Curative effect contributors of exercise in type one diabetes: Irisin and Sestrin

Type 1 Diabetes (T1DM) is a chronic metabolic disease characterized by hyperglycemia due to absolute insulin deficiency as a result of autoimmune damage of pancreatic beta cells. In its treatment, insulin, medical nutrition therapy and exercise is recommended. Although it is known that exercise contributes to disease control, the mechanism of these effects has not been fully clarified. It is thought that myokines such as irisin and sestrin, can be effective by secreting with exercise, turning white fat tissue into brown. Aim(s): This study aimed to compare serum irisin and sestrin levels between patients with T1DM and healthy controls, determine the changes in the clinical and laboratory findings of the patients with T1DM before and after exercise program and evaluate relationships of these changes with the levels of irisin and sestrin. Material(s) and Method(s): 33 patients with T1DM diagnosis and 36 control groups were involved. Firstly, exercise capacities (MaxVO2) and Physical Activity Status (PAS) were determined in T1DM and control groups and serum Irisin and sestrin levels measured in both groups. Secondly T1DM patients attended to the online exercise program 3 days a week for 3 months due to COVID19 restictions. At the end of the exercise program, 10 of the T1DM patients (exercised group) participated in at least 50% of the program. MaxVO2, PAS, serum irisin and sestrin levels were reevaluated and compared with the previous results in exercised and non-exercised groups. Their examinations were obtained from file data and computer records. Changes in laboratory and clinical findings were compared. Result(s): Sestrin level was higher in the T1DM group than in the control group (p=0.003). This is the first data on sestrin and type one diabetes. There was no significant difference in irisin levels between T1DM and control groups (p=0.511). Both groups were sedentary due to the Covid19 lockdown. There was positive correlation between Irisin and maxVO2 in the patients with T1DM and control groups (r=0,34, p=0,02). In the second part of the study, irisin levels increased in the exercised group (p=0.012) and sestrin levels decreased in the non-exercised group (p<0.001). Physical activity score improved in the exercised group (p=0,028) and exercise capacity increased in both groups (<0,001). HbA1c levels decreased (p=0,032) and basal insulin requirement decreased (p=0,038) in the exercised group, unlike the non-exercised group. Conclusion(s): Our findings suggest that the irisin and sestrin could contribute to the curative effects of exercise in type one diabetic children.

POTENTIAL PREDICTORS of OUTCOME for ANAKINRA TREATMENT in COVID-19 PATIENTS with MACROPHAGE ACTIVATION SYNDROME

Background: A hyperinfammatory response compatible with features of macrophage activation syndrome (MAS) contributes to this worse outcome in patients with Coronavirus Disease 2019 (COVID-19). Glucocorticoids have become the standard of care for those requiring oxygen support or mechanical ventilation. More targeted anti-infammatory treatments with tocilizumab and anakinra have also been shown to be effective. Objectives: More studies are being awaited to clarify the features of patients who would beneft more, and we investigated the characteristics of the surviving and dead patients who received anakinra. Methods: The records of hospitalized adult patients between March 2020 and May 2021 in a tertiary referral center were evaluated. Diagnosis of COVID-19-re-lated MAS was based on the expert opinion and preliminary criteria developed by our group that patients with a score of ≥45 were accepted COVID-19-related MAS.1 Patients who received anakinra constituted the study group. Anakinra dose was determined according to the clinical and infammatory parameters;and doses varied between daily 100-300 mg SC to 400-800 mg IV. Laboratory data of surviving and died patients were comparatively analyzed by using the ANCOVA method on the relevant days (baseline, anakinra-onset day, frst response to anakinra treatment, and discharge or death). The temporal variation (drug onset day-frst response day, drug onset day-discharge, or death day) was evaluated using the ANOVA method. A 50% reduction of CRP compared to the anakinra start day was accepted as the frst response to the treatment. Results: Out of 1080 hospitalized patients, 218 (151 male, 67 female, mean age 60.0±14.1) who received anakinra were identifed. Among them, 125 (57.3%) patients were followed in the ward, 21 (9.6%) did not need oxygen treatment during the hospitalization;69 (31.6%) patients were followed at ICU, 40 of them were intubated, 30 (13.7%) died in ICU. Anakinra had been started in a mean of 4.8 days of hospitalization. Twenty had tocilizumab initially and then received anak-inra because of ongoing infammatory parameters. The majority (83.5%) received steroid treatment (79.5% methylprednisolone, 5% of dexamethasone), and 6 received one IV pulse 250 mg of methylprednisolone;36 (16.5%) were followed before September 2020 and received anakinra without steroids because of the standard of care at that period. Only CRP was different between the alive and dead patients for the baseline parameters (p=0.05). On the frst day of drug treatment, CRP and procalcitonin values were signifcantly higher in dead patients (Table 1). A 50% decrease in CRP level was achieved in 3.1 days in survivors and 4.7 days in dead patients. D-dimer (p=0.018), CRP (p=0.006), LDH (p=0.003), procalcitonin (p=0.005), creatinine kinase (p=0.001), and fbrinogen levels (p=0.05) were significantly different between the surviving and dead patients when the measurements between the frst drug administration day and response day were compared. Neu-trophil, lymphocyte count, ferritin, D-dimer, CRP, LDH, AST, procalcitonin, creati-nine kinase, and fbrinogen levels were signifcantly different between the patients when the parameters between the frst drug administration day and discharge/death day were compared. Dead patients had higher CRP values and they did not show a continuing CRP decrease with the steroids and anakinra (Figure 1). Conclusion: Retrospective analysis of 218 patients suggests that starting anakinra earlier in hospitalized patients may provide better results, and a decrease in CRP, ferritin, D-dimer values, as well as an increase in lymphocyte count, are associated with favorable outcomes. Increasing values of D-dimer and troponin during treatment are associated with worse outcomes, possibly indicating cardiovascular and thrombotic pathologies not responding to anakinra. Changes in the CRP values are found to help monitor the response to anakinra. Other infammatory pathways could be targeted in those who are not responding to appropriate doses of anakinra within 5 days.

ANTIPHOSPHOLIPID ANTIBODY (aPL) PRESENCE IN COVID-19 PATIENTS

Objective: In our study, we aimed to show whether there is a relationship between antiphospholipid antibody (aPL) positivity and complications of COVID-19. Material and Methods: Eighty-three patients who were diagnosed with COVID-19 infection and hospitalized in the intensive care unit (ICU) of Bakirkoy Dr. Sadi Konuk Research and Training Hospital were included in our study as the case group and 79 healthy volunteers as the control group. Only patients with a positive polymerase chain reaction (PCR) test were included in the case group. Serum antiphospholipid antibodies (aPL IgM/G), C-Reactive Protein (CRP), ferritin, procalcitonin (PCT), plasma D-Dimer levels, prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT) were analyzed by routine laboratory methods. Results: Both groups were found statistically similar in terms of gender (chi(2) test, p=0.236). The mean age of the case group and control group was 60.54 +/- 16.86 and 51.47 +/- 14.64 years, respectively. When aPL positivity was evaluated between the case and control groups, a statistically remarkable difference was found between the groups (p=0.046). The case group showed an aPL positivity of 7.5% and the control group 1%. The correlation between D-Dimer, PT, INR, aPTT levels, and aPL IgM/G positivity in the case group was significant. Conclusion: Our results revealed that aPL positivity in patients with COVID-19 infection relate to the severity of the disease, in-dependent from age and gender. To confirm the result of this study further studies with participation of larger patient groups from national and international hospitals are required.

Preliminary criteria for macrophage activation syndrome associated with coronavirus disease-19

Background: COVID-19 runs a severe disease associated with acute respiratory distress syndrome in a subset of patients, and a hyperinflammatory response developing in the second week contributes to the worse outcome. Inflammatory features are mostly compatible with macrophage activation syndrome (MAS) observed in other viral infections despite resulting in milder changes. Early detection and treatment of MAS may be associated with a better outcome. However, available criteria for MAS associated with other causes have not been helpful. Objectives: To identify distinct features of MAS associated with COVID-19 using a large database enabling to assess of dynamic changes. Methods: PCR-confirmed hospitalized COVID-19 patients followed between March and September 2020 constituted the discovery set. Patients considered to have findings of MAS by experienced physicians and given anakinra or tocilizumab were classified as the MAS group and the remaining patients as the non-MAS group. The MAS group was then re-grouped as the cases with exact-MAS and borderline-MAS cases by the study group. Clinical and laboratory data including the Ct values of the PCR test were obtained from the database, and dynamic changes were evaluated especially for the first 14 days of the hospitalization. The second set of 162 patients followed between September-December 2020 were used as the replication group to test the preliminary criteria. In the second set, hospitalization rules were changed, and all patients required oxygen support and received dexamethasone 6mg/day or equivalent glucocorticoids. Daily changes were calculated for the laboratory items in MAS, borderline, and non-MAS groups to see the days differentiating the groups, and ROC curves and lower and upper limits (10-90%) of the selected parameters were calculated to determine the cutoff values. Results: A total of 769 PCR-confirmed hospitalized patients were analysed, and 77 of them were classified as MAS and 83 as borderline MAS patients. There was no statistically significant difference in the baseline viral loads of MAS patients compared to the non-MAS group according to the Ct values. Daily dynamic changes in the MAS group differed from the non-MAS group especially around the 6th day of hospitalization, and more than a twofold increase in ferritin and a 1.5-fold increase in D-dimer levels compared to the baseline values help to define the MAS group. Twelve items selected for the criteria are given in Table 1 below. The total score of 45 provided 79.6% sensitivity for the MAS (including borderline cases) and 81.3% specificity around days 5 and 6 in the discovery set, and a score of 60 increased the specificity to 94.9% despite a decrease in sensitivity to 40.8%. The same set provided a similar sensitivity (80.3%) in the replication, but a lower specificity (47.4-66% on days 6 to 9) due to a group of control patients with findings of MAS possibly masked by glucocorticoids. Conclusion: This study defined a set of preliminary criteria using the most relevant items of MAS according to the dynamic changes in the parameters in a group of COVID-19 patients. A score of 45 would be helpful to define a possible MAS group with reasonable sensitivity and specificity to start necessary treatments as early as possible.