Successful Formulation Window for the design of pharmaceutical tablets with required mechanical properties.

Pharmaceutical tablet formulations combine the active ingredient with processing aids and functional components. This paper evaluates compressibility based predictive models for binary and ternary formulations to establish an acceptable range of tablet compression parameters that satisfy prescribed quality target criteria for tablets including minimum tablet strength and processing constraints such as maximum ejection stress and maximum compaction pressure. The concept of Successful Formulation Window (SFW) is introduced. A methodology is proposed to determine the SFW for a given formulation based on compaction simulator data collected for individual formulation components. The methodology is validated for binary and ternary mixtures and lubricated formulations. The SFW analysis was developed to support tablet formulation design to meet mechanical requirements.

Determinants of label non-adherence to non-vitamin K oral anticoagulants in patients with newly diagnosed atrial fibrillation.

Aims: To evaluate the extent and determinants of off-label non-vitamin K oral anticoagulant (NOAC) dosing in newly diagnosed Dutch AF patients. Methods and results: In the DUTCH-AF registry, patients with newly diagnosed AF (<6 months) are prospectively enrolled. Label adherence to NOAC dosing was assessed using the European Medicines Agency labelling. Factors associated with off-label dosing were explored by multivariable logistic regression analyses. From July 2018 to November 2020, 4500 patients were registered. The mean age was 69.6 ± 10.5 years, and 41.5% were female. Of the 3252 patients in which NOAC label adherence could be assessed, underdosing and overdosing were observed in 4.2% and 2.4%, respectively. In 2916 (89.7%) patients with a full-dose NOAC recommendation, 4.6% were underdosed, with a similar distribution between NOACs. Independent determinants (with 95% confidence interval) were higher age [odds ratio (OR): 1.01 per year, 1.01-1.02], lower renal function (OR: 0.96 per ml/min/1.73 m2, 0.92-0.98), lower weight (OR: 0.98 per kg, 0.97-1.00), active malignancy (OR: 2.46, 1.19-5.09), anaemia (OR: 1.73, 1.08-2.76), and concomitant use of antiplatelets (OR: 4.93, 2.57-9.46). In the 336 (10.3%) patients with a reduced dose NOAC recommendation, 22.9% were overdosed, most often with rivaroxaban. Independent determinants were lower age (OR: 0.92 per year, 0.88-0.96) and lower renal function (OR: 0.98 per ml/min/1.73 m2, 0.96-1.00). Conclusion: In newly diagnosed Dutch AF patients, off-label dosing of NOACs was seen in only 6.6% of patients, most often underdosing. In this study, determinants of off-label dosing were age, renal function, weight, anaemia, active malignancy, and concomitant use of antiplatelets.

Management of ileocolic intussusception in the Czech Republic.

INTRODUCTION: Ileocolic intussusception is one of the most frequent causes of acute abdomen in infants and toddlers. The purpose of this study was to evaluate the treatment of ileocolic intussusception in the Czech Republic in 2019. METHODS: Fourteen departments of paediatric surgery participated in this multicentre retrospective study. A SurveyMonkey Inc. questionnaire was used for anonymous data collection of patients with ileocolic intussusception. RESULTS: In 2019, ileocolic intussusception was diagnosed in 162 patients; median age was 30 months (3 months to 9.5 years). Contrast enema was indicated in 133 patients, primary surgery in 14 patients and spontaneous reduction was found in 15 patients. All departments using contrast enema had a success rate of 89.5%; 12 departments approached the contrast enema procedure under general anaesthesia (including myorelaxation at 7 departments) and 2 departments under sedation. Contrast enema under general anaesthesia with/without myorelaxation was significantly more successful than contrast enema under sedation (108/113, 95.6% vs 11/20, 55%; p.

Methodology to estimate the break force of pharmaceutical tablets with curved faces under diametrical compression.

This paper develops a methodology to estimate the break force of curved faced tablets under diametrical compression. Common excipients used in pharmaceutical tablet formulations, including microcrystalline cellulose, calcium phosphate and mannitol as well as their mixtures were characterised. Compacts of different densities were manufactured and their compressive and tensile strength was measured. The break force of curved face tablets having a comprehensive range of face curvatures and thickness was measured using the diametrical compression method ("hardness" test). Equation σd=FπD2atD+bWD-1 introduced by Shang et al. (2013) was used to relate the break force (F) to tablet geometry (D, t, W) and material tensile strength (σd). Here, we propose a method to estimate the parameters a and b using data for flat faced tablets. The method was validated for four mixtures. The errors were analysed and compared with the USP29 method σd=10FπD2(2.84(t/D)-0.126t/W+3.15(W/D)+0.01)-1. The proposed method has better accuracy, however, requires additional characterisation of the compressive strength of the material.

Distinct mutational signatures characterize concurrent loss of polymerase proofreading and mismatch repair.

Fidelity of DNA replication is maintained using polymerase proofreading and the mismatch repair pathway. Tumors with loss of function of either mechanism have elevated mutation rates with characteristic mutational signatures. Here we report that tumors with concurrent loss of both polymerase proofreading and mismatch repair function have mutational patterns that are not a simple sum of the signatures of the individual alterations, but correspond to distinct, previously unexplained signatures: COSMIC database signatures 14 and 20. We then demonstrate that in all five cases in which the chronological order of events could be determined, polymerase epsilon proofreading alterations precede the defect in mismatch repair. Overall, we illustrate that multiple distinct mutational signatures can result from different combinations of a smaller number of mutational processes (of either damage or repair), which can influence the interpretation and discovery of mutational signatures.

Is the consumption of snail meat actually healthy? An analysis of the osteotropic influence of snail meat as a sole source of protein in growing rats.

The study was aimed at determining the osteotropic effects of diets containing snail meat as a sole protein source. In our experiment, we tested three different diets incorporating snail meat originating from Helix pomatia (HP), Cornu.aspesa maxima (CAM) and Cornu.aspersum aspersum (CAA) and compared these to a control diet (CON) in which casein was the source of protein. In all diets, the protein content amounted to 10%, as calculated on a dry weight basis. In the study, forty male Wistar rats with an initial body mass of 50 ± 2 g were randomly placed within the control and three experimental groups. After 28 days of experimental feeding, the rats were sacrificed, and the body mass, total skeletal density and body composition were recorded. Moreover, blood serum (osteocalcin, CTX) and isolated tibia (pQCT, DXA, 3D micro-CT, 3-point bending test) were stored for further analysis. The results reveal that a diet incorporating snail meat significantly decreased BMC (bone mineral content), as well as area of total skeleton and isolated tibia, and was without influence on BMD (bone mineral density). Furthermore, the 3D micro-CT analysis of trabecular compartment documented a reduced Tb.Th (trabecular thickness), as well as Tb.N (trabecular number), and an increased Tb.Sp (trabecular separation). Beyond the aforementioned, the snail-based diets had an influence upon the architectonical properties of the tibia-decreasing its resistance to mechanical loading. Finally, snail meat, when used as an alone source of protein, negatively influenced the metabolism of the bone tissue in growing animals-making bone smaller and weaker.

Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution.

Patients with chromosome 13q deletion or normal cytogenetics represent the majority of chronic lymphocytic leukaemia (CLL) cases, yet have relatively few driver mutations. To better understand their genomic landscape, here we perform whole-genome sequencing on a cohort of patients enriched with these cytogenetic characteristics. Mutations in known CLL drivers are seen in only 33% of this cohort, and associated with normal cytogenetics and unmutated IGHV. The most commonly mutated gene in our cohort, IGLL5, shows a mutational pattern suggestive of activation-induced cytidine deaminase (AID) activity. Unsupervised analysis of mutational signatures demonstrates the activities of canonical AID (c-AID), leading to clustered mutations near active transcriptional start sites; non-canonical AID (nc-AID), leading to genome-wide non-clustered mutations, and an ageing signature responsible for most mutations. Using mutation clonality to infer time of onset, we find that while ageing and c-AID activities are ongoing, nc-AID-associated mutations likely occur earlier in tumour evolution.

[Campylobacteriosis at the Department of Infectious Diseases of the University Hospital Brno in 2011-2013: a retrospective study]. / Kampylobakteriózy na Klinice infekcních chorob Fakultní nemocnice Brno v letech 2011-2013: retrospektivní studie.

OBJECTIVE: To provide basic clinical, laboratory, and microbiological characteristics of adult patients with campylobacteriosis admitted to the Department of Infectious Diseases University Hospital Brno (UHB), in 2011-2013. MATERIALS AND METHODS: A retrospective analysis of clinical and laboratory parameters of 160 patients hospitalized with campylobacteriosis at the Department of Infectious Diseases, UHB from 1 January 2011 to 31 December 2013. RESULTS: There was no lethality or bacteremia reported in the study group of 160 adult patients (n=160) with campylobacteriosis. A more severe form of the disease with signs of systemic inflammatory response syndrome (SIRS) occurred in 24 patients, i.e. 15% of the study population. Transient mild to moderate leukocytopenia and thrombocytopenia were seen in 16 (10.0%) and 24 patients (15.0%), respectively, and seven patients (4.4%) had bicytopenia. The following factors correlated statistically significantly with the intestinal form of the disease and SIRS: age under 70 years (p=0.037), absence of arterial hypertension (p=0.044), immunosuppressive treatment (p=0.008), leukocyte count in the peripheral blood over 12.0×10(9)/l (p=0.023), and body temperature over 38.0 °C (p<0.001). Antibiotic treatment was used in 96.3% of patients with the intestinal form and in 100.0% of patients with SIRS. The average duration of antibiotic treatment was 8.8 and 9.3 days, respectively. Postantibiotic colitis due to Clostridium difficile occurred in seven patients (4.4%). There were no organ or autoimmune complications observed. CONCLUSIONS: Campylobacteriosis with SIRS occurs preferentially in persons under 70 years of age. Empirical antibiotic treatment is used too frequently without being adequately deescalated.

Cognitive and White Matter Tract Differences in MS and Diffuse Neuropsychiatric Systemic Lupus Erythematosus.

BACKGROUND AND PURPOSE: Multiple sclerosis and neuropsychiatric systemic lupus erythematosus are autoimmune diseases with similar CNS inflammatory and neurodegenerative characteristics. Our aim was to investigate white matter tract changes and their association with cognitive function in patients with MS and those with neuropsychiatric systemic lupus erythematosus compared with healthy controls by using diffusion tensor imaging. MATERIALS AND METHODS: Thirty patients with relapsing-remitting MS and 23 patients with neuropsychiatric systemic lupus erythematosus matched for disease severity and duration and 43 healthy controls were scanned with 3T MR imaging. The DTI was postprocessed, corrected for lesions, and analyzed with tract-based spatial statistics. Cognitive assessment included examination of processing speed; visual, auditory/verbal, and visual-spatial memory; and sustained attention and executive function. Differences were considered significant at P < .05. RESULTS: Tract-based spatial statistics analysis revealed significantly decreased fractional anisotropy and increased mean diffusivity in patients with MS compared with healthy controls, decreased fractional anisotropy in patients with MS compared with those with neuropsychiatric systemic lupus erythematosus, and an increased mean diffusivity in patients with neuropsychiatric systemic lupus erythematosus compared with healthy controls. Patients with MS showed decreased fractional anisotropy throughout central WM pathways, including the corpus callosum and the inferior longitudinal and fronto-occipital fasciculi compared with those with neuropsychiatric systemic lupus erythematosus. Altered cognitive scores in patients with MS were significantly associated with decreased fractional anisotropy and increased mean diffusivity in all examined domains, while in patients with diffuse neuropsychiatric systemic lupus erythematosus, only decreased fractional anisotropy in the superior WM pathways showed significant association with executive function. CONCLUSIONS: Patients with MS and neuropsychiatric systemic lupus erythematosus showed widespread WM tract alterations outside overt lesions, though more severe changes were identified in patients with MS. The WM tract changes were associated with cognitive dysfunction in all explored domains only in patients with MS.

[Hepatitis E--overview of the latest knowledge]. / Hepatitida E--prehled soucasných poznatku.

Hepatitis E (HE) is a ubiquitous infection, occurring both in developing and in developed countries. It is caused by the hepatitis E virus (HEV), a small, non-enveloped RNA virus. The reported incidence in the Czech Republic in 2013 was 2 cases per 100,000 inhabitants and the number of HE cases has been growing over the past years. Besides the long known fecal-oral transmission, zoonotic and blood product transmission of HEV has recently been observed in industrialized countries. Most infections are asymptomatic. Symptomatic infection may present as acute hepatitis with nonspecific flu-like symptoms and liver enzymes elevation. In immunocompromised patients, HEV can lead to chronic hepatitis E and can even cause acute liver failure in pregnant women. Several extrahepatic manifestations have also been reported. Antiviral therapy has been successfully used in chronic hepatitis E. The first vaccine available for clinical use is licensed in China so far.

[Fecal bacteriotherapy for the treatment of recurrent Clostridium difficile colitis used in the Clinic of Infectious Diseases of the University Hospital Brno in 2010-2014 - a prospective study]. / Fekální bakterioterapie v lécbe rekurentní kolitidy zpusobené Clostridium difficile na Klinice infekcních chorob Fakultní nemocnice Brno v letech 2010-2014 - prospektivní studie.

INTRODUCTION: The aim of the study is to assess the efficacy of fecal bacteriotherapy in the treatment of Clostridium difficile colitis. MATERIALS AND METHODS: A prospective study of fecal bacteriotherapy in 80 adult patients hospitalized in the Clinic of Infectious Diseases, University Hospital Brno between 1 January 2010 and 31 December 2014. RESULTS: During the study period, 80 patients were treated with fecal bacteriotherapy. The majority of the study group received fecal bacteriotherapy via a nasojejunal tube (n=78) and two patients via a rectal enema. Six patients were instilled with 20 g of feces, with a success rate of 50 %. The outcomes of nine patients were unevaluable. In the rest of 65 patients, the success rate with 40 g of feces was 83.1 %. There were no severe adverse events or mortality associated with fecal bacteriotherapy. CONCLUSIONS: Fecal bacteriotherapy is a safe and effective treatment modality in Clostridium difficile colitis.

[Infections caused by non-typhi serovars of Salmonella at the Infectious Diseases Clinic of the University Hospital Brno in 2011-2013]. / Infekce zpusobené netyfovými sérovary salmonel na Klinice infekcních chorob Fakultní nemocnice Brno v letech 2011-2013--retrospektivní studie.

INTRODUCTION: The aim of the study is to describe the basic clinical, laboratory, and microbiological characteristics in adult patients with salmonellosis hospitalized at the Infectious Diseases Clinic of the University Hospital Brno in 2011-2013. MATERIALS AND METHODS: A retrospective analysis of clinical and laboratory parameters of 161 patients hospitalized at the Infectious Diseases Clinic of the University Hospital Brno from 1 January 2011 to 31 December 2013. RESULTS: Invasive salmonellosis was seen in 22.4% of the study group. The overall lethality rate reached 3.1%. Treatment with antibiotics was used in 93.8% of patients. Transient mild to moderate leukocytopenia was reported in 4.3% of patients and thrombocytopenia in 9.3% of patients. Transient changes in white blood cells as well as in the thrombocyte count were not clinically important. Long-term treatment with proton pump inhibitors is a risk factor for salmonellosis (p=0.128), but not for invasive salmonellosis. Long-term use of opioids (p=0.003) and/or acetylsalicylic acid (p=0.015) is a risk factor for invasive salmonellosis. Other risk factors for invasive disease are: age over 70 years (p=0.011), arterial hypertension (p=0.004), disease duration of less than three days (p=0.006), serum creatinine level above 250 µmol/l (p=0.01), peripheral leucocyte count above 12x10(9)/l (p=0.001), and body temperature above 38 °C (p=0.001). Hypokalemia does not represent a risk factor for invasive salmonellosis. CONCLUSIONS: Aged patients on long-term opioids or acetylsalicylic acid, with disease duration of less than three days, and meeting the criteria for systemic inflammatory response syndrome are at the highest risk for invasive salmonellosis. Empirical antibiotics are prescribed too often and the treatment is not properly de-escalated.

[Prenatal diagnosis of skeletal dysplasia in first trimester of pregnancy X-linked dominant chondrodysplasia punctata]. / Prenatální diagnóza skeletální dysplazie v prvním trimestru tehotenství X-vázaná dominantní chondrodysplasia punctata.

Case report describes successful prenatal diagnosis of skeletal dysplasia in the first trimester of pregnancy in a female patient affected with X-linked dominat chondrodysplasia punctata (CDPX2). Her first pregnancy was terminated in the second trimester due to skeletal dysplasia of the foetus. The diagnosis in the following pregnancy was finished in the first trimester - before the end of the 13th gestational week. The diagnosis was established on the basis of ultrasonographic (US) examination and mutation analysis of the EBP gene in the material of chorionic villus sampling (CVS).

[Pathophysiology and pathogenesis of Salmonella sepsis]. / Patofyziologie a patogeneze salmonelové sepse

The authors present a review of current knowledge about complex pathogenetic and pathophysiologic mechanisms involved in the development of sepsis in salmonellosis. Mechanisms such as lipopolysacharide-induced NOD-like receptor activation, escaping lysosomal degradation, intracellular replication niche formation, cytoskeleton reorganization, proapoptotic mechanism induction, changes in cytokine levels (IL-1ß, TNF-α) and function of omptin proteases are discussed.

[A case report of ocular complications of leptospirosis]. / Kazuistika ocní komplikace leptospirózy.

Ocular complications are very frequent in leptospirosis and may develop in both the acute (bacteriemic) and the second (immunologic) phases of the disease. A delayed onset of these complications, even after months or years, is also possible. Keratoconjunctivitis and panuveitis belong to the most frequent signs. Targeted search for patients suspected of having leptospirosis and regular ophthalmological examinations even after cure of the acute illness may lead to early detection of ocular complications and to their specific treatment. Presented are a case report of complicated uveitis due to infection with Leptospira grippotyphosa and a literature overview.

Effect of age on MRI phase behavior in the subcortical deep gray matter of healthy individuals.

BACKGROUND AND PURPOSE: It has been demonstrated that increased levels of iron in the brain occur with aging. In this study we investigated the nature of the association between age and SWI-filtered phase values, indicative of iron content, in the subcortical deep gray matter of healthy individuals. MATERIALS AND METHODS: A total of 210 healthy individuals (men: n = 89, women: n = 121), mean age, 39.8 years (standard deviation = 15.5; range = 6-76 years), were imaged on a 3T scanner. Mean MRI phase, mean phase of low-phase voxels, and normalized volumes were determined for total subcortical deep gray matter, caudate, putamen, globus pallidus, thalamus, pulvinar nucleus, hippocampus, amygdala, nucleus accumbens, red nucleus, and substantia nigra. Linear and nonlinear regression models were used to explore the relationship between phase and volume measures, and aging. RESULTS: Mean phase values of subcortical deep gray matter structures showed a quadratic relationship, with individuals in late middle age (40-59 years) having the lowest mean phase values, followed by a reversal of this trend in the elderly. In contrast, mean phase of low-phase voxel measurements showed strong negative linear relationships with aging. Significantly lower phase values were detected in women compared with men (P < .001), whereas no sex differences were observed for mean phase of low-phase voxels. Normalized volume measurements were also linearly related to aging, and women showed smaller normalized volumes of subcortical deep gray matter structures than men (P < .001). Lower mean phase of low-phase voxels was related to decreased volume measures. CONCLUSIONS: A strong association between phase (quadratic effect; phase decreases are followed by increases), mean phase of low-phase voxels (linear effect), volume (linear effect), and age was observed. Low phase was related to brain atrophy.

[Febrile pancytopenia and hepatosplenomegaly as leading symptoms of visceral leishmaniasis]. / Febrilní pancytopenie a hepatosplenomegalie jako hlavní symptomy viscerální leishmaniózy.

The authors present a case report of a patient with febrile pancytopenia, hepatosplenomegaly and weight loss as main symptoms of visceral leishmaniasis. Standard treatment regimen with amphothericin B led to relapse of the disease after several weeks. The definitive cure of the disease was achieved with cytostatic miltefosin (Impavido©), which is not registered in the Czech Republic. The aim of this article is to point out this imported protozoan infection and its basic clinical and laboratory features.

[Warning about risk of invasive infections in splenectomized patients. Experiences from University Hospital Brno, Czech Republic, in 2011]. / Upozornení na nebezpecí invazivních infekcí u splenektomovaných pacientu. Zkusenosti z FN Brno 2011.

Syndrome of fulminant sepsis in splenectomized (overwhelming postsplenectomy infection - OPSI) is feared and often fatal infectious complication in patients after splenectomy. The risk of syndrome of fulminant sepsis in splenectomized in these persons persists lifelong and doesn't diminish during the time. Etiologically, encapsulated bacterias like Streptococcus pneumoniae, Haemophilus influenzae group b and Neisseria meningitidis are involved. As the mortality of syndrome of fulminant sepsis in splenectomized is very high, it is indispensable to educate and vaccinate persons in risk. The authors present case reports of three splenectomized patients who were hospitalized for invasive pneumococcal infection in the University Hospital Brno, Czech Republic, in 2011.