COVID-19's natural course among ambulatory monitored outpatients.

Research objective was to detail COVID-19's natural trajectory in relation to the Czech population's viral load. Our prospective detailed daily questionnaire-based telemonitoring study evaluated COVID-19's impact among 105 outpatients. In accordance with government quarantine requirements, outpatients were divided into a cohort with two negative tests at the end of the disease (40 patients) and a cohort with a new algorithm (65 patients) following a 14-day quarantine. Median follow-up differed significantly between the 2 groups (23 days vs. 16 days). Only 6% of patients were asymptomatic during the entire telemonitoring period. Another 13% of patients were diagnosed asymptomatic, as suspected contacts, yet later developed symptoms, while the remaining 81% were diagnosed as symptomatic on average 6 days following symptom onset. Telemonitoring enabled precise symptom status chronicling. The most frequently reported complaints were fevers, respiratory issues, and anosmia. Six patients were eventually hospitalized for complications detected early after routine telemonitoring. During the extended follow-up (median 181 days), anosmia persisted in 26% of patients. 79% of patients in the new quarantine algorithm cohort reported no symptoms on day 11 compared to just 56% of patients in the two negative test cohort upon first testing negative (median-19 days). The highest viral load occurred within 0-2 days of initial symptom onset. Both the PCR viral load and two consecutive PCR negative sample realizations indicated high interindividual variability with a surprisingly fluctuating pattern among 43% of patients. No definitive COVID-19 symptoms or set of symptoms excepting anosmia (59%) and/or ageusia (47%) were identified. No preexisting medical conditions specifically foreshadowed disease trajectory in a given patient. Without a PCR negativity requirement for quarantine cessation, patients could exhibit fewer symptoms. Our study therefore highlights the urgent need for routine ambulatory patient telemedicine monitoring, early complication detection, intensive mass education connecting disease demeanor with subsequent swift diagnostics, and, notably, the need to reevaluate and modify quarantine regulations for better control of SARS-CoV-2 proliferation.

Bronchoalveolar lavage fluid and serum 1,3-ß-D-glucan testing for invasive pulmonary aspergillosis diagnosis in hematological patients: the role of factors affecting assay performance.

Invasive fungal disease (IFD) early diagnosis improves hematological patient survival. Non-culture-based methods may reduce diagnostic time to identify IFD. As complex data on the value of 1,3-ß-D-glucan (BDG) from bronchoalveolar lavage fluid (BALF) compared to serum for the most frequent invasive pulmonary aspergillosis (IPA) diagnosis are scarce, particularly including evaluation of potential factors adversely affecting BDG assay, we provided prospective single-center analysis evaluating 172 episodes of pulmonary infiltrates with BDG detection in BALF and serum samples collected in parallel among hematological patients from 2006 to 2015. Proven and probable IPA were documented in 13.4% of the episodes. Sensitivity (SEN), specificity (SPE), positive and negative predictive value (PPV; NPV), and diagnostic odds ratio (DOR) of the BDG assay using standard (80 pg/ml) cut-off for BALF were: 56.5%; 83.2%; 34.2%; 92.5%, and 6.5, respectively, and for serum were: 56.5%; 82.6%; 33.3%; 92.5%, and 6.2, respectively. The same BDG assay parameters employing a calculated optimal cut-off for BALF (39 pg/ml) were: 78.3%; 72.5%; 30.5%; 95.6%, and 9.5, respectively; and for serum (40 pg/ml) were: 73.9%; 69.1%; 27.0%; 94.5%, and 6.3, respectively. While identifying acceptable SEN, SPE, and DOR, yet low PPV of both BALF and serum BDG assay for IPA diagnosis, neither the combination of both materials nor the new optimal BDG cut-off led to significant test quality improvement. Absolute neutrophil count and aspirated BALF volume with a significant trend affected BDG assay performance. The BDG test did not outperform galactomannan assay.

Ptolemaic political activities on the west coast of Hellenistic Asia Minor had a significant impact on the local spread of the Isiac cults: A spatial network analysis.

During the reign of the first Ptolemaic kings in Egypt, mainly in the 3rd and 2nd centuries BCE, the Egyptian cults related to the divine couple of Isis and Sarapis (i.e. the Isiac cults) spread successfully from Egypt to ports and coastal cities of the ancient Mediterranean. The discussion on the topic of the factors involved in the process of the early spread of these cults outside Egypt is still open and, so far, the research in this area has been conducted mainly by using established historiographical methods. However, these methods are limited when dealing with the interplay among different variables involved in complex historical processes. This article aims to overcome these limits by using a quantitative spatial network analysis. The results of our previous published research, which focused on a quantitative evaluation of the impact of individual factors on the early spread of the Isiac cults across the ancient Aegean Islands, suggest that the process was promoted by military and commercial activities of the Ptolemaic dynasty, and that the Ptolemaic military operations were the most influential factor. Following these results, this article focuses on the early spread of the Isiac cults on the west coast of Hellenistic Asia Minor, i.e. the region which the Ptolemies attempted to control in the 3rd and 2nd centuries BCE. The statistically significant results presented in this article support the hypothesis that the Ptolemaic political engagement in Asia Minor had a positive impact on the early spread of the Isiac cults. The results also suggest that the activities of the Seleucid dynasty, a political rival of the Ptolemies, in the area of interest could have constituted an immunological factor limiting the spread of the Isiac cults further to the eastern parts of Asia Minor.

Ptolemaic military operations were a dominant factor in the spread of Egyptian cults across the early Hellenistic Aegean Sea.

Early in the Ptolemaic era, Egyptian cults, particularly those of Isis and Sarapis, spread successfully to ports across the ancient Aegean Sea. Leading researchers in the field claim that the spread of these cults was influenced by multiple factors, ones that were mainly economic or political in character. However, the question of which factors had more weight or impact than others in the process of the early spread of Egyptian cults has not yet been answered in academic discussion. This could be related to the fact that the issue of the spread of religious innovations in the ancient Mediterranean has been addressed mainly by established historiographical methods such as the collection and critical analysis of archaeological and literary sources. Hypotheses and conclusions derived from these methods are, however, often unable to reflect the complexity of historical processes. A possible solution can be found in supplementing this established methodological apparatus by formalized methods, e.g. the coding of relevant datasets, statistics, geospatial modeling, and network analysis. To be able to compare the possible impacts of different factors on the spread of Egyptian cults in the Aegean Sea region, we 1) constructed a model of the ancient maritime transportation network as a platform for quantitative analysis, 2) transformed selected factors of possible influence into georeferenced parameters of the network, and 3) defined a mathematical model that allowed us to determine which parameters of the network explain the spatial dissemination of archaeological evidence connected to Egyptian cults. The results suggest that the most significant correlation is between the placement of Ptolemaic garrisons and the distribution of Egyptian temples and artefacts in the early Hellenistic Aegean Sea region. The interpretation would be that Egyptian military forces potentially played a significant role in the spread of Egyptian cults.

Prognostic markers of sarcoidosis: an analysis of patients from everyday pneumological practice.

INTRODUCTION: Although sarcoidosis is a well-known disease, sarcoidosis patient outcome and the role of prognostic markers in everyday practice have not yet been well described. Therefore, the goal of the present study was to analyse the fate of sarcoidosis patients and the factors influencing the disease's behaviour in routine practice. METHODS: The study was a retrospective analysis of 306 consecutive patients (181 females and 125 males; median age 45 years) diagnosed with sarcoidosis in the years 2003-2012. RESULTS: Through the use of uniparametric analysis, it was determined that the stage of the disease, organ involvement, CD4/CD8 ratio in the bronchoalveolar lavage fluid (BALF), serum and urine calcium levels, smoking, and pulmonary functions had a significant influence on spontaneous sarcoidosis resolution. Multiparametric analysis revealed that spontaneous resolution was significantly positively influenced by female gender, a less advanced disease stage, a higher CD4/CD8 ratio in the BALF, lymphocytosis in the BALF and normal pulmonary functions at diagnosis. During follow-up, only three patients died. The causes of death were respiratory failure with pneumonia (n = 2) and heart attack caused by sarcoidosis heart involvement (n = 1). CONCLUSION: The data show sarcoidosis as a disorder with high variability in clinical and laboratory findings but with good general prognosis.

Efficacy of rituximab in primary immune thrombocytopenia: an analysis of adult pretreated patients from everyday hematological practice.

Although rituximab has seen increasing use in the treatment of immune thrombocytopenia (ITP) for many years, its therapeutic role in this disease remains unclear. We retrospectively analyzed data of all patients with ITP treated with rituximab (375 mg/m(2) once weekly for four consecutive weeks) and consecutively entered the findings into the databases of six large academic centers in the Czech Republic. A total of 114 patients were included in the analysis. All of the patients received rituximab as a second or additional line of therapy. The overall response rate (ORR) after rituximab therapy was 72 % [48 % complete response (CR), 24 % partial response (PR)] at month 6, and 69 % (45 % CR, 24 % PR) at month 12. For the group of patients with newly diagnosed (acute) ITP, the results of treatment were significantly better than for the group of patients with persistent or chronic ITP; nonetheless, this group of patients was far too small (n = 18) for our findings to be generalized. Multivariate analysis revealed that the ORR was significantly influenced primarily by the number of therapies prior to rituximab (the more previous therapies, the worse treatment response). The results of our analysis "from everyday hematological practice" confirm the high efficiency of rituximab treatment in pretreated adult patients with ITP.

Estimation of current cumulative incidence of leukaemia-free patients and current leukaemia-free survival in chronic myeloid leukaemia in the era of modern pharmacotherapy.

BACKGROUND: The current situation in the treatment of chronic myeloid leukaemia (CML) presents a new challenge for attempts to measure the therapeutic results, as the CML patients can experience multiple leukaemia-free periods during the course of their treatment. Traditional measures of treatment efficacy such as leukaemia-free survival and cumulative incidence are unable to cope with multiple events in time, e.g. disease remissions or progressions, and as such are inappropriate for the efficacy assessment of the recent CML treatment. METHODS: Standard nonparametric statistical methods are used for estimating two principal characteristics of the current CML treatment: the probability of being alive and leukaemia-free in time after CML therapy initiation, denoted as the current cumulative incidence of leukaemia-free patients; and the probability that a patient is alive and in any leukaemia-free period in time after achieving the first leukaemia-free period on the CML treatment, denoted as the current leukaemia-free survival. The validity of the proposed methods is further documented in the data of the Czech CML patients consecutively recorded between July 2003 and July 2009 as well as in simulated data. RESULTS: The results have shown a difference between the estimates of the current cumulative incidence function and the common cumulative incidence of leukaemia-free patients, as well as between the estimates of the current leukaemia-free survival and the common leukaemia-free survival. Regarding the currently available follow-up period, both differences have reached the maximum (12.8% and 20.8%, respectively) at 3 years after the start of follow-up, i.e. after the CML therapy initiation in the former case and after the first achievement of the disease remission in the latter. CONCLUSIONS: Two quantities for the evaluation of the efficacy of current CML therapy that may be estimated with standard nonparametric methods have been proposed in this paper. Both quantities reliably illustrate a patient's disease status in time because they account for the proportion of patients in the second and subsequent disease remissions. Moreover, the model is also applicable in the future, regardless of what the progress in the CML treatment will be and how many treatment options will be available, respectively.

Modern and conventional prognostic markers of chronic lymphocytic leukaemia in the everyday haematological practice.

OBJECTIVES: The impact of modern prognostic markers on clinical course of chronic lymphocytic leukaemia (CLL) in everyday practice has been not yet well defined, especially in large series of patients. Therefore, the goal of this study was to assess the influence of conventional as well as modern prognostic factors on overall survival (OS) and time to therapy (TTT) of patients with CLL. METHODS: We retrospectively analysed data of all patients consecutively entered into the databases of five large academic centres in the Czech Republic. The total of 1300 patients was included in the analysis. RESULTS AND CONCLUSION: Through the use of uniparametric analysis, it was determined that gender, clinical stage Rai II-IV, unmutated IgVH status, deletion 17p (for both 5% and 20% cut-off), deletion 11q, ZAP-70 positivity and high expression of CD38 had significant negative influence on OS. TTT was significantly influenced by gender, Rai stage, IgVH status, deletion 11q, deletion 17p, deletion 13q and CD38 expression. Multiparametric analysis revealed that OS was significantly influenced by gender, age, IgVH status and deletion 17p. If only patients who died of CLL were included, gender, age, Rai stage, IgVH status and deletion 17p had significant influence on OS. Based on our results, the examination of biological prognostic markers can give an insight into the possible disease evolution in daily clinical practice. Biological prognostic markers are, however, not ready (maybe except deletion 17p in younger patients) to be used for guidance of therapy at least outside of clinical trials.

Constant BCR-ABL transcript level >or=0.1% (IS) in patients with CML responding to imatinib with complete cytogenetic remission may indicate mutation analysis.

OBJECTIVE: Of 140 chronic myeloid leukemia patients responding to imatinib with complete cytogenetic remission, 32 exhibited a plateau of BCR-ABL values at >or=0.1% level in a minimum of three subsequent samples (minimal duration, 6 - 9 months). Median follow-up of unchanged BCR-ABL transcript level was 12 months (range, 6 - 64). We tested this group of patient for BCR-ABL mutations to reveal resistance development and to evaluate the risk of disease progression. MATERIALS AND METHODS: Altogether, 134 samples of peripheral blood of these 32 patients were tested for mutation in BCR-ABL kinase domain. RESULTS: Mutation was detected by direct sequencing in 9 of 32 patients (28%). Loss of complete cytogenetic remission or 1 log rise of BCR-ABL was observed in five of nine patients at a median of 5 months (range, 4-17) since first detection of mutation. One patient with no mutation relapsed 12 months after the start of the BCR-ABL plateau. In 5 of 32 patients without mutation (16%), BCR-ABL level significantly decreased after the first plateau to levels that stayed unchanged for a median of 11 months (range, 7-28). CONCLUSION: We show here that the BCR-ABL constant levels >or=0.1% (BCR-ABL plateau) in imatinib-responding patients may indicate mutation analysis. This approach highly reduces the number of examinations for mutation in chronic myeloid leukemia responders and may present cost-effective alternative applicable in clinical practice.

Detection and treatment of molecular relapse in acute myeloid leukemia with RUNX1 (AML1), CBFB, or MLL gene translocations: frequent quantitative monitoring of molecular markers in different compartments and correlation with WT1 gene expression.

OBJECTIVE: Our objective was to determine the value of frequent minimal residual disease (MRD) monitoring in acute myeloid leukemia (AML) as a robust marker of impending relapse, and whether treatment benefits patients during the MRD-positive phase of their disease. MATERIALS AND METHODS: Frequent MRD monitoring was performed in all AML treatment phases using real-time quantitative polymerase chain reaction for fusion transcripts (CBFB/MYH11; RUNX1/RUNX1T1 fusion transcripts of MLL gene) and for the Wilms' tumor (WT1) gene. A total of 2,664 samples, taken from 79 AML patients and 6 healthy volunteers, were examined. Presence of fusion gene was detected in 25 of 79 examined patients. RESULTS: Vast correlation was discovered for fusion transcripts as well as for the WT1 gene between levels in bone marrow (BM), peripheral blood, CD34(+) BM cells, and CD34(-) BM cells. WT1 expression, however, was usually positive for cases showing fusion transcripts negativity and in healthy volunteers. Moreover, no universal value of the WT1 expression could unequivocally discriminate between remission and relapse. Therefore, detection of molecular relapses relied on fusion transcripts only and was characterized by strong expression in CD34(+) cells. Considering relapsed patients, duration from molecular to hematological relapse was 8 to 79 days (median: 25.5 days). Twelve patients were treated (chemotherapy, gemtuzumab ozogamicin, or immunomodulation after allogeneic transplantation) for 21 molecular relapses and 14 responses to treatment were observed. CONCLUSIONS: Frequent quantitative monitoring of fusion transcripts is useful for reliably predicting hematological relapse in AML patients. Treatment for molecular relapse of AML can be successful.

Successful treatment of steroid-refractory hepatitic variant of liver graft-vs-host disease with pulse cyclophosphamide.

OBJECTIVE: Corticosteroid-resistant graft-vs-host disease (GVHD) is difficult to manage and is associated with high morbidity and mortality. No standard treatment exists. We have previously seen good results with pulse cyclophosphamide (Cy) in the treatment of liver GVHD in contrast to gastrointestinal GVHD, and here we report results of pulse Cy protocol in the treatment of steroid-refractory hepatitic variant of liver GVHD, with no association to the gut. MATERIALS AND METHODS: Cy was infused at a dose of 1,000 mg/m(2). Twenty-nine cyclophosphamide administrations were given to 21 patients. Median time of GVHD onset and Cy administration after transplantation, or donor lymphocyte infusion, were 58 and 69 days, respectively. RESULTS: Eleven patients (52%) achieved complete remission and 6 patients (29%) achieved partial remission. Four patients (19%) did not respond, however, their condition stabilized and, upon additional therapy, three achieved partial remission and one complete remission. Overall survival of all 21 patients is 86%, with median and maximal follow-up of 33 and 81 months, respectively. Toxicity was mild and easily manageable without influencing chimerism or disease status. CONCLUSIONS: Pulse Cy seems to be an effective treatment for steroid-refractory hepatitic variant of liver GVHD with a good toxicity profile, which may favor its use instead of drugs with more pronounced immunosuppressive effects.

Hazard function for cancer patients and cancer cell dynamics.

The aim of the paper is to develop a procedure for an estimate of an analytical form of a hazard function for cancer patients. Although a deterministic approach based on cancer cell population dynamics yields the analytical expression, it depends on several parameters which should be estimated. On the other hand, a kernel estimate is an effective nonparametric method for estimating hazard functions. This method provides the pointwise estimate of the hazard function. Our procedure consists of two steps: in the first step we find the kernel estimate of the hazard function and in the second step the parameters in the deterministic model are obtained by the least squares method. A simulation study with different types of censorship is carried out and the developed procedure is applied to real data.

Seroprevalence of H1N1, H3N2 and H1N2 influenza viruses in pigs in seven European countries in 2002-2003.

OBJECTIVES: Avian-like H1N1 and human-like H3N2 swine influenza viruses (SIV) have been considered widespread among pigs in Western Europe since the 1980s, and a novel H1N2 reassortant with a human-like H1 emerged in the mid 1990s. This study, which was part of the EC-funded 'European Surveillance Network for Influenza in Pigs 1', aimed to determine the seroprevalence of the H1N2 virus in different European regions and to compare the relative prevalences of each SIV between regions. DESIGN: Laboratories from Belgium, the Czech Republic, Germany, Italy, Ireland, Poland and Spain participated in an international serosurvey. A total of 4190 sow sera from 651 farms were collected in 2002-2003 and examined in haemagglutination inhibition tests against H1N1, H3N2 and H1N2. RESULTS: In Belgium, Germany, Italy and Spain seroprevalence rates to each of the three SIV subtypes were high (> or =30% of the sows seropositive) to very high (> or =50%), except for a lower H1N2 seroprevalence rate in Italy (13.8%). Most sows in these countries with high pig populations had antibodies to two or three subtypes. In Ireland, the Czech Republic and Poland, where swine farming is less intensive, H1N1 was the dominant subtype (8.0-11.7% seropositives) and H1N2 and H3N2 antibodies were rare (0-4.2% seropositives). CONCLUSIONS: Thus, SIV of H1N1, H3N2 and H1N2 subtype are enzootic in swine producing regions of Western Europe. In Central Europe, SIV activity is low and the circulation of H3N2 and H1N2 remains to be confirmed. The evolution and epidemiology of SIV throughout Europe is being further monitored through a second 'European Surveillance Network for Influenza in Pigs'.

Symptomatic intravenous antipyretic therapy: efficacy of metamizol, diclofenac, and propacetamol.

Fever is a common symptom in cancer patients. The most frequent causes of fever are infections, malignancy itself, various medications, transfusions, and allergy. Although it is necessary to treat the cause of fever, if possible, symptomatic fever management is also important. Surprisingly, little attention is paid to this topic in the medical literature, despite the fact that it is a very frequent problem. In order to support symptomatic fever therapy, we wanted to study the patients' discomfort accompanying fever and the beneficial effects of the symptomatic fever management. To the best of our knowledge, there is an absence of studies in this area, despite the fever discomfort can be an important reason for the antipyretic treatment, mainly in cancer patients. In this non-randomized open label pilot study, three intravenous antipyretics were tested in five groups of patients: diclofenac (75 mg, brief intravenous [IV] infusion) vs. metamizol (2500 mg or 1000 mg, brief IV infusion) vs. propacetamol (2000 mg or 1000 mg, slow IV injection or brief IV infusion). The study included 254 febrile episodes mainly in hemato-oncological patients with axillary temperature at least 38 degrees C. The main study endpoints were: changes in axillary temperature, improvement in patient comfort, and number and nature of adverse events. To support justification for symptomatic fever management in febrile patients, we asked the first 45 study subjects to fill in a questionnaire concerning their opinions about fever, fever-associated discomfort, and relief upon antipyretic therapy. All study medications had a significant antipyretic effect. However, metamizol at the dose 2500 mg was considered as the most effective, while propacetamol at the dose 1000 mg showed the lowest antipyretic efficacy. Concerning tolerability and adverse events, there were significant differences among the treatment groups. Diclofenac and metamizol (both 2500 mg and 1000 mg) were tolerated at best. All tested antipyretics significantly improved comfort in febrile patients. Overall, 87% of patients declared improvement in their comfort after administration of antipyretics. Based on the results of the present study, the choice of the antipyretic drug should depend on the clinical status of patient, contraindications, and potential adverse events and risks of the selected agent. It is advisable to use proparacetamol at the higher dosage and to administer it as a brief IV infusion in order to avoid injection-related adverse events. The symptomatic antipyretic treatment in febrile cancer patients is supported by patients themselves and has a significant role in the complex supportive care. Discomfort of patients during fever episodes may be greater than previously thought.