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The entire world has been suffering from the coronavirus disease 2019 (COVID‐19) pandemic since March 11, 2020. More than a year later, the COVID‐19 vaccination brought hope to control this viral pandemic. Here, we review the unknowns of the COVID‐19 vaccination, such as its longevity, asymptomatic spread, long‐term side effects, and its efficacy on immunocompromised patients. In addition, we discuss challenges associated with the COVID‐19 vaccination, such as the global access and distribution of vaccine doses, adherence to hygiene guidelines after vaccination, the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants, and vaccine resistance. Despite all these challenges and the fact that the end of the COVID‐19 pandemic is still unclear, vaccines have brought great hope for the world, with several reports indicating a significant decline in the risk of COVID19‐related infection and hospitalizations., peer-reviewed

This chapter briefly describes the universal intricacies caused by the COVID-19 pandemic, from the ineffectiveness of distance measures, the massive economic impacts, and the severe mental health challenges to the failure of finding a vaccine, a therapeutic agent or even accurately diagnosing the infection. The entire world is suffering, but every country is trying to combat this pandemic individually, and this deed is the main barrier that prevents reaching a peaceful end.

Background: CCL11 (eotaxin) is a chemokine with an important role in allergic conditions. Recent evidence indicates that CCL11 plays a role in brain disorders as well. Aims: This paper reviews the associations between CCL11 and aging, neurodegenerative, neuroinflammatory and neuropsychiatric disorders.Methods: Electronic databases were searched for original articles examining CCL11 in neuropsychiatric disorders.Results: CCL11 is rapidly transported from the blood to the brain through the brain-blood barrier. Age-related increases in CCL11 are associated with cognitive impairments in executive functions, episodic and semantic memory and, therefore, this chemokine was described as an “endogenous cognition deteriorating chemokine” (ECDC) or “accelerated brain-aging chemokine” (ABAC). In schizophrenia, increased CCL11 is not only associated with impairments in cognitive functions, but also with key symptoms including formal thought disorders. Some patients with mood disorders and premenstrual syndrome show increased plasma CCL11 levels. In diseases of old age, CCL11 is associated with lowered neurogenesis and neurodegenerative processes and, as a consequence, increased CCL11 increases risk towards Alzheimer's Disease. Polymorphisms in the CCL11 gene are associated with stroke. Increased CCL11 also plays a role in neuroinflammatory disease including multiple sclerosis. In animal models, neutralization of CCL11 may protect against nigrostriatal neurodegeneration. Increased production of CCL11 may be attenuated by glucocorticoids, minocycline, resveratrol and anti-CCL11 antibodies.Conclusion: Increased CCL11 production during inflammatory conditions may play a role in human disease including age-related cognitive decline, schizophrenia, mood disorders and neurodegenerative disorders. Increased CCL11 production is a new drug target in the treatment and prevention of those disorders.

Psychoneuroendocrinoimmunology (PNEI) is an integrative discipline studying the processes by which mental events modulate immune functions and how the immune system in turn can alter brain function. The central nervous system (CNS) is the only system in the body lacking its own anatomically defined lymphatic vessels. The glymphatic system is an adaptation mechanism developed by the CNS for fluid balance and waste clearance. Prolonged exposure to stress – chronic stress, can be detrimental for the functioning of the central nervous system and the glymphatic system. Methods: Electronic databases including PubMed/MEDLINE, Google Scholar, and Scopus were searched for original articles examining stress and its effects on the glymphatic system.Results: Numerous everyday situations can be defined as “stressful” – work environment, exams, physical and psychological stress due to illness, trauma, etc. The body’s response to stress is a combination of adjustments known as “fight-flight-freeze” response – hormonal and physiologic changes helping the body fight a threat or flee to safety. Increase in stress is associated with impaired sleep and considering that the brain’s waste clearing system is shown to be active during sleep, it can be suggested that this is a mechanism in which stress affects glymphatic function.Conclusion: The research on the impact of stress on the glymphatic function is still lacking, but there are clear indications that researching the topic is valuable. It is promising to evaluate if through stress management there can be an improvement in waste-clearing in the brain and the prognosis of diseases characterized by accumulation of metabolites.

Objective(s): A variety of cytokines are involved in cognitive functioning. Balance restoration between protective and degenerative neuro-inflammation is of great interest in newer therapeutic approaches. In the current study, we investigated the effect of pramipexole (PMX) on memory functions, hippocampal amyloid deposition, serum cytokines, and brain-derived neurotrophic factor (BDNF) levels in lipopolysaccharide (LPS) challenged-rats. Materials and Methods: Male Wistar rats were divided into 5 groups (n=8): control (saline), lipoppolysacharide (LPS 250 mcg/kg bw), and experimental groups (LPS and PMX 0.5, 1, and 3 mg/kg bw). Learning and memory were assessed by the novel object recognition test (NORT), Y-maze, and step-through test. Immunological and histological assays were performed. Results: In memory tasks, LPS-challenged rats showed reduction in the observed parameters. In NORT, PMX 1 mg/kg increased recognition index compared with controls, whereas the other two doses increased this index only against the LPS-control. In Y-maze, all doses of PMX significantly had increased alternation when compared with LPS. In the step-through test, only the lowest dose of PMX extended the latency compared with LPS. Histological examination revealed that PMX at doses of 0.5 and 1 mg/kg reduced amyloid deposition in the hippocampus. Interleukin (IL)-10 serum levels were elevated by 1 mg/kg PMX. Tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β1 serum levels remained under the detectable minimum in all experimental groups. PMX at all doses significantly decreased BDNF serum concentration.Conclusion: In rats with LPS-induced neuro-inflammation PMX improved hippocampal-dependent memory and exerted immuno-modulatory effects by increasing IL-10.

Most cases of acute diarrhea in adults are of infectious etiology, likely viral and self-limited. Among those with severe diarrhea, however, bacterial causes are responsible for most cases.Apart from the standard stool cultures, to increase the positive yield a novel multiplex molecular test can be performed simultaneously. The authors present a patient with recurrent diarrhea and detection of Aeromonas hydrophila by culturing and Rotavirus and Clostridioides difficile by multiplex molecular test. They discuss and justify which is the most likely actionable pathogen. Good communication between the physicians and interpretation on the multiple positive results in the context of clinical picture and the test employed were important for a better management and favourable outcome of the patient.

Background: Increased intestinal permeability with heightened translocation of Gramnegative bacteria, also known as “leaky gut”, is associated with the pathophysiology of neuroimmune disorders, such as Major Depressive Disorder (MDD), Chronic Fatigue Syndrome (CSF) and (deficit) schizophrenia, as well as with general medical disorders, including irritable bowel syndrome. This review aims to summarize clinical biochemistry and molecular immunology tests that may aid in the recognition of leaky gut in clinical practice. Methods: We searched online libraries, including PubMed/MEDLINE, Google Scholar and Scopus, with the key words “diagnosis” or “biomarkers” and “leaky gut”, “bacterial translocation”, and “intestinal permeability” and focused on papers describing tests that may aid in the clinical recognition of leaky gut. Results: To evaluate tight junction barrier integrity, serum IgG/IgA/IgM responses to occludin and zonulin and IgA responses to actomyosin should be evaluated. The presence of cytotoxic bacterial products in serum can be evaluated using IgA/IgM responses to sonicated samples of common Gram-negative gut commensal bacteria and assays of serum lipopolysaccharides (LPSs) and other bacterial toxins, including cytolethal distenting toxin, subunit B. Major factors associated with increased gut permeability, including gut dysbiosis and yeast overgrowth, use of NSAIDs and alcohol, food hypersensitivities (IgE-mediated), food intolerances (IgG-mediated), small bacterial overgrowth (SIBO), systemic inflammation, psychosocial stressors, some infections (e.g., HIV) and dietary patterns, should be assessed. Stool samples can be used to assay gut dysbiosis, gut inflammation and decreased mucosal defenses using assays of fecal growth of bacteria, yeast and fungi and stool assays of calprotectin, secretory IgA, β-defensin, α- antitrypsin, lysozyme and lactoferrin. Blood and breath tests should be used to exclude common causes of increased gut permeability, namely, food hypersensitivities and intolerances, SIBO, lactose intolerance and fructose malabsorption. Discussion: Here, we propose strategies to recognize “leaky gut” in a clinical setting using the most adequate clinical chemistry and molecular immunology assays.

BACKGROUND: Allergic contact dermatitis (ACD) is common in clinical practice, but the aetiology of this disease is quite varied. A leading pathogenetic mechanism is a cell-mediated immunity. The combinations of ACD with other allergic and systemic autoimmune diseases are relatively rare, but these conditions are undoubtedly a professional challenge for practitioners. CASE REPORT: We present a case of ACD combined with other immune-allergic conditions. Aetiology and pathogenesis in these cases are not well understood. CONCLUSION: Based on the data from the general and targeted allergic history, patient’s subjective complaints, clinical picture, allergenic status, paraclinical results, and the presented photo material, the final diagnosis is as follows: Contact allergic dermatitis-acute form.

Background: Recent studies have suggested increased levels of pro-inflammatory cytokines in depression. Aim: The present study aimed to evaluate the effect of extracts from Rhodiola and Curcuma on immunoreactivity of animals subjected to a chronic mild stress (CMS) model followed by lipopolysaccharide-induced inflammation. Materials and methods: Male Wistar rats (n=56) divided in 7 groups were treated orally with: distilled water 10 ml/kg (control and CMS model groups); Rhodiola 250 mg/kg; Rhodiola 500 mg/kg; Curcuma 250 mg/kg; Curcuma 500 mg/kg, Rhodiola 250 mg/kg and Curcuma 250 mg/kg. All groups except the control were stressed daily according to a CMS protocol. Changes in glucose preference, weight gain and locomotor activity were recorded. In the sixth week the animals were challenged with LPS and rats’ sera were obtained for ELISA evaluation of TNF-α and IL-6 levels. Results: The animals from the model group decreased their weight gain, glucose preference and locomotor activity compared to controls. The groups exposed to stress and treated with Rhodiola 500 mg/kg, Curcuma 500 mg/kg and their combination increased their locomotor activity compared to the model group. High expression of the pro-inflammatory cytokines TNF-α and IL-6 were found in all groups exposed to CMS and challenged by LPS. Conclusions: The groups exposed to the stress procedure showed a variety of depression-like behavioral changes. In addition, ELISA tests showed that CMS is affecting rats’ immunity by increasing the cytokines’ levels. These changes could be reversed by administration of Rhodiola and Curcuma in combination suggesting synergic interaction regarding their anti-inflammatory and anti-stress effects.

The interplay of chronic stress, neuroinflammation and altered immune reactivity has been shown to be important for the pathophysiology of brain disorders such as schizophrenia, depressive disorders and post-traumatic stress disorder. This immuno-inflammatory theory has been extensively studied in the past three decades leading to the formation of the integrative discipline of psychoneuroimmunology. Targeting of the central nervous system by conventional pharmacotherapeutic methods is mainly through modulation of neuroendocrine systems such as the dopaminergic, GABA-ergic, adrenergic and serotoninergic systems. In recent years an increasing number of both experimental and clinical studies have shown that antidepressants can affect the immune system by reducing the production of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. However, due to the serious adverse effects accompanying the chronic administration of psychoactive drugs there is a continuous need to produce novel therapeutics that are both potent and safe. The present review aims to summarize the current knowledge in the field of psychoneuroimmunology and to delineate the main interactions between stress, inflammation, immunity and the brain. Additionally, this paper explores the use of plant-derived molecules that display a strong anti-stress effect and simultaneously modulate the immune response as an alternative or adjuvant to classical antidepressant drugs.

Deregulated cytokines' production is found in depressed patients. Salidroside and curcumin both have been described with potential antidepressant-like activities. The present study investigated the effect of pure salidroside, curcumin and their combination on the immunoreactivity of animals, subjected to a chronic mild stress (CMS) model, followed by lipopolysaccharide (LPS)-induced inflammation. Wistar male rats were separated in the following six groups: control, CMS model, fluoxetine (2.5 mg/kg, oral), salidroside (5 mg/kg, oral), curcumin (20 mg/kg, oral) and salidroside + curcumin (5 mg/kg + 20 mg/kg, oral). Changes in glucose preference, spatial learning and exploratory behavior were recorded. The IL-6 levels in the rats' sera and of the TNF-α levels in the rats' sera and the brain tissue homogenate were evaluated. The groups exposed to stress and treated with fluoxetine, salidroside, curcumin or salidroside + curcumin showed increase in the glucose preference and locomotor activity, as well as, decrease in the escape latency and the cytokines' levels compared to the CMS model group. The chronic stress induced behavioral alternations and increased cytokines’ levels in rats which were reversed by administration of salidroside and curcumin, suggesting antidepressant-like effects comparable to that of fluoxetine and potential synergistic interaction regarding the anti-inflammatory and anti-stress effects.

Background: Pre-eclampsia (PE) affects 2% to 5% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality worldwide. Since PE has complex pathogenesis and treatment is still not found, effective methods for prediction and prevention of PE are still actively searched. Aim: The aim of this study was to find the mean maternal serum concentration of four proteins in Bulgarian pregnant women and to investigate the correlation with uterine artery pulsatility index in the first and second trimester of pregnancy. Materials and methods: In this prospective case-control study, maternal serum concentrations of corin, sEndoglin, PP13, and sFlt-1 were measured, pulsatility index of uterine artery (PI-UA) was assessed in 40 women with Doppler, twice during pregnancy – at the 11th – 13th weeks of gestation and the 20th gestational week. They were randomized in two groups: an experimental group: with increased PIUA at gestational week 13 and a control group: with normal PI-UA. All pregnancies were followed up until the day of delivery and outcomes were recorded. Results: There was no significant difference in the APGAR score and birth weight of the newborns between groups. We found no significant difference in the mean concentration of sEnd, sFlt-1 and PP13 between 11-13 weeks of gestation and 20 week of gestation in the control and experimental groups. Statistically significant difference was found only in the mean concentrations of corin between weeks 11-13 and week 20 in both control (t=3.27; p=0.004) and experimental group (t=3.22; p=0.005). Corin levels and the mean PI of uterine arteries tended to decrease with progression of pregnancy in both groups. Conclusions: Further prospective studies of larger populations are required to develop a panel of multiple predictors for PE.

Objective: To determine the current use and potential acceptance (by tuberculosis experts worldwide) of novel rapid tests for the diagnosis of tuberculosis that are in line with World Health Organization target product profiles. Methods: A multilingual survey was disseminated online between July and November of 2016. Results: A total of 723 individuals from 114 countries responded to the survey. Smear microscopy was the most commonly used rapid tuberculosis test (available to 90.9% of the respondents), followed by molecular assays (available to 70.7%). Only a small proportion of the respondents in middle- and low-income countries had access to interferon-gamma-release assays. Serological and lateral flow immunoassays were used by more than a quarter (25.4%) of the respondents. Among the respondents who had access to molecular tests, 46.7% were using the Xpert assay overall, that proportion being higher in lower middle-income countries (55.6%) and low-income countries (76.6%). The data also suggest that there was some alignment of pricing for molecular assays. Respondents stated they would accept novel rapid tuberculosis tests if available, including molecular assays (acceptable to 86.0%) or biomarker-based serological assays (acceptable to 81.7%). Simple biomarker-based assays were more commonly deemed acceptable in middle- and low-income countries. Conclusions: Second-generation molecular assays have become more widely available in high- and low-resource settings. However, the development of novel rapid tuberculosis tests continues to be considered important by tuberculosis experts. Our data also underscore the need for additional training and education of end users.