Correction: Serial measurement of cytokines strongly predict COVID-19 outcome.

[This corrects the article DOI: 10.1371/journal.pone.0260623.].

Evaluation of long-term antibody kinetics in healthcare workers vaccinated with inactivated COVID-19 Vero cell vaccine (CoronaVac), a propensity score-matched observational study.

OBJECTIVES: This study aimed to evaluate the long-term antibody kinetics after vaccinating with an inactivated COVID-19 Vero cell vaccine (CoronaVac) in healthcare workers (HCWs) at a single center in Turkey. METHODS: For this prospective observational study, Chemiluminescence immunoassay (CLIA) and enzyme-linked immunosorbent assay (ELISA) were used for the determination of binding antibodies (bAb) and neutralizing antibodies (nAb), respectively. Antibody kinetics were compared for the potential influencing factors, and propensity score analysis was performed to match the subcohort for age. RESULTS: Early bAb and nAb response was achieved in all 343 participants. Titers of bAbs against SARS-CoV-2 on 42 days post-vaccination (dpv) were higher in HCWs who were aged <40 years and who had a history of COVID-19. SARS-CoV-2 bAb levels in HCWs on days 42 (n = 97), 90 (n = 97), and 180 (n = 97) were 175 IU/ml (3.9-250), 107 IU/ml (2.4-250), and 66.1 IU/ml (2.57-250), respectively (p<0.001). SARS-CoV-2 bAb (p<0.001) and nAb (p<0.001) titers decreased significantly over time. There was a high negative correlation between SARS-CoV-2 antibody titers and inverse optic density of nAb responses (Pearson correlation coefficient: -0.738, p<0.001). CONCLUSIONS: When the antibody responses were compared, it was seen that the vaccine immunogenicity was better in those who had prior COVID-19 history and were aged <40 years. In the course of time, it was determined that there was a significant decrease in bAb and nAb responses after the 90th day. These results may guide approval decisions for booster COVID-19 vaccines.

Effects of smoking on the bone alkaline phosphatase in peri-implant crevicular fluid and implant stability quotient around implants before loading.

We aimed to examine the implant stability quotient (ISQ), alveolar bone level measurements (ABL), and bone alkaline phosphatase (BALP) in peri-implant crevicular fluid (PICF) around implants in smokers and non-smokers before loading in 3 months. 44 dental implants were placed into smoker and non-smoker patients equally. ISQ was measured at baseline and 3 months after surgery. The levels of PICF BALP and alveolar bone were measured. ISQ values significantly increased in smokers and non-smokers in the 3rd month (p < 0.05). ABL measurements were lower at 3 months compared to baseline in both groups (p < 0.05). Although ISQ and ABL values were higher in non-smokers than smokers at 3 months, the difference between the groups did not show any statistical significance. The PICF BALP levels in the 3rd month changed in both groups. But, these differences were insignificant. Although some of the measurements presented differences between the groups during the assessment periods, they were not indicative of the hazardous effects of smoking on bone healing around implants after surgery till functional loading in 3 months. However, smoking is an important factor to be considered for osseo-integration outcomes. Further studies are needed to clarify the influence of smoking on osseo-integration.

Serial measurement of cytokines strongly predict COVID-19 outcome.

PURPOSE: Cytokines are major mediators of COVID-19 pathogenesis and several of them are already being regarded as predictive markers for the clinical course and outcome of COVID-19 cases. A major pitfall of many COVID-19 cytokine studies is the lack of a benchmark sampling timing. Since cytokines and their relative change during an infectious disease course is quite dynamic, we evaluated the predictive value of serially measured cytokines for COVID-19 cases. METHODS: In this single-center, prospective study, a broad spectrum of cytokines were determined by multiplex ELISA assay in samples collected at admission and at the third day of hospitalization. Appropriateness of cytokine levels in predicting mortality were assessed by receiver-operating characteristic (ROC) analyses for both sampling times in paralel to conventional biomarkers. RESULTS: At both sampling points, higher levels of IL-6, IL-7, IL-10, IL-15, IL-27 IP-10, MCP-1, and GCSF were found to be more predictive for mortality (p<0.05). Some of these cytokines, such as IL-6, IL-10, IL-7 and GCSF, had higher sensitivity and specificity in predicting mortality. AUC values of IL-6, IL-10, IL-7 and GCSF were 0.85 (0.65 to 0.92), 0.88 (0.73 to 0.96), 0.80 (0.63 to 0.91) and 0.86 (0.70 to 0.95), respectively at hospital admission. Compared to hospital admission, on the 3rd day of hospitalization serum levels of IL-6 and, IL-10 decreased significantly in the survivor group, unlike the non-survivor group (IL-6, p = 0.015, and IL-10, p = 0.016). CONCLUSION: Our study results suggest that single-sample-based cytokine analyzes can be misleading and that cytokine levels measured serially at different sampling times provide a more precise and accurate estimate for the outcome of COVID-19 patients.

Autoimmune Lymphoproliferative Syndrome in Children with Nonmalignant Organomegaly, Chronic Immune Cytopenia, and Newly Diagnosed Lymphoma

This study investigated the frequency of and predictive factors for autoimmune lymphoproliferative syndrome (ALPS) in children with lymphoma, chronic immune cytopenia, and nonmalignant organomegaly. Thirty-four children with suspected ALPS (n=13, lymphoma; n=12, immune cytopenia; n=9, nonmalignant organomegaly) were included. Double-negative T-cells, lymphocyte apoptosis, and genetic findings were analyzed. Patients were stratified into two groups as proven/probable ALPS and clinically suspected patients according to the ALPS diagnostic criteria. Of the 34 patients, 18 (53%) were diagnosed with proven/probable ALPS. One patient had a mutation (c.652-2A>C) in the FAS gene. The remaining 16 (47%) patients were defined as clinically suspected patients. Predictive factors for ALPS were anemia and thrombocytopenia in patients with lymphoma, splenomegaly and lymphadenopathy in patients with immune cytopenia, and young age in patients with nonmalignant organomegaly. ALPS may not be rare in certain risk groups. Our study indicates that screening for ALPS may be useful in children having lymphoma with cytopenia at diagnosis, in those having nonmalignant organomegaly with immune cytopenia, and in those having chronic immune thrombocytopenic purpura or autoimmune hemolytic anemia with organomegaly developing during follow-up.

Design, Synthesis and Investigation of New Diphenyl Substituted Pyridazinone Derivatives as Both Cholinesterase and Aß-Aggregation Inhibitors.

BACKGROUND: With respect to the increase in the average life expectancy, Alzheimer Disease (AD), the most common form of age-related dementia, has become a major threat to the population over the age of 65 during the past several decades. The majority of AD treatments are focused on cholinergic and amyloid hypotheses. OBJECTIVE: In this study, three series of diphenyl-2-(2-(4-substitutedpiperazin-1-yl)ethyl)pyridazin- 3(2H)-one derivatives were designed, synthesized and investigated for their ability to inhibit both cholinesterase enzymes and amyloid-ß aggregation. METHOD: The inhibitory activities of the synthesized compounds on AChE (from electric eel) and BChE (from equine serum) were determined by the modified Ellman's method. The reported thioflavin T-based fluorometric assay was performed to investigate the effect of the selected compounds on the aggregation of Aß1-42. The cytotoxic effect of the compounds (4g, 11g and 18g) was monitored in 3T3 cell lines to gain insight into therapeutic potential of the compounds by using MTT assay. The crystal structures of the AChE (1EVE) and BChE (1P0I) enzymes were retrieved from the RCSB Protein Data Bank and Molecular Operating Environment (MOE) software was used for molecular docking of the ligands. RESULTS: Among the tested compounds, 5,6-diphenyl derivative 18g was identified as the most potent and selective AChE inhibitor (IC50 = 1.75 µM, Selectivity Index for AChE > 22.857). 4,6- Diphenyl derivative 11g showed the highest and the most selectivity for BChE (IC50= 4.97 µM, SI for AChE < 0.124). Interestingly, 4,5-diphenyl derivative 4g presented dual cholinesterase inhibition (AChE IC50= 5.11 µM; BChE IC50= 14.16 µM, SI for AChE = 2.771). CONCLUSION: Based on biological activity results and low toxicity of the compounds, it can be said that diphenyl substituted pyridazinone core is a valuable scaffold. Especially, dual inhibitory potencies of 4,5-diphenylpyridazin-3(2H)-one core for the cholinesterase enzymes and Aß- aggregation makes this core a promising disease-modifying agent.

Design and synthesis of some new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring and the investigation of their inhibitory potential on in-vitro acetylcholinesterase and butyrylcholinesterase.

A series of new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring were designed, synthesized and evaluated for their ability to inhibit both cholinesterase enzymes. In addition, a series of carboxamide and propanamide derivatives bearing biphenyl instead of phenylpyridazine were also synthesized to examine the inhibitory effect of pyridazine moiety on both cholinesterase enzymes. The inhibitory activity results revealed that compounds 5b, 5f, 5h, 5j, 5l pyridazine-3-carboxamide derivative, exhibited selective acetylcholinesterase (AChE) inhibition with IC50 values ranging from 0.11 to 2.69 µM. Among them, compound 5h was the most active one (IC50 = 0.11 µM) without cytotoxic effect at its effective concentration against AChE. Additionally, pyridazine-3-carboxamide derivative 5d (IC50 for AChE = 0.16 µM and IC50 for BChE = 9.80 µM) and biphenyl-4-carboxamide derivative 6d (IC50 for AChE = 0.59 µM and IC50 for BChE = 1.48 µM) displayed dual cholinesterase inhibitory activity. Besides, active compounds were also tested for their ability to inhibit Aß aggregation. Theoretical physicochemical properties of the compounds were calculated by using Molinspiration Program as well. The Lineweaver-Burk plot and docking study showed that compound 5 h targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.

Evaluation of serum procollagen C-proteinase enhancer 1 level as a fibrosis marker in patients with chronic hepatitis B.

AIM: Although liver biopsy has long been considered the gold standard for staging fibrosis, because of the disadvantages and risks of biopsy, several noninvasive processes such as serum biomarkers have been introduced for the assessment of liver fibrosis. The aim of this study was to assess the diagnostic value of serum procollagen C-proteinase enhancer 1 (PCPE-1) as a noninvasive fibrosis marker in treatment-naive chronic hepatitis B patients. PATIENTS AND METHODS: This study included 126 patients with biopsy-proven hepatitis B and 50 healthy controls. Fibrosis stage was determined using the Ishak scoring system. The PCPE-1 level was measured using the enzyme-linked immunosorbent assay assay, and the aspartate aminotransferase to platelet ratio index and the FIB-4 index were calculated using the formulas described in Appendix 1 (Supplemental digital content 1, http://links.lww.com/EJGH/A277). RESULTS: Serum PCPE-1 levels of chronic hepatitis B patients were found to be significantly lower than those of the healthy control group (4.49±2.74 vs. 42.9±59.6 pg/ml, respectively, P<0.001). There was a statistically significant negative correlation between serum PCPE-1 level and fibrosis stage (P=0.011; r=-0.226). A statistically significant negative correlation was found between serum PCPE-1 level and necroinflammatory activity (P=0.030; r=-0.194). PCPE-1 levels of patients with liver fibrosis scores of F1-2 were statistically significantly lower than those of the healthy control group (P<0.001) (area under the receiver operating characteristic: 0.955). The area under the receiver operating characteristic of the PCPE-1 level was 0.615 for the prediction of fibrosis (F0 vs. F1-6) (P=0.039). CONCLUSION: Serum PCPE-1 might be used as a noninvasive marker of liver fibrosis. Further animal and human studies are needed to assess the utility of this marker.

The Effects of Local and Systemic Growth Hormone Treatment on Germ Cell Population and Fertility in an Experimental Unilateral Testicular Torsion and Orchiectomy Model.

PURPOSE: We evaluated the effects of local and systemic growth hormone on the germ cell population of the contralateral testes of pubertal rats subjected to unilateral testicular torsion and orchiectomy 24 hours later. MATERIALS AND METHODS: A total of 40 male Wistar-Albino rats at age 3 weeks were divided into 5 groups. In the sham operated group the right testis was sutured and orchiectomy was performed 24 hours later. In groups 2 to 5 orchiectomy was performed 24 hours later following testicular torsion. In groups 3 and 4 unloaded and growth hormone loaded gelatin films, respectively, were sutured on the contralateral testes. In group 5 systemic growth hormone was administered for 7 days. Five weeks later each rat was cohabited with 2 female rats and the left testes were removed for evaluation. Mean seminiferous tubular diameter, mean testicular biopsy score and the mean haploid cell percentage were calculated. Mating studies were performed and fertility parameters were assayed. RESULTS: Mean seminiferous tubular diameter, mean testicular biopsy score and the mean haploid cell percentage of the contralateral testes were significantly decreased in the control and gelatin groups compared with the other groups. There was no difference between the local and systemic growth hormone groups regarding the haploid cell percentage. There were no differences between the groups in mean fetus numbers, mating or fertility and fecundity indexes except in the gelatin group, in which the mean fetus number was significantly lower. CONCLUSIONS: Fertility is not affected in rats after 24 hours of testicular torsion and orchiectomy, although there is germ cell injury and a decrease in the percent of haploid cells. Growth hormone administration resulted in the restoration of germ cell histology and an increase in the haploid cell percentage of the contralateral testes. Growth hormone may improve fertility after unilateral testicular torsion and orchiectomy.