Imbalanced brain connectome: A possible link behind functional somatic disorders, multiple chemical sensitivity, and long COVID patients

Background: Functional Somatic Disorders (FSDs) are characterized by persistent physical symptoms that cannot be explained by other somatic or psychiatric conditions. Multiple Chemical Sensitivity (MCS) is a non-allergic FSD characterized by odour intolerance and various somatic symptoms being attributed to the influence of toxic environmental chemicals in low, usually harmless doses. The pathophysiology of FSDs are still not clear. Smell and taste complaints were also among the notable symptoms characterizing the covid epidemic and the latest evidence suggests overlaps between long COVID and FSDs. Method(s): The study includes advanced analysis of MRI-derived functional and structural connectomes acquired on a 3 T MR scanner. Furthermore, it includes questionnaires and paraclinical tests, e.g. the Sniffin' Stick olfactory test, Mini-Mental State Examination, and Sino-Nasal Outcome test 22. The pilot part of the project included 6 MCS patients who were compared with 6 matched healthy participants. Later follow-up included analysis of 8 multiorgan FSD and 4 post-COVID patients. Result(s): The MCS group showed important brain structural connectivity differences in 34 tracts. Notably, for MCS patients, the olfactory cortex (especially in the right hemisphere) showed decreased connectivity with regions in the emotional system. Conclusion(s): We plan to extend these findings with whole-brain modelling of the functional connectivity in the patient groups. Long-term this could be used as a 'fingerprint' which could help with diagnosis and treatment monitoring in FSDs as well as with new diagnoses such as long-COVID.Copyright © 2023

Plasma cytokine profile in patients with severe COVID-19

Background/Objectives: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease (COVID-19) enters the lung tissue through exocytosis, leading to the release of a large amount of pro-inflammatory cytokines called 'cytokine storm'. The aim was to provide more insight into relationship between plasma cytokines profile and fatal outcome of COVID-19. Method(s): Plasma cytokines (IL-17F,GM-CSF,IFNg,IL-10,CCL20/ MIP3a,IL-12P70,IL-13, IL-15,IL-17A,IL-22,IL-9,IL-1b,IL-33,IL-2,IL-21,IL-4,IL-23,IL-5,IL-6,IL-17E/IL-25,IL-27,IL-31,TNFa,TNFb,IL-28A) were detected in 30 patients with severe COVID-19 by a Luminex assay system with Milliplex Human Th17 Magnetic Premix 25 Plex Kit (HT17MG-14K-PX-25, Merk-Millipore, USA) according to the instructions. Patients were followed up for 30 days since admission to intensive care. 18 patients died and 12 patients survived during the period of observation. The control group comprised 10 individuals who had never been diagnosed with COVID-19. Result(s): IL-10 and CCL20/MIP3a plasma levels were elevated in non-survivors patients with COVID-19 compared to controls (p = 0.0027, p = 0.012, respectively). IL-15, IL-6, IL-27 plasma levels were higher in survivors with COVID-19 compared to controls (p = 0.049, p = 0.026, p = 0.00032, respectively). Interestingly, IL-15, IL-27 plasma levels were increased in non-survivors with COVID-19 compared to controls and survivors with severe COVID-19 (IL-15: p = 0.00098, p = 0.00014, respectively;IL-27: p = 0.011, p < 0.0001, respectively). Receiver operating characteristic (ROC) analysis has been conducted for IL-15 and IL-27. Cut-off value was estimated as 25.50 pg/ml for IL-15 and 1.51 pg/ml for IL-27. Conclusion(s): Our study demonstrated a more pronounced immune response in non-surviving patients with severe COVID-19. IL-15, IL-27 could be considered as a sensitive biomarker of the fatal outcome from COVID-19.

Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2-33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.

Hairy Cell Leukemia in a Filipino Male during the COVID-19 Pandemic - Report of a Rare Case

Hairy cell leukemia (HCL) is a rare, chronic, mature B-cell lymphoproliferative disorder accounting for 2% of all leukemias. In this paper, we would like to present our experience in the management of HCL in a financially limited setting where other diagnostic tests and chemotherapy are unavailable. The case report aims to emphasize the recognition of the distinctive morphology of hairy cells in the peripheral blood in the consideration of the initial diagnosis. A 60-year-old Filipino male was incidentally found to have anemia, thrombocytopenia and an absolute neutrophilic count below 1,000 in a pre-operative clearance for elective herniorrhaphy. Blood smear revealed atypical lymphocytes with hair like cytoplasmic projections. CT-scan of the abdomen showed splenomegaly and prominent paraaortic nodes. Flow cytometry of the bone marrow aspirate was consistent with an involvement of a Mature B cell neoplasm markers CD19, CD20, CD22 and surface immunoglobulin lambda and hairy cell leukemia markers CD11c, CD103 and CD25. He responded to six-weekly sessions of Cladribine with remission of the bone marrow and hematologic parameters. HCL is a rare type of a mature B cell neoplasm characterized by pancytopenia, splenomegaly, bone marrow fibrosis and the presence of atypical lymphoid cells with hairy projections in blood, bone marrow and spleen. Immunophenotyping express CD11c, CD103, CD123, and CD25. BRAF V600E mutation is the disease defining genetic event. Cladribine and Pentostatin are the first line of treatment. Cases of leukemia can be easily overlooked because of the mild derangement in the complete blood count. A meticulous differential review of the atypical lymphocyte, is the first step in the diagnosis of this rare disease.Copyright © 2022, Philippine College of Physicians. All rights reserved.

C-reactive protein to lymphocyte ratio is a significant predictive factor for poor short-term clinical outcomes of SARS-CoV-2 BA.2.2 patients.

Objective: The aim of the present study is to assess the utility of C-reactive protein to Lymphocyte Ratio (CLR) in predicting short-term clinical outcomes of patients infected by SARS-CoV-2 BA.2.2. Methods: This retrospective study was performed on 1,219 patients with laboratory-confirmed SARS-CoV-2 BA.2.2 to determine the association of CLR with short-term clinical outcomes. Independent Chi square test, Rank sum test, and binary logistic regression analysis were performed to calculate mean differences and adjusted odds ratios (aORs) with their 95% CI, respectively. Results: Over 8% of patients admitted due to SARS-CoV-2 BA.2.2. were critically ill. The best cut-off value of CLR was 21.25 in the ROC with a sensitivity of 72.3% and a specificity of 86%. After adjusting age, gender, and comorbidities, binary logistic regression analysis showed that elevated CLR was an independent risk factor for poor short-term clinical outcomes of COVID-19 patients. Conclusion: C-reactive protein to Lymphocyte Ratio is a significant predictive factor for poor short-term clinical outcomes of SARS-CoV-2 BA.2.2 inflicted patients.

The abundance of Interleukin-22, 37, and 38 post-vaccination and following COVID-19 recuperation

The SARS-CoV-2 virus causes a contagious disease known as Coronavirus Disease 2019 (COVID-19). It began spreading globally in 2019 and is still producing pandemics today. Different COVID-19 vaccinations offer protection against this illness. Pfizer-BioNTech and Sinopharm were the two vaccine manufacturers with the highest usage in Iraq. Both vaccines use a different method to activate the immune system. This study seeks to compare the IL-22, IL-37, and IL-38 levels in those who received either the Sinopharm or the Pfizer-BioNTech COVID-19 vaccination. IL-22, IL-37, IL-38 levels have been shown to be upregulated in COVID-19 patients. In this study, IL-22, IL-37, and IL-38 levels were tested in 80 healthy controls and 100 COVID-19 patients 14-21 days after recovery. Additionally, people who received the Sinopharm or Pfizer-BioNTech vaccine (50 each) were monitored 21 days after the first dosage and 21 days after the second dose. In comparison to controls, serum levels were noticeably higher in recovered patients. Except for the first dosage of Pfizer BioNTech, the first and second doses of Sinopharm and Pfizer BioNTech were linked to considerably higher levels of IL-22, IL-37, and IL-38 compared to controls or recovered patients. where IL-22, IL-37, and IL-38 levels did not show significant differences compared to recovered patients. In conclusion, lower IL-37 and IL-38 molecule levels were linked to recovery from COVID-19, although these levels remained considerably greater in recovered patients compared to uninfected controls. Vaccination with Sinopharm or Pfizer-BioNTech confirmed the up-regulating effects of SARS-CoV-2 on IL-22, IL-37, and IL-38 levels.Copyright © 2023, Codon Publications. All rights reserved.

Olfactory training in long COVID-19 patients with lasting symptoms including olfactory dysfunction

INTRODUCTION. Two-thirds of patients with COVID-19 developed smell and taste dysfunction, of whom half experienced improvement within the first month. After six months, 5-15% still suffered from significant olfactory dysfunction (OD). Before COVID-19, olfactory training (OT) was proved to be effective in patients with post-infectious OD. Therefore, the present study aimed to investigate the progress of olfactory recovery with and without OT in patients with long COVID-19. METHODS. Consecutive patients with long COVID-19 referred to the Flavour Clinic at Godstrup Regional Hospital, Denmark, were enrolled. The diagnostic set-up at the first visit and follow-up included smell and taste tests, questionnaires, ENT examination and instructions in OT. RESULTS. From January 2021 to April 2022, 52 patients were included due to long COVID-19-related OD. The majority of patients complained of distorted sensory quality, in particular, parosmia. Two-thirds of the patients reported a subjective improvement of their sense of smell and taste along with a significant decline in the negative impact on quality of life (p = 0.0001). Retesting at follow-up demonstrated a significant increase in smell scores (p = 0.023) where a minimal clinically important difference (MCID) in smell scores was found in 23% of patients. Full training compliance was significantly associated with the probability of MCID improvement (OR = 8.13;p = 0.04). CONCLUSIONS. The average effect of OT is modest;however, full training compliance was significantly associated with an increased probability of a clinically relevant olfactory improvement. FUNDING. none. TRIAL REGISTRATION. not relevant.Copyright © 2023, Almindelige Danske Laegeforening. All rights reserved.

Distinct profiles and kinetics of soluble infammatory markers in patients with acute and chronic HCV-infections and SARS-CoV-2-infections: Implications for the long-term consequences of viral infections?

Background and Aims Viral infections occur acutely but can also progress chronically, with the immune system having a central role in immunopathoge-nesis. The question arises whether all alterations in immune responses are reversible after viral elimination (spontaneously or by therapy). Therefore, the aim of this study is to compare soluble infammatory markers (SIM) during and after infection with SARS-CoV-2 and acute and chronic HCV-infections. Patients and Method Patients with acute HCV (n = 29), chronic HCV (n = 54), SARS-CoV-2 (n = 39) and 31 healthy-controls were included. Blood samples were tested at baseline, end of treatment/infection, and follow-up ( >= 9 months after baseline). IL-12p70, IL-1b, IL-4, IL-5, IL-6, IL-8, TNF, IFN-g, IL-10, IL-22, CXCL-10, MCP-1, MIP-1b, ITAC were quantified using the HD-SP-X Imaging and Analysis SystemTM. Results SIM profiles in patients with acute HCV were substantially elevated at baseline and the decrease during follow-up was considerably less compared to the SARS-CoV-2 cohort. In chronic HCV-patients, viral elimination by therapy resulted in a decrease in SIM, although not always to those of controls. Cirrhotic HCV patients had higher SIM levels after HCV elimination than non-cirrhotic chronic HCV-patients. In the SARS-CoV-2 cohort, most SIM returned to levels of controls 3 months after baseline. Conclusions SIM profiles and kinetics after viral elimination difer between blood-borne acute and chronic HCV- and respiratory SARS-CoV-2-infections. The immunologic imprint 9 months after cured HCV-infection (both acute and chronic) appears to be more pronounced than after SARS-CoV-2-infection. Further analysis is needed to correlate the SIM profle with the clinical pheno-type (long-HepC vs. long-COVID-19).

COVID-19 Anxiety and Washing Obsessive-compulsive Symptoms: Stress Coping Styles as a Mediator

Background: The COVID-19 pandemic has significantly impacted people's psychological functioning, including how they cope with anxiety. This study aimed to assess the role of coping styles in the relationship between COVID-19 anxiety and Washing ObsessiveCompulsive Disorder (W-OCD) symptoms. Methods: A cross-sectional study was performed on 420 people living in Kashan city (Iran) from March to April, 2020. Participants were selected by the convenience sampling method due to the difficulties brought about by COVID-19 and completed the contamination subscale of the Padua Inventory, COVID-19 anxiety inventory, and coping strategies scale. Data were analyzed by structural equation modeling (SEM) using AMOS-22. Results: The results revealed that emotion-focused, somatization and social support coping strategies were significantly associated with W-OCD symptoms. Also, there was a significant correlation between COVID-19 anxiety and the W-OCD symptoms. SEM results revealed that emotion-focused and somatization coping strategies positively mediated the relationship between COVID-19 and W-OCD symptoms. Conclusion: Emotion-focused and somatization coping strategies increase W-OCD symptoms following COVID-19 anxiety. Psychoeducation interventions addressing COVID-19's physical and psychological impacts on health, discriminating the rational and adaptive behavior and obsessive and compulsive behaviors, and restricting the information gathering from numerous sources, which may lead to increased negative emotions, might be helpful. © 2023 Bentham Science Publishers.

Rapid Assessment of COVID-19 Mortality Risk with GASS Classifiers.

Risk prediction models are fundamental to effectively triage incoming COVID-19 patients. However, current triaging methods often have poor predictive performance, are based on variables that are expensive to measure, and often lead to hard-to-interpret decisions. We introduce two new classification methods that can predict COVID-19 mortality risk from the automatic analysis of routine clinical variables with high accuracy and interpretability. SVM22-GASS and Clinical-GASS classifiers leverage machine learning methods and clinical expertise, respectively. Both were developed using a derivation cohort of 499 patients from the first wave of the pandemic and were validated with an independent validation cohort of 250 patients from the second pandemic phase. The Clinical-GASS classifier is a threshold-based classifier that leverages the General Assessment of SARS-CoV-2 Severity (GASS) score, a COVID-19-specific clinical score that recently showed its effectiveness in predicting the COVID-19 mortality risk. The SVM22-GASS model is a binary classifier that non-linearly processes clinical data using a Support Vector Machine (SVM). In this study, we show that SMV22-GASS was able to predict the mortality risk of the validation cohort with an AUC of 0.87 and an accuracy of 0.88, better than most scores previously developed. Similarly, the Clinical-GASS classifier predicted the mortality risk of the validation cohort with an AUC of 0.77 and an accuracy of 0.78, on par with other established and emerging machine-learning-based methods. Our results demonstrate the feasibility of accurate COVID-19 mortality risk prediction using only routine clinical variables, readily collected in the early stages of hospital admission.

Predictive Value of Specific Cytokines for Lethal Covid-19 Outcome

In our study, we aimed to evaluate the significance of specific cytokines in blood plasma as predictive markers of COVID-associated mortality. Materials and methods. In plasma samples of 29 patients with PCR-confirmed COVID-19 we measured the concentrations of 47 molecules. These molecules included: interleukins and selected pro-inflammatory cytokines (IL-1alpha, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A/CTLA8, IL-17-E/IL-25, IL-17F, IL-18, IL-22, IL-27, IFNalpha2, IFNgamma, TNFalpha, TNFbeta/Lymphotoxin-alpha(LTA));chemokines (CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL7/MCP-3, CCL11/Eotaxin, CCL22/MDC, CXCL1/GROalpha, CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10, CX3CL1/Fractalkine);anti-inflammatory cytokines (IL-1Ra, IL-10);growth factors (EGF, FGF-2/FGF-basic, Flt-3 Ligand, G-CSF, M-CSF, GM-CSF, PDGF-AA, PDGFAB/BB, TGFalpha, VEGF-A);and sCD40L. We used multiplex analysis based on xMAP technology (Luminex, USA) using Luminex MagPix. As controls, we used plasma samples of 20 healthy individuals. Based on the results, we applied Receiver Operating Characteristic (ROC) analysis and Area Under Curve (AUC) values to compare two different predictive tests and to choose the optimal division point for disease outcome (survivors/non-survivors). To find optimal biomarker combinations, we as used cytokines concentrations as dependent variables to grow a regression tree using JMP 16 Software.Results. Out of 47 studied cytokines/chemokines/growth factors, we picked four pro-inflammatory cytokines as having high significance in evaluation of COVID-19 outcome: IL-6, IL-8, IL-15, and IL-18. Based on the results received, we assume that the highest significance in terms of predicting the outcome of acute COVID-19 belongs to IL-6 and IL-18. Conclusion. Analyzing concentrations of IL-6 and IL-18 before administering treatment may prove valuable in terms of outcome prognosis. Copyright © Arsentieva N.A. et al., 2022.

Potential Role of the Antidepressants Fluoxetine and Fluvoxamine in the Treatment of COVID-19.

Mapping non-canonical cellular pathways affected by approved medications can accelerate drug repurposing efforts, which are crucial in situations with a global impact such as the COVID-19 pandemic. Fluoxetine and fluvoxamine are well-established and widely-used antidepressive agents that act as serotonin reuptake inhibitors (SSRI-s). Interestingly, these drugs have been reported earlier to act as lysosomotropic agents, inhibitors of acid sphingomyelinase in the lysosomes, and as ligands of sigma-1 receptors, mechanisms that might be used to fight severe outcomes of COVID-19. In certain cases, these drugs were administered for selected COVID-19 patients because of their antidepressive effects, while in other cases, clinical studies were performed to assess the effect of these drugs on treating COVID-19 patients. Clinical studies produced promising data that encourage the further investigation of fluoxetine and fluvoxamine regarding their use in COVID-19. In this review, we summarize experimental data and the results of the performed clinical studies. We also provide an overview of previous knowledge on the tissue distribution of these drugs and by integrating this information with the published experimental results, we highlight the real opportunity of using these drugs in our fight against COVID-19.

IS PSORIATIC ARTHRITIS A RISK FACTOR for SEVERE COVID-19 INFECTION? DATA from the ARGENTINIAN REGISTRY SAR-COVID

Background: Comorbidities, particularly cardio-metabolic disorders, are highly prevalent in patients with psoriatic arthritis (PsA) and they were associated with an increased risk of atherosclerotic cardiovascular disease, which have been associated with higher morbidity and mortality. Whether PsA enhances the risk of SARS-CoV-2 infection or affects the disease outcome remains to be ascertained. Objectives: To describe the sociodemographic, clinical and treatment characteristics of patients with PsA with confrmed SARS-CoV-2 infection from the SAR-COVID registry and to identify the variables associated with poor COVID-19 outcomes, comparing them with those with rheumatoid arthritis (RA). Methods: Cross-sectional observational study including patients ≥18 years old, with diagnosis of PsA (CASPAR criteria) and RA (ACR/EULAR 2010 criteria), who had confrmed SARS-CoV-2 infection (RT-PCR or serology) from the SAR-COVID registry. Recruitment period was between August 13, 2020 and July 31, 2021. Sociodemographic variables, comorbidities, and treatments were analyzed. To assess the severity of the infection, the ordinal scale of the National Institute of Allergy and Infectious Diseases (NIAID)1 was used, and it was considered that a patient met the primary outcome, if they presented criteria of categories 5 or higher on the severity scale. For this analysis, Chi2 test, Fisher's test, Student's test or Wilcoxon test, and binomial logistic regression using NIAID>=5 as dependent variable were performed. Results: A total of 129 PsA patients and 808 with RA were included. Clinical characteristics are shown in Table 1. Regarding PsA treatment, 12.4% of PsA were receiving IL-17 inhibitors, 5.4% IL12-23 inhibitors, one patient apremilast and one abatacept. The frequency of NIAID≥5 was comparable between groups (PsA 19.5% vs RA 20.1%;p=0.976). (Figure 1). PsA patients with NIAID≥5 in comparison with NIAID<5 were older (58.6±11.4 vs 50±12.5;p=0.002), had more frequently hypertension (52.2% vs 23%;p=0.011) and dyslipidemia (39.1% vs 15%;p=0.017). In the multivariate analysis, age (OR 1.06;95% CI 1.02-1.11) was associated with a worse outcome of the COVID-19 (NIAID≥5) in patients with PsA, while those who received methotrexate (OR 0.34;95% CI 0.11-0.92) and biological DMARDs (OR 0.28;95% CI 0.09-0.78) had a better outcome. Conclusion: Although PsA patients have a higher frequency of cardiovascular and metabolic comorbidities than those with RA, the COVID-19 severity was similar. Most of the patients had mild SARS-CoV-2 infection and a low death rate.

Evaluation of nasal function in patients with COVID-19: nasal secretion, nasal clearance, and SNOT-22 score

Objective: This study aimed to investigate the nasal findings in patients who tested positive for the coronavirus disease 2019 (COVID-19) and objectively evaluate the amount of nasal secretion and nasal clearance. Methods: The study included 40 patients who tested positive and 40 volunteers who tested negative for COVID-19 infection. The self-administered Turkish version of the sinonasal outcome test -22 (SNOT-22) questionnaire was used to evaluate the sinonasal findings, the nasal Schirmer test was used to evaluate the amount of nasal secretion, and the saccharin test was used to evaluate nasal clearance. The results of both groups were compared. Results: The SNOT-22 score averages were 23.3±14.5 and 11.2±11.7 for the COVID-19-positive group and COVID-19-negative controls, respectively. In the COVID-19 positive group, SNOT-22 results were statistically significantly higher than those of the controls (p≤0.001). The nasal Schirmer and nasal saccharin test results in the COVID-19-positive group were statistically significantly higher than those of the controls (p≤0.002 and p≤0.001). Conclusion: In patients who tested positive for COVID-19 infection, increased amounts of nasal secretion and prolonged nasal clearance time were observed. They also had higher SNOT-22 scores than those of the negative controls. Although these findings demonstrate that there may be changes in nasal functions in patients positive for COVID-19 infection, new studies are needed to elucidate the nasal effects in detail.

Polycystic ovary syndrome as a predictor of metabolic syndrome in women of reproductive age

Relevance: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. The prevalence rates of PCOS depend on the diagnostic criteria used and the characteristics of the population sample, and in the general population of women of reproductive age, the prevalence of the syndrome ranges from 6-9% to 19.9% [1,2]. According to modern criteria adopted by the consensus in Rotterdam, then systematically updated by ESHRE / ASRM (2014), the presence of two of the three criteria in a patient simultaneously allows to diagnose PCOS if other pathological conditions are excluded (thyroid pathology, congenital adrenal hyperplasia, adrenogenitalsyndrome, androgen-secreting tumors, Itsenko-Cushing syndrome). Modern international diagnostic criteria include the following signs: (1) signs of polycystic ovaries according to information from pelvic ultrasound investigation (the presence of more than 10 follicles in each ovary);(2) oligo-anovulation;(3) clinical (presence of hirsutism) or biochemical (increased androgen levels) development of ovarian hyperandrogenism [3, 4]. Polycystic ovary syndrome is closely related to many diseases, including metabolic syndrome. Although insulin resistance is an important risk factor for metabolic syndrome and other diseases associated with PCOS, hyperandrogenismmay also be an independent risk factor for type 2 diabetes, obesity, cardiovascular disease (CVD), and metabolic syndrome in female patients. Obesity is the most common symptom in PCOS patients (33-88%), which has a large impact on fertility and can lead to adverse effects such as menstrual irregularities, anovulation, infertility and abortion. Therefore, weight management in early PCOS is essential to improve fertility and quality of life. Hyperandrogenism plays a decisive role in abdominal obesity in obese women during adolescence, adulthood and menopause [5]. Although some studies have shown a negative association between plasma androgen levels (A4, DHEA and DHEAS) and obesity [6,7]. But the mechanism of how androgens affect fat cells in women is poorly understood. A number of observations show that among obese women with PCOS, metabolic disorders associated with insulin resistance and obesity, in many cases, play a more important role in the mechanism of anovulation in PCOS than excess androgens. In recent years, it has been established that in PCOS there is a frequent combination of hyperandrogenism and insulin resistance. With insulin resistance, there is a decrease in the response of insulin-sensitive tissues to the hormone insulin with its sufficient level in the blood. Insulin resistance is found in 30-70% of patients with PCOS who are overweight or obese, and in patients with normal body weight it occurs in 20-25% of cases. The above facts, as well as our own observations, prompted us to analyze the studied women of fertile age with impaired reproductive system against the background of overweight and obesity. Considering the above, the aim of this study was to identify the relationship between insulin resistance and reproductive disorders in women with overweight and obesity. Material and research methods. The study included 123 women with clinical development of HA and impaired reproductive function, who consulted the consultative clinic of the RSSPMC of Obstetrics and Gynecology of the Ministry of Health of the Republic of Uzbekistan. The criteria for inclusion in the main group were: age of women from 18 to 35 years (average age was 25.8 .. 3.28 years), absence of pregnancy, body mass index over 25 kg / m2. Exclusion criteria from the main group: type 1 and 2 diabetes, pituitary tumors, hypogonadotropichypogonadism, congenital adrenal hyperplasia, hypothyroidism, severe somatic pathology. All patients who applied for the consultation underwent: (1) Collection of anamnestic information. (2) Measurement of anthropometric indicators (height, weight, waist and hip circumference) and assessment of body hair growth using the Ferriman-Hallway scale. (3) Body mass index was

Antiviral potential of garlic (Allium sativum) and its organosulfur compounds: A systematic update of pre-clinical and clinical data.

BACKGROUND: Garlic (Allium sativum L.) is a common herb consumed worldwide as functional food and traditional remedy for the prevention of infectious diseases since ancient time. Garlic and its active organosulfur compounds (OSCs) have been reported to alleviate a number of viral infections in pre-clinical and clinical investigations. However, so far no systematic review on its antiviral effects and the underlying molecular mechanisms exists. SCOPE AND APPROACH: The aim of this review is to systematically summarize pre-clinical and clinical investigations on antiviral effects of garlic and its OSCs as well as to further analyse recent findings on the mechanisms that underpin these antiviral actions. PubMed, Cochrane library, Google Scholar and Science Direct databases were searched and articles up to June 2020 were included in this review. KEY FINDINGS AND CONCLUSIONS: Pre-clinical data demonstrated that garlic and its OSCs have potential antiviral activity against different human, animal and plant pathogenic viruses through blocking viral entry into host cells, inhibiting viral RNA polymerase, reverse transcriptase, DNA synthesis and immediate-early gene 1(IEG1) transcription, as well as through downregulating the extracellular-signal-regulated kinase (ERK)/mitogen activated protein kinase (MAPK) signaling pathway. The alleviation of viral infection was also shown to link with immunomodulatory effects of garlic and its OSCs. Clinical studies further demonstrated a prophylactic effect of garlic in the prevention of widespread viral infections in humans through enhancing the immune response. This review highlights that garlic possesses significant antiviral activity and can be used prophylactically in the prevention of viral infections.

Human ACE2 and TMPRSS2 interaction with SARS-CoV-2 in COVID-19 patient: a review on male reproductive disorders

Since its inception in 2019 from China, the novel Coronavirus has caused an unprecedented havoc in the economic and public health sector. Many countries were forced to close their borders and cross-border interactions in order to limit the spread of the disease. Furthermore, many economic and commercial activities were adversely affected as many businesses had to close. The only ones that the pandemic spared were the ones providing essential services. By March 2020, many public healthcare facilities had already been overrun. Other governments devised alternative means of managing significant cases of COVID-19, such as introducing home-based care to give room for more critical cases to be taken care of in intensive care units. It is imperative to identify the disease's risk factors to mitigate the unexpected devastation caused by the SARS-CoV-2. Global epidemiological results indicate that men, especially the elderly, are more susceptible to Coronavirus infection. The number of reported Coronavirus cases varies by gender, and this disparity continues to grow in favor of male participants until they reach the age of 60. Other studies have also established that men more than women are susceptible to coronavirus infection. Further, male patients diagnosed with coronavirus infection were shown to have an elevated mortality rate. SARS-CoV-2 is the Covid-19 pathogen that is transmitted via respiratory globules, through indirect or direct interaction. Evaluation of the genome has revealed that SARS-CoV-2 is 79% similar to SARS-CoV-2;they employ ACE2 receptors to attack cells, meanwhile it has been established that TMPRSS2 promotes ACE2, therefore causing more severe reactions in comparison to the other types of coronaviruses. Studies describe ACE2 as a gateway for viruses to enter cells. It is directly associated with the COVID-19 clinical symptoms. Research has shown that TMPRSS2 and ACE2 are expressed in the male reproductive system tract and testis and are controlled by testosterone. Thus, the male reproductive system has all the mechanism needed to bid SARs-CoV-2, and these possibilities raise the capability of ACE2 and TMPRSS2 as potential vectors of COVID-19. This review examines how the novel Coronavirus find its way into the human cells through known receptors such as ACE2, antibody Fcy R, etc. The examination is also done on the mechanisms of its spike proteins transition with the help of proteases such as cathepsins, Furin, and TMPRSS2. The study reviewed six articles selected based on PRISMA criteria.

Fractionated Inotuzumab Ozogamicin Combined with Low-Intensity Chemotherapy Provides Very Good Outcome in Older Patients with Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: First Results from the EWALL-INO Study

On behalf of the GRAALL group, the Czech Republic ALL group, the Finland ALL group and the EWALL group. Introduction. Treatment of older patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains an unmet medical need. Inotuzumab ozogamicin (INO), an anti-CD22 antibody conjugated to calicheamicin, is approved for the treatment of relapsed/refractory BCP-ALL in adults, sinusoidal obstruction syndrome (SOS) being the major adverse event associated with INO. A previous first line study conducted by the MDACC in pts 60 years or older successfully used INO in combination with a lower intensity version of the hyper-CVAD (mini-hyper-CVD). Due to the occurrence of SOS, the total doses were fixed at 1.3 mg/m² for cycle 1 followed by 3 cycles at 1 mg/m² (Kantarjian H et al. Lancet Oncol, 2018). Here, we aimed to assess the activity and safety of fractionated INO at a reduced dosage in combination with low-intensity chemotherapy as frontline therapy for older pts with CD22+ Philadelphia chromosome-negative (Ph-neg) BCP-ALL. Methods. EWALL-INO is a single arm prospective phase 2 multicentric study conducted in European centers belonging to the EWALL group. Eligibility criteria were pts aged 55y or older, performance status ≤2, and newly diagnosed CD22+ (20% or more of positive blast cells) Ph-neg BCP-ALL without central nervous system involvement. After a prephase including 5 days (D) of dexamethasone (DEX) 10mg per D and a single intrathecal injection (IT), the induction regimen was begun and split in 2 parts. Induction part I (Induc1) consisted of one triple IT, vincristine (VCR) 2 mg (1 mg over 70y) D1 D8 D15 D22 and DEX 20 mg D1D2 D8D9 D15D16 D22D23 combined with 3 injections of INO (0.8 mg/m² D1, 0.5 mg/m² D8 and D15). Induction part II (Induc2) was offered to pts in CR or CRp (CR with platelets < 100 G/l) after Induc1 or as salvage therapy. Induc2 consisted of DEX 20mg D1D8, cyclophosphamide (CY) 300 mg/m² D1 to D3, one triple IT D2 and 2 injections of INO (0.5 mg/m² D1 and D8). Pts in CR/CRp were programmed to receive 6 blocks of consolidation (Ara-C 1.5g/m²/12h adapted to renal clearance D1D2 and DEX 10mg/12h D1D2, cycles 1 and 4;Methotrexate (MTX) 1.5 g/m² over 24h D1, VCR 1 or 2 mg D1, one triple IT D2 and 6-mercaptopurin (6-MP) D1 to D7, cycles 2 and 5;CY 500 mg/m² D1D2, VP16 75 mg/m² D1D2, one triple IT D2 and MTX 25 mg/m² D1, cycles 3 and 6) followed by a POMP maintenance (VCR, 6-MP, MTX, DEX) during 18 months. Allograft was allowed after at least 3 blocks of consolidation at the discretion of the investigators. The evaluable population was pts who received at least 1 dose of INO. Analyses were by modified intention to treat and performed JUN 28, 2021. All pts gave informed consent. The study is registered at ClinicalTrials.gov under the NCT number: NCT03249870. Results. Between DEC 29, 2017 and JUN 22, 2021, 115 pts (out of 130 planned pts) were enrolled including 6 pts with screen failure. The first 90 eligible pts (up to MAR 1, 2021) were considered for this analysis to obtain a minimum of 4 months follow-up. Median age was 69y (range 55-84) and median follow-up for alive pts was 1.18 years (range 0.3-3.5). At time of analysis, 90 and 88 pts had started induc1 and induc2, respectively. Treatment related mortality was 2.2% (2/90) and CR/CRp rate was 85.5% (77/90, 6 CRp) after induc1. Three cases relapsed between induc1 and induc2 and 5 pts were salvaged by induc2 allowing to a CR/CRp rate of 87.7% (79/90, 8 CRp) after induc2. One pts died from refractory disease during induc2. One, 2, 3 4 and 5 injections of INO were administered to 2 (2.2%), 2(2.2%), 11 (12.2%), 2 (2.2%) and 73 pts (81.1%) respectively. Only 6 pts were allografted. One-year OS was estimated to be 78.5% (95%CI 68-85.9) and median OS was not reached. One-year relapse free survival was 74.5% (95CI 63.5-82.6) (Figure 1). Grade 3-4 liver toxicity was observed in 8 pts (8.8%) during the study including 3 pts (3.3%) developing SOS, 2 related to INO during induc1 and one occurred after transplant. Twenty-nine pts died during the follow-up, 16 from relapses (overall incidence 18%) and 13 from adverse events (overall incidence 14.4%), including one COVID19 fatal infection during consolidation. Conclusion. Fractionated inotuzumab ozogamicin at reduced doses (0.8/0.5/0.5/0.5 mg/m²) combined with low-intensity chemotherapy is a very active and well tolerated frontline therapy for older patients with CD22+ Ph-neg BCP-ALL. [Formula presented] Disclosures: Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Huguet: Novartis: Other: Advisor;Jazz Pharmaceuticals: Other: Advisor;Celgene: Other: Advisor;BMS: Other: Advisor;Amgen: Other: Advisor;Pfizer: Other: Advisor. Raffoux: ABBVIE: Consultancy;PFIZER: Consultancy;CELGENE/BMS: Consultancy;ASTELLAS: Consultancy. Boissel: CELGENE: Honoraria;Servier: Consultancy, Honoraria;Incyte: Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Research Funding;Bristol-Myers Squibb: Honoraria, Research Funding;PFIZER: Consultancy, Honoraria;JAZZ Pharma: Honoraria, Research Funding;SANOFI: Honoraria. Dombret: Amgen: Honoraria, Research Funding;Incyte: Honoraria, Research Funding;Jazz Pharmaceuticals: Honoraria, Research Funding;Novartis: Research Funding;Pfizer: Honoraria, Research Funding;Servier: Research Funding;Abbvie: Honoraria;BMS-Celgene: Honoraria;Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia

Adoptive Immune Responses to Sars-Cov2 Vaccination in CART19 Treated Patients

Background: The two FDA approved mRNA-based SARS-CoV2 vaccines have shown >90% efficacy at preventing COVID and eliciting protective immunity in nearly all healthy individuals. However, the extent of vaccine induced antibody and T cell immunity in immunocompromised patients is not well known. Our study objective is to determine if patients with hematologic malignancies treated with B-cell targeting chimeric antigen receptor (CAR) T cell therapies can mount antibody and T cell immune responses to SARS-CoV2 vaccines. A prospective single-center study to evaluate the SARS-CoV2 immune responses in immunocompromised individuals (COVAX Study) was initiated at University of Pennsylvania following the IRB guidelines. The study enrolled 8 healthy adults,12 patients are in remission after treatment (average of 40.6 months) with CART cells targeting either CD19 or CD19+CD22 and received both doses of SARS-CoV2 vaccine. Methods and Results: Serology to SARS-CoV2 spike-receptor binding domain (RBD) IgG, RBD-IgA, RBD-IgM and spike-specific T cell responses were measured prior to vaccination and serially up to 28 days after booster vaccination. RBD-IgG and RBD-IgA were detected in 8/8 and 7/8 healthy subjects compared to 5/12 and 2/12 CART patients, respectively (Figure A). In the CART cohort, several patients who demonstrated an induction of RBD-IgG (57.2/uL +/- 20.2) compared to those who were RBD-IgG-negative (9/uL +/- 10.1, ANOVA with multiple comparisons test p=0.017) have higher level of circulating B cells. No association was found with time since CART infusion, age, disease type, or vaccine manufacturer. All 8 healthy subjects demonstrated induction of SARS-Cov2 spike-specific CD4 + T cell immunity compared to 7 out of 11 CART patients (Figure B). RBD-IgG responses were not correlated with CD4 + T cell activation (Pearson correlation, R=0.21, p=0.53). Indeed, 3 CART patients demonstrated robust CD4 + T cell activation despite absence of antibody induction. Overall, 8/12 CART patients demonstrated induction of either or both humoral and T cell immune responses. Conclusions: We show that immune responses to SARS-CoV2 mRNA vaccines are induced in majority of patients who have been treated with CART therapies targeting B-cell lineage antigens. Induction of vaccine-specific antibody was strongly associated with the level of circulating B cells. However, in CART cohort patients despite severe humoral immune deficiency, strong CD4 + T cell responses were observed suggestive of a sufficient protective immunity. [Formula presented] Disclosures: Frey: Novartis: Research Funding;Sana Biotechnology: Consultancy;Kite Pharma: Consultancy;Syndax Pharmaceuticals: Consultancy. Garfall: Amgen: Honoraria;CRISPR Therapeutics: Research Funding;GlaxoSmithKline: Honoraria;Janssen: Honoraria, Research Funding;Novartis: Research Funding;Tmunity: Research Funding. Porter: American Society for Transplantation and Cellular Therapy: Honoraria;Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months;ASH: Membership on an entity's Board of Directors or advisory committees;DeCart: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Membership on an entity's Board of Directors or advisory committees;National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding;Tmunity: Patents & Royalties;Wiley and Sons Publishing: Honoraria. June: AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy;Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company;Novartis: Patents & Royalties.

[Point-of-care testing: place of France in the world National survey in healthcare establisments in 2019]. / Examens de biologie médicale délocalisée : place de la France dans le monde Enquête nationale en 2019 dans les établissements de santé.

The point-of-care tests (POCT) are subject to accreditation. A national inventory survey provides a synthesis of knowledge. The survey distributed 31 questions in 2019. 147 responses were received (75% biologists, 49% CHU, 42% CHG). Only 20.41% are accredited ISO22870, the majority for <50% of the medical departments; 70% say they are going there at the end of 2019 or in 2020. The maps are unknown for 32% (EBMD) and 82% (TROD). Visibility is poor with: medical establishment committee (40%), IT department (31%). Connection is necessary for 87-95% depending on the criterion (QC, authorizations, etc.) and 66% of answers highlight that less than 50% of connexion is effective. The major advantage is the delay of the result (62.5%), then the relationship with the health teams (33.3%). The disadvantages: difficulty of the quality approach (45%), cost of tests (34.3%). Human resource requirements are identified for technicians (82%) and biologists (76%). The multiplicity of sites, devices and operators means that it is difficult to set up and maintain. Biology outside the laboratories, under biological responsibility, must meet a rigorous imperative quality approach.