Patients and Methods: Patients were hospitalized under a diagnosis of pulmonary embolism, which was confirmed on the basis of the following criteria: clinical picture, changes in the electrocardiogram (ECG), serum D-dimer values and computed tomography (CT) angiography with contrast. The PAOI score was determined according to CT findings. On admission, systolic, diastolic and pulse pressure were measured.

Background: Monoclonal antibodies (mAbs) represent the most numerous and significant group of biotherapeutics. While mAbs have undoubtedly improved treatment for many chronic diseases, including inflammatory diseases, they are typically expensive for health care systems and patients. Consequently, access to mAbs has been a problem for many patients especially among Central and Eastern European (CEE) countries. However, biosimilars can potentially help with costs, although there are concerns with their effectiveness and safety. This includes biosimilars for long-acting insulin analogues. Aim: Assess the availability and use of biological medicines, including biosimilars within Bosnia and Herzegovina (B&H). Methods: Assess the availability of mAbs via the current lists of approved and accessed mAbs versus those licenced in Europe and the United States and their utilisation, as well as specifically insulin glargine and its biosimilars, within B&H. Results: The availability of the mAbs in B&H appears satisfactory, which is encouraging. However, current usage is limited to a few mAbs which is a concern for subsequent patient care especially with limited use of biosimilars to address issues of affordability. We also see limited use of biosimilar insulin glargine. Conclusion The limited use of mAbs including biosimilars needs to be addressed in B&H to improve the future care of patients within finite resources. We will monitor these developments.

ACCEpTED: December 18, 2020 Aim: To present a therapeutic modality of rhabdomyolysis after acute myocardial infarction (AMI). Case report: A 45-year-old patient was admitted to Urgent Care Center due to chest pain. Due to repeated attacks of ventricular fibrillation (11 direct-current cardioversion defibrillation was done), and after successful cardiopulmonary resuscitation (CPR) he was intubated. Computed tomography (CT) of the head was without pathological findings. At admission laboratory findings were as follows: urea 17.5 mmol/L, creatinine 143 μmol/L, AST 584 IU/L, ALT 162 IU/L, creatine kinase 6220 IU/L, C-reactive protein 249.5 mg/L, troponin I 0.12 ug/L (in two days increased to 6.31 ug/L). In the resuscitation procedure, gastric contents were aspirated, and shadowing of the right lung was radiographically verified. Patient from admission was febrile up to 40° Celsius despite received therapy (positive finding on Haemophilus influenzae B was received subsequently). Ejection fraction of left ventricle was reduced (estimated about 30-35%) along with anteroseptal medioapical akinesia, while stroke volume was 46 mL. Hypokinesia of right ventricular free wall was verified. Tricuspid annular plane systolic excursion was 15mm, along with moderate tricuspid regurgitation. On the fourth day deep vein thrombosis of the left leg was verified. On the ninth day of hospitalization, a high increase in creatine kinase was verified (up to 127.100 IU/L) with consecutive renal failure (urea 38.1 mmol/L, creatinine 620 μmol/L) and rhabdomyolysis with acute renal failure was diagnosed. The patient was included in the acute hemodialysis program (six hemodialysis were performed, diuresis was up to a maximum of 250 mL/day). The patient’s condition gradually stabilized, and the patient was taken of mechanical ventilation after 16 days. During next twenty days, kidney function was improving, and the patient was discharged home. Follow-up examination after two months verified anteroseptal and medioapical akinesia of left ventricle, with satisfactory renal function. Percutaneous coronary intervention was indicated.

ACCEPTED: December 18, 2020 Aim: To present a therapeutic modality of peripartum cardiomyopathy (PPCM). Case report: A 24-year-old female patient, with no prior known diagnosis, was admitted to the Department of Cardiology with signs of acute heart failure. A 45 days prior to admission she delivered a healthy baby (first pregnancy) via cesarean section, while 20 days before hospitalization she developed symptoms like dyspnea, orthopnea, fatigue, weakness and extremely low tolerance to effort. Upon admission on X-ray, heart shadow was enlarged and, while on electrocardiogram (ECG) there was a sinus tachycardia with negative T waves from V1-V5. Echocardiography on admission showed initial dilatation of cardiac chambers, reduced ejection fraction of left ventricle (EFLV; estimated about 25%) with global hypokinesia, signs of moderate to severe mitral and tricuspid regurgitation with mild pulmonary hypertension, along with hemodynamically nonsignificant circumferential pericardial effusion (diastolic separation of 8mm). Laboratory findings were as follows: NT-pro BNP 1810.0 pg/mL; signs of anemia, while inflammatory parameters, cardiac necrosis markers, urea, creatinine, D-dimer and thyroid hormones values remained in reference values. Testing for known cardiotropic viruses was not positive and PPCM was diagnosed. The patient was treated with cardio selective beta blocker (metoprolol), angiotensin-converting enzyme (ACE) inhibitor (ramipril), diuretics (furosemide), spironolactone, and digoxin along with supportive therapy. After twelve days of hospital treatment, there was significant improvement of the clinical status of our patient. Her symptoms were notably ameliorated. EFLV before discharge improved to 40%, heart chambers dimensions were in referral values, while mitral and tricuspid regurgitation were significantly reduced into a mild grade, while pericardial effusion was also in regression. Follow-up examination after two and six months showed further improvement of patients’ conditions while after six months only beta-blocker and acetylsalicylic acid were prescribed in therapy.

Case report : Severe mitral regurgitation due to rupture of the chordae tendineae and mitral valve pro-lapse (Barlow’s disease), with a left atrial volume of 37.6 mL/m 2 was verified in 43-year old patient. He was admitted for an examination due to frequent palpitations and fast and irregular heartbeats. In the anamnestic data, thrombosis of the veins of the right leg was verified (thrombosis of popliteal, posterior tibial and great saphenous vein during previous years). He carries mutations: heterozygote of factor V Leiden, with MTHFR C677T heterozygote (CT), PAI- 1 heterozygote (4G⁄5G) and MTHFR A1298C heterozygote. The surgical treatment was done, and mechanical valve was implanted. In the follow-ing months, the patient complained on frequent dizziness, with crises of consciousness, and a short-ness of breath. He was not suitable for beta-blocker therapy, as well as propafenone and amiodarone, which had been prescribed in therapy in the meantime. The 24-hour ECG Holter monitoring described various arrhythmias, most of the time AV block of the first degree with PQ interval up to 320 msec, oc-casionally second-degree atrioventricular block Mobitz II, polymorphic ventricular extrasystoles and one attack of non-sustained ventricular tachycardia (6 ventricular extrasystoles in row), with intermit-tent nodal rhythm, junctional tachycardia and atrial flutter with AV ratio 2:1. An electrophysiological study was performed, and the cavotricuspid isthmus (CTI) dependent atrial flutter was verified, and radiofrequent ablation was done. After the procedure patient was in sinus rhythm. During the next follow up visits, the patient was in sinus rhythm, on therapy with a low dose of nebivolol (inability to tolerate beta blockers) and ivabradine, along with vitamin K antagonists. Conclusion

Churg-Strauss syndrome (CCS) or eosinophilic granulomatosis with polyangiitis is a rare condition, which is a challenge for both diagnosis and treatment in clinical work. Occurrences of cardiac complications represent a negative predictor of treatment outcome for these patients. The aim of this article is to present the diagnostic and therapeutic modality of a 33-year-old male diagnosed with? CCS. Treatment of these patients should be multidisciplinary, with a comprehensive therapeutic modality, while early diagnosis is imperative.

Abiotic stressors such as extreme temperatures, drought, flood, light, salt, and heavy metals alter biological diversity and crop production worldwide. Therefore, it is important to know the mechanisms by which plants cope with stress conditions. Polyphenols, which are the largest group of plant-specialized metabolites, are generally recognized as molecules involved in stress protection in plants. This diverse group of metabolites contains various structures, from simple forms consisting of one aromatic ring to more complex ones consisting of large number of polymerized molecules. Consequently, all these molecules, depending on their structure, may show different roles in plant growth, development, and stress protection. In the present review, we aimed to summarize data on how different polyphenol structures influence their biological activity and their roles in abiotic stress responses. We focused our review on phenolic acids, flavonoids, stilbenoids, and lignans.

ABSTRACT Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) show a large overlap in clinical presentation, which presents diagnostic challenges. As a consequence, invasive and burdensome endoscopies are often used to distinguish between IBD and IBS. Here, we aimed to develop a noninvasive fecal test that can distinguish between IBD and IBS and reduce the number of endoscopies. We used shotgun metagenomic sequencing to analyze the composition and function of gut microbiota of 169 IBS patients, 447 IBD patients and 1044 population controls and measured fecal Calprotectin (FCal), human beta defensin 2 (HBD2), and chromogranin A (CgA) in these samples. These measurements were used to construct training sets (75% of data) for logistic regression and machine learning models to differentiate IBS from IBD and inactive from active IBD. The results were replicated on test sets (remaining 25% of the data) and microbiome data obtained using 16S sequencing. Fecal HBD2 showed high sensitivity and specificity for differentiating between IBD and IBS (sensitivity = 0.89, specificity = 0.76), while the inclusion of microbiome data with biomarkers (HBD2 and FCal) showed a potential for improvement in predictive power (optimal sensitivity = 0.87, specificity = 0.93). Shotgun sequencing–based models produced comparable results using 16S-sequencing data. HBD2 and FCal were found to have predictive power for IBD disease activity (AUC ≈ 0.7). HBD2 is a novel biomarker for IBD in patients with gastro-intestinal complaints, especially when used in combination with FCal and potentially in combination with gut microbiome data.

Abstract Studies published earlier this year demonstrated the association of the solute carrier SLC6A20 gene with the risk and severity of COVID-19. The SLC6A20 protein product (Sodium-dependent Imino Transporter 1 (SIT1)) is involved in the transport of amino acids, including glycine. Here we summarized the results of recent studies demonstrating the interaction of SIT1 with the ACE2 receptor for SARS-CoV-2 as well as an observed association of SLC6A20 with the risk and traits of Type 2 diabetes (T2D). Recently, it was also proposed that SLC6A20 represents the novel regulator of glycine levels and that glycine has beneficial effects against the proinflammatory cytokine secretion induced by SARS-CoV-2 infection. Ivermectin, as a partial agonist of glycine-gated chloride channels, was also recently suggested to interfere with the COVID-19 cytokine storm by inducing the activation of glycine receptors. Furthermore, plasma glycine levels are found to be decreased in diabetic patients. Thus, further clinical trials are warranted to confirm the potential favorable effects of targeting the SIT1 transporter and glycine levels in the treatment of COVID-19, particularly for the severe case of disease associated with hyperglycemia, inflammation, and T2D. These findings suggest that SIT1 may potentially represent one of the missing pieces in the complex puzzle observed between these two pandemic diseases and the potential novel target for their efficient treatment.

The hemibiotrophic fungus Magnaporthe oryzae (Mo) is the causative agent of rice blast and can infect aerial and root tissues of a variety of Poaceae, including the model Brachypodium distachyon (Bd). To gain insight in gene regulation processes occurring at early disease stages, we comparatively analyzed fungal and plant mRNA and sRNA expression in leaves and roots. A total of 310 Mo genes were detected consistently and differentially expressed in both leaves and roots. Contrary to Mo, only minor overlaps were observed in plant differentially expressed genes (DEGs), with 233 Bd-DEGs in infected leaves at 2 days post inoculation (DPI), compared to 4978 at 4 DPI, and 138 in infected roots. sRNA sequencing revealed a broad spectrum of Mo-sRNAs that accumulated in infected tissues, including candidates predicted to target Bd mRNAs. Conversely, we identified a subset of potential Bd-sRNAs directed against fungal cell wall components, virulence genes and transcription factors. We also show a requirement of operable RNAi genes from the DICER-like (DCL) and ARGONAUTE (AGO) families for fungal virulence. Overall, our work elucidates the extensive reprogramming of transcriptomes and sRNAs in both plant host (Bd) and fungal pathogen (Mo), further corroborating the critical role played by sRNA species in the establishment of the interaction and its outcome.

ABSTRACT In oral-cancer, the number of tumor-infiltrating lymphocytes (TILs) associates with improved survival, yet the prognostic value of the cellular composition and localization of TILs is not defined. We quantified densities, localizations, and cellular networks of lymphocyte populations in 138 patients with T1-T2 primary oral-tongue squamous cell carcinoma treated with surgical resections without any perioperative (chemo)radiotherapy, and correlated outcomes to overall survival (OS). Multiplexed in-situ immunofluorescence was performed for DAPI, CD4, CD8, CD20, and pan-cytokeratin using formalin-fixed paraffin-embedded sections, and spatial distributions of lymphocyte populations were assessed in the tumor and stroma compartments at the invasive margin (IM) as well as the center of tumors. We observed a high density of CD4, CD8, and CD20 cells in the stroma compartment at the IM, but neither lymphocyte densities nor networks as single parameters associated with OS. In contrast, assessment of two contextual parameters within the stroma IM region of tumors, i.e., the number of CD20 cells within 20 µm radii of CD20 and CD4 cells, termed the CD20 Cluster Score, yielded a highly significant association with OS (HR 0.38; p = .003). Notably, the CD20 Cluster Score significantly correlated with better OS and disease-free survival in multivariate analysis (HR 0.34 and 0.47; p = .001 and 0.019) as well as with lower local recurrence rate (OR: 0.13; p = .028). Taken together, our study showed that the presence of stromal B-cell clusters at IM, in the co-presence of CD4 T-cells, associates with good prognosis in early oral-tongue cancer patients.

Background: The human angiotensin I converting enzyme 1 (ACE1) gene insertion/deletion (I/D) polymorphism is classified based on the presence or absence of a 287 bp Alu sequence. The ACE1 D allele is associated with higher ACE1 concentrations in tissues. Previous research has shown that susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is primarily determined by the affinity between the viral receptor-binding domain and the host human receptor angiotensin-converting enzyme 2 (hACE2) receptor. In the human genome, ACE2 is identified as a homolog to ACE1. Objective: The purpose of this study was to characterize the ACE1 D allele distribution in Bosnia and Herzegovina (B&H), so as to compare it to population data from other European countries and to investigate the potential correlation between D allele frequencies and coronavirus disease 2019 (COVID-19) epidemiological findings in selected European populations. Methods: The ACE1 D allele frequencies in 18 selected European populations were analyzed and compared with COVID-19 prevalence, mortality, and severity using multivariate linear regression analysis. Results and Discussion: The ACE1 D allele distribution within the B&H population was similar to its distribution in other European populations. Regression analysis showed no significant correlation between the D allele frequency and the incidence of infections between the examined populations, nor with the rates of fatality and severe cases. Conclusion: There is no clear statistical evidence that the ACE1 D allele is associated with increased or decreased COVID-19 incidence, mortality, and case severity within the investigated populations.