FORECASTING THE NUMBER OF SPORT TOURISM ARRIVALS IN SOUTHWEST BULGARIA

This paper presents an application of some forecasting methods concerning sport tourism arrivals in Southwest Bulgaria: linear trend forecasting, double exponential forecasting (Holts method), triple exponential forecasting (the Holt-Winters Method), and the ARIMA method. A specially designed model for estimating the weight coefficient needed for determining the size of the sport tourisms sector in the time series of the available data and in the forecast values is presented. In order to test the forecasting methods and produce forecasts up to the year 2030, a time series and past period predictions have been constructed based on statistical records since 1964. Several major problems in the application of the exponential smoothing methods for the purpose of the long-run forecasting and the needs of the sport tourism subsector of Bulgaria tourism industry are addressed. These problems include (a) finding a suitable general indicator, (b) calculating short-term and long-term forecasts, (c) comparing the results of the forecast techniques on the basis of the errors in the forecasts, (d) estimating the size of the sport tourism in Southwest Bulgaria in certain terms so that the forecast(s) of the above-mentioned general indicator could be particularized especially for examined sub-sector and region. The results from the different forecasting methods and techniques are presented and conclusions are drawn regarding the reliability of the forecasts

Pudendal nerve block as a countermeasure to postoperative chronic pain after removal of Bartholin's cyst

The chronic pain syndrome is a serious post-operative complication. In our practice we have discovered a certain percent of neuralgia of the pudendal nerve in vaginal surgery – more precisely in Bartholin’s cyst removal. As a highly efficient countermeasure we propose a nerve block of the pudendal nerve. We have performed a retrospective study of patients who underwent a Bartholin’s cyst removal in the span of 1 year from January 1st 2019 to December 31st 2019. All of the patients included are diagnosed with chronic pain in the area innervated from the pudendal nerve. In all of the patients a pudendal nerve block with local anesthetic was performed under the guidance of ultrasound. A total of 11 patients were included in the study. There was a time interval between the Bartholin’s cyst removal surgery and the performance of the nerve block. All patients expressed moderate pain before the procedure. In only 1 case a repeat of the nerve block was imposed. There were no short- or long-term complications of any kind. The patients have been followed-up in the duration of 1 year and 100% has been reported. Accurate and precise pain assessment is vital of the diagnosing and subsequent treatment of the chronic pain syndrome. There are many ways of treating the syndrome both conventional (non-steroidal anti-inflammatory drugs, opioids, topical analgesics and adjuvant analgesics) and unconventional. Chronic pain syndrome is an important multilayered problem that requires personal approach. The nerve block of the pudendal nerve is a highly efficient method of coping with that disease

Quantification of Bile Acids in Cerebrospinal Fluid: Results of an Observational Trial

(1) Background: Bile acids, known as aids in intestinal fat digestion and as messenger molecules in serum, can be detected in cerebrospinal fluid (CSF), although the blood–brain barrier is generally an insurmountable obstacle for bile acids. The exact mechanisms of the occurrence, as well as possible functions of bile acids in the central nervous system, are not precisely understood. (2) Methods: We conducted a single-center observational trial. The concentrations of 15 individual bile acids were determined using an in-house LC-MS/MS method in 54 patients with various acute and severe disorders of the central nervous system. We analyzed CSF from ventricular drainage taken within 24 h after placement, and blood samples were drawn at the same time for the presence and quantifiability of 15 individual bile acids. (3) Results: At a median time of 19.75 h after a cerebral insult, the concentration of bile acids in the CSF was minute and almost negligible. The CSF concentrations of total bile acids (TBAs) were significantly lower compared to the serum concentrations (serum 0.37 µmol/L [0.24, 0.89] vs. 0.14 µmol/L [0.05, 0.43]; p = 0.033). The ratio of serum-to-CSF bile acid levels calculated from the respective total concentrations were 3.10 [0.94, 14.64] for total bile acids, 3.05 for taurocholic acid, 14.30 [1.11, 27.13] for glycocholic acid, 0.0 for chenodeoxycholic acid, 2.19 for taurochenodeoxycholic acid, 1.91 [0.68, 8.64] for glycochenodeoxycholic acid and 0.77 [0.0, 13.79] for deoxycholic acid; other bile acids were not detected in the CSF. The ratio of CSF-to-serum S100 concentration was 0.01 [0.0, 0.02]. Serum total and conjugated (but not unconjugated) bilirubin levels and serum TBA levels were significantly correlated (total bilirubin p = 0.031 [0.023, 0.579]; conjugated bilirubin p = 0.001 [0.193, 0.683]; unconjugated p = 0.387 [−0.181, 0.426]). No correlations were found between bile acid concentrations and age, delirium, intraventricular blood volume, or outcome measured on a modified Rankin scale. (4) Conclusions: The determination of individual bile acids is feasible using the current LC-MS/MS method. The results suggest an intact blood–brain barrier in the patients studied. However, bile acids were detected in the CSF, which could have been achieved by active transport across the blood–brain barrier

Biomarkers of Cholestasis and Liver Injury in the Early Phase of Acute Respiratory Distress Syndrome and Their Pathophysiological Value

Background: Impaired liver function and cholestasis are frequent findings in critically ill patients and are associated with poor outcomes. We tested the hypothesis that hypoxic liver injury and hypoxic cholangiocyte injury are detectable very early in patients with ARDS, may depend on the severity of hypoxemia, and may be aggravated by the use of rescue therapies (high PEEP level and prone positioning) but could be attenuated by extracorporeal membrane oxygenation (ECMO). Methods: In 70 patients with ARDS, aspartate-aminotransferase (AST), alanin-aminotransferase (ALT) and gamma glutamyltransferase (GGT) were measured on the day of the diagnosis of ARDS and three more consecutive days (day 3, day 5, day 10), total bile acids were measured on day 0, 3, and 5. Results: AST levels increased on day 0 and remained constant until day 5, then dropped to normal on day 10 (day 0: 66.5 U/l; day 3: 60.5 U/l; day 5: 63.5 U/l, day 10: 32.1 U/l), ALT levels showed the exact opposite kinetic. GGT was already elevated on day 0 (91.5 U/l) and increased further throughout (day 3: 163.5 U/l, day 5: 213 U/l, day 10: 307 U/l), total bile acids levels increased significantly from day 0 to day 3 (p = 0.019) and day 0 to day 5 (p < 0.001), but not between day 3 and day 5 (p = 0.217). Total bile acids levels were significantly correlated to GGT on day 0 (p < 0.001), day 3 (p = 0.02), and in a trend on day 5 (p = 0.055). PEEP levels were significantly correlated with plasma levels of AST (day 3), ALT (day 5) and GGT (day 10). Biomarker levels were not associated with the use of ECMO, prone position, the cause of ARDS, and paO2. Conclusions: We found no evidence of hypoxic liver injury or hypoxic damage to cholangiocytes being caused by the severity of hypoxemia in ARDS patients during the very early phase of the disease. Additionally, mean PEEP level, prone positioning, and ECMO treatment did not have an impact in this regard. Nevertheless, GGT levels were elevated from day zero and rising, this increase was not related to paO2, prone position, ECMO treatment, or mean PEEP, but correlated to total bile acid levels

Characteristics of patients with severe asthma in primary and secondary care settings considered eligible for biological therapy – the Bulgarian RECOGNISE study

Introduction: Asthma is a major non-communicable disease. It affects both children and adults, but is the most common chronic condition among the former. While inhaled controller drugs stabilize the disease in most asthma patients, there are a certain number of people who suffer from severe asthma, which requires treatment escalation. Oral corticosteroids are usually added, but they are associated with various side effects that may limit their application. The introduction of biologicals targeting inflammatory mediators has opened a new era of asthma treatment highlighting the importance of patient characterization. Aim: The RECOGNISE study sought to provide real-world insight into the characteristics of patients deemed eligible for biological therapy based on the judgment of the clinical investigator in primary and secondary care settings. Materials and methods: The RECOGNISE study was a multicenter, observational, cross-sectional, one-visit study to characterize those severe asthma patients who are considered eligible for biological therapy among asthma patients in primary and secondary care settings in Bulgaria. Female and male asthma patients over 18 years of age were enrolled at four sites across the country. Severe asthma diagnosis had to be in agreement with the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines. Patients provided patient-reported outcomes on asthma control and health-related quality of life (HRQoL). Investigators completed specifically designed electronic case report forms (eCRFs), which included demographics and medical history. Medical history included lung function, biomarkers, comorbidities, exacerbations, Healthcare Resource Utilization (HRU), and prescribed asthma medication in the last 12 months as well as adherence to medication. Results: Ninety-two severe asthma patients were enrolled in the Bulgarian RECOGNISE study (females prevailing – 65.22%). The median age (range) at diagnosis was 40 (18, 74) years. Most patients were never-smokers (n=72, 78.26%). For eligible patients, the median total EOS blood count was 431.0 cells/µl (n=19) and the blood EOS percentage was 5.95% (n=64). Chronic OCS use (treatment maintenance with OCS for ≥50% of the previous year) was documented for 30.1% of eligible patients. The results from the Bulgarian RECOGNISE cohort show that 90.2% of the severe asthma patients from the primary and secondary care sites are eligible for treatment with the approved biologicals. Conclusions: The current findings emphasize how crucial it is for patients with severe asthma to be monitored by an asthma specialist who can determine when it is time to switch to biologicals

Can texture analysis of pre-immunotherapy CT imaging predict clinical outcomes for patients with advanced NSCLC treated with Nivolumab?

e20720 Background: Targeted therapies are ineffective in most NSCLC patients and response rates remain 1.5). Fifteen additional texture features trended toward statistical significance with p-values from .05 to .10. In all, 26 out of the 92 texture features showed significant association or trended toward significance with duration of OS. Conclusions: This preliminary study suggests that texture features on pre-immunotherapy CT imaging may help in predicting OS duration for patients with advanced NSCLC treated with Nivolumab monotherapy. We are in the process of validating a multivariate predictive model. Future directions include expansion of this study across the full database, survival analyses and correlation of texture features with tissue biology

Layered <i>P</i>3‑Na_<i>x</i>Co_1/3Ni_1/3Mn_1/3O₂ versus Spinel Li₄Ti₅O₁₂ as a Positive and a Negative Electrode in a Full Sodium–Lithium Cell

The development of lithium and sodium ion batteries without using lithium and sodium metal as anodes gives the impetus for elaboration of low-cost and environmentally friendly energy storage devices. In this contribution we demonstrate the design and construction of a new type of hybrid sodium–lithium ion cell by using unique electrode combination (Li₄Ti₅O₁₂ spinel as a negative electrode and layered Na_3/4Co_1/3Ni_1/3Mn_1/3O₂ as a positive electrode) and conventional lithium electrolyte (LiPF₆ salt dissolved in EC/DMC). The cell operates at an average potential of 2.35 V by delivering a reversible capacity of about 100 mAh/g. The mechanism of the electrochemical reaction in the full sodium–lithium ion cell is studied by means of postmortem analysis, as well as <i>ex situ</i> X-ray diffraction analysis, HR-TEM, and electron paramagnetic resonance spectroscopy (EPR). The changes in the surface composition of electrodes are examined by <i>ex situ</i> X-ray photoelectron spectroscopy (XPS)

Effects of the Particle Size Distribution and of the Electrolyte Salt on the Intercalation Properties of <i>P</i>3‑Na_2/3Ni_1/2Mn_1/2O₂

Sodium-deficient nickel–manganese oxides with a layered type of structure are, nowadays, of great interest as electrode materials for both lithium- and sodium-ion batteries since they are able to intercalate lithium and sodium ions reversibly within a broad concentration range. Herein, we report new data on the effects of the particle sizes and of the electrolyte salt on the intercalation properties of Na_2/3Ni_0.5Mn_0.5O₂ with a <i>P</i>3-type of structure. The morphology of layered Na_2/3Ni_0.5Mn_0.5O₂ oxides has been varied by changing the type of the precursor used: from Na–Ni–Mn acetates to Na–Ni–Mn mixed nitrate acetates. The structure, particle dimensions, and particle size distribution of oxides have been determined by means of powder X-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light-scattering measurements, and X-ray photoelectron spectroscopy (XPS). The intercalation properties of Na_2/3Ni_0.5Mn_0.5O₂ have been studied in model electrochemical cells versus Li metal as the anode. We used two kinds of lithium salts dissolved in organic solutions as the electrolytes: 1 M LiPF₆ in EC:DMC and 1 M LiBF₄ in EC:DMC. The mechanism of the lithium intercalation into Na_2/3Ni_0.5Mn_0.5O₂ is discussed on the basis of <i>e</i><i>x situ</i> XRD, HRTEM, and X-ray photoelectron spectroscopy analyses. It has been discovered that the lithium salt in the electrolyte salt contributes to the mechanism of the electrochemical reaction, while particle dimensions determine the capacity stability during continuous cycling, as well as the surface reactivity of oxide electrodes

Circulating Bile Acids in Liver Failure Activate TGR5 and Induce Monocyte DysfunctionSummary

Background &amp; Aims: Retention of bile acids in the blood is a hallmark of liver failure. Recent studies have shown that increased serum bile acid levels correlate with bacterial infection and increased mortality. However, the mechanisms by which circulating bile acids influence patient outcomes still are elusive. Methods: Serum bile acid profiles in 33 critically ill patients with liver failure and their effects on Takeda G-protein–coupled receptor 5 (TGR5), an immunomodulatory receptor that is highly expressed in monocytes, were analyzed using tandem mass spectrometry, novel highly sensitive TGR5 bioluminescence resonance energy transfer using nanoluciferase (NanoBRET, Promega Corp, Madison, WI) technology, and in vitro assays with human monocytes. Results: Twenty-two patients (67%) had serum bile acids that led to distinct TGR5 activation. These TGR5-activating serum bile acids severely compromised monocyte function. The release of proinflammatory cytokines (eg, tumor necrosis factor α or interleukin 6) in response to bacterial challenge was reduced significantly if monocytes were incubated with TGR5-activating serum bile acids from patients with liver failure. By contrast, serum bile acids from healthy volunteers did not influence cytokine release. Monocytes that did not express TGR5 were protected from the bile acid effects. TGR5-activating serum bile acids were a risk factor for a fatal outcome in patients with liver failure, independent of disease severity. Conclusions: Depending on their composition and quantity, serum bile acids in liver failure activate TGR5. TGR5 activation leads to monocyte dysfunction and correlates with mortality, independent of disease activity. This indicates an active role of TGR5 in liver failure. Therefore, TGR5 and bile acid metabolism might be promising targets for the treatment of immune dysfunction in liver failure

Immunosuppressive effects of circulating bile acids in human endotoxemia and septic shock: patients with liver failure are at risk

Abstract Background Sepsis-induced immunosuppression is a frequent cause of opportunistic infections and death in critically ill patients. A better understanding of the underlying mechanisms is needed to develop targeted therapies. Circulating bile acids with immunosuppressive effects were recently identified in critically ill patients. These bile acids activate the monocyte G-protein coupled receptor TGR5, thereby inducing profound innate immune dysfunction. Whether these mechanisms contribute to immunosuppression and disease severity in sepsis is unknown. The aim of this study was to determine if immunosuppressive bile acids are present in endotoxemia and septic shock and, if so, which patients are particularly at risk. Methods To induce experimental endotoxemia in humans, ten healthy volunteers received 2 ng/kg E. coli lipopolysaccharide (LPS). Circulating bile acids were profiled before and after LPS administration. Furthermore, 48 patients with early (shock onset within  0.4 μg/kg/min) and 48 healthy age- and sex-matched controls were analyzed for circulating bile acids. To screen for immunosuppressive effects of circulating bile acids, the capability to induce TGR5 activation was computed for each individual bile acid profile by a recently published formula. Results Although experimental endotoxemia as well as septic shock led to significant increases in total bile acids compared to controls, this increase was mild in most cases. By contrast, there was a marked and significant increase in circulating bile acids in septic shock patients with severe liver failure compared to healthy controls (61.8 µmol/L vs. 2.8 µmol/L, p = 0.0016). Circulating bile acids in these patients were capable to induce immunosuppression, as indicated by a significant increase in TGR5 activation by circulating bile acids (20.4% in severe liver failure vs. 2.8% in healthy controls, p = 0.0139). Conclusions Circulating bile acids capable of inducing immunosuppression are present in septic shock patients with severe liver failure. Future studies should examine whether modulation of bile acid metabolism can improve the clinical course and outcome of sepsis in these patients. Graphical abstrac