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This work presents a new electrochemical method (i.e. new electrolyte composition and electrolysis regimes) for direct formation of Al2O3 on different metal substrates from non-aqueous electrolytes, data on the kinetics of the electrochemical processes and scanning electron microscopy (SEM) and XPS studies of the morphology, structure, dispersion and chemical composition of deposited Al2O3. [Copyright &y& Elsevier]

We study two-variable Engel-like relations and identities characterizing finite-dimensional solvable Lie algebras and, conjecturally, finite solvable groups and introduce some invariants of finite groups associated with such relations. Bibliography: 29 titles. [ABSTRACT FROM AUTHOR]

The authors discuss their response on the comments regarding their article on transient elastography for staging liver fibrosis in alcoholic liver disease. They agree that their article is based on their Cochrane systematic review but stress that including data from the two studies will not influence the results of the meta-analyses. They argue against the comment that the mixed aetiology in the 50% of the included studies is a limitation of their review.

Mutations in the receptor of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) are used as biomarkers for predicting the response of treatment with EGFR tyrosine kinase inhibitors (EGFR TKIs). Non-small cell lung cancer patients usually have activating EGFR mutations that leads to a very good response when they are treated with EGFR TKIs. Our tumor samples were examined for the presence of sensitive mutations in the EGFR gene, resistant mutations or the absence of mutations. To identify the types of the mutation, we used a real-time polymerase chain reaction (RT-PCR) method. Additionally, we evaluated the frequency of EGFR mutations and their association with smoking status, gender and histology. The tumor samples (n = 551) were tested for 29 somatic mutations in the EGFR gene. Sensitive mutations in the EGFR genes were found in 55 NSCLC samples (10.0%). The prevalence of EGFR mutations was much higher for females than for males (27.1 vs. 3.9%, p <0.001). The prevalence of EGFR mutations was greater in subjects who had never smoked than in smokers (15.0 vs. 6.08%, p <0.003). Additionally, the frequency of EGFR mutations was higher in adenocarcinomas than in other histological types (14.9 vs. 5.1%; p <0.001). Our results show that activating mutations on the EGFR gene are more frequent in females than in males, in adenocarcinoma than other histological types and in non smokers than smokers. [ABSTRACT FROM AUTHOR]

A response by the G. Bjelakovic and colleagues to a letter to the editor on their article "Metaanalysis: antioxidant supplements for liver disease: the Cochrane Hepato-Biliary Group" in the 2010 issue is presented.

Sunflower oil hydrogenation process was studied on silica supported nickel catalysts. Three texturally different silica gel materials were used as supports for synthesis of Ni/Si02 catalyst precursors. After precursors' reduction and paraffin oil impregnation, obtained catalysts were used in sunflower oil hydrogenation reaction. For catalytic test, a new type of catalyst feeder was constructed and presented. The hydrogenation activity of catalysts was monitored through the decrease of refractive index and hydrogen consumption. A correlation between iodine value, refractive index and hydrogen consumption was established. The reaction rate constants were obtained from fatty acid composition of partially hydrogenated oil and further studied for the investigation of possible reaction pathways. Kinetics and mechanisms were evaluated and tested with the aim to reduce the number of reactions participating in the reaction scheme. A set of ordinary differential equations, corresponding to the investigated model, was solved numerically by Gear' s algorithm. It was shown that a number of significant reactions in a model depend on the activity of catalysts. More active catalyst results in more reaction pathways and more side chemical reactions. [ABSTRACT FROM AUTHOR]

The article focuses on understanding the influence of the anthropomorphic thinking of Bulgarian children on their conceptions of the natural world. The authors aim to determine the dynamics of the conceptions of pre-school and primary school children. They state that there are differences in the literary images of plants and animals by the scientific description with children.

Competing Interests: Declaration of interests None.

Inspired by our finding that metallic Ni particles could be uniformly distributed on a reduced CeO 2 surface and stabilized on Ce 3+ sites, we suppose a possible improvement in the activity and selectivity of the MgNi/SiO 2 vegetable oil hydrogenation catalyst by increasing the surface metal Ni availability via modification by ceria. The proposed approach involved the addition of a CeO 2 modifier to the SiO 2 carrier and as a catalyst component. Evaluation of the structure, reducibility, and surface and electronic states of the CeO 2 -doped MgNi/SiO 2 catalyst was performed by means of the Powder X-ray diffraction (PXRD), Scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS), and X-ray photoelectron spectroscopy (XPS) combined with High-resolution transmission electron microscopy (HRTEM), Temperature-programmed reduction with hydrogen (H2-TPR), and H 2 -chemisortion techniques. So far, no studies related to this approach of designing Ni/SiO 2 catalysts for the partial hydrogenation of vegetable oil have been reported. The added ceria impact was elucidated by comparing fatty acid compositions obtained by the catalysts at an iodine value of 80. In summary, tuning the hydrogenation performance of Ni-based catalysts can be achieved by structural reconstruction using 1 wt.% CeO 2 . The introduction mode changed the selectivity towards C18:1- cis and C18:0 fatty acids by applying ceria as a carrier modifier, while hydrogenation activity was improved upon ceria operation as the catalyst dopant.

Background: Hepatocellular carcinoma is the most common type of liver cancer, accounting for 70% to 85% of individuals with primary liver cancer. Gene therapy, which uses genes to treat or prevent diseases, holds potential for treatment, especially for tumours. Trials on the effects of gene therapy in people with hepatocellular carcinoma have been published or are ongoing., Objectives: To evaluate the benefits and harms of gene therapy in people with hepatocellular carcinoma, irrespective of sex, administered dose, and type of formulation., Search Methods: We identified randomised clinical trials through electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We searched five online clinical trial registries to identify unpublished or ongoing trials. We checked reference lists of the retrieved studies for further trials. The date of last search was 20 January 2023., Selection Criteria: We aimed to include randomised clinical trials assessing any type of gene therapy in people diagnosed with hepatocellular carcinoma, irrespective of year, language of publication, format, or outcomes reported., Data Collection and Analysis: We followed Cochrane methodology and used Review Manager to prepare the review. The primary outcomes were all-cause mortality/overall survival (whatever data were provided), serious adverse events during treatment, and health-related quality of life. The secondary outcomes were proportion of people with disease progression, adverse events considered non-serious, and proportion of people without improvement in liver function tests. We assessed risk of bias of the included trials using RoB 2 and the certainty of evidence using GRADE. We presented the results of time-to-event outcomes as hazard ratios (HR), dichotomous outcomes as risk ratios (RR), and continuous outcomes as mean difference (MD) with their 95% confidence intervals (CI). Our primary analyses were based on intention-to-treat and outcome data at the longest follow-up., Main Results: We included six randomised clinical trials with 364 participants. The participants had unresectable (i.e. advanced inoperable) hepatocellular carcinoma. We found no trials assessing the effects of gene therapy in people with operable hepatocellular carcinoma. Four trials were conducted in China, one in several countries (from North America, Asia, and Europe), and one in Egypt. The number of participants in the six trials ranged from 10 to 129 (median 47), median age was 55.2 years, and the mean proportion of males was 72.7%. The follow-up duration ranged from six months to five years. As the trials compared different types of gene therapy and had different controls, we could not perform meta-analyses. Five of the six trials administered co-interventions equally to the experimental and control groups. All trials assessed one or more outcomes of interest in this review. The certainty of evidence was very low in five of the six comparisons and low in the double-dose gene therapy comparison. Below, we reported the results of the primary outcomes only. Pexastimogene devacirepvec (Pexa-Vec) plus best supportive care versus best supportive care alone There is uncertainty about whether there may be little to no difference between the effect of Pexa-Vec plus best supportive care compared with best supportive care alone on overall survival (HR 1.19, 95% CI 0.78 to 1.82; 1 trial (censored observation at 20-month follow-up), 129 participants; very low-certainty evidence) and on serious adverse events (RR 1.42, 95% CI 0.60 to 3.33; 1 trial at 20 months after treatment, 129 participants; very low-certainty evidence). The trial reported quality of life narratively as "assessment of quality of life and time to symptomatic progression was confounded by the high patient dropout rate." Adenovirus-thymidine kinase with ganciclovir (ADV-TK/GCV) plus liver transplantation versus liver transplantation alone There is uncertainty about whether ADV-TK/GCV plus liver transplantation may benefit all-cause mortality at the two-year follow-up (RR 0.39, 95% CI 0.20 to 0.76; 1 trial, 45 participants; very low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life. Double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation alone There is uncertainty about whether double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation may benefit all-cause mortality at five-year follow-up (RR 0.40, 95% CI 0.22 to 0.73; 1 trial, 86 participants; low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life. Recombinant human adenovirus-p53 with hydroxycamptothecin (rAd-p53/HCT) versus hydroxycamptothecin alone There is uncertainty about whether there may be little to no difference between the effect of rAd-p53/HCT versus hydroxycamptothecin alone on the overall survival at 12-month follow-up (RR 3.06, 95% CI 0.16 to 60.47; 1 trial, 48 participants; very low-certainty evidence). The trial did not report serious adverse events or quality of life. rAd-p53/5-Fu (5-fluorouracil) plus transarterial chemoembolisation versus transarterial chemoembolisation alone The trial included 46 participants. We had insufficient data to assess overall survival. The trial did not report serious adverse events or quality of life. E1B-deleted (dl1520) adenovirus versus percutaneous ethanol injection The trial included 10 participants. It did not report data on overall survival, serious adverse events, or health-related quality of life. One trial did not provide any information on sponsorship; one trial received a national research grant, one trial by the Pedersen foundation, and three were industry-funded trials. We found five ongoing randomised clinical trials., Authors' Conclusions: The evidence is very uncertain about the effects of gene therapy on the studied outcomes because of high risk of bias and imprecision of outcome results. The trials were underpowered and lacked trial data on clinically important outcomes. There was only one trial per comparison, and we could not perform meta-analyses. Therefore, we do not know if gene therapy may reduce, increase, or have little to no effect on all-cause mortality or overall survival, or serious adverse events in adults with unresectable hepatocellular carcinoma. The impact of gene therapy on adverse events needs to be investigated further. Evidence on the effect of gene therapy on health-related quality of life is lacking., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objectives: This systematic review with meta-analyses of randomised trials evaluated the preventive effects of vitamin A supplements versus placebo or no intervention on clinically important outcomes, in people of any age., Methods: We searched different electronic databases and other resources for randomised clinical trials that had compared vitamin A supplements versus placebo or no intervention (last search 16 April 2024). We used Cochrane methodology. We used the random-effects model to calculate risk ratios (RRs), with 95% CIs. We analysed individually and cluster randomised trials separately. Our primary outcomes were mortality, adverse events and quality of life. We assessed risks of bias in the trials and used Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) to assess the certainty of the evidence., Results: We included 120 randomised trials (1 671 672 participants); 105 trials allocated individuals and 15 allocated clusters. 92 trials included children (78 individually; 14 cluster randomised) and 28 adults (27 individually; 1 cluster randomised). 14/105 individually randomised trials (13%) and none of the cluster randomised trials were at overall low risk of bias. Vitamin A did not reduce mortality in individually randomised trials (RR 0.99, 95% CI 0.93 to 1.05; I ² =32%; p=0.19; 105 trials; moderate certainty), and this effect was not affected by the risk of bias. In individually randomised trials, vitamin A had no effect on mortality in children (RR 0.96, 95% CI 0.88 to 1.04; I ² =24%; p=0.28; 78 trials, 178 094 participants) nor in adults (RR 1.04, 95% CI 0.97 to 1.13; I ² =24%; p=0.27; 27 trials, 61 880 participants). Vitamin A reduced mortality in the cluster randomised trials (0.84, 95% CI 0.76 to 0.93; I ² =66%; p=0.0008; 15 trials, 14 in children and 1 in adults; 364 343 participants; very low certainty). No trial reported serious adverse events or quality of life. Vitamin A slightly increased bulging fontanelle of neonates and infants. We are uncertain whether vitamin A influences blindness under the conditions examined., Conclusions: Based on moderate certainty of evidence, vitamin A had no effect on mortality in the individually randomised trials. Very low certainty evidence obtained from cluster randomised trials suggested a beneficial effect of vitamin A on mortality. If preventive vitamin A programmes are to be continued, supporting evidence should come from randomised trials allocating individuals and assessing patient-meaningful outcomes., Prospero Registration Number: CRD42018104347., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Lymphoplasmacytic lymphoma (LPL) is a malignant proliferation of small lymphocytes, lymphoplasmocytoid cells and plasmocytes affecting the bone marrow, lymph nodes and spleen. Its incidence is 1/100,000 and represents 8% of all lymphomas. A total of ~5% of patients with LPL may secrete non-IgM of IgG, IgA, kappa or lambda type or be non-secretory. In the present study, a case of a 62-year-old female patient who was diagnosed with non-IgM LPL with kappa light chain monoclonal paraprotein production and normal serum immunoglobulin levels was reported. The MYD88 L265P mutation was detected by molecular genetic analysis using a sample of the bone marrow. The patient underwent initial treatment with a combination of Bendamustine-Rituximab, and later on, Ibrutinib (a Bruton kinase inhibitor) was added to the treatment protocol. The authors' aim was to describe a case of a rare type of LPL studied and cured at the University Hospital 'St. Ivan Rilski', as well as to show the methods used for its diagnosis and their applicability. The difficulty in diagnosing such rare cases of LPL which are associated with marked plasmacytic differentiation and IgA paraprotein secretion resembling plasma cell neoplasia was addressed. From the other side, the characteristic features in favor of LPL diagnosis are the immunophenotype profile of plasmocytes, as well as the presence of MYD88 L265P mutation. Finally, the methods of management and treatment of this type of lymphoma were reported, highlighting the favorable effect of the treatment with Bruton TK inhibitor (Ibrutinib)., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Nikolova et al.)

Introduction: The use of herbal medicine as a part of the Complementary and Alternative Medicine is increasing worldwide. Herbal remedies are used to better different conditions including gastritis., Material and Methods: We conducted a prospective randomized control clinical trial on a total sample of 72 patients with gastritis in order to examine the effects of the commercial herbal product Gastro Protect. After 6 weeks of conventional therapy the patients were divided into two groups with 36 patients each. As a continuation of the treatment, Group 1 received conventional therapy + Gastro Protect and Group 2 received conventional therapy + Placebo. We analyzed 14 selected gastrointestinal symptoms, five related to digestive problems, and nine related to stool and bowel problems. For assessing the selected symptoms we used seven point gastrointestinal symptom rating scale (GSRS)., Results: The Gastro Protect group had a significantly lower GSRS score (better condition) compared to the Placebo group related to all five selected symptoms of digestive problems as: abdominal pain (p=0.0250), hunger pain (p=0.0276), nausea (p=0.0019), heartburn (p=0.00001), and acid reflux (p=0.0017). The Gastro Protect group, also had a significantly lower GSRS score (better condition) compared to the Placebo group related to three out of nine selected bowel symptoms: rumbling (p=0.0022), abdominal distension (p=0.0029), and gas or flatus (p=0.0039)., Conclusion: Gastro protect was effective in treating gastritis and other gastrointestinal symptoms. It was safe for usage and showed almost no side effects. In our study, Gastro Protect reduced the examined gastric symptoms and related examined intestinal symptoms., (© 2024 Dafina Nikolova et al., published by Sciendo.)

Background: Individuals can experience difficulties pursuing their goals amid multiple competing priorities in their environment. Effective goal dynamics require flexible and generalizable pursuit skills. Supporting successful goal pursuit requires a perpetually adapting intervention responsive to internal states., Objective: The purpose of this study was to (1) develop a flexible intervention that can adapt to an individual's changing short to medium-term goals and be applied to their daily life and (2) examine the feasibility and acceptability of the just-in-time adaptive intervention for goal pursuit., Methods: This study involved 3 iterations to test and systematically enhance all aspects of the intervention. During the pilot phase, 73 participants engaged in an ecological momentary assessment (EMA) over 1 month. After week 1, they attended an intervention training session and received just-in-time intervention prompts during the following 3 weeks. The training employed the Capability, Opportunity, Motivation, and Behavior (COM-B) framework for goal setting, along with mental contrasting with implementation intentions (MCII). Subsequent prompts, triggered by variability in goal pursuit, guided the participants to engage in MCII in relation to their current goal. We evaluated feasibility and acceptability, efficacy, and individual change processes by combining intensive (single-case experimental design) and extensive methods., Results: The results suggest that the digital intervention was feasible and acceptable to participants. Compliance with the intervention was high (n=63, 86%). The participants endorsed high acceptability ratings relating to both the study procedures and the intervention. All participants (N=73, 100%) demonstrated significant improvements in goal pursuit with an average difference of 0.495 units in the outcome (P<.001). The results of the dynamic network modeling suggest that self-monitoring behavior (EMA) and implementing the MCII strategy may aid in goal reprioritization, where goal pursuit itself is a driver of further goal pursuit., Conclusions: This pilot study demonstrated the feasibility and acceptability of a just-in-time adaptive intervention among a nonclinical adult sample. This intervention used self-monitoring of behavior, the COM-B framework, and MCII strategies to improve dynamic goal pursuit. It was delivered via an Ecological Momentary Intervention (EMI) procedure. Future research should consider the utility of this approach as an additional intervention element within psychological interventions to improve goal pursuit. Sustaining goal pursuit throughout interventions is central to their effectiveness and warrants further evaluation., (©Ciarán O'Driscoll, Aneesha Singh, Iya Chichua, Joachim Clodic, Anjali Desai, Dara Nikolova, Alex Jie Yap, Irene Zhou, Stephen Pilling. Originally published in JMIR Formative Research (https://formative.jmir.org), 20.03.2024.)

Stachys scardica Griseb. is a Balkan endemic species listed in The Red Data Book of Bulgaria with the conservation status "endangered". Successful micropropagation was achieved on MS medium supplemented with 1.5 mg/L benzyladenine (BA), followed by a subsequent ex vitro adaptation in an experimental field resulting in 92% regenerated plants. Using nuclear magnetic resonance (NMR), phenylethanoid glycosides (verbascoside, leucosceptoside A), phenolic acids (chlorogenic acid), iridoids (allobetonicoside and 8-OAc-harpagide), and alkaloids (trigonelline) were identified, characteristic of plants belonging to the genus Stachys . High antioxidant and radical scavenging activities were observed in both in situ and ex vitro acclimated S. scardica plants, correlating with the reported high concentrations of total phenols and flavonoids in these variants. Ex vitro adapted plants also exhibited a well-defined anti-inflammatory potential, demonstrating high inhibitory activity against the complement system. Employing a disk diffusion method, a 100% inhibition effect was achieved compared to positive antibiotic controls against Staphylococcus epidermidis and Propionibacterium acnes , with moderate activity against Bacillus cereus . The induced in vitro and ex vitro model systems can enable the conservation of S. scardica in nature and offer future opportunities for the targeted biosynthesis of valuable secondary metabolites, with potential applications in the pharmaceutical and cosmetic industries.

Dry rose extract (DRE) obtained industrially by aqueous ethanol extraction from R. damascena flowers and its phenolic-enriched fraction, obtained by re-extraction with ethyl acetate (EAE) were the subject of this study. 1 H NMR of DRE allowed the identification and quantitation of fructose and glucose, while the combined use of HPLC-DAD-ESIMS and HPLC-HRMS showed the presence of 14 kaempferol glycosides, 12 quercetin glycosides, 4 phenolic acids and their esters, 4 galloyl glycosides, 7 ellagitannins, and quinic acid. In addition, the structures of 13 of the flavonoid glycosides were further confirmed by NMR. EAE was found to be richer in TPC and TFC and showed better antioxidant activity (DPPH, ABTS, and FRAP) compared to DRE. Both extracts displayed significant activity against Propionibacterium acnes , Staphylococcus aureus , and S. epidermidis , but showed no activity against Candida albicans. Toxicity tests on normal human skin fibroblasts revealed low toxicity for both extracts with stronger effects observed at 24 hours of treatment that were compensated for over the following two days. Human hepatocarcinoma (HepG2) cells exhibited an opposite response after treatment with a concentration above 350 µg/mL for EAE and 500 µg/mL for DRE, showing increased toxicity after the third day of treatment. Lower concentrations were non-toxic and did not significantly affect the cell cycle parameters of either of the cell lines.

Medical therapies used for Inflammatory Bowel Disease (IBD) include conventional (e.g. 5-aminosalicylates, steroids, immunomodulators) and biologic (e.g. inhibitors of tumor necrosis factor - alpha, integrin inhibitors, interleukin inhibitors) medications. Biologics, due to their high cost, were unfortunately not covered by the public health insurance system in North Macedonia until 2019 and, therefore, not widely utilized for our IBD patients. In 2019, the University Clinic of Gastroenterology and Hepatology in Skopje developed a biologic therapy supply, provided by the National Health Insurance Fund, making this therapy available for a larger number of patients. This report presents the initial results of our prospective, single tertiary-care center study on the effects of biologic therapy in patients with IBD in North Macedonia. The study is focused on the evaluation of clinical outcomes after anti-tumor necrosis factor alpha (anti TNF-alpha) therapy in IBD patients with prior inadequate response to conventional medications., (© 2023 Gjorgi Deriban et al., published by Sciendo.)

Introduction : Anal fissure is a longitudinal tear of the mucosa of the anal canal extending from the outer anal orifice in the direction of the dentate line of the inner anal opening. Fissures are divided into primary and secondary, and acute or chronic. Besides minimal rectal bleeding, itching and soiling, primary chronic anal fissures (PCAF) manifest with anal pain as theirs main determinant. It is described as the most troubling symptom. Aim : To compare the effect of injection therapy with botulinum toxin A (ITBT) vs. anal dilation (AD), and local nifedipine with lidocaine (LNL) in pain treatment of PCAF. Materials and Methods : This controlled retrospective prospective longitudinal study covered 94 patients, divided in 3 groups. The first was treated with ITBT, the second with AD and third using LNL (31, 33 and 30 patients respectively). Clostridium botulinum toxin A was used, dissolved with saline to concentration of 200 U/ml. The solution was applied to both sides of PCAF at dose of 40U. Modified technique of AD was done using 3 fingers of a single hand, progressively introduced into the anal canal, followed by gradual lateral distraction during 1 min. LNL therapy was conducted using nifedipine (0.3%) with lidocaine (1.5%) ointment, applied twice daily for 3 weeks. To measure pain, a visual analog scale (VAS) was used. The follow-up period was 12 weeks with checkup at week 4. Results : The median age of participants was 46.6±13.9 years (50 males vs. 44 females). The type of therapy had a significantly different effect on pain at week 4 (p=0.0003). Severe pain was present in only 2 ITBT patients, 16 AD, and 6 LNL patients. Post hoc analyses showed different pain disappearance time by week 12 (p <0.0001). The mean time was shortest in ITBT group (6.1±1.5 weeks). Anal pain intensity significantly differed among the 3 groups (Fisher exact, p=0.002). Namely, 71% in ITBT group rated the pain as weakest (VAS score 1) compared to 18.2% in AD and 30% of patients in LNL group. The overall pain reduction significance was in favor of ITBT, due to the differences between the ITBT and AD groups (p=0.00024) and ITBT compared to LNL group (p=0.018). Conclusion : ITBT is superior to AD and LNL in reducing pain in PCAF., (© 2023 Vladimir Andreevski et al., published by Sciendo.)

Testicular mixed germ cell tumors (TMGCTs) are aggressive neoplasms that often have metastases at the time of diagnosis, primarily in the lungs, bones, and brain. Gastrointestinal metastases are rare, occurring in less than 5% of cases, while duodenal involvement is extremely rare, with only few reported cases. Furthermore, gastrointestinal bleeding is an atypical initial presentation of metastatic TMGCTs. Herein, we present a very rare case of upper gastrointestinal bleeding caused by a duodenal metastasis of a TMGCT in a 24-year-old man. The patient was admitted to our hospital due to abdominal pain and melena with a hemoglobin level of 52 g/L. He had no history of testicular swelling, or any other symptoms or signs of a testicular tumor. Upper gastrointestinal endoscopy revealed a duodenal tumor mass with irregular bleeding, and abdominal ultrasound and computed tomography showed a duodenal mass that infiltrate retroperitoneum. Emergency surgery was performed, and the histopathological findings of the resected specimen were consistent with TMGCT metastasis. Subsequently, a testicular tumor was confirmed and surgically removed; however, multiple metastatic deposits were observed in the lungs. Due to the patient's poor general condition, chemotherapy was not performed. The patient died 3 months after the initial diagnosis. This case suggests that, although duodenal metastatic TMGCTs are rare, they should be considered in the differential diagnosis of gastrointestinal bleeding in young male patients., (© 2023 Emilija Nikolovska Trpchevska et al., published by Sciendo.)

The applicability of two lactic acid bacterial strains with probiotic potential and bioprotective properties as additions in the starter culture in yogurt fermentation was examined. The studied strains, Lactobacillus delbrueckii subsp. bulgaricus KZM 2-11-3 and Lactiplantibacillus plantarum KC 5-12, inhibited the growth of Kluyveromyces lactis , Kluyveromyces marxianus , and Saccharomyces cerevisiae . The strain L. delbrueckii subsp. bulgaricus KZM 2-11-3 directly inhibited Escherichia coli . The important characteristics for the quality of the yogurt product, such as physicochemical parameters during fermentation and storage, rheological characteristics, and sensory changes during the storage of samples were determined. The yogurt samples with the strains did not differ in most parameters from the control yogurt with the commercial starter. The added strains showed stable viability in the yogurt samples during storage. The yogurt sample with L. delbrueckii subsp. bulgaricus KZM 2-11-3 and the sample with both strains based on the total evaluation were very similar to the control yogurt with the commercial starter. Using these strains as probiotic supplements to enrich the starter cultures in yogurt production will contribute to developing new products with benefits to human health.

Oral probiotic lactic acid bacteria can exhibit antagonistic activities against pathogens associated with diseases in the oral cavity. Therefore, twelve previously isolated oral strains were assessed for antagonistic evaluation against selected oral test microorganisms Streptococcus mutans and Candida albicans . Two separate co-culturing analyses were performed, where all tested strains showed the presence of antagonistic activity and four strains, Limosilactobacillus fermentum N 2, TC 3-11, and NA 2-2, and Weissella confusa NN 1, significantly inhibited Streptococcus mutans by 3-5 logs. The strains showed antagonistic activity against Candida albicans , and all exhibited pathogen inhibition by up to 2 logs. Co-aggregation capability was assessed, showing co-aggregative properties with the selected pathogens. Biofilm formation and antibiofilm activity of the tested strains against the oral pathogens were assayed, where the strains showed specificity in self-biofilm formation and well-expressed antibiofilm properties by most of them above 79% and 50% against Streptococcus mutans and Candida albicans , respectively. The tested LAB strains were assayed by a KMnO 4 antioxidant bioassay, where most of the native cell-free supernatants exhibited total antioxidant capacity. These results show that five tested strains are promising candidates to be included in new functional probiotic products for oral healthcare.

Yttrium-doped barium cerate (BCY15) was used as ceramic matrix to obtain Ni/BCY15 anode cermet for application in proton-conducting solid oxide fuel cells (pSOFC). Ni/BCY15 cermets were prepared in two different types of medium, namely deionized water (W) and anhydrous ethylene glycol (EG) using wet chemical synthesis by hydrazine. An in-depth analysis of anodic nickel catalyst was made aiming to elucidate the effect of anode tablets' preparation by high temperature treatment on the resistance of metallic Ni in Ni/BCY15-W and Ni/BCY15-EG anode catalysts. On purpose reoxidation upon high-temperature treatment (1100 °C for 1 h) in air ambience was accomplished. Detailed characterization of reoxidized Ni/BCY15-W-1100 and Ni/BCY15-EG-1100 anode catalysts by means of surface and bulk analysis was performed. XPS, HRTEM, TPR, and impedance spectroscopy measurements experimentally confirmed the presence of residual metallic Ni in the anode catalyst prepared in ethylene glycol medium. These findings were evidence of strong metal Ni network resistance to oxidation in anodic Ni/BCY15-EG. Enhanced resistance of the metal Ni phase contributed to a new microstructure of the Ni/BCY15-EG-1100 anode cermet getting more stable to changes that cause degradation during operation.

Natural alkaloid galantamine is widely used for the treatment of mild to moderate Alzheimer's dementia. Galantamine hydrobromide (GH) is available as fast-release tablets, extended-release capsules, and oral solutions. However, its oral delivery can cause some unwanted side effects, such as gastrointestinal disturbances, nausea, and vomiting. Intranasal administration is one possible way to avoid such unwanted effects. In this work, chitosan-based nanoparticles (NPs) were studied as potential GH delivery vehicles for nasal application. The NPs were synthesized via ionic gelation and studied using dynamic light scattering (DLS) as well as by spectroscopic and thermal methods. The GH-loaded chitosan-alginate complex particles were also prepared as a way to modify the release of GH. The high loading efficiency of the GH was confirmed for both types of particles, at 67% for the GH-loaded chitosan NPs and 70% for the complex chitosan/alginate GH-loaded particles. The mean particle size of the GH-loaded chitosan NPs was about 240 nm, while the sodium alginate coated chitosan particles loaded with GH were expectedly bigger, with a mean particle size of ~286 nm. GH release profiles in PBS at 37 °C were obtained for both types of NPs, and it was found that the GH-loaded chitosan NPs allowed the prolonged release of the incorporated drug for a period of 8 h, while the complex GH-loaded chitosan/alginate NPs released the incorporated GH faster. The stability of the prepared GH-loaded NPs was also demonstrated after 1 year of storage at 5 °C ± 3 °C.

The study reveals the development of novel hydrogels based on sulfobetaine methacrylate (SB) and vinyl pyrrolidone (VP) copolymers as potential contact lenses delivery systems of timolol maleate (TM). The novel copolymer networks demonstrated composition dependent swelling kinetics, where the hydrophilicity of VP and the physical network of SB monomeric units play significant roles. TM loading efficiency appeared to slightly depend on the copolymeric composition, increasing upon VP monomeric unit increase. In contrast, the TM release was prolonged when the SB monomeric units content in the copolymers increased, reaching full drug release for 48 h for the SB-rich networks. The transparency of the hydrogels was also studied and the obtained values demonstrate their applicability as potential materials for soft contact lenses. The study has revealed the potential of these novel copolymeric hydrogels as materials for contact lenses delivery systems of timolol maleate.

Introduction: EGFR targeted therapies, have been proved beneficial for patients with HCC, nevertheless additional research on EGFR immunoexpresion and EGFR mutations is still needed, especially in population in which it has not been done yet. The aim of this study is to evaluate EGFR immunoexpression in HCC without EGFR exons 18-21 mutations and to evaluate its influence on survival in HCC patients in North Macedonia. Methods: We studied 31 cases of HCC for EGFR immunohistochemical expression and EGFR exons 18-21 mutations. The following clinical parameters were analyzed: Hepatitis B and C virus infection, presence of cirrhosis, tumor size, enlarged lymph nodes, metastases, alpha fetoprotein level and overall survival. Presence of the EGFR immunosignal (membranous and cytoplasmic) and the percentage of positive tumor cells in the entire tumor tissue specimen were semi-quantitatively determined. Results: Hepatitis B and C virus infection, tumor size, metastatic disease and EGFR immunoexpression have influence on patient's survival. No EGFR exons 18-21 mutations were detected in this group of HCCs. EGFR expression of 61%-80% in tumor tissue significantly influenced survival of the patients (p < 0.01). Multiple Cox regression confirmed tumor size of 5-10 cm (p < 0.05), tumor size > 10 cm (p < 0.01) and EGFR expression in range of 61% to 80% (p < 0.05) as independent survival predictors in patients with HCC. Conclusion: EGFR overexpression in range of 61% to 80% was an independent survival predictor in patients with HCC, implying that these patients could benefit from EGFR inhibition. However, the absence of EGFR mutations in exons 18-21 in any of the cases of this study suggest that single drug EGFR targeted therapy in patients with HCC may be insufficient., (© 2022 Dafina Nikolova et al., published by Sciendo.)

Introduction: Myelofibrosis (MF) belongs to a group of conditions known as Philadelphia-negative myeloproliferative neoplasms (MPN). Bleeding or various vascular complications could be the main causes of morbidity and mortality in patients with MF. MPNrelated thrombosis is a multifactorial process and in the case of myelofibrosis, little is known. The risk factors for thrombotic complications in MF have been rarely assessed., Aim: The purpose of this study was to investigate the incidence of thrombotic events in MF and the role of JAK2 V617F mutation as a risk factor for thrombotic incidents in patients with MF., Materials and Methods: In our study of 37 patients, 35% had thrombotic events in the past. All patients were admitted to the Clinic of Hematology, St Ivan Rilski University Hospital, Sofia, Bulgaria between 2016 and 2019 and diagnosed based on the WHO criteria of 2016., Results: The majority of patients (23, 62%) proved positive for JAK2 (Janus kinase) V617F mutation carrying one (16, 70%) or two (7, 30%) mutated alleles. Thirteen of the patients (35%) had a thrombotic event in the past and 9 of them (69%) were carriers of JAK2 V617F mutation. Fourteen patients of those without thrombotic history (24, 58%) were also carriers of JAK2 V617F mutation., Conclusions: As a whole, we did not find a statistically significant difference between JAK2 V617F mutation and the frequency of thrombotic events. Rendering an account to the possible life-threatening complications, treatment decisions should be undertaken upon possible antithrombotic prevention in MF., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Median arcuate ligament syndrome (MALS) is a rare condition that is often overlooked as a result of its nonspecific symptoms. It is usually presented with nausea, bloating, abdominal postprandial pain, and weight loss. The diagnosis of MALS is usually delayed and made by excluding other causes for the symptoms. The diagnosis of this syndrome is based on clinical presentation and radiological findings on computer tomography angiography (CTA) or magnetic resonance angiography (MRA). Surgery is treatment of choice, with promising results from laparoscopic surgery., (© 2022 Dafina Nikolova et al., published by Sciendo.)

Yttrium-doped barium cerate (BCY15) was used as an anode ceramic matrix for synthesis of the Ni-based cermet anode with application in proton-conducting solid oxide fuel cells (pSOFC). The hydrazine wet-chemical synthesis was developed as an alternative low-cost energy-efficient route that promotes 'in situ' introduction of metallic Ni particles in the BCY15 matrix. The focus of this study is a detailed comparative characterization of the nickel state in the Ni/BCY15 cermets obtained in two types of medium, aqueous and anhydrous ethylene glycol environment, performed by a combination of XRD, N 2 physisorption, SEM, EPR, XPS, and electrochemical impedance spectroscopy. Obtained results on the effect of the working medium show that ethylene glycol ensures active Ni cermet preparation with well-dispersed nanoscale metal Ni particles and provides a strong interaction between hydrazine-originating metallic Ni and cerium from the BCY15 matrix. The metallic Ni phase in the pSOFC anode is more stable during reoxidation compared to the Ni cermet prepared by the commercial mechanical mixing procedure. These factors contribute toward improvement of the anode's electrochemical performance in pSOFC, enhanced stability, and a lower degradation rate during operation.

Background: Vitamin D deficiency is often reported in people with chronic liver diseases. Improving vitamin D status could therefore be beneficial for people with chronic liver diseases., Objectives: To assess the beneficial and harmful effects of vitamin D supplementation in adults with chronic liver diseases., Search Methods: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We also searched ClinicalTrials.gov  and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and enquired experts and pharmaceutical companies as to additional trials. All searches were up to November 2020., Selection Criteria: Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D 3 (cholecalciferol) or vitamin D 2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol))., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of evidence., Main Results: We included 27 randomised clinical trials with 1979 adult participants. This review update added 12 trials with 945 participants. We assessed all trials as at high risk of bias. All trials had a parallel-group design. Eleven trials were conducted in high-income countries and 16 trials in middle-income countries. Ten trials included participants with chronic hepatitis C, five trials participants with liver cirrhosis, 11 trials participants with non-alcoholic fatty liver disease, and one trial liver transplant recipients. All of the included trials reported the baseline vitamin D status of participants. Participants in nine trials had baseline serum 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), whilst participants in the remaining 18 trials were vitamin D insufficient (less than 20 ng/mL). Twenty-four trials administered vitamin D orally, two trials intramuscularly, and one trial intramuscularly and orally. In all 27 trials, the mean duration of vitamin D supplementation was 6 months, and the mean follow-up of participants from randomisation was 7 months. Twenty trials (1592 participants; 44% women; mean age 48 years) tested vitamin D 3 (cholecalciferol); three trials (156 participants; 28% women; mean age 54 years) tested vitamin D 2 ; four trials (291 participants; 60% women; mean age 52 years) tested 1,25-dihydroxyvitamin D; and one trial (18 participants; 0% women; mean age 52 years) tested 25-hydroxyvitamin D. One trial did not report the form of vitamin D. Twelve trials used a placebo, whilst the other 15 trials used no intervention in the control group. Fourteen trials appeared to be free of vested interest. Eleven trials did not provide any information on clinical trial support or sponsorship. Two trials were funded by industry. We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on all-cause mortality (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.51 to 1.45; 27 trials; 1979 participants). The mean follow-up was 7 months (range 1 to 18 months). We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) (follow-up: 12 months); serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants); myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants); thyroiditis (RR 0.33, 95% CI 0.01 to 7.91; 1 trial; 68 participants); circular haemorrhoidal prolapse (RR 3.00, 95% CI 0.14 to 65.9; 1 trial; 20 participants); bronchopneumonia (RR 0.33, 95% CI 0.02 to 7.32; 1 trial 20 participants); and non-serious adverse events. The certainty of evidence for all outcomes is very low. We found no data on liver-related morbidity such as gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, ascites, or liver cancer. There were also no data on health-related quality of life. The evidence is also very uncertain regarding the effect of vitamin D versus placebo or no intervention on rapid, early, and sustained virological response in people with chronic hepatitis C., Authors' Conclusions: Given the high risk of bias and insufficient power of the included trials and the very low certainty of the available evidence, vitamin D supplementation versus placebo or no intervention may increase or reduce all-cause mortality, liver-related mortality, serious adverse events, or non-serious adverse events in adults with chronic liver diseases. There is a lack of data on liver-related morbidity and health-related quality of life. Further evidence on clinically important outcomes analysed in this review is needed., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Supported gold on co-precipitated nanosized NiAl layered double hydroxides (LDHs) was studied as an effective catalyst for medium-temperature water-gas shift (WGS) reaction, an industrial catalytic process traditionally applied for the reduction in the amount of CO in the synthesis gas and production of pure hydrogen. The motivation of the present study was to improve the performance of the Au/NiAl catalyst via modification by CeO 2 . An innovative approach for the direct deposition of ceria (1, 3 or 5 wt.%) on NiAl-LDH, based on the precipitation of Ce 3+ ions with 1M NaOH, was developed. The proposed method allows us to obtain the CeO 2 phase and to preserve the NiAl layered structure by avoiding the calcination treatment. The synthesis of Au-containing samples was performed through the deposition-precipitation method. The as-prepared and WGS-tested samples were characterized by X-ray powder diffraction, N 2 -physisorption and X-ray photoelectron spectroscopy in order to clarify the effects of Au and CeO 2 loading on the structure, phase composition, textural and electronic properties and activity of the catalysts. The reduction behavior of the studied samples was evaluated by temperature-programmed reduction. The WGS performance of Au/NiAl catalysts was significantly affected by the addition of CeO 2 . A favorable role of ceria was revealed by comparison of CO conversion degree at 220 °C reached by 3 wt.% CeO 2 -modified and ceria-free Au/NiAl samples (98.8 and 83.4%, respectively). It can be stated that tuning the properties of Au/NiAl LDH via CeO 2 addition offers catalysts with possibilities for practical application owing to innovative synthesis and improved WGS performance.

Metastasis of renal cell carcinoma (RCC) to the pancreas is a rare entity accounting only 0.25-3% of all pancreatic tumors. We present a rare case of isolated three focal pancreatic metastases from RCC, occurring 15 years after the left nephrectomy. The majority of the pancreatic metastases are asymptomatic, as it was in case of our patient excluding the weight loss for the last three months. We demonstrate the importance of the medical history, radiological examinations, histological and immunohistochemical analysis in making a definitive diagnosis.

Purpose: The aim of this study was to compare the levels of hyperglycosylated human chorionic gonadotropin (hCG-H) secreted from balanced and unbalanced human embryos., Methods: Single-step culture media samples from 155 good quality embryos, derived from 90 good prognosis patients undergoing intracytoplasmic sperm injection (ICSI), were collected on the fifth day of embryo cultivation. All embryos were tested by next-generation sequencing (NGS) technique. The hCG-H levels in the culture media were evaluated by ELISA kit (Cusabio Biotech, CBS-E15803h) according to the manufacturer's instructions. Statistical analysis was performed using SPSS v.21 (IBM Corp., Armonk, NY, USA)., Results: The NGS analysis revealed that 36% of the embryos (n = 56) were balanced, and 64% of the embryos were unbalanced (n = 99). The presence of hCG-H was confirmed in all embryo culture media samples but was absent in the negative control. In addition, hCG-H concentration was significantly higher in the culture media from unbalanced embryos compared with the balanced ones (0.72 ± 0.30 mIU/ml vs. 0.62 ± 0.12 mIU/ml, p = 0.02, respectively). Furthermore, the mean levels of hCG-H were significantly increased in the samples from embryos with multiple abnormalities. Finally, the highest levels of hCG-H were expressed from embryos with monosomy of chromosome 11 (1.28 ± 0.04 mIU/ml) and those with trisomies of chromosomes 21 (2.23 mIU/ml) and 4 (1.02 ± 0.35 mIU/ml)., Conclusion: Our results suggest that chromosomal aberrations in human embryos are associated with an increased secretion of hCG-H. However, hCG-H concentration in embryo culture media as a single biomarker is not sufficient for an accurate selection of balanced embryos.

Objectives: The aim of the present study was to evaluate the clinical relevance of mutations in tumor suppressor genes using whole-exome sequencing data from centenarians and young healthy individuals., Methods: Two pools, one of centenarians and one of young individuals, were constructed and whole-exome sequencing was performed. We examined the whole-exome sequencing data of Bulgarian individuals for carriership of tumor suppressor gene variants., Results: Of all variants annotated in both pools, 5080 (0.06%) are variants in tumor suppressor genes but only 46 show significant difference in allele frequencies between the two studied groups. Four variants (0.004%) are pathogenic/risk factors according to single nucleotide polymorphism database: rs1566734 in PTPRJ , rs861539 in XRCC3 , rs203462 in AKAP10 , and rs486907 in RNASEL ., Discussion: Based on their high minor allele frequencies and presence in the centenarian group, we could reclassify them from pathogenic/risk factors to benign. Our study shows that centenarian exomes can be used for re-evaluating the clinically uncertain variants.

Chronic myeloid leukemia (CML) is one of the most common hematological malignancies and accounts for 15-20% of all leukemia cases. The cytogenetic marker of CML is the presence of Philadelphia chromosome (Ph) in >95% of patients. The current case reports a 83-year old woman who was directed to the genetic laboratory for a cytogenetic and molecular-genetic analysis suspected to be Ph positive [(+)]. Karyotype analysis of a bone marrow sample revealed a hyperdiploid karyotype in a part of Ph (+) cells with additional chromosomes 8, 10 and 12. Restriction analysis for V617F JAK2 mutation was negative, while the quantitative RT-qPCR assay indicated BCR-ABL/ABL transcript at the level of 120% International Scale ( IS ). Generally cytogenetic complexities are important in the prognostic evaluation of CML. Besides the Ph chromosome, a variet of chromosomal aberrations may be associated with CML. A total of 5-10% of these cases show complex translocations involving another chromosome. The current case is Ph(+) demonstrating an additional hyperdiploid karyotype clone with three additional autosomes (8, 10 and 12). This case highlights the significance of cytogenetic abnormalities on the prognosis of CML., (Copyright © 2019, Spandidos Publications.)

Background: Chronic hepatitis B is associated with high morbidity and mortality. Chronic hepatitis B requires long-term management aiming at reduction of the risks of hepatocellular inflammatory necrosis, liver fibrosis, decompensated liver cirrhosis, liver failure, and liver cancer, and improving health-related quality of life. The Chinese herbal medicine formula Xiao Chai Hu Tang has been used to decrease discomfort and replication of the virus in people with chronic hepatitis B. However, the benefits and harms of Xiao Chai Hu Tang formula have never been established with rigorous review methodology., Objectives: To assess the benefits and harms of Xiao Chai Hu Tang formula versus placebo or no intervention in people with chronic hepatitis B., Search Methods: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, and seven other databases to 1 March 2019. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry for ongoing or unpublished trials to 1 March 2019., Selection Criteria: We included randomised clinical trials, irrespective of publication status, language, and blinding, comparing Xiao Chai Hu Tang formula versus no intervention or placebo in people with chronic hepatitis B. We included participants of any sex and age, diagnosed with chronic hepatitis B according to guidelines or as defined by the trialists. We allowed co-interventions when the co-interventions were administered equally to all the intervention groups., Data Collection and Analysis: Review authors independently retrieved data from reports and after correspondence with investigators. Our primary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered 'not to be serious'. We presented the meta-analysed results as risk ratios (RR) with 95% confidence intervals (CI). We assessed the risks of bias using risk of bias domains with predefined definitions. We used GRADE methodology to evaluate our certainty in the evidence., Main Results: We included 10 randomised clinical trials with 934 participants, but only five trials with 490 participants provided data for analysis. All the trials compared Xiao Chai Hu Tang formula with no intervention. All trials appeared to have been conducted and published only in China. The included trials assessed heterogeneous forms of Xiao Chai Hu Tang formula, administered for three to eight months. One trial included participants with hepatitis B and comorbid tuberculosis, and one trial included participants with hepatitis B and liver cirrhosis. The remaining trials included participants with hepatitis B only. All the trials were at high risk of bias, and the certainty of evidence for all outcomes that provided data for analyses was very low. We downgraded the evidence by one or two levels because of outcome risk of bias, inconsistency or heterogeneity of results (opposite direction of effect), indirectness of evidence (use of surrogate outcomes instead of clinically relevant outcomes), imprecision of results (the CIs were wide), and publication bias (small sample size of the trials). Additionally, 47 trials lacked the necessary methodological information needed to ensure the inclusion of these trials in our review. None of the included trials aimed to assess clinically relevant outcomes such as all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, or hepatitis B-related morbidity. The effects of Xiao Chai Hu Tang formula on the proportion of participants with adverse events considered 'not to be serious' is uncertain (RR 0.43, 95% CI 0.02 to 11.98; I 2 = 69%; very low-certainty evidence). Only three trials with 222 participants reported the proportion of people with detectable hepatitis B virus DNA (HBV-DNA), but the evidence that Xiao Chai Hu Tang formula reduces the presence of HBV-DNA in the blood (a surrogate outcome) is uncertain (RR 0.62, 95% CI 0.45 to 0.85; I 2 = 0%; very low-certainty evidence). Only two trials with 160 participants reported the proportion of people with detectable hepatitis B virus e-antigen (HBeAg; a surrogate outcome) (RR 0.72, 95% CI 0.50 to 1.02; I 2 = 38%; very low-certainty evidence) and the evidence is uncertain. The evidence is also uncertain for separately reported adverse events considered 'not to be serious'., Funding: two of the 10 included trials received academic funding from government or hospital. None of the remaining eight trials reported information on funding., Authors' Conclusions: The clinical effects of Xiao Chai Hu Tang formula for chronic hepatitis B remain unclear. The included trials were small and of low methodological quality. Despite the wide use of Xiao Chai Hu Tang formula, we lack data on all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. The evidence in this systematic review comes from data obtained from a maximum three trials. We graded the certainty of evidence as very low for adverse events considered not to be serious and the surrogate outcomes HBeAg and HBV-DNA. We found a large number of trials which lacked clear description of their design and conduct, and hence, these trials are not included in the present review. As all identified trials were conducted in China, there might be a concern about the applicability of this review outside China. Large-sized, high-quality randomised sham-controlled trials with homogeneous groups of participants and transparent funding are lacking., (Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Myelofibrosis (MF) is characterized by a presence of an extra fibrous tissue in the bone marrow and additional hematopoiesis. The somatic mutation in the Janus kinase 2 ( JAK2 ) gene (V617F) occurs gradually and is detected in about 50.0% of myelofibrosis or essential thrombo-cytopenia (ET) patients. Our aim was to determine the genotype status according to the carriers of the V617F mutation in patients with MF at the Hematology Ward of the University Hospital "Ivan Rilski" in Sofia, Bulgaria. DNA samples were isolated from venous blood of patients with various hematological disorders. DNA was amplified by polymerase chain reaction (PCR) and subsequent restriction analysis was performed using a Bsa XI restriction enzyme. The genotype status was determined on 2.0% agarose gel. We analyzed 38 patients initially suspected of carrying MF or osteomyelofibrosis (OMF). After trepanobiopsy, 20 out of 38 patients were confirmed as myelofibrotic (52.6%), 5/38 (13.2%) were diagnosed as ET, 1/38 (2.6%) was diagnosed as myeloproliferative neoplasm (MPN), 6/38 (15.8%) had polycythemia vera (PV). In six patients, the presence of disease was rejected. Patients with MF were divided into three groups according to the JAK2 V617F genotype status: homozygous for the mutation (3/20 or 15.0%), heterozygous (9/20 or 45.0%) and homozygous for the wild type allele (8/20 or 40.0%). The triggering factor of MF is still unknown. It was considered that this factor could have a genetic nature. Mutations in three genes were mainly accepted as an actual predisposing events to this disease: point mutations leading to amino acid substitutions in JAK2 (V617F) and in MPL (W515L, W515K), as well as insertion or deletion in CALK We have proven that carriers of the V617F mutation prevailed in the group of patients with MF (altogether 12 patients or 60.0%). Previous studies also showed that JAK2 V617F is present in more than half of MF patients within their blood-forming cells. Therefore, the risk of evolution to MF could be associated with V617F-mutant allele burden in patients with MPN.

Background: Chronic hepatitis B is a liver disease associated with high morbidity and mortality. Chronic hepatitis B requires long-term management aiming to reduce the risks of hepatocellular inflammatory necrosis, liver fibrosis, decompensated liver cirrhosis, liver failure, and liver cancer, as well as to improve health-related quality of life. Acupuncture is being used to decrease discomfort and improve immune function in people with chronic hepatitis B. However, the benefits and harms of acupuncture still need to be established in a rigorous way., Objectives: To assess the benefits and harms of acupuncture versus no intervention or sham acupuncture in people with chronic hepatitis B., Search Methods: We undertook electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP), Wanfang Data, and SinoMed to 1 March 2019. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry (ChiCTR) for ongoing or unpublished trials until 1 March 2019., Selection Criteria: We included randomised clinical trials, irrespective of publication status, language, and blinding, comparing acupuncture versus no intervention or sham acupuncture in people with chronic hepatitis B. We included participants of any sex and age, diagnosed with chronic hepatitis B as defined by the trialists or according to guidelines. We allowed co-interventions when the co-interventions were administered equally to all intervention groups., Data Collection and Analysis: Review authors in pairs individually retrieved data from reports and through correspondence with investigators. Primary outcomes were all-cause mortality, proportion of participants with one or more serious adverse events, and health-related quality of life. Secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered not to be serious. We presented the pooled results as risk ratios (RRs) with 95% confidence intervals (CIs). We assessed the risks of bias using risk of bias domains with predefined definitions. We put more weight on the estimate closest to zero effect when results with fixed-effect and random-effects models differed. We evaluated the certainty of evidence using GRADE., Main Results: We included eight randomised clinical trials with 555 randomised participants. All included trials compared acupuncture versus no intervention. These trials assessed heterogeneous acupuncture interventions. All trials used heterogeneous co-interventions applied equally in the compared groups. Seven trials included participants with chronic hepatitis B, and one trial included participants with chronic hepatitis B with comorbid tuberculosis. All trials were assessed at overall high risk of bias, and the certainty of evidence for all outcomes was very low due to high risk of bias for each outcome, imprecision of results (the confidence intervals were wide), and publication bias (small sample size of the trials, and all trials were conducted in China). Additionally, 79 trials lacked the necessary methodological information to ensure their inclusion in our review.None of the included trials aim to assess all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. We are uncertain whether acupuncture, compared with no intervention, has an effect regarding adverse events considered not to be serious (RR 0.67, 95% CI 0.43 to 1.06; I² = 0%; 3 trials; 203 participants; very low-certainty evidence) or detectable hepatitis B e-antigen (HBeAg) (RR 0.64, 95% CI 0.11 to 3.68; I² = 98%; 2 trials; 158 participants; very low-certainty evidence). Acupuncture showed a reduction in detectable hepatitis B virus (HBV) DNA (a non-validated surrogate outcome; RR 0.45, 95% CI 0.27 to 0.74; 1 trial, 58 participants; very low-certainty evidence). We are uncertain whether acupuncture has an effect regarding the remaining separately reported adverse events considered not to be serious.Three of the eight included trials received academic funding from government or hospital. None of the remaining five trials reported information on funding., Authors' Conclusions: The clinical effects of acupuncture for chronic hepatitis B remain unknown. The included trials lacked data on all-cause mortality, health-related quality of life, serious adverse events, hepatitis-B related mortality, and hepatitis-B related morbidity. The vast number of excluded trials lacked clear descriptions of their design and conduct. Whether acupuncture influences adverse events considered not to be serious is uncertain. It remains unclear if acupuncture affects HBeAg, and if it is associated with reduction in detectable HBV DNA. Based on available data from only one or two small trials on adverse events considered not to be serious and on the surrogate outcomes HBeAg and HBV DNA, the certainty of evidence is very low. In view of the wide usage of acupuncture, any conclusion that one might try to draw in the future should be based on data on patient and clinically relevant outcomes, assessed in large, high-quality randomised sham-controlled trials with homogeneous groups of participants and transparent funding.

Alcoholic hepatitis (AH) is a form of alcoholic liver disease. Glucocorticosteroids (GCS) are used as anti - inflammatory drugs for people with alcoholic hepatitis., Aim: To assess the benefits and harms of GCS in people with AH., Material and Methods: We identified trials through electronic searches in Cochrane Hepato-Biliary's (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, and Science Citation Index Expanded. We considered for inclusion randomised clinical trials (RCTs) assessing GCS versus placebo/no intervention in adult participants with AH. We allowed co - interventions in the trial groups if they were similar. We followed Cochrane methodology, CHB Group methodology using Review Manager 5 and Trial Sequential Analysis(TSA) to perform meta - analysis (M-A), assessed bias risk of the trials, certainty of evidence using GRADE., Results and Discussion: Sixteen trials fulfilled the inclusion criteria. Fifteen trials provided data for analysis (927 participants received GCS, 934 - placebo/no intervention). The GCS were administered to adult participants at different stages of AH orally or parenterally for a median of 28 days. There was no evidence of effect of GCCs on our primary outcomes all - cause mortality up to 3 months following randomisation (RR 0.90, 95% CI 0.70-1.15; n=1861), on health - related quality of life (MD - 0.04 points; 95% CI -0.11-0.03; n=377; trial = 1) (EQ-5D-3L scale), on the occurrence of serious adverse events during treatment (RR 1.05, 95% CI 0.85-1.29; n=1861). We found no evidence of a difference between the intervention groups. The risk of bias was high in all the trials except one. The certainty of evidence was very low or low. One of the trials seems to be not industry - funded., Conclusion: We found no evidence of a difference between GCS and placebo or no intervention on all - cause mortality, health - related quality of life, and serious adverse events during treatment. We cannot exclude increases in adverse events and cannot rule out significant benefits and harms of GCSs. Future trials ought to report depersonalised individual participant data.

Background: Intrahepatic cholestasis of pregnancy is a pregnancy-specific liver disorder, possibly associated with an increased risk of severe fetal adverse events. Total serum bile acids (TSBA) concentration, alone or in combination with serum aminotransferases, have been the most often used biomarkers for the diagnosis of intrahepatic cholestasis of pregnancy in clinical practice. Serum bile acid profile, composed of primary or secondary, conjugated or non-conjugated bile acids, may provide more specific disease information., Objectives: To assess and compare, independently or in combination, the diagnostic accuracy of total serum bile acids or serum bile acids profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women, presenting with pruritus. To define the optimal cut-off values for components of serum bile acid profile; to investigate possible sources of heterogeneity., Search Methods: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE Ovid, Embase Ovid, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, BIOSIS, CINAHL, two Chinese databases (CKNI, VIP), Latin American and Caribbean Health Sciences Literature (LILACS), Scientific Electronic Library Online (SciELO), Evidence Search: Health and Social Care by the National Institute for Health and Care Excellence (NICE), the World Health Organization (WHO) Reproductive Health Library (RHL), and the Turning Research into Practice database (TRIP). The most recent date of search was 6 May 2019. We identified additional references by handsearching the references of articles, meta-analyses, and evidence-based guidelines retrieved from the computerised databases, on-line trial registries, and grey literature through OpenSIGLE, National Technical Information Service (NTIS), ProQuest Dissertations & Thesis Database, and Index to Theses in Great Britain and Ireland., Selection Criteria: Prospective or retrospective diagnostic case-control or cross-sectional studies, irrespective of publication date, format, and language, which evaluated the diagnostic accuracy of total serum bile acids (TSBA) or components of serum bile acid profile for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women of any age or ethnicity, in any clinical setting, symptomatic for pruritus., Data Collection and Analysis: We selected studies by reading titles, abstracts, or full texts, and assessing their fulfilment of our inclusion criteria. We emailed primary authors to request missing data or individual participant data. Having extracted data from each included study, we built the two-by-two tables for each primary study and for all the index tests considered. We estimated sensitivity and specificity with their 95% confidence intervals (CI). We presented data in coupled forest plots, showing sensitivities and specificities of each study, and we plotted the studies in the Receiver Operating Characteristic (ROC) space. We performed meta-analyses adopting the hierarchical summary ROC model (HSROC) or the bivariate model to meta-analyse the data. We made indirect comparisons of the considered index tests by adding the index tests as covariates to the bivariate or HSROC models. We performed heterogeneity analysis and sensitivity analysis on studies assessing TSBA accuracy. We used Review Manager 5 (RevMan 5) and SAS statistical software, release 9.4 (SAS Institute Inc., Cary, NC, USA), to perform all statistical analyses. We used QUADAS-2 domains to assess the risk of bias of the included studies., Main Results: Our search yielded 5073 references, but at the end of our selection process, only 16 studies fulfilled the review inclusion criteria. Nine of these provided individual participant data. We analysed only data concerning TSBA, cholic acid (CA), glycocholic acid (GCA), chenodeoxycholic acid (CDCA), and CA/CDCA because the remaining planned index tests were assessed in few studies. Only one study had low risk of bias in all four QUADAS-2 domains. The most biased domains were the patient sampling and the reference standard domains. When considering all studies with a cut-off of 10 μmol/L, TSBA overall sensitivity ranged from 0.72 to 0.98 and specificity ranged from 0.81 to 0.97. After a sensitivity analysis excluding case-control studies, TSBA sensitivity ranged from 0.48 to 0.66 and specificity from 0.52 to 0.99. After a sensitivity analysis excluding studies in which TSBA was part of the reference standard, TSBA sensitivity ranged from 0.49 to 0.65 and specificity from 0.53 to 0.99. We found the estimates of the overall accuracy for some serum bile acid components (CA, GCA, CDCA, and CA/CDCA) to be imprecise, with the CI for sensitivity and specificity very wide or impossible to calculate. Indirect comparisons between serum bile acid profile components and TSBA were not statistically significant. None of the heterogeneity analysis performed was statistically significant, except for the timing of assessment of TSBA (onset of symptoms, peak value among multiple assessments, delivery) but without clinically relevant results. We could not analyse the diagnostic accuracy of combinations of index tests because none of the included studies carried them out, and because of the small number of included studies., Authors' Conclusions: The overall high risk of bias, the existing concern regarding applicability of the results in clinical practice, and the great heterogeneity of the results in the included studies prevents us from making recommendations and reaching definitive conclusions at the present time. Thus, we do not find any compelling evidence to recommend or refute the routine use of any of these tests in clinical practice. So far, the diagnostic accuracy of TSBA for intrahepatic cholestasis of pregnancy might have been overestimated. There were too few studies to permit a precise estimate of the accuracy of serum bile acid profile components. Further primary clinical research is mandatory. We need both further phase II and phase III diagnostic studies.

Background: Plasma volume expanders are used in connection to paracentesis in people with cirrhosis to prevent reduction of effective plasma volume, which may trigger deleterious effect on haemodynamic balance, and increase morbidity and mortality. Albumin is considered the standard product against which no plasma expansion or other plasma expanders, e.g. other colloids (polygeline , dextrans, hydroxyethyl starch solutions, fresh frozen plasma), intravenous infusion of ascitic fluid, crystalloids, or mannitol have been compared. However, the benefits and harms of these plasma expanders are not fully clear., Objectives: To assess the benefits and harms of any plasma volume expanders such as albumin, other colloids (polygeline, dextrans, hydroxyethyl starch solutions, fresh frozen plasma), intravenous infusion of ascitic fluid, crystalloids, or mannitol versus no plasma volume expander or versus another plasma volume expander for paracentesis in people with cirrhosis and large ascites., Search Methods: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, CNKI, VIP, Wanfang, Science Citation Index Expanded, and Conference Proceedings Citation Index until January 2019. Furthermore, we searched FDA, EMA, WHO (last search January 2019), www.clinicaltrials.gov/, and www.controlled-trials.com/ for ongoing trials., Selection Criteria: Randomised clinical trials, no matter their design or year of publication, publication status, and language, assessing the use of any type of plasma expander versus placebo, no intervention, or a different plasma expander in connection with paracentesis for ascites in people with cirrhosis. We considered quasi-randomised, retrieved with the searches for randomised clinical trials only, for reports on harms., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. We calculated the risk ratio (RR) or mean difference (MD) using the fixed-effect model and the random-effects model meta-analyses, based on the intention-to-treat principle, whenever possible. If the fixed-effect and random-effects models showed different results, then we made our conclusions based on the analysis with the highest P value (the more conservative result). We assessed risks of bias of the individual trials using predefined bias risk domains. We assessed the certainty of the evidence at an outcome level, using GRADE, and constructed 'Summary of Findings' tables for seven of our review outcomes., Main Results: We identified 27 randomised clinical trials for inclusion in this review (24 published as full-text articles and 3 as abstracts). Five of the trials, with 271 participants, assessed plasma expanders (albumin in four trials and ascitic fluid in one trial) versus no plasma expander. The remaining 22 trials, with 1321 participants, assessed one type of plasma expander, i.e. dextran, hydroxyethyl starch, polygeline, intravenous infusion of ascitic fluid, crystalloids, or mannitol versus another type of plasma expander, i.e. albumin in 20 of these trials and polygeline in one trial. Twenty-five trials provided data for quantitative meta-analysis. According to the Child-Pugh classification, most participants were at an intermediate to advanced stage of liver disease in the absence of hepatocellular carcinoma, recent gastrointestinal bleeding, infections, and hepatic encephalopathy. All trials were assessed as at overall high risk of bias. Ten trials seemed not to have been funded by industry; twelve trials were considered unclear about funding; and five trials were considered funded by industry or a for-profit institution.We found no evidence of a difference in effect between plasma expansion versus no plasma expansion on mortality (RR 0.52, 95% CI 0.06 to 4.83; 248 participants; 4 trials; very low certainty); renal impairment (RR 0.32, 95% CI 0.02 to 5.88; 181 participants; 4 trials; very low certainty); other liver-related complications (RR 1.61, 95% CI 0.79 to 3.27; 248 participants; 4 trials; very low certainty); and non-serious adverse events (RR 1.04, 95% CI 0.32 to 3.40; 158 participants; 3 trials; very low certainty). Two of the trials stated that no serious adverse events occurred while the remaining trials did not report on this outcome. No trial reported data on health-related quality of life.We found no evidence of a difference in effect between experimental plasma expanders versus albumin on mortality (RR 1.03, 95% CI 0.82 to 1.30; 1014 participants; 14 trials; very low certainty); serious adverse events (RR 0.89, 95% CI 0.10 to 8.30; 118 participants; 2 trials; very low certainty); renal impairment (RR 1.17, 95% CI 0.71 to 1.91; 1107 participants; 17 trials; very low certainty); other liver-related complications (RR 1.10, 95% CI 0.82 to 1.48; 1083 participants; 16 trials; very low certainty); and non-serious adverse events (RR 1.37, 95% CI 0.66 to 2.85; 977 participants; 14 trials; very low certainty). We found no data on heath-related quality of life and refractory ascites., Authors' Conclusions: Our systematic review and meta-analysis did not find any benefits or harms of plasma expanders versus no plasma expander or of one plasma expander such as polygeline, dextrans, hydroxyethyl starch, intravenous infusion of ascitic fluid, crystalloids, or mannitol versus albumin on primary or secondary outcomes. The data originated from few, small, mostly short-term trials at high risks of systematic errors (bias) and high risks of random errors (play of chance). GRADE assessments concluded that the evidence was of very low certainty. Therefore, we can neither demonstrate or discard any benefit of plasma expansion versus no plasma expansion, and differences between one plasma expander versus another plasma expander.Larger trials at low risks of bias are needed to assess the role of plasma expanders in connection with paracentesis. Such trials should be conducted according to the SPIRIT guidelines and reported according to the CONSORT guidelines.