Fungal infection frequency in newly diagnosed acute myeloid leukaemia patients treated with venetoclax plus azacitidine with or without antifungal prophylaxis.

Our observational study analysed fungal infection frequency within cohorts with versus without antifungal prophylaxis (AFP) among newly diagnosed first-line venetoclax and azacitidine (VEN + AZA)-treated acute myeloid leukaemias in Czech, Austrian and Slovak haematology centres. Among 186 patients, 85 (46%) received antifungal prophylaxis, while 101 (54%) received no prophylaxis. Fungal infections occurred in 1/85 patients with prophylaxis (1%) and 5/101 patients without prophylaxis (5%) (p = 0.222). No significant difference was recorded between cohorts with and without AFP in terms of death rate (p = 0.296) and overall survival (p = 0.844). In conclusion, most infections were not severe, developing during the first treatment-cycle and did not affect patients' overall outcome.

Low incidence of severe acute and chronic graft-versus-host disease in a long-term retrospective study with ATG Grafalon routine use.

Since 2006, combined graft-versus-host disease (GVHD) prophylaxis with ATG Grafalon has been our department's base of peri-transplant supportive care. This recent retrospective study included 398 patients who underwent their first allogeneic hematopoietic stem cell transplantation after receiving a defined dose of ATG Grafalon. Our observations recorded reduced incidence of severe acute and chronic GVHD without negative impact on overall survival in a nonselected group with standard and uniform GVHD prophylaxis.

Early ganglion stellate blockade as part of two-step treatment algorithm suppresses electrical storm and need for intubation.

BACKGROUND: For the treatment of patients with electrical storm (ES), we established a two-step algorithm comprising standard anti-arrhythmic measures and early ultrasound-guided stellate ganglion blockade (SGB). In this single-center study, we evaluated the short-term efficacy of the algorithm and tested the hypothesis that early SGB might prevent the need for intubations. METHODS: Overall, we analyzed data for 70 ES events in 59 patients requiring SGB (mean age 67.7 ± 12.4 years, 80% males, left ventricular ejection fraction 30.0% ± 9.1%), all with implantable cardioverter-defibrillators (ICDs). RESULTS: The mean time from ES onset to SGB was 13.2 ± 12.3 hours. Percentage and mean absolute reduction in shocks at 48 hours after SGB reached 86.8% (-6.3 shocks), and anti-tachycardiac pacing (ATP) declined by 65.9% (-51.1 ATPs; all P < 0.001). Patients with the highest sustained ventricular arrhythmia (VA) burden (shocks ≥10/48 h; ATPs 10-99/48 h and ≥100/48 h) experienced the highest percentage decrease in ICD therapy (shocks -99.1%; ATPs -92.1% and -100.0%, respectively). For clinical response by defined criteria and two outcome periods (1/no sustained VA ≤48 hours post SGB, and 2/no ICD shock or <3 ATPs/day from day 3 to discharge/catheter ablation/day 8), 75.7% and 76.1% experienced complete response, respectively. Catecholamine support, no/low-dose ß-blocker therapy, polymorphic/mixed-type VA, and baseline sinus rhythm versus atrial fibrillation were more frequent in patients with early arrhythmia recurrence. Temporary Horner's syndrome occurred in 67.1%, and no other adverse events were recorded. Intubation and general anesthesia during and after SGB were not needed. CONCLUSION: The presented two-step algorithm for treating ES proved efficacious and safe. The results support implementation of early SGB in routine ES management.

Incidence of muscle wasting in the critically ill: a prospective observational cohort study.

Loss of muscle mass occurs rapidly during critical illness and negatively affects quality of life. The incidence of clinically significant muscle wasting in critically ill patients is unclear. This study aimed to assess the incidence of and identify predictors for clinically significant loss of muscle mass in this patient population. This was a single-center observational study. We used ultrasound to determine the rectus femoris cross-sectional area (RFcsa) on the first and seventh day of ICU stay. The primary outcome was the incidence of significant muscle wasting. We used a logistic regression model to determine significant predictors for muscle wasting. Ultrasound measurements were completed in 104 patients. Sixty-two of these patients (59.6%) showed ≥ 10% decreases in RFcsa. We did not identify any predictor for significant muscle wasting, however, age was of borderline significance (p = 0.0528). The 28-day mortality rate was higher in patients with significant wasting, but this difference was not statistically significant (30.6% versus 16.7%; p = 0.165). Clinically significant muscle wasting was frequent in our cohort of patients. Patient age was identified as a predictor of borderline significance for muscle wasting. The results could be used to plan future studies on this topic.Trial registration: ClinicalTrials.gov NCT03865095, date of registration: 06/03/2019.

Orally Administered Probiotics in the Prevention of Chemotherapy (± Radiotherapy)-Induced Gastrointestinal Toxicity: A Systematic Review With Meta-Analysis of Randomized Trials.

BACKGROUND: Chemoradiotherapy-induced gastrointestinal toxicity may lead to a significant impairment of the oncological patient's quality of life, as well as to reduced adherence to the treatment, which may have a negative impact on survival and mortality rates. OBJECTIVE: The aim of this review was to investigate whether oral probiotic administration prevents chemotherapy (± radiotherapy)-induced gastrointestinal toxicity, particularly diarrhea. METHODS: We searched the MEDLINE, Web of Science, and SCOPUS databases for randomized controlled trials in English published between 1990 and 2020. We conducted statistical data analyses expressing the treatment effect size as a risk ratio (RR) together with a 95% confidence interval (CI). Implications are based on trials rated as having a low risk of bias (RoB). RESULTS: We included 8 trials (n = 697 participants), from which 3 studies rated as low RoB contained primary endpoint data; the risk of developing grade 3/4 diarrhea in patients receiving probiotics was reduced by 78% compared to the control group (RR = 0.22 [95% CI 0.05-1.08]; P = .06; n = 114 participants). Probiotics showed preventive effects in patients treated with chemotherapy alone (RR = 0.34 [0.12-0.94]; P = .04, n = 121 participants) and in patients with colorectal cancer (RR = 0.56 [0.34-0.92]; P = .02; n = 208 participants). The reduction in the incidence of overall diarrhea was not significant. CONCLUSIONS: Probiotics failed to prove a preventive effect of statistical significance against the development of severe and overall diarrhea in cancer patients treated with chemotherapy (± radiotherapy). However, we cannot rule out that the effects of probiotics are clinically relevant, especially in certain subgroups of patients. This needs to be clarified in further well-performed studies.

Palliative care practice and moral distress during COVID-19 pandemic (PEOpLE-C19 study): a national, cross-sectional study in intensive care units in the Czech Republic.

BACKGROUND: Providing palliative care at the end of life (EOL) in intensive care units (ICUs) seems to be modified during the COVID-19 pandemic with potential burden of moral distress to health care providers (HCPs). We seek to assess the practice of EOL care during the COVID-19 pandemic in ICUs in the Czech Republic focusing on the level of moral distress and its possible modifiable factors. METHODS: Between 16 June 2021 and 16 September 2021, a national, cross-sectional study in intensive care units (ICUs) in Czech Republic was performed. All physicians and nurses working in ICUs during the COVID-19 pandemic were included in the study. For questionnaire development ACADEMY and CHERRIES guide and checklist were used. A multivariate logistic regression model was used to analyse possible modifiable factors of moral distress. RESULTS: In total, 313 HCPs (14.5% out of all HCPs who opened the questionnaire) fully completed the survey. Results showed that 51.8% (n = 162) of respondents were exposed to moral distress during the COVID-19 pandemic. 63.1% (n = 113) of nurses and 71.6% of (n = 96) physicians had experience with the perception of inappropriate care. If inappropriate care was perceived, a higher chance for the occurrence of moral distress for HCPs (OR, 1.854; CI, 1.057-3.252; p = 0.0312) was found. When patients died with dignity, the chance for moral distress was lower (OR, 0.235; CI, 0.128-0.430; p < 0.001). The three most often reported differences in palliative care practice during pandemic were health system congestion, personnel factors, and characteristics of COVID-19 infection. CONCLUSIONS: HCPs working at ICUs experienced significant moral distress during the COVID-19 pandemic in the Czech Republic. The major sources were perceiving inappropriate care and dying of patients without dignity. Improvement of the decision-making process and communication at the end of life could lead to a better ethical and safety climate. TRIAL REGISTRATION: NCT04910243 .

Prediction of Vagal Nerve Stimulation Efficacy in Drug-Resistant Epilepsy (PRECISE): Prospective Study for Pre-implantation Prediction/Study Design.

Background: Vagal nerve stimulation (VNS) can be indicated in patients with drug-resistant epilepsy, who are not eligible for resective epilepsy surgery. In VNS therapy, the responder rate (i.e., percentage of subjects experiencing ≥50% seizure reduction) is ~50%. At the moment, there is no widely-accepted possibility to predict VNS efficacy in a particular patient based on pre-implantation data, which can lead to unnecessary surgery and improper allocation of financial resources. The principal aim of PRediction of vagal nerve stimulation EfficaCy In drug-reSistant Epilepsy (PRECISE) study is to verify the predictability of VNS efficacy by analysis of pre-implantation routine electroencephalogram (EEG). Methods: PRECISE is designed as a prospective multicentric study in which patients indicated to VNS therapy will be recruited. Patients will be classified as predicted responders vs. predicted non-responders using pre-implantation EEG analyses. After the first and second year of the study, the real-life outcome (responder vs. non-responder) will be determined. The real-life outcome and predicted outcome will be compared in terms of accuracy, specificity, and sensitivity. In the meantime, the patients will be managed according to the best clinical practice to obtain the best therapeutic response. The primary endpoint will be the accuracy of the statistical model for prediction of response to VNS therapy in terms of responders and non-responders. The secondary endpoint will be the quantification of differences in EEG power spectra (Relative Mean Power, %) between real-life responders and real-life non-responders to VNS therapy in drug-resistant epilepsy and the sensitivity and specificity of the model. Discussion: PRECISE relies on the results of our previous work, through which we developed a statistical classifier for VNS response (responders vs. non-responders) based on differences in EEG power spectra dynamics (Pre-X-Stim). Trial Registration: www.ClinicalTrials.gov, identifier: NCT04935567.

Real-world effectiveness and safety of fingolimod in patients with multiple sclerosis in the Czech Republic: results from core and extension parts of the GOLEMS study up to 48 months.

BACKGROUND: Fingolimod, an oral sphingosine 1-phosphate receptor immunomodulator, is approved in Europe for people with multiple sclerosis (pwMS) with highly active disease despite a full and adequate course of treatment with ≥ 1 disease-modifying therapy or patients with rapidly evolving severe relapsing-remitting MS. GOLEMS, a national, multicenter, non-interventional, single-arm, real-world study showed a favorable benefit-risk profile of 12-month treatment with fingolimod in pwMS in the Czech Republic. Here, we evaluated the long-term effectiveness and safety of fingolimod and its impact on disability progression and work capability for up to 48 months in pwMS. METHODS: The endpoints assessed were the incidence and severity of MS relapses in fingolimod-treated patients and the proportion of relapse-free patients up to 48 months of fingolimod treatment, change from baseline in the Expanded Disability Status Scale (EDSS) score, and change from baseline in work capability assessment. Efficacy outcomes were analyzed in the completed and efficacy sets, and safety was evaluated in all the enrolled patients. RESULTS: Of 240 enrolled patients, 237 were included into efficacy set. Patients with a minimum of a 12-month observation period in the core study who continued fingolimod treatment, were eligible to participate in the extension phase. Of 211 patients enrolled in extension study, 155 were evaluated in the completed set. Based on analysis of 48-month period of fingolimod treatment, 95/237 patients (40.1%) in the efficacy set, 54/155 (34.8%) in the completed set were free of relapses. The majority of relapses reported were moderate in intensity. Mean EDSS score remained stable throughout 48-month study period (Baseline, 3.4; Month 48, 3.6). No trend was observed in changes in work capability assessment or number of missed days of work. Of 240 enrolled patients, 147 (61.3%) had ≥ 1 treatment-emergent adverse event (AE) and 20 (8.3%) reported serious AEs. In total, 45 patients (18.8%) permanently discontinued treatment because of AEs related to study drug; two patients reported pregnancy after treatment initiation and subsequently discontinued the treatment; no deaths were reported. CONCLUSION: GOLEMS study demonstrated the sustained effectiveness and manageable safety profile of fingolimod under real-world conditions over 48 months in patients with MS. TRIAL REGISTRATION: Not applicable.

Cardiac sequelae after COVID-19: Results of a 1-year follow-up study with echocardiography and biomarkers.

Objective: To evaluate the need for cardiac monitoring in unselected patients recovered from COVID-19 and to estimate the risk of heart complications after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Materials and methods: During March 2020 and January 2021, 106 patients who had recovered from SARS-CoV-2 (alpha and beta variants) were enrolled in prospective observational cohort study CoSuBr (Covid Survivals in Brno). The diagnosis was based on a reverse transcription-polymerase chain reaction swab test of the upper respiratory tract. Demographic parameters, patient history, clinical evaluation, cardiac biomarkers, ECG and echocardiography were recorded during three visits (Visit 1 at least 6 weeks after infection, Visit 2 three months later, and Visit 3 one year after Visit 1). Results: 58.5% of the study group (n = 106) were female, while the mean age was 46 years (range 18-77 years). The mean time interval between the onset of infection and the follow-up visit was 107 days. One quarter (24.5%) of the patients required hospitalization during the acute phase of the disease; the rest recovered at home. 74% suffered a mild form of the disease, with 4.8, 18.1, and 2.9% suffering moderate, severe, and critical forms, respectively. At the time of enrolment, 64.2% of the patients reported persistent symptoms, while more than half of the whole group (50.9%) mentioned at least one symptom of possible cardiac origin (breathing problems, palpitations, exercise intolerance, fatigue). In the 1-year follow-up after COVID-19 infection, left ventricle ejection fraction showed no significant decrease [median (IQR) change was -1.0 (-6.0; 4.0)%, p = 0.150], and there were no changes of troponin (mean change -0.1 ± 1.72 ng/L; p = 0.380) or NT-proBNP [median (IQR) change 2.0 (-20.0; 29.0) pg/mL; p = 0.315]. There was a mild decrease in right ventricle end diastolic diameter (-mean change 2.3 ± 5.61 mm, p < 0.001), while no right ventricle dysfunction was detected. There was very mild progress in left ventricle diastolic diameter [median (IQR) change 1.0 (-1.0; 4.0) mm; p = 0.001] between V1 and V3, mild enlargement of the left atrium (mean change 1.2 ± 4.17 mm; p = 0.021) and a non-significant trend to impairment of left ventricle diastolic dysfunction. There was a mild change in pulmonary artery systolic pressure [median (IQR) change 3.0 (-2.0; 8.0) mmHg; p = 0.038]. Conclusion: Despite a lot of information regarding cardiac impairment due to SARS-CoV2, our study does not suggest an increased risk for developing clinically significant heart changes during the 1-year follow-up. Based on our results, routine echocardiography and biomarkers collection is currently not recommended after COVID-19 recovery.

N-of-1 Trials in Pediatric Oncology: From a Population-Based Approach to Personalized Medicine-A Review.

Pediatric oncology is a critical area where the more efficient development of new treatments is urgently needed. The speed of approval of new drugs is still limited by regulatory requirements and a lack of innovative designs appropriate for trials in children. Childhood cancers meet the criteria of rare diseases. Personalized medicine brings it even closer to the horizon of individual cases. Thus, not all the traditional research tools, such as large-scale RCTs, are always suitable or even applicable, mainly due to limited sample sizes. Small samples and traditional versus subject-specific evidence are both distinctive issues in personalized pediatric oncology. Modern analytical approaches and adaptations of the paradigms of evidence are warranted. We have reviewed innovative trial designs and analytical methods developed for small populations, together with individualized approaches, given their applicability to pediatric oncology. We discuss traditional population-based and individualized perspectives of inferences and evidence, and explain the possibilities of using various methods in pediatric personalized oncology. We find that specific derivatives of the original N-of-1 trial design adapted for pediatric personalized oncology may represent an optimal analytical tool for this area of medicine. We conclude that no particular N-of-1 strategy can provide a solution. Rather, a whole range of approaches is needed to satisfy the new inferential and analytical paradigms of modern medicine. We reveal a new view of cancer as continuum model and discuss the "evidence puzzle".

An Investigation into the Prevalence of Migraine and Its Prophylactic Treatment Patterns in the Czech Republic: An Observational Study.

PURPOSE: A national primary and secondary healthcare-level study in the Czech Republic has not yet been conducted to evaluate the prevalence of migraine. We analyzed the current treatment patterns (acute and prophylactic) in migraine patients and the number of migraine patients potentially eligible for treatment with recent calcitonin gene-related peptide (CGRP) pathway-targeted therapies. METHODS: This retrospective study utilized the Ministry of the Interior Health Insurance Fund claims database of the Czech Republic wherein every citizen is insured. Migraine patients with or without aura, and potentially on triptan therapy were included in this study (index years 2012-2016). The prevalence approach included all patients (new and old) present in each index year. Prophylactic therapies were followed f0or three and seven years prior to the index year, including the index year, until 2010. The incidence approach included all patients first diagnosed in each index year. Prophylactic therapies were followed for the next three years, including the index year, until 2017 following incidence approach. The primary endpoint of this study was to determine the rate of migraine prevalence and diagnosis for each index year during the period 2012-2016. The study also evaluated prophylactic and acute treatment patterns and comorbidities among patients in 2016. RESULTS: The rate of migraine prevalence was 1% and the rate of diagnosis was 0.2-0.4%. By prevalence approach, approximately 39% of the patients were on prophylactics, and 11.2% and 21.6% of the patient population had two prior treatment failures (three- and seven-year recall period, respectively). Antiepileptics (26%) and beta blockers (15.8%) were the most prescribed prophylactics, and sumatriptan was the predominant triptan used (12%) for acute treatment. CONCLUSION: Taking into account the number of inhabitants in the Czech Republic (10.7 million), there could be up to 23,000 adult patients eligible for novel CGRP therapies.

Comparison of continuous versus intermittent enteral nutrition in critically ill patients (COINN): study protocol for a randomized comparative effectiveness trial.

BACKGROUND: Enteral nutrition is part of the treatment of critically ill patients. Administration of enteral nutrition may be associated with signs of intolerance, such as high gastric residual volumes, diarrhea, and vomiting. Clinical trials regarding the effects of the mode of administration of enteral nutrition on the occurrence of these complications have yielded conflicting results. This trial aims to investigate whether the mode of administration of enteral nutrition affects the time to reach nutritional targets, intolerance, and complications. METHODS: COINN is a randomized, monocentric study for critically ill adult patients receiving enteral nutrition. Patients will be randomly assigned to two groups receiving (1) continuous or (2) intermittent administration of enteral nutrition. Enhancement of enteral nutrition will depend on signs of tolerance, mainly the gastric residual volume. The primary outcome will be the time to reach the energetic target. Secondary outcomes will be the time to reach the protein target, tolerance, complications, hospital and ICU lengths of stay, and 28-day mortality. DISCUSSION: This trial aims to evaluate whether the mode of application of enteral nutrition affects the time to reach nutritional targets, signs of intolerance, and complications. TRIAL REGISTRATION: ClinicalTrials.gov NCT03573453. Registered on 29 June 2018.

Relative bioavailability of a pediatric dispersible tablet and adult film-coated tablet of macitentan in healthy volunteers.

To compare the pharmacokinetic (PK) properties of the pediatric dispersible tablet formulation of macitentan and the adult film-coated tablet formulation of macitentan in healthy subjects. A randomized, open-label, single-dose, two-sequence, two-period, crossover, Phase 1 study was conducted in 12 healthy adults. Subjects were randomized to one of the two possible treatment sequences A/B or B/A on Day 1 under fasted conditions. Treatment A was a single 10 mg dose of macitentan (film-coated adult formulation) and Treatment B was a single 10 mg dose of macitentan, consisting of two 5 mg dispersible tablets (pediatric formulation). PK sampling over 216 hours was conducted, and PK parameters were derived using non-compartmental methods. For macitentan, geometric means ratio of peak plasma concentrations (Cmax ), plasma concentration-time curve from zero to the time of the last quantifiable concentration (AUC0-t ), and plasma concentration-time curve from zero to infinity (AUC0-∞ ) were 1.140, 0.974, and 0.974, respectively. The corresponding 90% confidence intervals fell entirely within the referenced range of 0.8000 to 1.2500, which is used for evaluation of bioequivalence. These results indicate no significant differences between the pediatric dispersible tablet and the adult film-coated tablet. Both formulations were well tolerated. The pediatric dispersible tablet is biocomparable to the adult film-coated tablet formulation.

Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects.

BACKGROUND: Macitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug-drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH. OBJECTIVE: Two Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan. METHODS: Healthy male subjects received a single oral dose of rosuvastatin 10 mg (n = 20) or riociguat 1 mg (n = 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0-t), the AUC from zero to infinity (AUC0-∞) and the terminal elimination half-life (t½) of rosuvastatin, riociguat and riociguat's metabolite, M1. The difference in the time to reach maximum plasma concentration (tmax) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout. RESULTS: Ninety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80-1.25. There was no significant difference between test and reference tmax. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs. CONCLUSIONS: Macitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects. EudraCT numbers: 2017-003095-31 and 2017-003502-41.

Addition of Basal Insulin to Oral Antidiabetic Agents in Patients with Inadequately Controlled Type 2 Diabetes Leads to Improved HbA1c Levels: Metabolic Control, Frequency of Hypoglycemia, and Insulin Titration Analysis as Results of a Prospective Observational Study (BALI Study).

INTRODUCTION: Despite the continuously growing number of therapeutic options for patients with type 2 diabetes mellitus (T2DM), a large percentage of these individuals fail to achieve their glycated hemoglobin (HbA1c) target. The aim of this study was to determine the change in metabolic control in insulin-naïve T2DM patients inadequately controlled with oral antidiabetic drugs (OADs) at 6 months after initiating basal insulin treatment as add-on to existing OADs. METHODS: This was a non-interventional prospective study conducted from June 2013 to December 2014 in 137 centers in the Czech Republic under routine clinical practice conditions. Adult patients whose diabetes was uncontrolled on their current OAD treatment (HbA1c ≥ 53 mmol/mol; Diabetes Control and Complications Trial [DCCT]-HbA1c 7%) and whose physician had decided to initiate treatment on a basal insulin regimen were documented over a 6-month period beginning from the time of initiation of basal insulin treatment. RESULTS: Overall, 1426 T2DM patients were included in the study, of whom 53% were male. The mean age of the study population was 63.8 ± 10.1 years, mean body mass index was 31.5 ± 5.3 kg/m2, and mean duration of diabetes was 10.2 ± 5.3 years. At the 6-month follow-up, the target HbA1c level of 53 mmol/mol (DCCT < 7%) was achieved by 18% of patients. The mean HbA1c overall had decreased from 77.2 ± 15.1 mmol/mol (DCCT 9.21 ± 1.38%) at baseline to 63.2 ± 12.5 mmol/mol (DCCT 7.93 ± 1.14 %) at the 6-month follow-up. This difference was significant at p < 0.001. The largest mean reduction in HbA1c, i.e., 20.9 mmol/mol (DCCT 2.4 %) was observed in the group of patients with a baseline HbA1c of ≥ 9%. The mean daily basal insulin dose at 6 months was 18.8 ± 8.9 units. Symptomatic hypoglycemia was reported in 12.3% of patients, of those only one patient (0.1%) suffered from severe hypoglycemia. CONCLUSION: The addition of basal insulin to the therapeutic regimen of insulin-naïve T2DM on OAD treatment resulted in an improved metabolic control of diabetes after 6 months of treatment. However, most patients did not achieve their HbA1c target, probably also due to inadequate titration of basal insulin. FUNDING: Sanofi, Czech Republic.

Egg maturity assessment prior to ICSI prevents premature fertilization of late-maturing oocytes.

PROPOSE: The presence of metaphase II (MII) spindle together with the polar body (PB) indicates completion of oocyte maturation. This study was designed to explore if spindle imaging can be used to optimize timing of intracytoplasmic sperm injection (ICSI). METHODS: The study involved 916 oocytes from 234 conventionally stimulated ICSI cycles with an unexpectedly poor ovarian response. All PB-displaying oocytes were subjected to polarized light microscopy (PLM) prior to ICSI. When MII spindle was absent in the majority of oocytes, ICSI was postponed and performed after additional spindle imaging. Fertilization, embryo development, and clinical outcome were evaluated with respect to the observed spindle pattern. RESULTS: The visible spindle was absent in 32.64% of PB-displaying oocytes. The late-maturing oocytes extruding PB in vitro were less likely to exhibit a spindle signal than in vivo matured MII oocytes (38.86% vs. 89.84%). When fertilization was postponed, 59.39% of initially spindle-negative oocytes developed detectable MII spindle. Spindled eggs had significantly higher developmental potential, and the presence of the spindle has been identified as an independent measure for predicting the formation of the blastocyst. Embryos derived from spindle-positive oocytes also showed a higher chance to implant and develop to term. Notably, 11 children were conceived by finely timed fertilization of late-maturing oocytes which are normally discarded. CONCLUSIONS: The study confirms the prognostic value of spindle imaging and demonstrates that immature oocytes can be clinically utilized and give rise to live births when the timing of ICSI is adjusted to their developmental stage.

Viral genome changes and the impact of viral genome persistence in myocardium of patients with inflammatory cardiomyopathy.

INTRODUCTION: Viral infections are considered the most frequent cause of myocarditis and dilated cardiomyopathy (DCM). MATERIAL AND METHODS: We investigated the changes in viral presence and the impact of viral genome persistence in the myocardium on echocardiographic parameters, functional status and some laboratory parameters in a 6-month follow-up. Fifty-four patients with recent onset DCM, left ventricular ejection fraction < 40% and biopsy-proven myocarditis (> 14 mononuclear leukocytes/mm2 and/or > 7 T-lymphocytes/mm2) were enrolled. Polymerase chain reaction (PCR) was performed to detect pathogens in the myocardium. Patients were divided according to the administered therapy: standard heart failure medication (46 patients) and immunosuppressive therapy (8 patients). RESULTS: In the standard heart failure medication group viral clearance was observed in 13 patients and viral persistence in 24 patients in the follow-up period. Comparing both groups, there was no statistically significant difference - LVEF improvement of 12.0 ±11.4% vs. 18.3 ±12.6%, decrease in NYHA class of 0.7 ±0.7 vs. 1.0 ±0.7, decline in NT-proBNP of 1335 ±1933 ng/l vs. 1942 ±3242 ng/l and decrease in infiltrating leukocytes of 11.1 ±15.8 vs. 6.7 ±23.0 cells/mm2 and T-lymphocytes of 5.8 ±15.1 vs. 1.8 ±10.9 cells/mm2 (all p = NS). A decrease in PCR positive patients from 37 to 29 was observed. The number of PVB19 positive PCR findings decreased from 5 to 4 in patients with immunosuppressive therapy. CONCLUSIONS: A decrease in the number of positive PCR findings in control endomyocardial biopsy was observed. Viral genome persistence was not associated with worse outcome in short-term follow-up.

Current Level of Glycemic Control and Clinical Inertia in Subjects Using Insulin for the Treatment of Type 1 and Type 2 Diabetes in the Czech Republic and the Slovak Republic: Results of a Multinational, Multicenter, Observational Survey (DIAINFORM).

INTRODUCTION: The aim of the study was to determine the level of metabolic control in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients in the Czech and Slovak Republics. METHODS: A non-interventional prospective (observational) study was conducted from January 2015 until April 2016 in routine clinical practice settings at 141 centers in the Czech and Slovak Republics. Data were analyzed from a total of 425 patients with T1DM and 1034 patients with T2DM, proportionally corresponding to the number of patients in both countries. The primary objective of the study was to determine the percentage of patients with HbA1c < 7% (53 mmol/mol). RESULTS: Patients with T1DM: In this group of patients (55.8% males, mean age 45.9 ± 14.83 years, BMI 25.8 ± 4.21 kg/m², diabetes duration 12.1 ± 9.44 years), 29.9% reached HbA1c levels < 53 mmol/mol. Patients with T2DM: In this group of patients (50.3% male, mean age 63.9 ± 9.65 years, BMI 31.0 ± 5.19 kg/m², diabetes duration 12.4 ± 7.47 years, duration of insulin therapy 5.8 ± 4.71 years), 33.4% reached HbA1c levels < 53 mmol/mol. CONCLUSION: The overall percentage of patients with HbA1c < 53 mmol/mol in the T1DM group was 29.9% and in the T2DM group was 33.4%. Despite an increasing number of treatment options, most patients still fail to reach the recommended HbA1c targets. FUNDING: Sanofi, Czech Republic.

Effectiveness and safety of lixisenatide for treatment of diabetes in the real world: data from the Monitoring Registry in a Real-Life Cohort in the Czech and Slovak Republic.

INTRODUCTION: GLP1 receptor agonist lixisenatide has demonstrated its efficacy in numerous clinical trials, nevertheless its real-life effectiveness data is limited. AIM: To describe effectiveness and safety of lixisenatide in routine clinical practice in the Czech Republic and the Slovak Republic, as recorded by the Registry-Based Observational Study. METHODS: Multinational, multicenter, observational, non-interventional, 6-month prospective product registry of patients with type 2 diabetes mellitus aged > 18 years who were initiating therapy with lixisenatide. Patients were enrolled into this registry, provided written informed consent, between 1 May 2013 and 31 December 2015. Evaluations were performed at baseline and after 3 and 6 months of lixisenatide treatment. The primary objective of the study was the absolute change in glycated hemoglobin (HbA1c) from baseline to month 6 after lixisenatide initiation. The study was approved by responsible ethics committees and performed in accordance with the Helsinki Declaration. Informed consent was obtained from all patients before enrolment in the study. RESULTS: Overall 772 eligible patients (51.4 % males), mean age 56.7 (± 9.3) years, with mean diabetes duration 7.7 (± 5.5) years, mean duration of treatment with oral antidiabetic drugs 6.8 (± 4.9) years, and body mass index 37.6 (± 5.9) kg/m2 were enrolled in the study. Overall, 93.6 % were obese, 86.3 % subject were treated for hypertension, and 76.0 % for dyslipidemia. In total 96.1 % of patients completed the 6 months therapy. Lixisenatide significantly reduced HbA1c (decrease by 9.7 ± 14.4 mmol/mol [3.1 ± 0.2 % DCCT] after 6 months in per protocol population), and body weight (decrease by 3.5 ± 5.4 kg). The best responders to the treatment were younger patients with higher BMI, who had a shorter duration of diabetes. Overall safety profile of lixisenatide was satisfactory in the study. The most frequent adverse events were functional disorders affecting the gastrointestinal system. There was no episode of severe hypoglycemia reported throughout the study. CONCLUSION: In a real-life practice cohort of patients with type 2 diabetes mellitus 6 months treatment with once-daily GLP1 receptor agonist lixisenatide significantly improved glucose control and decreased body weight without increasing the risk of symptomatic and/or severe hypoglycemia risk. FUNDING: Sanofi Czech Republic.Key words: GLP1 receptor agonist - glycated hemoglobin - HbA1c - lixisenatide - oral antidiabetic drugs (OAD) - observational study - hypoglycemia - type 2 diabetes mellitus.