Lipopolysaccharide Primes Human Macrophages for Noncanonical Inflammasome-Induced Extracellular Vesicle Secretion.

Human macrophages secrete extracellular vesicles (EVs) loaded with numerous immunoregulatory proteins. Vesicle-mediated protein secretion in macrophages is regulated by poorly characterized mechanisms; however, it is now known that inflammatory conditions significantly alter both the quantities and protein composition of secreted vesicles. In this study, we employed high-throughput quantitative proteomics to characterize the modulation of EV-mediated protein secretion during noncanonical caspase-4/5 inflammasome activation via LPS transfection. We show that human macrophages activate robust caspase-4-dependent EV secretion upon transfection of LPS, and this process is also partially dependent on NLRP3 and caspase-5. A similar effect occurs with delivery of the LPS with Escherichia coli-derived outer membrane vesicles. Moreover, sensitization of the macrophages through TLR4 by LPS priming prior to LPS transfection dramatically augments the EV-mediated protein secretion. Our data demonstrate that this process differs significantly from canonical inflammasome activator ATP-induced vesiculation, and it is dependent on the autocrine IFN signal associated with TLR4 activation. LPS priming preceding the noncanonical inflammasome activation significantly enhances vesicle-mediated secretion of inflammasome components caspase-1, ASC, and lytic cell death effectors GSDMD, MLKL, and NINJ1, suggesting that inflammatory EV transfer may exert paracrine effects in recipient cells. Moreover, using bioinformatics methods, we identify 15-deoxy-Δ12,14-PGJ2 and parthenolide as inhibitors of caspase-4-mediated inflammation and vesicle secretion, indicating new therapeutic potential of these anti-inflammatory drugs.

Cholesin receptor signalling is active in cardiovascular system-associated adipose tissue and correlates with SGLT2i treatment in patients with diabetes.

BACKGROUND: Recently deorphanized G protein-coupled receptor 146 (GPR146) was shown to respond to signal from a newly identified hormone-cholesin-and to play a role in hepatic lipid metabolism. However, the importance of its biological activity in human organism remains elusive, mainly due to the lack of studies on human tissues up to this point. This study aimed to identify the cholesin receptor-associated genes and clinical factors linked with their expression in cardiovascular system and associated adipose tissues. METHODS: Right cardiac auricle, aortic wall, saphenous vein, and adipose tissue (periaortic-PAT, epicardial-EAT, thymic-TAT) samples were collected during coronary artery bypass grafting. Clinical records of the study participants were assessed for the presence of diabetes, medications taken and serum cholesterol levels. GPR146 mRNA expression in all gathered tissues was assessed with qPCR, and RNA seqencing was performed in selected tissues of 20 individuals to identify pathways associated with GPR146 expression. RESULTS: We included 46 participants [37 male, 23 with type 2 diabetes, median age 68.50 (Q1-Q3: 63.00-72.00) years, BMI 28.39 (26.06-31.49) kg/m2]. GPR146 expression in adipose tissues significantly correlated with BMI, c-peptide, total cholesterol, and LDL concentrations. Selected metabolic pathways were significantly and positively enriched in GPR146-dependent manner. GPR146-coexpressed genes contained key regulators of lipid metabolism involved in such pathways as fatty acid metabolism, tricarboxilic acid cycle and peroxisomal metabolism. Those genes correlated positively with serum concentrations of LDL, HDL, and total cholesterol. SGLT2i treatment was associated with inversion of GPR146-related signature in EAT, suggesting potential impact on cholesin-GPR146 network. CONCLUSIONS: GPR146 expression is associated with serum lipids and metabolically-relevant transcriptomic changes in EAT similar to SGLT2i-associated ones.

Impact of factory-calibrated Freestyle Libre System with new glucose algorithm measurement accuracy and clinical performance in children with type 1 diabetes during summer camp.

BACKGROUND: Factory-calibrated intermittently-scanned Continuous Glucose Monitoring (isCGM) device FreeStyle Libre (FSL) has recently received improvements in its glucose tracking algorithm and calibration procedures, which are claimed to have improved its accuracy. OBJECTIVE: To compare the accuracy of two generations of 14-days FSL devices (A in 2016, B in 2019) to self-monitored blood glucose measurements (SMBG) in children with type 1 diabetes in real-life conditions during a summer camp. MATERIALS AND METHODS: Two largely independent groups of youth with type 1 diabetes took part in summer camps. In 2016 they used FSL-A, in 2019 FSL-B. On scheduled days, participants performed supervised 8-point glucose profiles with FSL and SMBG. The accuracy vs SMBG was assessed with mean absolute relative difference (MARD) and clinical surveillance error grid (SEG). RESULTS: We collected 1655 FSL-SMBG measurement pairs from 78 FSL-A patients (age 13 ± 2.3 years old; HbA1c: 7.6 ± 0.8%) and 1796 from 58 in FSL-B group (age 13.8 ± 2.3 years old, HbA1c: 7.5 ± 1.1%)-in total 3451 measurements. FSL-B displayed lower MARD than FSL-A (11.3 ± 3.1% vs 13.7 ± 4.6%, P = .0003), lower SD of errors (20.2 ± 6.7 mg/dL vs 24.1 ± 9.6 mg/dL, P = .0090) but similar bias (-7.6 ± 11.8 mg/dL vs -6.5 ± 8 mg/dL, P = .5240). Both FSL-A and FSL-B showed significantly higher MARD when glycaemia was decreasing >2 mg/dL/min (FSL-A:22.3 ± 18.5%; FSL-B:17.9 ± 15.8%, P < .0001) compared with stable conditions (FSL-A: 11.4 ± 10.4%, FSL-B:10.1 ± 9.1%) and when the system could not define the glycaemic trend (FSL-A:16.5 ± 16.3%; FSL-B:15.2 ± 14.9%, P < .0001). Both generations demonstrated high percentage of A-class and B-class results in SEG (FSL-A: 96.4%, FSL-B: 97.6%) with a significant shift from B (decrease by 3.7%) to A category (increase by 3.9%) between generations (FSL-A: 16/80.4%; FSL-B:12.3/85.3%, P = .0012). CONCLUSION: FSL-B demonstrated higher accuracy when compared to FSL-A However, when glycemia is decreasing or its trend is uncertain, the verification with a glucose meter is still advisable.

Assessing Public Interest Based on Wikipedia's Most Visited Medical Articles During the SARS-CoV-2 Outbreak: Search Trends Analysis.

BACKGROUND: In the current era of widespread access to the internet, we can monitor public interest in a topic via information-targeted web browsing. We sought to provide direct proof of the global population's altered use of Wikipedia medical knowledge resulting from the new COVID-19 pandemic and related global restrictions. OBJECTIVE: We aimed to identify temporal search trends and quantify changes in access to Wikipedia Medicine Project articles that were related to the COVID-19 pandemic. METHODS: We performed a retrospective analysis of medical articles across nine language versions of Wikipedia and country-specific statistics for registered COVID-19 deaths. The observed patterns were compared to a forecast model of Wikipedia use, which was trained on data from 2015 to 2019. The model comprehensively analyzed specific articles and similarities between access count data from before (ie, several years prior) and during the COVID-19 pandemic. Wikipedia articles that were linked to those directly associated with the pandemic were evaluated in terms of degrees of separation and analyzed to identify similarities in access counts. We assessed the correlation between article access counts and the number of diagnosed COVID-19 cases and deaths to identify factors that drove interest in these articles and shifts in public interest during the subsequent phases of the pandemic. RESULTS: We observed a significant (P<.001) increase in the number of entries on Wikipedia medical articles during the pandemic period. The increased interest in COVID-19-related articles temporally correlated with the number of global COVID-19 deaths and consistently correlated with the number of region-specific COVID-19 deaths. Articles with low degrees of separation were significantly similar (P<.001) in terms of access patterns that were indicative of information-seeking patterns. CONCLUSIONS: The analysis of Wikipedia medical article popularity could be a viable method for epidemiologic surveillance, as it provides important information about the reasons behind public attention and factors that sustain public interest in the long term. Moreover, Wikipedia users can potentially be directed to credible and valuable information sources that are linked with the most prominent articles.

Correction: Assessing Public Interest Based on Wikipedia's Most Visited Medical Articles During the SARS-CoV-2 Outbreak: Search Trends Analysis.

[This corrects the article DOI: 10.2196/26331.].

Pain resolution and glucose control in pediatric patients with chronic pancreatitis after total pancreatectomy with islet auto-transplantation.

BACKGROUND: Chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP) in pediatric patients are strongly associated with genetic mutations and lead to pan-parenchymal disease refractory to medical and endoscopic treatment. Our aim was to assess pain resolution and glucose control in patients with CP and ARP following total pancreatectomy with islet auto-transplantation (TPIAT). METHODS: We retrospectively analyzed prospectively collected clinical data of 12 children who developed CP and ARP and underwent TPIAT when 21 years old or younger at the University of Chicago between December 2009 and June 2020. Patients with recurrent or persistent abdominal pain attributed to acute or chronic pancreatic inflammation and a history of medical interventions attempted for the relief of pancreatic pain were selected by a multi-disciplinary team for TPIAT. We followed patients post-operatively and reported data for pre-TPIAT, post-operative day 75, and yearly post-TPIAT. RESULTS: All 12 patients experienced complete resolution of pancreatic pain. The overall insulin-independence rate after 1 year was 66% (8/12) and 50% (3/6) at 4 years. Shorter duration of CP/ARP pre-TPIAT, higher mass of islets infused, and lower BMI, BMI percentile, and BSA were associated with insulin-independence post-TPIAT. CONCLUSIONS: TPIAT is a viable treatment option for pediatric patients with CP and ARP. Pediatric patients undergoing TPIAT for CP achieved resolution of pancreatic-type pain and reduced opioid requirements. The majority were able to achieve insulin-independence which was associated with lower pre-TPIAT BMI and higher islet mass transplanted (i.e., over 2000 IEQ/kg), the latter of which can be achieved by earlier TPIAT. LEVEL OF EVIDENCE: Treatment study, Level IV.

Assessment of Skin Autofluorescence and Its Association with Glycated Hemoglobin, Cardiovascular Risk Markers, and Concomitant Chronic Diseases in Children with Type 1 Diabetes.

Skin autofluorescence (sAF) measurement is a non-invasive method used to assess tissue advanced glycation end product (AGE) accumulation. This study aims to characterize sAF's association with (1) glycated hemoglobin (HbA1c) values, (2) cardiovascular risk markers, and (3) common comorbidities (autoimmune thyroiditis, celiac disease) in children with type 1 diabetes (T1D). MATERIALS AND METHODS: A total of 348 children with T1D aged 3-18 years and 85 age- and gender-matched control subjects were enrolled. sAF was quantified using an AGE Reader (Diagnoptics BV, The Netherlands). The analysis covered HbA1c, blood lipid, and C-reactive protein (CRP) levels, ambulatory blood pressure monitoring records, and body composition parameters. The associations between variables and sAF were assessed using the Mann-Whitney U test and Spearman correlation. RESULTS: We observed significantly higher sAF values in the T1D group compared to the control (1.40 [1.27-1.53] vs. 1.20 [1.07-1.30, AU]; p = 0.004), consistent across all tested age groups. In the T1D group, sAF was positively correlated with current HbA1c, mean of historical HbA1c values, and T1D duration (r values, respectively: 0.27, 0.22, 0.14, all p < 0.01). Percentage of body fat was positively correlated with sAF (r = 0.120; p = 0.044). No significant correlations were found between sAF and lipid fractions, Z-score of BMI, parameters from 24 h ambulatory blood pressure monitoring, or the amount of albumin excreted in urine. sAF was positively correlated with CRP (r = 0.17, p < 0.05). sAF was significantly higher in patients with concomitant celiac disease (1.53 [1.43-1.63] vs. 1.40 [1.27-1.53, AU], p = 0.001). CONCLUSION: Among young T1D patients with relatively brief diabetes duration, sAF effectively mirrors prior glycemic control, as presented by historical average HbA1c. However, associations with conventional CV risk markers are not evident. The higher sAF values in patients with celiac disease warrant further exploration.

Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity.

It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR's oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.

Lisdexamphetamine versus methylphenidate for paediatric patients with attention-deficit hyperactivity disorder and type 1 diabetes (LAMAinDiab): protocol for a multicentre, randomised cross-over clinical trial in an outpatient telemedicine-supported setting.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) affects 5%-10% of paediatric population and is reportedly more common in children with type 1 diabetes (T1D), exacerbating its clinical course. Proper treatment of ADHD in such patients may thus provide neurological and metabolic benefits. To test this, we designed a non-commercial second phase clinical trial comparing the impact of different pharmacological interventions for ADHD in children with T1D. METHODS AND ANALYSIS: This is a multicentre, randomised, open-label, cross-over clinical trial in children and adolescents with ADHD and T1D. The trial will be conducted in four reference paediatric diabetes centres in Poland. Over 36 months, eligible patients with both T1D and ADHD (aged 8-16.5 years, T1D duration >1 year) will be offered participation. Patients' guardians will undergo online once-weekly training sessions behaviour management for 10 weeks. Afterward, children will be randomised to methylphenidate (long-release capsule, doses 18-36-54 mg) versus lisdexamphetamine (LDX, 30-50-70 mg). Pharmacotherapy will continue for 6 months before switching to alternative medication. Throughout the trial, the participants will be evaluated every 3 months by their diabetologist and online psychological assessments. The primary endpoint (ADHD symptom severity, Conners 3.0 questionnaire) will be assessed by a blinded investigator. Secondary endpoints will include HbA1c, continuous glucose monitoring indices and quality-of-life (PedsQL). ETHICS AND DISSEMINATION: The trial is approved by Bioethical Committee at Medical University of Lodz and Polish regulatory agency (RNN/142/22/KE, UR/DBL/D/263/2022). The results will be communicated to the research and clinical community, and Polish agencies responsible for healthcare policy. Patient organisations focused on paediatric T1D will be notified by a consortium member. We hope to use the trial's results to promote collaboration between mental health professionals and diabetes teams, evaluate the economic feasibility of using LDX in patients with both diseases and the long run improve ADHD treatment in children with T1D. TRIAL REGISTRATION NUMBERS: EU Clinical Trials Register (EU-CTR, 2022-001906-24) and NCT05957055.

Association of low ficolin-2 concentration in cord serum with respiratory distress syndrome in preterm newborns.

Introduction: Ficolin-2 is a serum pattern recognition molecule, involved in complement activation via the lectin pathway. This study aimed to investigate the association of ficolin-2 concentration in cord blood serum with complications related to premature birth. Methods: 546 premature neonates were included. The concentration of ficolin-2 in cord blood serum was determined by a sandwich TRIFMA method. FCN2 genetic variants were analysed with RFLP-PCR, allele-specific PCR, Sanger sequencing or allelic discrimination using TaqMan probes method. Findings: Cord blood serum ficolin-2 concentration correlated positively with Apgar score and inversely with the length of hospitalisation and stay at Neonatal Intensive Care Unit (NICU). Multivariate logistic regression analysis indicated that low ficolin-2 increased the possibility of respiratory distress syndrome (RDS) diagnosis [OR=2.05, 95% CI (1.24-3.37), p=0.005]. Median ficolin-2 concentration was significantly lower in neonates with RDS than in premature babies without this complication, irrespective of FCN2 gene polymorphisms localised to promoter and 3'untranslated regions: for patients born <33 GA: 1471 ng/ml vs. 2115 ng/ml (p=0.0003), and for patients born ≥33 GA 1610 ng/ml vs. 2081 ng/ml (p=0.012). Ficolin-2 level was also significantly lower in neonates requiring intubation in the delivery room (1461 ng/ml vs. 1938 ng/ml, p=0.023) and inversely correlated weakly with the duration of respiratory support (R=-0.154, p<0.001). Interestingly, in the neonates born at GA <33, ficolin-2 concentration permitted differentiation of those with/without RDS [AUC=0.712, 95% CI (0.612-0.817), p<0.001] and effective separation of babies with mild RDS from those with moderate/severe form of the disease [AUC=0.807, 95% CI (0.644-0.97), p=0.0002]. Conclusion: Low cord serum ficolin-2 concentration (especially in neonates born at GA <33 weeks) is associated with a higher risk of developing moderate/severe RDS, requiring respiratory support and intensive care.

An investigation of the optimal inter-pregnancy interval following pregnancy with a fetus with congenital heart disease.

Introduction: Congenital heart defects (CHD) are one of the most commonly diagnosed congenital malformations in fetuses and newborns. The aim of the study was to determine whether inter-pregnancy interval (IPI), maternal age or number of pregnancies had any influence on the recurrence of congenital heart disease in subsequent pregnancies. Material and methods: We found in our database 144 women with subsequent pregnancies after CHD in a previous pregnancy. Each woman was selected according to the eligibility and exclusion criteria. Medical history as well as obstetrics history were recorded. Comparisons of groups with and without a recurrence of CHD were performed. We calculated hazard ratios for recurrence of CHD. We also performed analysis of the impact of confounding variables: maternal age and parity. Missing data were excluded from the analysis. Smoking habits as well as socio-demographic characteristics were not evaluated in this study. Results: A higher risk of recurrence of CHD correlated with a shorter IPI, with a median of 11 months compared with 24 months for the group of healthy fetuses in subsequent pregnancy. The results were statistically significant. Parity was proven to be an important confounder of the study. Multivariable analysis including parity and maternal age did not affect the confidence intervals of hazard ratios for IPI. Conclusions: The optimal IPI to reduce the risk of recurrence of CHD is 24 months. Shorter intervals are related to a higher risk of recurrence of CHD in the next pregnancy and are independent on the age of the woman and parity.

Reduced Carbohydrate Diet Influence on Postprandial Glycemia-Results of a Short, CGM-Based, Interventional Study in Adolescents with Type 1 Diabetes.

Therapy for type 1 diabetes (T1DM) focuses on maintaining optimal blood glucose levels, achieved with intensive insulin treatment, proper nutrition, and physical activity. The aim of this study was to investigate postprandial glycemic changes under low (30%) and standard (50%) carbohydrate diets in adolescents with T1DM. A single-center cross-over nutritional study was conducted, during which 26 adolescent patients provided 220 continuous glucose-monitored (CGM) meals data from the two consecutive 3-day nutritional plans. Overall, the 50% carbohydrate diet was associated with higher postprandial glucose variability in the small meals (afternoon snacks, second breakfast) and greater postprandial peaks for other meals (breakfast, dinner, supper). Nevertheless, after the adjustment of a patient's individual clinical variables (age, Tanner classification, glucose disposal rate), we observed that mean postprandial glucose was higher for afternoon snacks and lower for suppers in the 30% carbohydrate diet. Although a 30% carbohydrate diet seems to offer better postprandial glycemia, it requires additional attention from the physician and patient when it comes to modifying daily carbohydrate intake. Increased fat/protein content and size of the main meal lead to a prolonged postprandial glycemic response, which may affect the insulin treatment and result in suboptimal glycemic control.

Subtype-Specific Tumour Immune Microenvironment in Risk of Recurrence of Ductal Carcinoma In Situ: Prognostic Value of HER2.

Increasing evidence suggests that the significance of the tumour immune microenvironment (TIME) for disease prognostication in invasive breast carcinoma is subtype-specific but equivalent studies in ductal carcinoma in situ (DCIS) are limited. The purpose of this paper is to review the existing data on immune cell composition in DCIS in relation to the clinicopathological features and molecular subtype of the lesion. We discuss the value of infiltration by various types of immune cells and the PD-1/PD-L1 axis as potential markers of the risk of recurrence. Analysis of the literature available in PubMed and Medline databases overwhelmingly supports an association between densities of infiltrating immune cells, traits of immune exhaustion, the foci of microinvasion, and overexpression of HER2. Moreover, in several studies, the density of immune infiltration was found to be predictive of local recurrence as either in situ or invasive cancer in HER2-positive or ER-negative DCIS. In light of the recently reported first randomized DCIS trial, relating recurrence risk with overexpression of HER2, we also include a closing paragraph compiling the latest mechanistic data on a functional link between HER2 and the density/composition of TIME in relation to its potential value in the prognostication of the risk of recurrence.

Hypoplastic left heart syndrome with prenatally diagnosed foramen ovale restriction: diagnosis, management and outcome.

OBJECTIVE: Despite advances in prenatal diagnosis and postnatal intervention/surgery methods, patients with Hypoplastic Left Heart Syndrome (HLHS) and coexisting foramen oval restriction still achieve high mortality rates. Our objective was to determine survival predictors and to find answers to, why restriction develops in some, but not others. METHODS: We performed a retrospective analysis of prenatal history and postnatal sequel of 22 patients with HLHS and foramen ovale restriction between 2008 and 2017. RESULTS: There were 11 survivors and 11 nonsurvivors. The most significant difference between the two groups pertained to the average time of foramen ovale restriction diagnosis which was 33 weeks for survivors and 28 weeks for nonsurvivors (p = .0416) and the duration of in-utero restriction (9 versus 5 weeks, p = .0213). Twenty patients (20/22) exhibited possible signs of infection. CONCLUSIONS: (1) Earlier development and longer presence of foramen ovale restriction in the setting of HLHS is associated with higher short-term mortality regardless of the degree of restriction. (2) Ratio of forward pulmonary vein flow to reverse flow (f/r) expressed as a velocity-time integral (VTI) is a good emergent intervention predictor, but it does not correlate with foramen ovale size and maximal velocity, nor does it influence survival rates. (3) Ultrasonographic signs of possible infection of the fetus is a potential risk factor of foramen ovale restriction development in patients with HLHS.

Effect of Nutritional Habits on the Glycemic Response to Different Carbohydrate Diet in Children with Type 1 Diabetes Mellitus.

Unhealthy eating habits are associated with obesity, metabolic syndrome, and increased insulin resistance in young patients with type 1 diabetes mellitus (T1DM), and may impact the possible benefit from dietary interventions on glycaemic control. This study determines how nutritional patterns influence the quality of dietary intervention with a 30% or 50% carbohydrate diet in terms of glycaemic control measured with continuous glucose monitoring (CGM). Eating habits were obtained with a frequency-of-consumption questionnaire (FFQ-6) before the diet assessment. Altogether, we collected CGM and FFQ-6 data from 30 children (16 boys and 14 girls aged 10-17 years) with T1DM subjected to two consecutive 3-day nutritional plans. From these, 23 patients met the CGM data quality criteria for further analysis. Furthermore, high accuracy achieved in training (95.65%) and V-fold cross-validation (81.67%) suggest a significant impact of food habits in response to introduced nutritional changes. Patients who consumed more vegetables or grains (>4 times per day), more wheat products (>once per day), fewer fats (<1.5 times per day), and ranked fruit juice as the most common selection in the drinks category achieved glycaemic control more often after the introduction of a 30% carbohydrate diet, as opposed to those with different dietary patterns, whose glycaemic control was negatively impacted after switching to this diet. Additionally, the 50% carbohydrate diet was safe for all patients in the context of glycaemic control.

Improved Estimation of Glycated Hemoglobin from Continuous Glucose Monitoring and Past Glycated Hemoglobin Data.

Background: Accurate estimation of glycated hemoglobin (HbA1c) from continuous glucose monitoring (CGM) remains challenging in clinic. We propose two statistical models and validate them in real-life conditions against the current standard, glucose management indicator (GMI). Materials and Methods: Modeling utilized routinely collected data from patients with type 1 diabetes from central Poland (eligibility criteria: age >1 year, diabetes duration >3 months, and CGM use between 01/01/2015 and 12/31/2019). CGM records were extracted from dedicated Medtronic/Abbott databases and cross-referenced with HbA1c values; 28-day periods preceding HbA1c measurement with >75% of the sensor-active time were analyzed. We developed a mixed linear regression, including glycemic variability indices and patient's ID (glucose variability-based patient specific model, GV-PS) intended for closed-group use and linear regression using patient-specific error of GMI (proportional error-based patient agnostic model, PE-PA) for general use. Models were validated with either new HbA1cs from closed-group patients or separate patient-HbA1c pool. External validation was performed with data from clinical trials. Performance metrics included bias, its 95% confidence interval (95% CI), coefficient of determination (R2), and root mean square error (RMSE). Results: We included 723 HbA1c-CGM pairs from 174 patients (mean age 9.9 ± 4.4 years and diabetes duration 3.7 ± 3.6 years). GMI yielded R2 = 0.58, with different bias between Medtronic and Abbott devices [0.120% vs. -0.152%, P < 0.0001], and overall 95% CI = -0.9% to +1%, RMSE = 0.47%. GV-PS successfully captured patient-specific variance (closed-group validation: R2 = 0.83, bias = 0.026%, 95% CI = -0.562% to 0.591%, RMSE = 0.31%). PE-PA performed similarly on new patients (R2 = 0.76, bias = -0.069%, 95% CI = -0.790% to 0.653%, RMSE = 0.37%). In external validation GMI, GV-PS, and PE-PA produced 73.8%, 87.5%, and 91.0% predictions within 0.5% (5.5 mmol/mol) from the true value. Conclusion: Constructed models performed better than GMI. PE-PA provided an accurate estimate of HbA1c with fast and straightforward implementation.

Evaluation of Changes to the Oral Microbiome Based on 16S rRNA Sequencing among Children Treated for Cancer.

A child's mouth is the gateway to many species of bacteria. Changes in the oral microbiome may affect the health of the entire body. The aim of the study was to evaluate the changes in the oral microbiome of childhood cancer survivors. Saliva samples before and after anti-cancer treatment were collected from 20 patients aged 6-18 years, diagnosed de novo with cancer in 2018-2019 (7 girls and 13 boys, 7.5-19 years old at the second time point). Bacterial DNA was extracted, and the microbial community profiles were assessed by 16S rRNA sequencing. The relative abundances of Cellulosilyticum and Tannerella genera were found to significantly change throughout therapy (p = 0.043 and p = 0.036, respectively). However, no differences in the alpha-diversity were observed (p = 0.817). The unsupervised classification revealed two clusters of patients: the first with significant changes in Campylobacter and Fusobacterium abundance, and the other with change in Neisseria. These two groups of patients differed in median age (10.25 vs. 16.16 years; p = 0.004) and the length of anti-cancer therapy (19 vs. 4 months; p = 0.003), but not cancer type or antibiotic treatment.

Nocturnal Oxygen Saturation Parameters as Independent Risk Factors for Type 2 Diabetes Mellitus among Obstructive Sleep Apnea Patients.

Obstructive sleep apnea (OSA) is a recognized independent risk factor for metabolic disorders, type 2 diabetes mellites (DM2) in particular. Therefore, the study aimed to assess the influence of nocturnal oxygen saturation parameters on the onset of DM2 among OSA patients. The study consisted of 549 participants, who underwent polysomnography examination. Based on apnea hypopnea index (AHI), 465 patients were diagnosed with OSA. One hundred and seven individuals had comorbid DM2. Cox regression models were used to assess the effect of oxygen saturation parameters on the onset of DM2. Classification and regression trees (CART) analysis was used to assess the onset of the DM2 in the study group in context of oxygen saturation variables. One-way Cox regression showed higher risk of earlier DM2 for increased values of BMI, AHI, decreased basal O2 and O2 nadir value, while lowered mean O2 desaturation has not shown statistical significance. In the CART analysis, the following cut-off points 92.2%, 81.7%, 87.1% were determined for basal O2, O2 nadir and mean O2 desaturation, respectively, with the first two parameters being statistically significant. Therefore, basal O2 is independent from AHI, BMI and age is a risk factor of DM2 among OSA patients.

Responses to Low- and High-Intensity Exercise in Adolescents with Type 1 Diabetes in Relation to Their Level of VO2 Max.

The purpose of this study was to investigate the influence of maximal oxygen uptake (VO2 max) on the glycemic changes during low and high intensity exercises in young type 1 diabetic patients. Twenty boys (age: 14.3 ± 1.6 years; height: 171.0 ± 11.3 cm; weight; 59.5 ± 12.8 kg) were divided into low-fit group (LFG, n = 10) and high-fit group (HFG, n = 10). According to the experimental design, participants performed three physical efforts (VO2 max test, mixed aerobic-anaerobic effort and aerobic effort) on the cycloergometer, during which real-time glycemia was measured. Mixed aerobic-anaerobic exercise demanded significantly smaller carbohydrate supplementation (0.2 ± 0.2 g/kg during exercise) than the aerobic test session (0.4 ± 0.3 g/kg during exercise). Moreover, patients with higher VO2 max had lower tendency for glycemic changes during the aerobic effort. The results of the current study suggest that young type 1 diabetic patients should perform different intensity activities using continuous glycemic monitoring system to avoid acute and chronic complications of the disease.