Polycystic Ovary Syndrome and COVID-19.

Polycystic ovary syndrome (PCOS) is generally characterized by hyperandrogenism, obesity, chronic low-grade inflammation, abnormalities in carbohydrate and lipid metabolism, vit. D deficiency and gut microbiota dysbiosis. Each of the aforementioned disturbances might be considered as a risk factor for increased SARS-CoV-2 susceptibility and more severe COVID-19 infection in women with PCOS. Hyperandrogenism is thought to play an essential role for determining the grade of susceptibility as well as the risk of severe COVID-19 infection in PCOS. It could be explained by the expression of a specific cellular co-receptor - transmembrane serine protease-2 (TMPRSS2), the process of androgen-dependent immune modulation and that of the stimulated renin-angiotensin system (RAS). Android obesity, commonly seen in PCOS, represents a condition of chronic low-grade inflammation that leads to the development of immune dysfunction and increased sensitivity to SARS-CoV-2 among the carriers of this syndrome. In addition, vit. D deficiency and gut dysbiosis have been described as other potential pathophysiological factors contributing to an increased risk for severe COVID-19 in women with PCOS.Copyright © 2022 Medical Information Center. All rights reserved.

Polycystic Ovary Syndrome and COVID-19.

Polycystic ovary syndrome (PCOS) is generally characterized by hyperandrogenism, obesity, chronic low-grade inflammation, abnormalities in carbohydrate and lipid metabolism, vit. D deficiency and gut microbiota dysbiosis. Each of the aforementioned disturbances might be considered as a risk factor for increased SARS-CoV-2 susceptibility and more severe COVID-19 infection in women with PCOS. Hyperandrogenism is thought to play an essential role for determining the grade of susceptibility as well as the risk of severe COVID-19 infection in PCOS. It could be explained by the expression of a specific cellular co-receptor - transmembrane serine protease-2 (TMPRSS2), the process of androgen-dependent immune modulation and that of the stimulated renin-angiotensin system (RAS). Android obesity, commonly seen in PCOS, represents a condition of chronic low-grade inflammation that leads to the development of immune dysfunction and increased sensitivity to SARS-CoV-2 among the carriers of this syndrome. In addition, vit. D deficiency and gut dysbiosis have been described as other potential pathophysiological factors contributing to an increased risk for severe COVID-19 in women with PCOS.Copyright © 2022 Medical Information Center. All rights reserved.

The Impact of Post COVID Rehabilitation on the Level of Systemic Inflammation in Patients with Post COVID Syndrome

Rationale: Low-grade inflammation is a risk factor for adverse cardiovascular events including death from cardiovascular disease. Cardiovascular events are one of the most common manifestations of post covid syndrome, impacting the mortality in the post covid period. Methods: 260 post covid patients age 48-66 years were examined. All patients underwent rehabilitation in a Crimean sanitorium, that included climatologic therapy on the southern coast of Crimea;dietary therapy;pharmacologic therapy, and if necessary, breathing exercises using a variety of methods of respiratory therapy. The patients were examined for C-reactive protein (CRP) level in peripheral blood before and after the sanatorium rehabilitation. Results: The level of CRP of the patients who underwent rehabilitation did not differ significantly (p>0.05) from the initial values obtained on the day of admission to the rehabilitation center. At admission and upon discharge the CRP values corresponded to the lower limit of the levels characteristic of low-grade inflammation ranging from 3 mg/l to 10 mg/l). Conclusions: The currently available methods of physical rehabilitation of post covid patients as implemented in a Crimean sanitorium did not provide a reduction of the level of systemic inflammation as assessed by CRP determination. New less traditional approaches may be needed to reduce inflammation in post covid syndrome patients who are at risk for cardiovascular adverse consequences.

Evaluating the Relationship Between Obesity and the Humoral Immune Response to COVID-19 Vaccines

Background. The pro-inflammatory state associated with obesity leads to B- and T-lymphocyte dysfunction that may lead to an inadequate immune response to natural infection and vaccination. Preliminary studies, conducted outside of the US, involving multiple COVID-19 vaccines indicate that obesity may impact antibody response. The objective of this study was to evaluate the role of inflammatory status as a mediator in the relationship between obesity and COVID-19 vaccine immune response in a predominantly African-American population. Methods. This cross-sectional analysis involved 54 participants 18 years of age who had completed the primary dosing schedule and booster for Novavax's recombinant COVID-19 vaccine, NVX-CoV2373. Weight, height, and waist circumference (WC) measurements were taken. Medical history including COVID-19 vaccination and known COVID-19 infection were obtained. Blood samples were taken for measurement of c-reactive protein (CRP) and anti-SARS-CoV-2 spike protein IgG levels. Spearman correlation coefficient was used to assess the presence of a relationship between BMI and CRP, WC and CRP, CRP and spike protein IgG, BMI and spike protein IgG, and finally, WC and spike protein IgG. Mediation analysis was used to evaluate the moderating effect of plasma CRP on the relationship between WC and spike protein IgG while adjusting for suspected confounders. Statistical significance was defined as p < .05. Results. There was an expected positive relationship betweenWCand CRP, (rho = 0.37, p< .05). CRP and spike protein IgG trended towards a weak, negative relationship (rho= -0.13, p > .05). WC and BMI both trended towards a positive relationship with anti-SARS-CoV-2 spike protein IgG (rho = 0.29 and 0.15, respectively, p >.05). The mediation analysis showed that WC positively influenced spike protein IgG (p< .05), and this effect was not mediated by CRP. Conclusion. Inflammation may be negatively associated with antibody response to COVID-19 vaccines. WC and antibody response may be positively related in NVX-CoV2373 recipients, in spite of chronic low-grade inflammation. Further research is needed to fully characterize the impact of obesity on COVID-19 vaccine immunogenic responses.

The effects of low-grade inflammation and sleep loss on model-based and model-free control: Results of an experimental double hit model

Methods: In an ongoing study, we recruited 46 individuals who complete three sessions: sleep loss (2 nights of 4h in bed), normal sleep (2 nights of 9h in bed) (within-subjects), and a low-grade inflammation condition (COVID-19 vaccination) preceded by either sleep loss or normal sleep (between subjects). Blood samples were taken (not analyzed), sickness symptoms were assessed (SicknessQ with 10-point scale), and model-based and model-free control was quantified (a sequential decision task). Result(s): Sickness symptoms were highest after vaccination with sleep loss (M = 34.6), followed by vaccination with normal sleep (M = 24.3) and sleep loss (M = 23.8), and normal sleep only (M = 15.3). Model-free control increased in the vaccine as compared to the non-vaccine condition (b = 0.23, 95% CI 0.10, 0.37, p <.001), most clearly in the normal sleep condition. Model-based control decreased after sleep loss versus normal sleep (reward + common: b = -0.47, 95% CI -0.67, -0.28, p <.001, non-reward + rare: b = -0.43, 95% CI -0.63, -0.18, p <.001), which was not modulated by vaccination. Conclusion(s): These results suggest that low-grade inflammation and sleep loss independently attenuate behavioral control towards a cognitively less expensive but inflexible decision style. The potential role of sleep-immune pathways in model-based and model-free control will be discussed. Copyright © 2022

Experimental sleep loss and low-grade inflammation attenuate behavioural control towards a cognitively less expensive but inflexible decision style

Introduction: Behavioural control arises from a balance between model-based and model-free behaviour. Model-based behaviour is cognitively costly but enables adaptation to changes in the environment. In contrast, model-free control is fast, cognitively inexpensive, but inflexible. Overreliance on model-free control and/or reduced model-based control is found across various mental health conditions, suggesting that these modes of control may be influenced by common trans diagnostic processes. Since insufficient sleep and low-grade inflammation are highly common in mental ill-health, we assessed how they by themselves and in combination influence behavioural control Methods: In an ongoing study, we recruited 46 individuals who completed three sessions: Sleep loss (2 nights of 4 h in bed), normal sleep (2 nights of 9 h in bed) (within-subjects), and a low-grade inflammation condition (COVID-19 vaccination) preceded by either sleep loss or normal sleep (between subjects). Blood samples were taken (not analysed), sickness symptoms were assessed using the SicknessQ, and model-based and model-free control was quantified (using a sequential decision task). Result(s): Sickness symptoms were highest after vaccination with sleep loss (M = 34.6), followed by vaccination with normal sleep (M = 24.3) and sleep loss (M = 23.8), and normal sleep only (M = 15.3). Modelfree behaviour increased in the vaccine as compared to the nonvaccine condition (b = 0.23, 95% CI 0.10, 0.37, p < 0.001). Modelbased control decreased after sleep loss versus normal sleep (reward + common: B = -0.47, 95% CI -0.67, -0.28, p < 0.001, nonreward + rare: B = -0.43, 95% CI -0.63, -0.18, p < 0.001), which was not modulated by vaccination. Conclusion(s): These results suggest that sleep loss and low-grade inflammation independently attenuate behavioural control towards a cognitively less expensive but inflexible decision style.

IMMUNO-PSYCHIATRY AND INFLAMMATION

: The discovery that the immune system can influence brain function and structure has profoundly changed the landscape of psychiatry. Repeated report of association of pro-inflammatory cytokines with major psychiatric disorders led to exploration of the causes and consequences of this inflammatory background. This low-grade inflammation has been shown to be the consequence of interaction between environmental factors such as infections, stress, pollution, unhealthy lifestyle with immune-genetic background. Association with particular immune-genetic variants of Toll-like receptor genes possibly explain diminished response to infections (TLR, NOD), association with mitochondrial genes contribute to maintenance of inflammation, while association with particular HLA haplotypes explains induction of auto-immune phenomena and/or exaggerated synaptic pruning. For example, association with the complement genes can induce abnormal pruning and microglial activation thereby increasing the risk of neurodevelopmental disorders such as early onset schizophrenia. In the context of the SARS-Cov2 pandemic, increased severity of COVID-19 in psychiatric patients is probably due to their reduced ability to fight infection. Systemic inflammation and persistent infections induce different pathways paving the way to biomarker-guided personalized medicine. One of the best examples is the identification of “autoimmune psychosis” defined by presence of anti-neuronal antibodies that has been confounded for long with atypical, mild, or attenuated forms of autoimmune encephalitis. Persistent infections are associated to activation of Human endogenous retrovirus (HERV). Systemic inflammation induced by microbial infection or psychosocial factors can also be at the origin of the activation of human endogenous retrovirus. Inflammation is also known to be associated with gut dysbiosis and disturbance of the integrity of the digestive barrier leading to behavioral abnormalities. One last example can be found in the immune-metabolic abnormalities that pave the way to metabolic syndrome associated with psychiatric disorders. Although many aspects of the complex relationship between immunity and brain function are not yet fully elucidated, the findings that have accumulated so far have transformed our understanding of psychiatric disorders and favored the consideration of other possible cellular and molecular targets for their treatment than just alterations in neuronal transmitters. Disclosure: Nothing to disclose.

Understanding mental stress and skin aging connection among dermatologists and psychologists through real world evidence

Preaging is an emerging concept in China whereby young women are looking for skin aging solutions. Among the intrinsic and extrinsic causes of skin aging, mental stress was highlighted as a possible cause of preaging in young women. The COVID-19 pandemic has further impacted the mental well-being of the younger generation, with 44% of Asian women aged 18 to 34 under poor mental well-being based on WHO-5. While 76.5% of dermatologists agreed that there is a strong connection between stress and skin aging, there is limited evidence on the pathophysiology. The aim of this research is to explore how clinicians understand the impact of stress and the biologic pathways connecting stress and skin aging. A quantitative survey with 60 dermatologists and 60 psychologists from China and Japan was conducted to assess the link between stress and skin aging. Overall, 69.2% of both health care professionals agree that psychological stress has a significant link to skin aging. Three meta-themes were perceived by clinician as possible pathways connecting psychological stress and skin aging, including stress hormone, inflammation, and overactive immune system. While all health care professionals have heard of inflammaging, only 52% are very familiar with the concept. Both groups agree that unresolved acute inflammatory response can accelerate skin aging. Surprisingly, a significant difference was observed in that psychologists believe more strongly than dermatologists that chronic low-grade inflammation accelerates skin aging. This study highlights the need for further fundamental research, which could help clinicians provide appropriate recommendations for patients under psychological stress.

OA Biology

Purpose: The field of osteoarthritis (OA) biology is rapidly evolving and brilliant progress has been made this year as well. Methods: Landmark studies of OA biology published in 2021 and early 2022 were selected through PubMed searches and classified by their molecular mechanisms, and it was largely divided into the intra-cellular mechanisms and the inter-compartment or inter-cellular interaction in OA progression. Results: The intra-cellular mechanisms involving OA progression included 1) Piezo1/TRPV4-mediated calcium signaling, 2) low grade inflammation by TLR-CD14-LBP complex and IKKβ-NFkB signaling, 3) PGRN/TNFR2/14-3-3ε/Elk-1 anabolic cascade, 4) G protein-coupled receptor (GPCR) signaling, 5) mechanical loading-cilia/Ift88-hedgehog signaling, 6) mitochondrial fission by ERK1/2-DRP1 pathway, and 7) hypoxia-DOT1L-H3K79 methylation pathway. The studies on inter-compartment or inter-cellular interaction in OA progression included the following subjects: 1) the anabolic role of Lubricin, a proteoglycan from superficial zone cells, 2) osteoclast-chondrocyte interaction via exosomal miRNA and sphingosine 1-phosphate (S1P), 3) αV integrin-mediated TGFβ activation by mechanical loading, 4) TGFβ-mediated suppression of sclerostin in osteocytes, 5) catabolic role of Flightless I as a DAMPs-triggering molecule, and 6) catabolic role of paracrine signaling from fat. Conclusions: Despite the disastrous Covid-19 pandemic situation, many outstanding studies have expanded the boundary of OA biology. They give us not only critical insight on pathophysiology, but also clue for the treatment of OA.

ALTERED GUT MICROBIOTA and RESPIRATORY DYSFUNCTION 3 MONTHS after SEVERE COVID-19

Background: Although COVID-19 is primarily a respiratory infection, mounting evidence suggests that the GI tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and associate with long-term respiratory dysfunction is unknown. Methods: From the NOR-Solidarity trial (n=181), plasma was collected during hospital admission and after three months, and analyzed for markers of gut barrier dysfunction and inflammation. At the three-month follow-up, pulmonary function was assessed by measuring diffusing capacity of the lungs for carbon monoxide (DLCO), and rectal swabs for gut microbiota analyses were collected (n= 97) and analysed by sequencing of the 16S rRNA gene. Results: Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DLCO below lower limit of normal three months after hospitalization. These patients also had an altered global gut microbiota composition (Fig. 1), with reduced abundance of Erysipelotrichaceae UCG-003 and increased abundance of Flavonifractor and Veillonella, the latter potentially being linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2/fiO2-(P/F-ratio)<26.6 kPa. LBP levels remained elevated during and after hospitalization, and were associated with low-grade inflammation and respiratory dysfunction after three months. Figure 1 legend: Gut microbial composition in patients with respiratory dysfunction at the three-month follow-up (DLCO<="" div=""> Conclusion: Respiratory dysfunction after COVID-19 is associated with reduced biodiversity and gut microbiota alterations, along with persistently elevated LBP levels. Our results point to a potential gut-lung axis that should be further investigated in relation to long-term pulmonary dysfunction and long COVID.

Preliminary results of a complex program: Care for metabolic state of musculoskeletal system-a key to long-life independence in patients with osteoporosis and osteopenia

Objective: Ever since the times of ancient physicians and surgeons like Sushruta (600 BC) or Hippocrates (400 BC), it is clear that physical development of individuals with sedentary lifestyle is different from the one of the physically active individuals. Only after the year 2000, with the first discovery of causality of IL-6 and muscular movement, an intensive study of this problematics has begun. Currently, there are about 600 known operations (myokins) that are interrelated with muscle functions. Muscular tissue interrelates with others mechanistically, but it also forms humoral harmony in which the muscular tissue has a dominant and determining role. This phenomenon is relevant for pathophysiology of chronical low-grade inflammation, muscle loss, origin and development of noncommunicable diseases. These cause approx. 75% of deaths in population. Solution of this problem has been considerably affecting cost-effectivity in the health care system today and thus the state economy as well. Therapeutic recommendations together with the whole health care strategy need to be adjusted according to the above mentioned findings, including the patients with osteoporosis and osteopenia. There are, so far, no known suitable medicaments which would be used for solving problematics of muscular loss. This is a reason why more attention needs to be paid to the recommended physical regime (150 min/week, according to WHO) and dietary regime (basic diet + proteins). We have built a complex diagnostic and therapeutic program for our patients. Definition of pathological values follows EWGSOP and WHO. Methods: Patient cohorts: Osteoporosis 60-70 y, 70-80 y, osteopenia 60- 70 y and 70-80 y. Control group for osteopenia 60-80 y. We followed information about the control group during the COVID-19 time period, particularly their physical activity regime. 1) Instructions for patients used to be delivered in a form of lectures for different age groups. Now, during the COVID-19 time period, instructions are provided individually. 2) SarQol (Sarcopenia and Quality of Life) questionnaire (Beaudart 2015). Czech version used with agreement from sarqol.org. Assessment is now done individually only. 3) Measuring hand-grip is standardised according to Southampton protocol with a dynamometer Jamar. Values of 20 kg are found pathological (female values). 4) Determination of BMI, according to WHO, the border figure is 25 or 30 kg/m2 . 5) DXA method determination of selective muscle index as a measure for muscle mass. ALM/Ht2 for age above 60 y, border value for sarcopenia is ≤5.45 kg/m2 . 6) From laboratory examinations we aimed at IL-6 and CRP(hs) - these are not a subject of this report. Results: Conclusion: We have been running a physical activity and dietary program for our patients for more than 2 y. Physical activity is aimed at 150 min/week (WHO) and basic diet aims at the Mediterranean type + protein saturation, considerable stress is given to whey proteins enriched with Leucin. Patients have been instructed. Due to adherence to this regime we are able to report on statistically relevant changes in muscle power and also in complex muscle mass, even during the current pandemic situation. (Table Presented).

Post-COVID-19 syndrome, low-grade inflammation and inflammatory markers: a cross-sectional study.

OBJECTIVE: Post-COVID syndrome (PCS) is a poorly known entity. An underlying chronic, low-grade inflammation (LGI) has been theorized as a pathophysiological mechanism. Available data on biomarkers in PCS show conflicting results. Our aim was to know whether subjects with PCS present higher levels of inflammatory markers, after a mild COVID-19. METHODS: Analytical cross-sectional study. Cases of mild COVID-19 in a community setting were included. We collected epidemiological data (age, sex, BMI, smoking, comorbidities), variables of the acute COVID-19 (duration, symptoms), and data at 3 months after the acute phase (symptoms and laboratory test). Serum C-reactive protein (CRP), neutrophil and lymphocyte counts, neutrophil/lymphocyte ratio (NLR), lactate dehydrogenase, ferritin, fibrinogen, and D-dimer levels were analysed. LGI was defined as CRP >0.3 and <1.0 mg/dL. A subject was classified as PCS + if presented signs and symptoms >12 weeks after an infection consistent with COVID-19. Five composite indices (C1-C5) were developed, combining the upper ranges of biomarkers distributions. Multivariate analyses were performed. RESULTS: We analysed 121 mild COVID-19 cases (mean age = 45.7 years, 56.2% women). Among the acute symptoms, women presented a higher frequency of fatigue (54.4% vs 30.2%; p = .008). PCS affected 35.8% of women and 20.8% of men (p = .07), and the most reported symptoms were fatigue (42.8%), anosmia (40%), ageusia (22.8%), dyspnea (17.1%) and myalgia (11.4%). Neutrophil count, NLR, CRP and fibrinogen showed the best correlations with PCS and were selected to develop the indices. In women PCS+, C1, C3 and C4 indices were more frequently met, while in men PCS+, C2, C5 and CRP were in the range of LGI. Anosmia, ageusia and fatigue were related to higher neutrophil counts, with sex differences. Fibrinogen levels were higher in persistent myalgia (510 ± 82 mg/dL vs 394 ± 87; p = .013). In multivariable analysis, a woman with a neutrophil count above the median, or with fibrinogen level or NLR in the highest tertile, had a 4-5-fold increased risk of prevalent PCS. A man with CRP in the range of LGI, or fibrinogen level or a neutrophil count in the highest tertile, had a 10-17-fold increased risk of prevalent PCS. CONCLUSIONS: The data obtained in the present cross-sectional study seems to demonstrate a consistent association between PCS and upper ranges of the neutrophil count, NLR, fibrinogen, and CRP in the LGI range. Furthermore, composite indices appear useful in detecting relationships between slight elevations of biomarkers and PCS, and our study identifies relevant sex differences in symptoms and markers regarding the PCS.

Was it COVID19 or the vaccine a rare case of SARS-COV2 infection or post-vaccine triggered flare in juvenile dermatomyositis

Introduction: Vaccines and infection can cause flares of inflammatory conditions. Objectives: We describe a rare, rapid flare of Juvenile Dermatomyositis (JDM) preceded by confirmed Sars-Cov2 antibodies (asymptomatic infection or first vaccination). Methods: Data was extracted from electronic medical records and a literature review undertaken. Results: We present a 16 year old female of Bangladeshi origin with JDM diagnosed August 2019 (CK 29691, CMAS 23;Mi-2b, Ku, Mi-2a positive). On a background of suboptimal control with low grade inflammation (CK 659;CMAS 51) medications were altered in May 2020 adding Adalimumab and Mycophenolate Mofitil (MMF), to Methotrexate and Intravenous Immunoglobulin (IVIG). CK rose in August 2020 (15969). IVIG continued and physiotherapy input increased. After a stable 5 months (CK 100-300), CK grew to 2307 but as CMAS remained 50 treatment was not altered. Four weeks prior (Jan 2021) the patient received their first dose of Pfizer SARS-CoV2 vaccination. A family member was confirmed to be COVID-19 positive 8 weeks prior and the family isolated together. Our patient did not report any known COVID-19 symptoms. In March 2021 she presented with a 4 day history of acute active inflammation as demonstrated by malaise, increased rash, muscle pain and reduced function (CMAS 3, CK 52848). She was admitted for Multidisciplinary management of an acute flare and found to be SARS-CoV2 IgG positive consistent with prior infection. Adalimumab and MMF were swopped with tacrolimus alongside intravenous methylprednisolone, oral prednisolone and physiotherapy. CMAS scores remained considerably low (5) over the following 6 weeks, with a rapid rise (34) at week 7 with the patient discharged home. Literature review has identified a case of Anti-MDA5 JDM increased interstitial lung disease associated with active SARS-CoV2 infection1. Similarly there is a case presentation of Macrophage Activation Syndrome in Systemic Onset Juvenile Idiopathic Arthritis temporally associated with SARS-CoV2 infection2. There are no reported cases of vaccine mediated hyperinflammation of muscle or skin disease in JDM or Paediatric Inflammatory Multisystem Syndrome Temporally associated with COVID-19 (PIMSTS)3. Conclusion: This was a rare case of a rapid deterioration in function and hyperinflammation at a time of PIMSTS and other similar reactions in adolescents with Rheumatic diseases. We hypothesise that this such case may have been triggered by recent asymptomatic COVID-19 infection or following SARS-Cov2 vaccination.

Findings from Studies Are Congruent with Obesity Having a Viral Origin, but What about Obesity-Related NAFLD?

Infection has recently started receiving greater attention as an unusual causative/inducing factor of obesity. Indeed, the biological plausibility of infectobesity includes direct roles of some viruses to reprogram host metabolism toward a more lipogenic and adipogenic status. Furthermore, the probability that humans may exchange microbiota components (virome/virobiota) points out that the altered response of IFN and other cytokines, which surfaces as a central mechanism for adipogenesis and obesity-associated immune suppression, is due to the fact that gut microbiota uphold intrinsic IFN signaling. Last but not least, the adaptation of both host immune and metabolic system under persistent viral infections play a central role in these phenomena. We hereby discuss the possible link between adenovirus and obesity-related nonalcoholic fatty liver disease (NAFLD). The mechanisms of adenovirus-36 (Ad-36) involvement in hepatic steatosis/NAFLD consist in reducing leptin gene expression and insulin sensitivity, augmenting glucose uptake, activating the lipogenic and pro-inflammatory pathways in adipose tissue, and increasing the level of macrophage chemoattractant protein-1, all of these ultimately leading to chronic inflammation and altered lipid metabolism. Moreover, by reducing leptin expression and secretion Ad-36 may have in turn an obesogenic effect through increased food intake or decreased energy expenditure via altered fat metabolism. Finally, Ad-36 is involved in upregulation of cAMP, phosphatidylinositol 3-kinase, and p38 signaling pathways, downregulation of Wnt10b expression, increased expression of CCAAT/enhancer binding protein-beta, and peroxisome proliferator-activated receptor gamma 2 with consequential lipid accumulation.

The forgotten oral microbial transplantation for improving the outcomes of COVID-19.

Ever since the uncovering of the severe discrepancy of COVID-19 manifestations, irrespective of viral load, scientists have raced to locate and manage factors contributing to the genesis of a critical state. Recent evidence delineates the role of oral dysbiosis in the development of low-grade inflammation, characterized by the increase of inflammatory cytokines common to those fundamental to the development of severe COVID. Furthermore, high periodontopathic bacteria were recorded in severe acute respiratory syndrome in COVID patients, as well as its common provoking comorbidities such as diabetes and hypertension. This can be explained by the immigration and elimination of oral bacteria into the airways, which, in the context of an injured lung, allows for their preferential overgrowth familiar to that, causing the progression to advanced lung diseases. This is why we indicate the promising usage of oral microbiome transplantation as a treatment of oral microbial dysbiosis, not only associated with the worst outcomes of COVID-19 but also in other disorders of low-grade inflammation.

Problems of Pathogenesis and Pathogenetic Therapy of COVID-19 from the Perspective of the General Theory of Pathological Systems (General Pathological Processes).

The COVID-19 pandemic examines not only the state of actual health care but also the state of fundamental medicine in various countries. Pro-inflammatory processes extend far beyond the classical concepts of inflammation. They manifest themselves in a variety of ways, beginning with extreme physiology, then allostasis at low-grade inflammation, and finally the shockogenic phenomenon of "inflammatory systemic microcirculation". The pathogenetic core of critical situations, including COVID-19, is this phenomenon. Microcirculatory abnormalities, on the other hand, lie at the heart of a specific type of general pathological process known as systemic inflammation (SI). Systemic inflammatory response, cytokine release, cytokine storm, and thrombo-inflammatory syndrome are all terms that refer to different aspects of SI. As a result, the metabolic syndrome model does not adequately reflect the pathophysiology of persistent low-grade systemic inflammation (ChSLGI). Diseases associated with ChSLGI, on the other hand, are risk factors for a severe COVID-19 course. The review examines the role of hypoxia, metabolic dysfunction, scavenger receptors, and pattern-recognition receptors, as well as the processes of the hemophagocytic syndrome, in the systemic alteration and development of SI in COVID-19.

Review: Obesity and COVID-19: A Detrimental Intersection.

Obesity has been recognized as an independent risk factor for critical illness and major severity in subjects with coronavirus disease 2019 (COVID-19). The role of fat distribution, particularly visceral fat (often linked to metabolic abnormalities), is still unclear. The adipose tissue represents a direct source of cytokines responsible for the pathological modifications occurring within adipose tissue in obese subjects. Adipokines are a crucial connection between metabolism and immune system: their dysregulation in obesity contributes to chronic low-grade systemic inflammation and metabolic comorbidities. Therefore the increased amount of visceral fat can lead to a proinflammatory phenotypic shift. This review analyzes the interrelation between obesity and COVID-19 severity, as well as the cellular key players and molecular mechanisms implicated in adipose inflammation, investigating if adipose tissue can constitute a reservoir for viral spread, and contribute to immune activation and cytokines storm. Targeting the underlying molecular mechanisms might have therapeutic potential in the management of obesity-related complications in COVID-19 patients.

Obesity pandemic during COVID-19 outbreak: Narrative review and future considerations.

The high prevalence of obesity and obesity-related comorbidities has reached pandemic proportions, particularly in Western countries. Obesity increases the risk to develop several chronic noncommunicable disease, ultimately contributing to reduced survival. Recently, obesity has been recognized as major risk factor for coronavirus disease-19 (COVID-19)-related prognosis, contributing to worse outcomes in those with established COVID-19. Particularly, obesity has been associated with higher hospitalization rates in acute or intensive care and greater risk for invasive mechanical ventilation than lean people. Obesity is characterized by metabolic impairments and chronic low-grade systemic inflammation that causes a pro-inflammatory microenvironment, further aggravating the cytokine production and risk of cytokine storm response during Sars-Cov2 sepsis or other secondary infections. Moreover, the metabolic dysregulations are closely related to an impaired immune system and altered response to viral infection that can ultimately lead to a greater susceptibility to infections, longer viral shedding and greater duration of illness and severity of the disease. In individuals with obesity, maintaining a healthy diet, remaining physically active and reducing sedentary behaviors are particularly important during COVID-19-related quarantine to reduce metabolic and immune impairments. Moreover, such stategies are of utmost importance to reduce the risk for sarcopenia and sarcopenic obesity, and to prevent a reduction and potentially even increase cardiorespiratory fitness, a well-known independent risk factor for cardiovascular and metabolic diseases and recently found to be a risk factor also for hospitalizations secondary to COVID-19. Such lifestyle strategies may ultimately reduce morbility and mortality in patients with infectious disease, especially in those with concomitant obesity. The aim of this review is to discuss how obesity might increase the risk of COVID-19 and potentially affect its prognosis once COVID-19 is diagnosed. We therefore advocate for implementation of strategies aimed at preventing obesity in the first place, but also to minimize the metabolic anomalies that may lead to a compromized immune response and chronic low-grade systemic inflammation, especially in patients with COVID-19.

Assessment of cytokines, microRNA and patient related outcome measures in conversion disorder/functional neurological disorder (CD/FND): The CANDO clinical feasibility study.

BACKGROUND: Conversion disorder/functional neurological disorder (CD/FND) occurs often in neurological settings and can lead to long-term distress, disability and demand on health care services. Systemic low-grade inflammation might play a role, however, the pathogenic mechanism is still unknown. AIM: 1) To explore the feasibility to establish and assess a cohort of CD/FND with motor symptoms, involving persons with lived experience (PPI). 2) To generate proof of concept regarding a possible role for cytokines, microRNA, cortisol levels and neurocognitive symptoms in patients with motor CD/FND. METHOD: Feasibility study. RESULTS: The study showed active involvement of patients despite high clinical illness burden and disability, neurocognitive symptoms, childhood adverse experiences (ACE) and current life events. The study provided valuable knowledge regarding the feasibility of conducting a study in these patients that will inform future study phases. In the sample there were elevated levels of IL6, IL12, IL17A, IFNg, TNFa and VEGF-a, suggesting systemic low-grade inflammation. Also, microRNAs involved in inflammation and vascular inflammation were correlated with TNFa and VEGFa respectively, suggesting proof of concept for an epigenetic mechanism. Owing to the COVID-19 outbreak, the patient sample was limited to 15 patients. CONCLUSION: It is a novelty that this study is conducted in the clinical setting. This innovative, translational study explores stress-related SLI in CD/FND patients and the feasibility of a larger project aiming to develop new treatments for this vulnerable population. Given the positive findings, there is scope to conduct further research into the mechanism of disease in CD/FND.