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Acute Myeloid Leukemia (AML) is a heterogeneous malignancy involving the clonal expansion of myeloid stem and progenitor cells in the bone marrow and peripheral blood. Most AML patients eligible for potentially curative treatment receive intensive chemotherapy. Risk stratification is used to optimize treatment intensity and transplant strategy, and is mainly based on cytogenetic screening for structural chromosomal alterations and targeted sequencing of a selection of common mutations. However, the forecasting accuracy of treatment response remains modest. Recently,ex vivodrug screening has gained traction for its potential in personalized treatment selection, as well as a tool for identifying and mapping patient groups based on relevant cancer dependencies. We systematically evaluated the use of drug sensitivity profiling for predicting patient survival and clinical response to chemotherapy in a cohort of AML patients. We compared computational methodologies for scoring drug efficacy and characterized tools to counter noise and batch-related confounders pervasive in high-throughput drug testing. We show thatex vivodrug sensitivity profiling is a robust and versatile approach to patient prognostics that comprehensively maps functional signatures of treatment response and disease progression. In conclusion,ex vivodrug profiling can accurately assess risk of individual AML patients and may guide clinical decision-making.

The use of single-cell profiling of phenotypes is suggested to inform about chemoresistance and lack of treatment response in cancer. Mass cytometry by time-of-flight (CyTOF) allows high throughput multiparametric analysis at the single-cell level to perform for in-depth characterisation of heterogeneity in leukemia. However, computational identification of cell populations from CyTOF, and utilisation of single-cell data for biomarker discoveries is challenging. Here, we deployed a machine learning-based framework that enables automatic cell population annotation, and systematic exploration of interactions between signalling proteins in a CyTOF antibody panel. We applied the developed framework to analyse a cohort of 45 leukemia patients. We investigated associations between the cellular composition and clinicopathological and genetic features, and reported salient signalling interactions of Multipotent Progenitor-like leukemia cells that were sufficient to predict short-term survival at time of diagnosis. Our findings confirmed that targeting cell type-specific signalling interactions in leukemia might improve existing patient stratification methods with the potential to inform early about more precise treatment options.

The dysbiosis of oral microbiome (OM) precedes the clinical signs of periodontal disease. Its simple measure thus could indicate individuals at risk of periodontitis development; however, such a tool is still missing. Up to now, numerous microbial taxa were associated with periodontal health or periodontitis. The outputs of most studies could, nevertheless, be slightly biased from following two reasons: First, the healthy group is often characterized only by the absence of the disease, but the individuals could already suffer from dysbiosis without any visible signs. Second, the healthy/diseased OM characteristics are frequently determined based on average data obtained for whole groups of periodontally healthy persons versus patients. Especially in smaller sets of tested individuals the typical individual variability can thus complicate the unambiguous assignment of oral taxa to respective state of health. In this work the taxonomic composition of OM was evaluated for 20 periodontally healthy individuals and 15 patients with chronic periodontitis. The narrowed selection set of the most diseased patients (confirmed by clinical parameters) and the most distant group of healthy individuals with the lowest probability of dysbiosis was determined by clustering analysis and used for identification of marker taxa. Based on their representation in each individual oral cavity we proposed the numeric index of periodontal health called R/G value. Its diagnostic potential was further confirmed using independent set of 20 periodontally healthy individuals and 20 patients with periodontitis with 95 percent of samples assigned correctly. We also assessed the individual temporal OM dynamics in periodontal health and we compared it to periodontitis. We revealed that the taxonomic composition of the system changes dynamically but generally it ranges within values typical for periodontal health or transient state, but far from values typical for periodontitis. R/G value tool, formulated from individually evaluated data, allowed us to arrange individual OMs into a continuous series, instead of two distinct groups, thus mimicking the gradual transformation of a virtual person from periodontal health to disease. The application of R/G value index thus represents a very promising diagnostic tool for early prediction of persons at risk of developing periodontal disease.

The estimation of oral microbiome (OM) taxonomic composition in periodontally healthy individuals can often be biased because the clinically periodontally healthy subjects for evaluation can already experience dysbiosis. Usually, they are included just based on the absence of clinical signs of periodontitis. Additionally, the age of subjects is used to be higher to correspond well with tested groups of patients with chronic periodontitis, a disorder typically associated with aging. However, the dysbiosis of the OM precedes the clinical signs of the disease by many months or even years. The absence of periodontal pockets thus does not necessarily mean also good periodontal health and the obtained image of “healthy OM” can be distorted.To overcome this bias, we taxonomically characterized the OM in almost a hundred young students of dentistry with precise oral hygiene and no signs of periodontal disease. We compared the results with the OM composition of older periodontally healthy individuals and also a group of patients with severe periodontitis (aggressive periodontitis according to former classification system). The clustering analysis revealed not only two compact clearly separated clusters corresponding to each state of health, but also a group of samples forming an overlap between both well-pronounced states. Additionally, in the cluster of periodontally healthy samples, few outliers with atypical OM and two major stomatotypes could be distinguished, differing in the prevalence and relative abundance of two main bacterial genera: Streptococcus and Veillonella. We hypothesize that the two stomatotypes could represent the microbial succession from periodontal health to starting dysbiosis. The old and young periodontally healthy subjects do not cluster separately but a trend of the OM in older subjects to periodontitis is visible. Several bacterial genera were identified to be typically more abundant in older periodontally healthy subjects.

The tax havens in the world have become the global phenomenon related tax avoidance, tax fraud and evasion and money laundering. The aim of the paper is to analyze their scope and to assess economic and social consequences of their existence in the world society, world economy, international and national tax systems. Many analyzes of the current situation and reported cases show that tax havens are threatening the stable development of the world economy, causing negative consequences of the economic, social, security and humanitarian nature of the global scale. Combating tax avoidance, tax fraud and evasion through tax havens must be stronger and more effective all around the world.

Objective Chronic lymphocytic leukemia (CLL) treatment has changed dramatically, and landscape of second hematologic malignancies (SHM) evolves in the new era of targeted therapy. No data were available about the real‐world burden of SHM. Methods All 2631 patients with CLL in the Cancer registry of Norway registered 2003‐2012 were included. Results After median follow‐up of 6.6 years, 103 patients (4%) developed SHM. Diffuse large B‐cell lymphoma (DLBCL) was most common (n = 65; 63%). Median survival was 9.3 years (95% CI; 8.9‐9.8) in non‐SHM patients and 1.7 years in DLBCL, 0.8 years in Hodgkin lymphoma (n = 12), and 2.8 years in myeloid neoplasia (n = 15; 95% CI: 0.3‐2.6, 0.6‐2.9, and 0.4‐5.3, respectively; P < .001). Outcomes were poorest for SHM patients treated for CLL (HR 2.76, 95% CI 1.4‐5.5, P = 0.003). A higher proportion of men and younger age were found in SHM patients (median age 66 vs 72 years in non‐SHM; P < .001; men 68% vs 57%, P = .03). Myeloid neoplasia was rare (incidence rate 1/1000 person‐years; 95% CI: 0.6‐1.5) and tended to occur later than DLBCL in patients treated for CLL (median time from CLL to SHM 62 vs 45 months; P = .09). Conclusions SHM and especially myeloid malignancies were rare in chemoimmunotherapy era.

Introduction: COVID-19 induces a pro-inflammatory, hypercoagulable state with marked elevations of ferritin, C-reactive protein, interleukin, and D-dimers Observed consequences include pro-thrombotic disseminated intravascular coagulation (DIC) with a high rate of venous thromboembolism (VTE) and elevated D-dimers with high fibrinogen and low anti-thrombin levels Pulmonary congestion appears to be due to micro-vascular thrombosis and occlusion on pathological examination 1 The acquired pro-thrombotic state and associated poorer outcomes seen in critically ill COVID-19 patients 2,3 have led to such patients being treated empirically with systemic anticoagulants Unfractionated heparin (UFH) or low molecular weight heparin (LMWH) have both been used 2,3 Methods: Review of COVID-19 positive adult patients admitted to the critical care unit between 10th March and 13th May 2020 with severe respiratory failure requiring invasive ventilation Results: In that period we admitted 59 patients 6 (10%) females, 56 (90%) males 45 (76%) patients required therapeutic anticoagulation (27 UFH, 14 LMWH, 4 argatroban) 4 (8 9%) of the 45 anticoagulated patients suffered catastrophic intracranial haemorrhage and subsequently died Discussion: The risk for any significant haemorrhage in patients systemically anticoagulated for VTE with unfractionated heparin (UFH) is 2-3%, 4 and that of anticoagulant-related intracranial haemorrhage (AICH) in patients systemically anticoagulated with UFH is 1-2 7% (in patients treated for ischaemic stroke) and 4% with argatroban 5 We report a much higher incidence of nearly 9% The cases we present fulfilled the advised criteria for systemic anticoagulation Despite four-hourly monitoring of APPT and anti-Xa activity on the intensive care unit there were significant fluxes in these laboratory markers of anticoagulation These may be associated with the uncharted nature of this disease process It is impossible to disassociate the necessary therapeutic-intensity anticoagulation with the observed heightened frequency of life-ending intracranial haemorrhage in these patients

Introduction Heart failure (HF) is a global pandemic affecting at least 26 million people worldwide and is increasing in prevalence (1). Heart transplantation or implantation of durable mechanical circulatory support (MCS) are the sole therapies available for end-stage heart failure. Such patients have severely impaired systolic ventricular function due to end-stage cardiomyopathies but remain symptomatic despite optimal guideline-recommended treatment (2). Acute MCS can be effectively employed as a bridge to long-term MCS devices and heart transplantation. Heart transplantation has been limited by diminishing donor heart availability leading to a greater role of left ventricular assist device (LVAD) support. Methods Retrospective review of adult patients supported with HeartWare™ HVAD™ Pump as a first long term LVAD between January 2017 and February 2020. Results 73 patients received LVADs at our institution in that period. 59 (80%) males, 14 (20%) females, mean age 50. The most common indications were dilated (40%) and ischaemic (34%) cardiomyopathies. 27% of devices were implanted via sternotomy vs 76% via anterolateral thoracotomy. The most frequent complications were driveline infection 26 (36%), pump thrombosis 18 (25%) and ischaemic stroke 16 (22%). Overall, 30 days survival on LVAD was 85% and 1 year survival 65%. 1-year survival in the thoracotomy group was significantly greater compared to the sternotomy group 72% vs 49%, and less red cell transfusion rate (5.2 vs 9.8 units) in thoracotomy approach group was observed. 4 (5.5%) patients received heart transplant. Discussion Despite the excellent long-term survival data for heart transplantation, patients who are denied a transplant or who will not survive the long high-urgency waiting time, benefit more from a permanent LVAD and achieve outpatient status with acceptable quality of life for a reasonable period of time. The minimally invasive surgical approach implemented at our centre is associated with fewer mediastinal adhesions at time of transplant, which greatly facilitates heart implantation and reduces donor organ ischemic time resulting in improved graft performance (3). With new technology focused on limitations of the most common LVAD complications, implanted via thoracotomy, MCS remains valuable treatment tool and it might potentially play more important role in the future of the HF patients.

Background Transformation to aggressive lymphoma (Richter syndrome, RS) occurs in a substantial subset of patients who must discontinue targeted therapy for chronic lymphocytic leukemia (CLL). RS has an extremely poor prognosis. Methods Using the nation-wide database of The Cancer Registry of Norway of 7664 CLL patients registered between 1953–2012, we identified 107 patients experiencing RS. Results Seventy seven (72%) of RS patients were identified among 2631 CLL patients diagnosed between 2003–2012; diffuse large B-cell lymphoma (DLBCL) was identified in 65 (84%), Hodgkin lymphoma (HL) in 12 (16%) patients and the diagnosis was confirmed in 50 (65%) available biopsy specimens. The incidence rate in this period was 4.7/1000 person-years (95% CI: 3.8–5.9). The median survival from CLL diagnosis was 1.7 years (95% CI: 0.34–2.3) for RS patients while it was 10.3 years (95% CI: 9.5–10.9) for the remaining CLL patients. Male gender predominated among RS patients (69%) compared to CLL population (58%) and RS patients were diagnosed with CLL at a significantly younger age than the remaining patients (65 vs. 72 years). Median time from diagnosis of CLL to RS was 2 years (Range, 0–13 years). No CLL treatment was administered in 25 (33%) patients prior RS diagnosis; a median of 1 treatment line was administered to pretreated patients. The median duration of survival after RS diagnosis was 27 months (95% CI; 9–88). Conclusions Collectively, RS was a rare complication of CLL in the chemoimmunotherapy era, occurred early in the CLL course in younger, and both treatment naive and pretreated patients, and shortened survival substantially.

Background: Automatic pacing output management has been used for more than 20 years and it has been generally accepted as safe and device longevity prolonging mode of pacing. Despite that, accuracy of these algorithms in traditional VVI(R) and DDD(R) pacemakers on long term basis has not, to our knowledge, been defined. There is evidence that in patients with atrial fibrillation (AF) and low percentage of ventricular pacing (VP) this function might be less suitable. Methods: We have followed up a population of 559 patients with permanent pacemakers for 3 years and 8 months. 274 of them had the automatic output management (AOM) function activated. We have prospectively searched for inappropriately set pacing output in both subgroups. That is, either too high or too low. We have compared this subgroup to that with fixed output pacing (FOP). Patients with any mechanical complication and those having pacemaker implanted for less than three months were excluded from the study. Results: We have found 11 patients out of 274 in whom the value of pacing output was inappropriate. Conclusions: In our study, 99.6% of patients with AOM functions activated always had effective pacing and the percentage of ideal performance of this function was 96%. These numbers confirm safety of AOM functions with only a few caveats.

Introduction The SynCardia Total Artificial Heart (TAH) is a form of mechanical circulatory support where the patient's native ventricles and valves are explanted and replaced by a pneumatically powered artificial heart (1). Implantation is indicated in patients with irreversible biventricular cardiac failure (2). We have recently initiated a TAH program at Harefield Hospital for the UK patient population. The aim of this study is to review our initial experience in terms of success rate of bridging patients to transplantation and post cardiac transplant outcomes. Methods We analysed data from all patients who received a TAH from July 2014 until April 2019 at our institution to quantify the rate of successful bridging to transplantation and the subsequent post cardiac transplant outcomes. Results 22patients (males, n = 14; mean age 39 ± 17) received TAH implants due to severe, irrecoverable biventricular failure. Aetiologies were dilated (n = 11, 50%), ischaemic (n = 6, 27%) and valvular (n = 3, 13%) cardiomyopathies. 12 patients (55%) were on veno-arterial extra corporeal membrane oxygen support with mean duration of 8.3 ± 8.6 days prior to TAH implantation. Mean duration on TAH support was 95 ± 114 days. 7 patients (32%) suffered stroke, 8 (36%) required surgical exploration for bleeding and 7 (32%) developed sepsis. 9 patients (40%) were successfully bridged to and received a heart transplant, another 3 patients are on the waiting list. 6 patients (27%) are still living: 3 post heart transplantation and 3 remain on the waiting list for a heart transplant. Discussion We have successfully introduced The TAH program in the UK as an important and unique intervention for a high risk patient population with biventricular heart failure who are not candidates for left ventricular assist device. Despite high rate of perioperative and early mortality and postoperative complications TAH implantation provides a realistic alternative for these otherwise futile cases.

Chronic lymphocytic leukemia is a disease of the elderly, and despite major advances in treatment, remains incurable. The Cancer Registry of Norway has registered data on patients with chronic lymphocytic leukemia since 1953. We aimed to analyze trends in incidence and survival of chronic lymphocytic leukemia in Norway. We identified 7664 patients reported with chronic lymphocytic leukemia to the registry between 1953 and 2012. We gathered information on sex, age at diagnosis, date of death and basis for diagnosis. The age‐standardized incidence increased from 0.6/100.000 person‐years in 1953 to 3.1/100,000 person‐years in 2012. We found a significant decrease in median age between 1993–2002 and 2003–2012 (75 vs. 72 years, 95%CI: 2.52–3.98, P

The case of a patient who developed a femoral artery pseudoaneurysm (FAP) following cardiac catheterization is described. It is one of the most troublesome complications after various invasive cardiovascular procedures related to the femoral arterial access site. Iatrogenic pseudoaneurysms (IPA) form when an arterial puncture site fails to seal, allowing arterial blood to ooze into the surrounding tissues and form a pulsatile hematoma. The FAP occurs in 0.8% to 2.2% after interventional procedures. This problem has become more significant due to the exponential growth of interventional cardiology. Doppler flow mapping has been the mainstay of diagnosis. Diagnostic criteria include: swirling color flow in a mass separate from the affected artery, and a typical “to-and-fro” Doppler waveform in the pseudoaneurysm neck. Ultrasound-guided compression repair has replaced the need for surgical repair of FAP. It has been shown to be a safe and cost-effective method for achieving pseudoaneurysm thrombosis. However, it carries considerable drawbacks including long procedure times, discomfort to patients, high recurrence rate in patients receiving anticoagulant therapy and an overall 3.6% complication rate. Recently, percutaneous thrombin injection in the FAP has gained popularity despite complications associated with the initial use of high dose thrombin (average dose of 1,100 IU). The technique was refined when low-dose thrombin injections were studied and proved to have the same efficacy and consistently high success rates (average dose used 192 IU). However, there is a theoretical risk of developing type I IgE-mediated allergic reaction to bovine thrombin. The indications, advantages, disadvantages, and complications of the various treatment modalities are discussed in this report and review of the literature. Other treatments with collagen injection are also discussed in detail.

The goal of this paper is to describe prehospital status and treatment of patients with severe TBI in Austria.Data sets from 396 patients with severe TBI (Glasgow Coma Scale score9) included by 5 Austrian hospitals were available. The analysis focused on incidence and/or degree of severity of typical clinical signs, frequency of use of different management options, and association with outcomes for both. ICU mortality, 90-day mortality, final outcome (favorable = good recovery or moderate disability; unfavorable = severe disability, vegetative state, or death) after 6 or 12 months, and ratio of observed (90-day) to predicted mortality (O/E ratio) are reported for the selected parameters. Chi2 -test, t-test, Fisher's exact test, and logistic regression were used to identify significant (p0.05) differences for association with survival and favorable outcome (both coded as 1).The majority of patients were male (72%), mean age was 49 +/- 21 years, mean injury severity score (ISS) was 27 +/- 17, mean first GCS score was 5.6 +/- 2.9, and expected hospital survival was 63 +/- 30%. ICU mortality was 32%, 90-day mortality was 37%, and final outcome was favorable in 35%, unfavorable in 53%, unknown in 12%. We found that age60 years, ISS50 points, GCS score4, bilateral changes in pupil size and reactivity, respiratory rate10/min, systolic blood pressure (SBP)90 mm Hg, and heart rate60/min were associated with significantly higher ICU and 90-day mortality rates, and lower rates of favorable outcome. With regard to prognostic value the GCS motor response score is identical to the full GCS score. Administration of1000 ml of fluid and helicopter transport were associated with better outcomes than expected, while endotracheal intubation in the field had neither a positive nor a negative effect on outcomes. Administration of no or500 ml of fluids was associated with worse outcomes than expected. Outcomes were better than expected in the few patients (5%) who received hypertonic saline.Age, ISS, and initial neuro status are the factors most closely associated with outcome. Hypotension must be avoided. Fluids should be given to restore and/or maintain SBP110 mm Hg. Helicopter transport should be arranged for more seriously injured patients.

Aims: To investigate the activity response of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) of the rumen bacterium Streptococcus bovis following exposure to mercury(II) chloride (HgCl2) in the presence of plant antioxidants. Methods and Results:Streptococcus bovis was grown with 0 or 5 μg ml−1 of HgCl2 alone or together with antioxidant substances (AOS): seleno-l-methionine (Se), α-tocopherol (αtoc), β-carotene (βcar), melatonin (mel). The activities of SOD and GHPx were estimated in supernatants of disrupted bacterial cells. A significant decrease in the Strep. bovis SOD activity in the presence of HgCl2 and tested AOS, except mel, was observed. The GSHPx activity of Strep. bovis was under the same cultivation conditions nonsignificantly changed and a significant decrease in the GSHPx activity was recorded only in the presence of βcar. Conclusions: The positive effect of Se, αtoc and βcar on the elimination of environmental stress, evoked by mercury, in ruminal bacterium Strep. bovis in vitro was documented. Significance and Impact of the Study: The potential role of plant antioxidants in elimination of the environmental stress of ruminal bacteria evoked by heavy metals is discussed.