Dysfunction of peripheral somatic and autonomic nervous system in patients with severe forms of Crohn's disease on biological therapy with TNFα inhibitors-A single center study.

OBJECTIVE: Crohn's disease (CD) can be associated with a wide range of extraintestinal manifestations (EIMs), including neurological ones. Published studies differ in their conclusions about the epidemiology and etiopathogenesis of neurological EIMs. The aims of this study were to demonstrate the presence and find risk factors of peripheral (somatic and autonomic) neuropathy patients with severe CD on anti-TNFα biological therapy. MATERIAL AND METHODS: A clinical examination focusing on detection of peripheral sensor-motor nervous dysfunction (including Sudoscan) and examination of autonomic nervous system dysfunction (using Ewing´s battery tests and spectral analysis) together with laboratory tests and collection of demographic data followed by administration of questionnaires were performed on a total of 30 neurologically asymptomatic outpatients with severe CD on anti-TNFα biological therapy. RESULTS: Peripheral sensor-motor nervous function via clinical neurological examination was pathological in 36.7% and Sudoscan in 33.3% of cases. Statistically significant associations between vibration perception test and age, CD and biological therapy duration, body mass index and Crohn's Disease Activity Index were proved while statistically significant associations between temperature perception test and age and BMI were proved as well. Additionally, a decrease of total protein in a patient´s serum below the physiological cut-off in the 6 months prior to measurement was associated with a pathological result of a Sudoscan. Cardiovascular autonomic neuropathy based on Ewing´s battery tests was present in 56.7% of patients, no statistically significant risk factors were found. Our peripheral neuropathy questionnaire correlated with the results of the Sudoscan test and some tests of the clinical examination of peripheral sensor-motor nervous function (discriminatory contact perception test, temperature perception test). CONCLUSIONS: This study demonstrated a relatively high prevalence of peripheral (especially autonomic) neuropathy and verified some risk factors for the development of peripheral somatic neuropathy in asymptomatic patients with severe form of CD on anti-TNFα biological therapy.

Feasibility and Safety of Continuous Glucose Monitoring in Infants at Risk of Hypoglycemia in a Rooming-in Setting.

Background:Screening of neonatal hypoglycemia uses currently intermittent blood sampling. Continuous glucose monitoring (CGM) allows for tighter glucose control and better comfort for newborns and parents. CGM has previously been used in intensive care setting or blinded to clinicians. Our pilot study uses CGM in real time in rooming-in setting. Methods: CGM was attached within first two hours of life. Low glucose readings were verified to prevent overtreatment. Pairs of sensor readings and corresponding blood glucose measurements were assessed retrospectively. Neurodevelopmental evaluation was performed at 24 months. Results: 44 infants were enrolled. Three had verified hypoglycemia found due to CGM. No patient was below 2 standard deviations in any components of Bayley scales. Median scores were: Cognitive 100, language 86, motor 94. Conclusion: Use of CGM in a rooming-in environment is safe from clinical and neurodevelopmental point of view. Randomized trials are needed to evaluate superiority in longer term outcomes.

Direct Versus Iterated Multi-Step Forecasting of Glycaemia in Type 1 Diabetics Using Autoregressive Models.

The paper compares two approaches to multi-step ahead glycaemia forecasting. While the direct approach uses a different model for each number of steps ahead, the iterative approach applies one one-step ahead model iteratively. Although it is well known that the iterative approach suffers from the error accumulation problem, there are no clear outcomes supporting a proper choice between those two methods. This paper provides such comparison for different ARX models and shows that the iterative approach outperformed the direct method for one-hour ahead (12-steps ahead) forecasting. Moreover, the classical linear ARX model outperformed more complex non-linear versions for training data covering one-month period.

Ensemble methods in combination with compartment models for blood glucose level prediction in type 1 diabetes mellitus.

Backgroung: Type 1 diabetes is a disease that adversely affects the daily life of a large percentage of people worldwide. Daily glucose levels regulation and useful advices provided to patients regarding their diet are essential for diabetes treatment. For this reason, the interest of the academic community has focused on developing innovative systems, such as decision support systems, based on glucose prediction algorithms. The present work presents the predictive capabilities of ensemble methods compared to individual algorithms while combining each method with compartment models for fast acting insulin absorption simulation. Methods: An approach of combining widely used glycemia prediction algorithms is proposed and three different ensemble methods (Linear, Bagging and Boosting metaregressor) are applied and evaluated on their ability to provide accurate predictions for 30, 45 and 60 minutes ahead prediction horizon. Moreover, glycemia levels, long and short acting insulin dosages and consumed carbohydrates from six type one people with diabetes are used as input data and the results are evaluated in terms of root-mean square error and Clarke error grid analysis. Results: According to results, ensemble methods can provide more accurate glucose concentration in comparison to individual algorithms. Bagging metaregressor, specifically, performed better than individual algorithms in all prediction horizons for small datasets. Bagging ensemble method improved the percentage in zone A according to Clarkes error grid analysis by 4% and in some cases by 9%. Moreover, compartment models are proved to improve results in combination with any method at any prediction horizon. This strengthen the potential practical usefulness of the ensemble methods and the importance of building accurate compartment models.

Continuous glucose monitoring as a screening tool for neonatal hypoglycemia in infants of diabetic mothers.

Objective: To assess the plausibility of using the continuous glucose monitoring as a sole source of data for the screening of the neonatal hypoglycemia.Study design: Infants of mothers with diabetes were screened for neonatal hypoglycemia (less than 2.5 mmol/l after 4 h of life). Initial measurement was performed using point of care analyzer. We applied continuous glucose monitoring system subsequently. Infants were monitored up to 5 days or until discharge.Results: Out of 32 infants 11 had postnatal hypoglycemia resolved within 12 h of life. Two infants had hypoglycemia found due to continuous glucose monitoring after 24 h of life when sufficient feeding was established and they did not show any signs of hypoglycemia. We did not have any false negative measurements. No infant showed clinical signs of neonatal hypoglycemia.Conclusions: Continuous glucose monitoring is plausible and safe to use for screening of neonatal hypoglycemia. It operates well within the range that is accepted as safe for neurodevelopment. In addition, it can be used after first day of life where regular screening ends. Limitation of this method is possible alarm negligence of caregivers.

The impact of type 1 diabetes mellitus on male sexual functions and sex hormone levels.

Little is known about type 1 diabetes mellitus (T1DM) impact on the male sexual and reproductive functions. We aim to evaluate the influence of T1DM on male sexual function, quality of sexual life, and sex hormone levels. A total of 57 male patients aged 18 to 50 years (mean = 33) with T1DM (duration mean = 15 years) had a medical examination and completed a set of questionnaires - International Index of Erectile Function-5 (IIEF-5), Beck Depression Inventory (BDI) and Sexual quality of life questionnaire male (SQoL-M). The prevalence of erectile dysfunction was 28.1% (IIEF-5 ≤21). Patients without diabetic nephropathy had better erectile function (p = 0.008). Subjects with better glycemic control (HbA1c <65 mmol/mol) had also better erectile function (p = 0.041). At least 8.8% patients had retrograde ejaculation. Blood serum levels of sex hormones were determined and compared to laboratory reference values of healthy men. Total testosterone level was not significantly changed, sex hormone binding globulin was higher (p < 0.001) and its level correlated with daily insulin dose adjusted to body weight (p = 0.008). Free androgen index and calculated free testosterone were lower (p = 0.013; p < 0.001), estradiol was not significantly changed, LH was higher (p < 0.001), FSH was unchanged, and prolactin was higher (p < 0.001). Prostate-specific antigen (PSA) negatively correlated with HbA1c (p < 0.001). To conclude, we found significant changes in sexual functions and sex hormone blood concentrations that indicate impairment of sexual and reproductive functions in T1DM males.

Insulin pump therapy: education and its goals.

Insulin pump therapy represents nowadays the way of insulin administration most similar to the physiological insulin secretion. This form of intensified insulin regime is used mostly (but not exclusively) in type 1 diabetes patients. Insulin pump therapy can be efficiently combined with continuous glucose monitoring. Even there are available insulin pumps which can serve as continuous glucose monitoring signal receiver themselves and are capable to stop automatically basal insulin infusion to prevent hypoglycemia. By this technological combination it is possible to reach near normoglycemia without increasing the risk of severe hypoglycemia. In the Czech Republic this therapy is covered by insurance when defined indication criteria are fulfilled. To reach this therapy full potential the patient as well as the professionals must be trained properly to know all technical aspects of this therapy as well as it is necessary to gain further knowledge. Particularly important is knowledge on food nutrition content and on the glycemic effect of different meals. All these factors are discussed in details in the paper.

Comprehensive Analysis of the Real Lifestyles of T1D Patients for the Purpose of Designing a Personalized Counselor for Prandial Insulin Dosing.

Post-prandial hyperglycemia is still a challenging issue in intensified insulin therapy. Data of 35 T1D patients during a four-week period were analyzed: RT-CGM (real time continuous glucose monitoring) record, insulin doses, diet (including meal photos), energy expenditure, and other relevant conditions. Patients made significant errors in carbohydrate counting (in 56% of cooked and 44% of noncooked meals), which resulted in inadequate insulin doses. Subsequently, a mobile application was programmed to provide individualized advice on prandial insulin dose. When using the application, a patient chooses only the type of categorized situation (e.g., meals with other relevant data) without carbohydrates counting. The application significantly improved postprandial glycemia as normoglycemia was reached in 95/105 testing sessions. Other important findings of the study include: A high intake of saturated fat (median: 162% of recommended intake); a low intake of fiber and vitamin C (median: 42% and 37%, respectively, of recommended intake); an increase in overweight/obesity status (according to body fat measurement), especially in women (median of body fat: 30%); and low physical activity (in 16/35 patients). The proposed individualized approach without carbohydrate counting may help reach postprandial normoglycemia but it is necessary to pay attention to the lifestyle habits of T1D patients too.

Sexual Dysfunction in Women Treated for Type 1 Diabetes and the Impact of Coexisting Thyroid Disease.

INTRODUCTION: More sexual problems are reported among people treated for diabetes; however, this situation is less explored in women than in men. AIM: To analyze the presence and causal links of female sexual dysfunction (FSD) among Czech women treated for type 1 diabetes. METHODS: 40 women completed a national version of the Female Sexual Function Index (FSFI), Female Sexual Distress Scale-revised (FSDS-R), and Beck's Depression Inventory-II (BDI-II). A metabolic and endocrine analysis was done using blood samples. Data were statistically analyzed using SPSS v.24 and the R environment. MAIN OUTCOME MEASURES: Patient details (personal information, diabetes-related data, and sex history), sexual performance (the FSFI and FSDS-R scores), and level of depression (the BDI-II score) were measured. RESULTS: FSD was present in 58% of the participants (based on the FSFI score), and 38% women declared significant sexual distress (according to their FSDS-R score). Even though only 4 women fulfilled the criteria for depression, we observed a strong association between BDI-II and FSFI (for total FSFI score P = .012, ρ = -0.394) resp. FSDS-R scores (P < .001, ρ = 0.552). Although we were not able to establish a clear direct connection between FSD and metabolic control, BDI-II scores were closely correlated with glycosylated hemoglobin (P = .009, ρ = 0.407). The duration of diabetes (based on FSDS-R: P = .046) but neither age nor the presence of chronic diabetic microvascular complications was associated with a higher FSD occurrence. We also observed an association between FSD and the presence of autoimmune hypothyroidism, even when successfully treated (FSDS-R: P = .009; FSFI: P = .067). CONCLUSION: FSD is more common in women with type 1 diabetes than in healthy women, and coexisting thyroid autoimmune disease seems to exacerbate FSD. Women suffering from type 1 diabetes, and particularly those with additional endocrinopathies, should be actively screened for FSD. Stechova K, Mastikova L, Urbaniec K, et al. Sexual Dysfunction in Women Treated for Type 1 Diabetes and the Impact of Coexisting Thyroid Disease. Sex Med 2019;7:217-226.

Higher Total Insulin Dose Has Positive Effect on Corneal Nerve Fibers in DM1 Patients.

Purpose: Neuropathies are among the most common long-term complications of diabetes mellitus (DM) and good glycemic control is essential in prevention of this complication. DM patients with similar mean glucose levels or HbA1c levels often exhibit differences in glucose variability. We tested for possible associations between parameters of glycemia compensation and corneal sub-basal nerve fiber status. Methods: The study included 20 patients with DM type 1 treated using an intensified insulin regimen. The corneas of both eyes were examined using in vivo corneal confocal microscopy. Corneal nerve fiber density (NFD), nerve fiber length (NFL), and nerve branch density (NBD) were evaluated. Possible associations between parameters of glycemia compensation (HbA1c, glycemia SD, and insulin dose), and other clinical factors were analyzed. Results: NBD was the highest in those with higher glycemic variability (P = 0.023). HbA1c had a negligible effect on corneal nerve parameters. NFD, NFL, and NBD were statistically significantly higher in those with higher total insulin per kilogram (P = 0.02, P = 0.01, and P = 0.012, respectively). Among other factors, a positive correlation between free thyroxine (fT4) levels and NFD and NBD was also found (P = 0.041 and P = 0.015, respectively). Conclusions: Total insulin dose per kilogram may be an important factor influencing nerve fiber status and needs to be considered in future studies of diabetic neuropathy pathophysiology and its progression. Also, more attention must be paid to other possible factors when elucidating the development of diabetic complications.

Lessons Learned from Implementing a New Testing/Educational Tool for Patients Using an Insulin Pump.

BACKGROUND: To improve insulin pump therapy results, a special test for patients was devised. The model successfully used to achieve a license to operate different machines was followed. METHODS: The test (a practice and a full run, with a time limit) contained 42 questions, each with four optional choices, and could be answered online. Patients could familiarize themselves with the whole question pool first. Patients could repeat a full run attempt if they failed and were offered focused remedial education. The study group composed of adults, 46 females, and 54 males, all treated for type 1 diabetes, 38/100 newly introduced to insulin pump therapy. RESULTS: Eighty-five of 100 patients successfully completed their first full run attempt (80% or higher correct answers) and 3 of 100 on their second full run attempt; 12 of 100 patients were not able to succeed. The median of the test score was 2 mistakes (range 0-17 mistakes). The most problematic topics were diet and insulin regimens and their application. The crucial factor influencing the test score was the willingness to try practice run(s). Those who practiced had a significantly higher total test score with better results in 5 of 8 tested knowledge domains. Age and diabetes existing >15 years had an impact on the result, too. Both patients' and caregivers' opinions on the test were predominantly positive (or neutral). CONCLUSIONS: The type of test introduced is a good tool for checking a patient's theoretical knowledge and indirectly revealing a patient's level of motivation.

Not Only Glycaemic But Also Other Metabolic Factors Affect T Regulatory Cell Counts and Proinflammatory Cytokine Levels in Women with Type 1 Diabetes.

Type 1 diabetic (T1D) patients suffer from insulinopenia and hyperglycaemia. Studies have shown that if a patient's hyperglycaemic environment is not compensated, it leads to complex immune dysfunctions. Similarly, T1D mothers with poor glycaemic control exert a negative impact on the immune responses of their newborns. However, questions concerning the impact of other metabolic disturbances on the immune system of T1D mothers (and their newborns) have been raised. To address these questions, we examined 28 T1D women in reproductive age for the relationship between various metabolic, clinical, and immune parameters. Our study revealed several unexpected correlations which are indicative of a much more complex relationship between glucose and lipid factors (namely, glycosylated haemoglobin Hb1Ac, the presence of one but not multiple chronic diabetic complications, and atherogenic indexes) and proinflammatory cytokines (IL-1alpha and TNF-alpha). Regulatory T cell counts correlated with HbA1c, diabetic neuropathy, lipid spectra parameters, and IL-6 levels. Total T-helper cell count was interconnected with BMI and glycaemia variability correlated with lipid spectra parameters, insulin dose, and vitamin D levels. These and other correlations revealed in this study provide broader insight into the association of various metabolic abnormalities with immune parameters that may impact T1D mothers or their developing child.

Personal Portable Devices in the Light of the Internet of Things.

Personal portable devices have already gained their position in health services. However, mobile technologies and Internet of Things open new areas of applications. The possibility to collect many data types continuously over long time intervals brings various questions that must be answered in the design process. We also discuss briefly the role of the user. We illustrate the complexity of the field by a case study of diabetes management.

T regulatory lymphocytes in type 1 diabetes: Impaired CD25 expression and IL-2 induced STAT5 phosphorylation in pediatric patients.

T regulatory cells (Tregs) are essential for maintaining tolerance and preventing autoimmune diseases, such as type 1 diabetes (T1D). In our study, we investigated CD25 + FoxP3 + Tregs and thymic FoxP3 + Helios + Tregs in large cohorts of children with T1D at onset and with long-term T1D, and further in their relatives and healthy controls. We observed significantly decreased numbers of CD25 + FoxP3 + Tregs, but not FoxP3 + Helios + Tregs, in long-term patients compared with the control group and T1D onset. Furthermore, long-term T1D patients exhibited highly significant decrease of CD25 expression on both CD25 + FoxP3 + Tregs and FoxP3 + Helios + Tregs, independently on age or the duration of diabetes. A similar reduction of CD25 expression was also found in T1D relatives, more significant in those with positive autoantibodies. Low CD25 expression was associated with impaired signal transducer and activator of transcription 5 (STAT5) phosphorylation after IL-2 exposure. Our results show that the frequency of Tregs is altered in a large cohort of long-term T1D patients, a profound decrease in CD25 expression and altered IL-2 signaling are typical features of Tregs populations in long-term diabetic patients and their relatives.

Treated Autoimmune Thyroid Disease Is Associated with a Decreased Quality of Life among Young Persons with Type 1 Diabetes.

Type 1 diabetes (T1D) in children and adolescents is relatively often accompanied by other immunopathological diseases, autoimmune thyroid disease (AITD) or celiac disease (CD). Our aim was to assess whether these conditions are associated with changes in the health-related quality of life (HRQOL) in pediatric patients with T1D. In a cross-sectional study we identified eligible 332 patients with T1D aged 8-18 years, of whom 248 (75%) together with their parents responded to the PedsQL Generic and Diabetes Modules. Compared to 143 patients without thyroid autoantibodies, 40 patients with a thyroxine-treated AITD scored lower in the overall generic HRQOL (P = 0.014), as well as in the overall diabetes-specific HRQOL (P = 0.013). After adjustment for age, gender, duration of diabetes, type of diabetes treatment, and diabetes control, this association remained statistically significant for the generic HRQOL (P = 0.023). Celiac disease was not associated with a change in the generic or diabetes-specific HRQOL (P = 0.07 and P = 0.63, resp.). Parental scores showed no association with AITD or celiac disease, except a marginally significant decrease in the overall generic HRQOL (P = 0.039) in the T1D + AITD compared to T1D group. Our study indicates that, in pediatric patients with T1D, concomitant thyroxine-treated AITD is associated with lower quality of life.

The cytokine production of peripheral blood mononuclear cells reflects the autoantibody profile of patients suffering from type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disorder characterised by the immune-mediated destruction of insulin-producing pancreatic beta cells. The inflammatory process appears to be primarily mediated by pro-inflammatory Th1 lymphocytes, while the role Th17 cells in T1D is currently being investigated. T1D is characterised by the presence of autoantigen-specific autoantibodies. This study was conducted using patients with confirmed T1D and healthy control subjects. We examined the effect of the patient's autoantibody profile on peripheral blood mononuclear cell (PBMC) cytokine production following stimulation with the major diabetogenic autoantigens GAD65 and IA2. IFN-gamma and IL17 production was detected by ELISPOT and the ratio of basic cellular populations in PBMCs was measured by flow cytometry. We demonstrated a significant interaction between the patient's autoantibody profile and mode of stimulation. This suggests that autoantigen stimulation has a different effect on different groups of patients depending on their autoantibody profile. An increased production of IL17 was found in patients with high IA2 autoantibodies compared to patients with low levels of autoantibodies and healthy controls regardless of the mode of stimulation. The titre of IA2 autoantibodies positively correlates with the proportion of Tc lymphocytes and negatively correlates with the proportion of Th lymphocytes. Our results show that a patient's autoantibody profile reflects the type of cellular immune responses. It seems that the high titre of IA2 autoantibodies is related to increased production of IL17 and an increased proportion of Tc lymphocytes. This finding may be useful in designing immunointervention studies to prevent T1D.

Decreased dendritic cell numbers but increased TLR9-mediated interferon-alpha production in first degree relatives of type 1 diabetes patients.

OBJECTIVE: Dendritic cells (DCs) play an important role in pathogenesis of autoimmunity, including type 1 diabetes (T1D). In this study, we investigated DC subpopulations and their responses to TLR stimulation in T1D patients and their relatives. METHODS: We analyzed the frequency of myeloid (mDCs) and plasmacytoid DCs (pDCs) in 97 T1D patients (69 onset, 28 long-term), 67 first-degree relatives, and 64 controls. We additionally tested the IFN-alpha production by pDCs upon stimulation with TLR 7, 8 and 9 agonists. RESULTS: A lower number of mDCs and pDCs were found in T1D patients and their relatives. Of all the tested TLR ligands, only stimulation with CpG 2216 induced IFN-alpha production that was the highest in T1D relatives, except of autoantibody-negative relatives bearing the protective haplotypes. CONCLUSION: Our data demonstrate disturbances in DC number and function expressed most significantly in T1D relatives and point to a potential role of TLR9-induced IFN-alpha production in T1D development.

Experience with real time continuous glucose monitoring in stabilising fluctuating glycaemia during intensive care of the preterm infant of a diabetic mother.

OBJECTIVE: The newborns of diabetic mothers suffer from perinatal complications more frequently than the newborns of healthy women. METHODS: We used for 7 days a real time continuous glucose monitoring system (RT-CGMS) to monitor glucose homeostasis and manage glucose administration in a premature newborn of a diabetic mother. RESULTS: The boy was born at 35 + 5 gestational weeks with typical signs of diabetic fetopathy. RT-CGMS revealed 2 late hypoglycaemia episodes on the 2nd and 4th days. The sensor readings correlated well with glycaemia measured in the laboratory (r = 0.908, p = 0.005). To support conclusions of this case report, we attached the data of five other preterm newborns of diabetic mothers who were later successfully treated according to the RT-CGMS data as well. CONCLUSIONS: This approach allows timely response to glycaemia instability and is applicable even in preterm infants.