction.

Genetics and environmental and lifestyle factors deeply affect cardiovascular diseases, with atherosclerosis as the etiopathological factor (ACVD) and their early recognition can significantly contribute to an efficient prevention and treatment of the disease. Due to the vast number of these factors, only the novel "omic" approaches are surmised. In addition to genomics, which extended the effective therapeutic potential for complex and rarer diseases, the use of "omics" presents a step-forward that can be harnessed for more accurate ACVD prediction and risk assessment in larger populations. The analysis of these data by artificial intelligence (AI)/machine learning (ML) strategies makes is possible to decipher the large amount of data that derives from such techniques, in order to provide an unbiased assessment of pathophysiological correlations and to develop a better understanding of the molecular background of ACVD. The predictive models implementing data from these "omics", are based on consolidated AI best practices for classical ML and deep learning paradigms that employ methods (e.g., Integrative Network Fusion method, using an AI/ML supervised strategy and cross-validation) to validate the reproducibility of the results. Here, we highlight the proposed integrated approach for the prediction and diagnosis of ACVD with the presentation of the key elements of a joint scientific project of the University of Milan and the Almazov National Medical Research Centre.

Low 25(OH)D Level Is Associated with Severe Course and Poor Prognosis in COVID-19.

We evaluated associations between serum 25-hydroxyvitamin D [25(OH)D] level and severity of new coronavirus infection (COVID-19) in hospitalized patients. We assessed serum 25(OH)D level in 133 patients aged 21-93 years. Twenty-five (19%) patients had severe disease, 108 patients (81%) had moderate disease, and 18 (14%) patients died. 25(OH)D level ranged from 3.0 to 97.0 ng/mL (median, 13.5 [25%; 75%, 9.6; 23.3] ng/mL). Vitamin D deficiency was diagnosed in 90 patients, including 37 with severe deficiency. In patients with severe course of disease, 25(OH)D level was lower (median, 9.7 [25%; 75%, 6.0; 14.9] ng/mL), and vitamin D deficiency was more common than in patients with moderate course (median, 14.6 [25%; 75%, 10.6; 24.4] ng/mL, p = 0.003). In patients who died, 25(OH)D was 9.6 [25%; 75%, 6.0; 11.5] ng/mL, compared with 14.8 [25%; 75%, 10.1; 24.3] ng/mL in discharged patients (p = 0.001). Severe vitamin D deficiency was associated with increased risk of COVID-19 severity and fatal outcome. The threshold for 25(OH)D level associated with increased risk of severe course was 11.7 ng/mL. Approximately the same 25(OH)D level, 10.9 ng/mL, was associated with increased risk of mortality. Thus, most COVID-19 patients have vitamin D deficiency; severe vitamin D deficiency is associated with increased risk of COVID-19 severity and fatal outcome.