The First Molecular Characterization of Serbian SARS-CoV-2 Isolates From a Unique Early Second Wave in Europe

March 6, 2020 is considered as the official date of the beginning of the COVID-19 epidemic in Serbia. In late spring and early summer 2020, Europe recorded a decline in the rate of SARS-CoV-2 infection and subsiding of the first wave. This trend lasted until the fall, when the second wave of the epidemic began to appear. Unlike the rest of Europe, Serbia was hit by the second wave of the epidemic a few months earlier. Already in June 2020, newly confirmed cases had risen exponentially. As the COVID-19 pandemic is the first pandemic in which there has been instant sharing of genomic information on isolates around the world, the aim of this study was to analyze whole SARS-CoV-2 viral genomes from Serbia, to identify circulating variants/clade/lineages, and to explore site-specific mutational patterns in the unique early second wave of the European epidemic. This analysis of Serbian isolates represents the first publication from Balkan countries, which demonstrates the importance of specificities of local transmission especially when preventive measures differ among countries. One hundred forty-eight different genome variants among 41 Serbian isolates were detected in this study. One unique and seven extremely rare mutations were identified, with locally specific continuous dominance of the 20D clade. At the same time, amino acid substitutions of newly identified variants of concern were found in our isolates from October 2020. Future research should be focused on functional characterization of novel mutations in order to understand the exact role of these variations

Implantation and the Fetal Health

Implantation is one of the crucial periods in human reproduction. Increasing body of evidence suggests that the improper (dysfunctional) implantation and the formation of the placenta can endanger life and health of both the fetus and the mother, during prenatal life and decades after delivery. The idea of the inverted pyramid of prenatal care has emerged in the recent years, as the early detection and prevention of health disorders of the fetus are specially focusing on the first trimester. By applying this principle, disorders in the perinatal period could be prevented or treated with better outcome. The changes that lead to the deficient implantation should be sought in the preimplantation period, in relation between the embryo and the endometrium. It is possible that the time is approaching when the disorders of the pregnancy caused by dysfunctional implantation would be the indication for the application of a natural IVF (without ovarian stimulation) with the use of new biotechnological achievements. For better results of the perinatal medicine, it is necessary to apply earlier (in the preconception and preimplantation periods) the therapy based on the subcellular and genetic level by applying the latest biotechnological procedures

An insight into osteoarthritis susceptibility: Integration of immunological and genetic background

Osteoarthritis (OA) is a progressive degenerative disease that affects all synovial joints, causing the disability of the main locomotor diarthrodial joints. OA pathogenesis is caused by a complex interplay between a number of genetic and environmental risk factors, involved in the early onset and progression of this chronic inflammatory joint disease. Uncovering the underlying immunological and genetic mechanisms will enable an insight into OA pathophysiology and lead to novel and integrative approaches in the treatment of OA patients, together with a reduction of the disease risk, or a delay of its onset in susceptible patients

Immunomonitoring of Monocyte and Neutrophil Function in Critically Ill Patients: From Sepsis and/or Trauma to COVID-19.

Immune cells and mediators play a crucial role in the critical care setting but are understudied. This review explores the concept of sepsis and/or injury-induced immunosuppression and immuno-inflammatory response in COVID-19 and reiterates the need for more accurate functional immunomonitoring of monocyte and neutrophil function in these critically ill patients. in addition, the feasibility of circulating and cell-surface immune biomarkers as predictors of infection and/or outcome in critically ill patients is explored. It is clear that, for critically ill, one size does not fit all and that immune phenotyping of critically ill patients may allow the development of a more personalized approach with tailored immunotherapy for the specific patient. In addition, at this point in time, caution is advised regarding the quality of evidence of some COVID-19 studies in the literature

From Cytokine Storm to Cytokine Breeze: Did Lessons Learned from Immunopathogenesis Improve Immunomodulatory Treatment of Moderate-to-Severe COVID-19?

Complex immune response to infection has been highlighted, more than ever, during the COVID-19 pandemic. This review explores the immunomodulatory treatment of moderate-to-severe forms of this viral sepsis in the context of specific immunopathogenesis. Our objective is to analyze in detail the existing strategies for the use of immunomodulators in COVID-19. Immunomodulating therapy is very challenging; there are still underpowered or, in other ways, insufficient studies with inconclusive or conflicting results regarding a rationale for adding a second immunomodulatory drug to dexamethasone. Bearing in mind that a "cytokine storm" is not present in the majority of COVID-19 patients, it is to be expected that the path to the adequate choice of a second immunomodulatory drug is paved with uncertainty. Anakinra, a recombinant human IL-1 receptor antagonist, is a good choice in this setting. Yet, the latest update of the COVID-19 Treatment Guidelines Panel (31 May 2022) claims that there is insufficient evidence to recommend either for or against the use of anakinra for the treatment of COVID-19. EMA's human medicines committee recommended extending the indication of anakinra to include treatment of COVID-19 in adult patients only recently (17 December 2021). It is obvious that this is still a work in progress, with few ongoing clinical trials. With over 6 million deaths from COVID-19, this is the right time to speed up this process. Our conclusion is that, during the course of COVID-19, the immune response is changing from the early phase to the late phase in individual patients, so immunomodulating therapy should be guided by individual responses at different time points

Stem Cell Homing in Intrathecal Applications and Inspirations for Improvement Paths

A transplanted stem cell homing is a directed migration from the application site to the targeted tissue. Intrathecal application of stem cells is their direct delivery to cerebrospinal fluid, which defines the homing path from the point of injection to the brain. In the case of neurodegenerative diseases, this application method has the advantage of no blood–brain barrier restriction. However, the homing efficiency still needs improvement and homing mechanisms elucidation. Analysis of current research results on homing mechanisms in the light of intrathecal administration revealed a discrepancy between in vivo and in vitro results and a gap between preclinical and clinical research. Combining the existing research with novel insights from cutting-edge biochips, nano, and other technologies and computational models may bridge this gap faster

Follicular fluid thyroid autoantibodies, thyrotropin, free thyroxine levels and assisted reproductive technology outcome.

OBJECTIVE:Although there are substantial data linking thyroid autoimmunity (TAI) and infertility, data regarding assisted reproductive technology (ART) outcomes and TAI markers in follicular fluid (FF) of women undergoing ART are scarce. Objective of the study was to assess the association of the levels of thyroid autoantibodies in FF and ART outcome expressed as the achieved pregnancies. METHODS:This study enrolled 52 women undergoing ART (26 TAI positive subjects and 26 age and body mass index matched TAI negative controls). Blood samples were drawn before the initiation of protocol for controlled ovarian stimulation, and thyrotropin (TSH), free triiodothyronine (fT3), free thyroxine (fT4), thyroid peroxidase antibodies (TPOAbs) and thyroglobulin antibodies (TgAbs) levels were measured. TSH, fT4, TPOAbs, TgAbs and progesterone levels were also measured in FF. RESULTS:There were no significant differences between the groups regarding mean levels of FF TSH and FF fT4. Statistically significant correlation was discovered regarding the levels of serum and FF TPOAbs (0,961, p<0.001 in TAI positive, 0,438, p = 0.025 in TAI negative group) and TgAbs (0,945, p<0.001 in TAI positive, 0,554, p = 0.003 in TAI negative group). Pregnancies rates per initiated cycle and per embryotransfer cycle were significantly different between TAI positive and TAI negative group, (30.8% vs 61.5%), p = 0.026 and (34.8% vs 66.7%), p = 0.029, respectively. Multivariate analysis showed that TAI positive women had less chance to achieve pregnancy (p = 0.004, OR = 0.036, 95% CI 0.004-0.347). CONCLUSIONS:Higher levels of thyroid autoantibodies in FF of TAI positive women are strongly correlated with serum levels and may have effect on the post-implantation embryo development

Bone Marrow Aspirate Concentrate versus Platelet Rich Plasma or Hyaluronic Acid for the Treatment of Knee Osteoarthritis

Background: In the last decade, regenerative therapies have become one of the leading disease modifying options for treatment of knee osteoarthritis (OA). Still, there is a lack of trials with a direct comparison of different biological treatments. Our aim was to directly compare clinical outcomes of knee injections of Bone Marrow Aspirate Concentrate (BMAC), Platelet-rich Plasma (PRP), or Hyaluronic acid (HA) in the OA treatment. Methods: Patients with knee pain and osteoarthritis KL grade II to IV were randomized to receive a BMAC, PRP, and HA injection in the knee. VAS, WOMAC, KOOS, and IKDC scores were used to establish baseline values at 1, 3, 6, 9, and 12 months. All side effects were reported. Results: A total of 175 patients with a knee osteoarthritis KL grade II-IV were randomized; 111 were treated with BMAC injection, 30 with HA injection, and 34 patients with PRP injection. There were no differences between these groups when considering KL grade, BMI, age, or gender. There were no serious side effects. The mean VAS scores after 3, 7, 14, and 21 days showed significant differences between groups with a drop of VAS in all groups but with a difference in the BMAC group in comparison to other groups (p &lt; 0.001). There were high statistically significant differences between baseline scores and those after 12 months (p &lt; 0.001) in WOMAC, KOOS, KOOS pain, and IKDC scores, and in addition, there were differences between these scores in the BMAC group in comparison with other groups, except for the PRP group in WOMAC and the partial IKDC score. There were no differences between the HA and PRP groups, although PRP showed a higher level of clinical improvement. Conclusions: Bone marrow aspirate concentrate, Leukocyte rich Platelet Rich Plasma, and Hyaluronic acid injections are safe therapeutic options for knee OA and provide positive clinical outcomes after 12 months in comparison with findings preceding the intervention. BMAC could be better in terms of clinical improvements in the treatment of knee OA than PRP and HA up to 12 months. PRP provides better outcomes than HA during the observation period, but these results are not statistically significant. More randomized controlled trials and high quality comparative studies are needed for direct correlative conclusions

Bone Marrow Aspirate Concentrate versus Platelet Rich Plasma or Hyaluronic Acid for the Treatment of Knee Osteoarthritis

Background: In the last decade, regenerative therapies have become one of the leading disease modifying options for treatment of knee osteoarthritis (OA). Still, there is a lack of trials with a direct comparison of different biological treatments. Our aim was to directly compare clinical outcomes of knee injections of Bone Marrow Aspirate Concentrate (BMAC), Platelet-rich Plasma (PRP), or Hyaluronic acid (HA) in the OA treatment. Methods: Patients with knee pain and osteoarthritis KL grade II to IV were randomized to receive a BMAC, PRP, and HA injection in the knee. VAS, WOMAC, KOOS, and IKDC scores were used to establish baseline values at 1, 3, 6, 9, and 12 months. All side effects were reported. Results: A total of 175 patients with a knee osteoarthritis KL grade II-IV were randomized; 111 were treated with BMAC injection, 30 with HA injection, and 34 patients with PRP injection. There were no differences between these groups when considering KL grade, BMI, age, or gender. There were no serious side effects. The mean VAS scores after 3, 7, 14, and 21 days showed significant differences between groups with a drop of VAS in all groups but with a difference in the BMAC group in comparison to other groups (p p Conclusions: Bone marrow aspirate concentrate, Leukocyte rich Platelet Rich Plasma, and Hyaluronic acid injections are safe therapeutic options for knee OA and provide positive clinical outcomes after 12 months in comparison with findings preceding the intervention. BMAC could be better in terms of clinical improvements in the treatment of knee OA than PRP and HA up to 12 months. PRP provides better outcomes than HA during the observation period, but these results are not statistically significant. More randomized controlled trials and high quality comparative studies are needed for direct correlative conclusions

The role of osteoarthritis severity, BMI and age on clinical efficacy of bone marrow aspirate concentrate in the treatment of knee osteoarthritis.

Aim: The aim of this study was to assess whether BMI, severity of knee osteoarthritis, age and gender have any influence on the final clinical results of bone marrow aspirate concentrate injection. Method: A total of 111 study participants with painful knee osteoarthritis and different characteristics concerning before mentioned factors underwent bone marrow aspirate concentrate (BMAC) therapy and were followed up for 1 year. Result: Significant pain and functional improvement were observed in all participant groups. Participants' age and BMI did not influence the clinical outcome, but there was an influence of OA severity, especially among older patients. Conclusion: This study shows that BMAC therapy is effective. Younger patients with milder OA changes could be better candidates for long-lasting and more efficient BMAC therapy. Clinical Trial Registration: NCT03825133 (ClinicalTrials.gov)