The conditions that led to the formation of the first organisms and the ways that life originates from a lifeless chemical soup are poorly understood. The recent hypothesis of “RNA-peptide coevolution” suggests that the current close relationship between amino acids and nucleobases may well have extended to the origin of life. We now show how the interplay between these compound classes can give rise to new self-replicating molecules using a dynamic combinatorial approach. We report two strategies for the fabrication of chimeric amino acid/nucleobase self-replicating macrocycles capable of exponential growth. The first one relies on mixing nucleobase- and peptide-based building blocks, where the ligation of these two gives rise to highly specific chimeric ring structures. The second one starts from peptide nucleic acid (PNA) building blocks in which nucleobases are already linked to amino acids from the start. While previously reported nucleic acid-based self-replicating systems rely on presynthesis of (short) oligonucleotide sequences, self-replication in the present systems start from units containing only a single nucleobase. Self-replication is accompanied by self-assembly, spontaneously giving rise to an ordered one-dimensional arrangement of nucleobase nanostructures.

Recent studies have established a concept of tumour necrosis factor‐α (TNF‐α)/Fas signalling crosstalk, highlighting TNF‐α as a critical cytokine in sensitizing hepatocytes to death induced by Fas activation. However, in the exact inflammatory response, besides TNF‐α, many other mediators, that might modulate apoptotic response differentially, are released. To resolve the issue, we studied the effects of lipopolysaccharide (LPS), one of the crucial inductors of inflammation in the liver, on apoptotic outcome. We show that LPS‐induced inflammation diminishes the sensitivity of hepatocytes to Fas stimulus in vivo at caspase‐8 level. Analysis of molecular mechanisms revealed an increased expression of various pro‐inflammatory cytokines in non‐parenchymal liver cells and hepatocyte‐specific increase in Bcl‐xL, associated with signal transducer and activator of transcription 3 (Stat3) phosphorylation. Pre‐treatment with ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, prevented the LPS‐induced Stat3 phosphorylation and restored the sensitivity of hepatocytes to Fas‐mediated apoptosis. Furthermore, ruxolitinib pre‐treatment diminished the LPS‐induced Bcl‐xL up‐regulation without an inhibitory effect on LPS‐induced expression of pro‐inflammatory cytokines. In summary, although the reports are showing that the effects of isolated pro‐inflammatory mediators, such as TNF‐α or neutrophils, are pro‐apoptotic, the overall effect of inflammatory milieu on hepatocytes in vivo is Stat3‐dependent desensitization to Fas‐mediated apoptosis.

Abstract Methadone eliminates heroin use, reduces death rates and criminality associated with heroin use, and improves patients’ health and social productivity. This study included long-term addicts who completed a methadone therapy program as well as relapsed patients. Liver and renal markers important for methadone metabolism were analyzed. Renal markers included urea and creatinine, while hepatic markers included total bilirubin, AST, ALT, γGT, and LDH as nonspecific but significant parameters of liver metabolism. The study included 34 male and 6 female heroin-dependent patients undergoing a rehabilitation program with methadone maintenance treatment (MMT). During therapy, average values of all parameters remained within the reference interval but individual parameters in some patients were very high. Significant differences for urea (0.00) and very high individual variations in all parameters, especially γGT and LDH, were found in patients who were in relapse. Age of the patients did not show a correlation with the presence of significant differences in serum biochemical parameters during therapy. Prolonged use of methadone therapy stabilizes high variations of liver and renal markers. MMT achieves a stabilization of serum indicators relevant for methadone metabolism that correlates with the duration of consumption and the type of opioid substance. The most important hepato-renal markers as indicators of therapy success are γGT, LDH, and creatinine. The validity of former enzymatic tests (AST, ALP, and ALT) should be seriously reconsidered in terms of MTT treatment success and monitoring the health of heroin addicts.

Hydrops fetalis is a serious condition indicating a bad prognosis of affected fetuses. Incidence of immune hydropsfetalis is significantly decreasing, whereas more and more non-immune hydropsfetalisis are identified. We described a case of the most difficult manifestation of hemolytic disease of a newborn due to rhesus incompatibility. Immune hydrops fetalis occurred due to inadequate immune prophylaxis. While treating the newborn, we applied exchange transfusion, additional transfusion and immunoglobulin therapy. With sensitized pregnant patients, it is necessary to regularly monitor the condition of fetus and titer of mother’s antibodies. Considering a difficulty of affected fetuses’ disease, it is necessary to strengthen preventive measures by application of rhesus immunoglobulin with affected Rh negative mothers.

A noninvasive diagnostic procedure that allows for in vivo microscopic examination of the epidermis, the dermoepidermal junction, and the papillary dermis. This aids in the identification of specific diagnostic patterns related to color and cell structure to aid in differentiating malignant and benign lesions.

Aim To examine the correlation between personality traits, learning styles, and academic achievement and a difference between students' gender, residency status and academic achievement. Methods The study included 95 students of first year of the School of Medicine, University of Sarajevo. The survey used the sociodemographic questionnaire, Index of Learning Style and Big Five Inventory. Academic achievement was represented by a cumulative grade point of each student. Results There was significant difference between the students' gender, information processing style, i.e. active/reflective learning style and academic achievement. Academic achievement was correlated with extraversion (negatively), conscientiousness and active/reflexive learning style. Conclusion With this study we wanted to improve awareness of teachers about the importance and use of different styles during lecture, to show the importance of students knowing their own preferences and learning styles, and how personality traits can affect students' academic achievement. Academic performance is an important outcome for students. It can increase motivation, student participation in class and wish to volunteer in different activities.

Aim To compare the prevalence of premature rupture of membranes (PROM) and preterm premature rupture of membranes (PPROM) between adolescent and adult pregnancies, and the influence of gestational age and adolescent pregnancy on the frequency of occurrence of PROM and PPROM. Methods This prospective study included 300 pregnant patients, 13 to 35 years of age, divided into two groups. The first group consisted of 150 pregnant women aged 13-19 (experimental group) and the second group consisted of 150 pregnant women aged 20-35 (control group). Results There was a statistically significant higher incidence of both PPROM and PROM in the group of adolescent pregnant women compared to adult pregnant women (p<0.000001). Preterm delivery with PPROM was significantly more common in the group of adolescent pregnant women (p<0.004). Term delivery with PROM was statistically significantly more common in the adolescent pregnancy group than in the adult pregnancy group (p<0.001). Term delivery with PROM was statistically significantly more common than preterm delivery with PPROM in the group of adolescent pregnant women (p<0.0001). Conclusion Adolescent pregnancy has a greater impact on the frequency of PROM and PPROM.

Aim To describe the experience of healthcare professionals in assessing pain and communication in patients with hip fractures and dementia in an emergency department. Methods Data were collected through focus group interviews using open-ended questions, following an interview guide and qualitative content analysis. Twenty one registered nurses participated in the interviews, five male and 16 female, aged 26 to 55 years. Results The analysis of the interviews resulted in three main categories: "Arrival at the emergency department", "Hip track" and "Handover to the ward", including a number of subcategories. All nurses reported that the assessment of pain and communication with patients with dementia and hip fractures was a complex process. A great deal of stress, fast and brief communication, quick decisions and quick treatments in assessment of pain were only some of the difficulties the nurses emphasized. They also suggested a whole series of improvements for those patients. Conclusion The situation of patients with hip fracture and dementia on the emergency department and healthcare professionals who communicate and assess their pain can be said to be untenable. The care environment in the emergency department is not adapted to patients and can of course depend on several factors. To meet the needs of the future and increased numbers of those patients, some improvements such as more extensive research and more studies on the experiences of both the patients and healthcare professionals are required.

Aim To compare the localization of lung adenocarcinoma with tumour size and lymphovascular invasion (LVI) presence, and to determine the frequency of metastasis findings in hilar and mediastinal lymph nodes depending on the localization of the tumour and status of lymphovascular invasion. Method This observational cross-sectional study included 261 patients with complete resection of confirmed lung adenocarcinoma. The dependence between categorical variables were performed with χ2 and Fisher's exact tests. A p<0.05 was considered as statistically significant. Result Metastases to hilar lymph nodes at lung adenocarcinoma with central localization and presented lymphovascular invasion were more frequently found than tumours with peripheral localization (p<0.001). In tumours with peripheral localization, lymphovascular invasion was less frequent; even in tumours greater than 7 cm in the largest dimension the presence of LVI was not 100%. Metastases to mediastinal lymph nodes in tumours with central localization and presented lymphovascular invasion were less frequent than in tumours with peripheral localization and presented lymphovascular invasion (p=0.002). Conclusion In invasive adenocarcinoma, lymphovascular invasion was much more common in centrally positioned than in peripherally positioned tumours. Metastases to the hilar and mediastinal lymph nodes, regardless of the findings of lymphovascular invasion, usually originated from upper lobe tumours.

Aim To explore the experiences of registered nurses in assessing postoperative pain in hip fracture patients suffering from dementia in nursing homes. Methods The study was designed as a qualitative study using data from a self-reported questionnaire form. Data were collected through the self-administered questionnaire with 23 questions, mainly addressing demographic and social data, information about communication and pain assessment. Results All nurses reported that large part of verbal communication with dementia patients was lost, and non-verbal communication was very important to optimize the care of these patients in postoperative situations. An assessment of pain in patients with dementia and hip fractures was a complex process because cognitive ability of these patients was reduced. Conclusion Registered nurses need to know various and different forms of evaluation and tools to assess the experience of pain in patients with dementia who had undergone surgery for hip fractures. This is a complicated task, which requires a great deal of time, and means that nurses must work together with other medical staff, using a holistic approach.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1–4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53, in the 3′ untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available. Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.