Background: Clonal neoantigens are formed early in cancer evolution and have been identified as a subset of patient specific mutations that are associated with improved clinical benefit and represent great promise as targets for the next generation of T cell therapies. Developing T cell therapies that target multiple clonal neoantigens represents a unique personalized approach to treating solid cancer, as they are present on all cancer cells, minimizing the risk of tumour escape, and absent from healthy tissue, potentially eliminating off-target toxicities. Access to sequencing data from over 600 NSCLC patients enrolled in the UK TRACERx study has enabled the development of the Achilles PELEUSTM bioinformatic platform. By opening an ethically approved tissue collection study NCT03517917, enabling access to matched tumour and blood samples from patients with selected cancers, our clonal neoantigen reactive T cell (cNeT) manufacturing process and supply chain has been validated for use in clinical trials. Methods: Matched tumor and blood samples were procured at the time of routine surgery from ten patients (eight with newly diagnosed stage I-III NSCLC and two with metastatic melanoma) for at-scale GMP runs. Briefly, TIL were isolated from tumor fragments and immature dendritic cells (DCs) generated from whole blood, prior to cryopreservation as intermediate products. Patient-specific clonal neoantigens were predicted using our proprietary PELEUSTM bioinformatic platform, enabling the manufacture of synthetic peptide masterpools to be used for the enrichment of cNeT in the VELOSTM manufacturing process. Co-culture of pre-expanded TIL and patient DCs loaded with clonal neoantigen peptides drives the selective expansion of cNeT, eliminating the requirement for high non-physiological levels of IL-2. Results: Here we present the successful scaled GMP production of cNeT from both primary and metastatic tumors using the VELOSTM manufacturing process in ten patients. All final products met QC release criteria and were composed of both CD4+ and CD8+ T cells. Extensive characterization of T cell responses showed cNeT exhibited functional responses determined by cytokine secretion following re-challenge, and specificity in response to clonal neoantigen peptides. Peptide deconvolution of masterpools identified multiple single T cell clone reactivities to clonal neoantigens in the final product. Conclusions: The VELOSTM process incorporating the PELEUSTM bioinformatic platform for prediction of clonal neoantigens is a novel platform for generating personalized T cell products directed at multiple cancer clonal neoantigen targets and has the potential to be utilized across a variety of solid tumors. This study demonstrates the feasibility of generating cNeT for the treatment of both advanced NSCLC and recurrent or metastatic melanoma and supported the successful regulatory approval in two first-in-human studies (NCT04032847 and NCT03997474) which opened in the UK in 2019. Citation Format: Henrieta Fraser, Rebecca Pike, Sarah Thirkell, Asiya Arshad, Sam Jide-Banwo, Hollie Bartley, Evi Rologi, Michal Pruchniak, Shreenal Patel, Jennine Mootien, Jane Robertson, Andrew Craig, Max Salm, Katy Newton, Luke Goodsell, Fong Chan, Gareth Wilson, Stephen Frenk, Iraj Ali, Karl Peggs, Mark W. Lowdell, Lyra Del Rosio, Andrew Hayes, Samra Turajlic, Farah Islam, David Lawrence, Mariam Jamal-Hanjani, Martin D. Forster, Edward Samuel. The development of a personalized autologous clonal neoantigen T cell therapy for the treatment of solid cancer using the VELOSTM manufacturing platform generates highly potent and reactive CD8+ and CD4+ T cells for clinical use [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT054.

Adoptive transfer of tumor infiltrating lymphocytes (TIL) has generated objective clinical responses in patients with advanced metastatic cancers. Therapeutic exploitation of neoantigens as targets can potentially lead to safer and more effective treatment modalities with reduced toxicities. The Achilles Therapeutics trial NCT03517917 enabled the acquisition of matched tumor specimens and peripheral blood samples from patients undergoing routine surgery and facilitated the development of the proprietary VELOSTM manufacturing process, generating a personalized clonal neoantigen specific T cell product. An in-depth characterization of T cells expanded with the VELOSTM process was performed and compared to a standard TIL product. Samples were obtained from patients with primary NSCLC or metastatic melanoma. TIL were expanded from tumor fragments after dissection in the presence of IL-2. Peptide pools corresponding to the clonal mutations that were identified using the PELEUSTM bioinformatics platform were used to pulse dendritic cells (DC) generated from peripheral blood monocytes from each patient. Clonal neoantigen specific T cells (cNeT) were expanded using the VELOSTM process by co-culture of TIL with the peptide-pulsed autologous DC. As a comparison, TIL were expanded with a rapid expansion protocol (REP-TIL) in the presence of allogeneic feeders, anti-CD3 antibody and high-dose IL-2. Intracellular cytokine staining was performed following rechallenge with individual peptide pools encoding the clonal mutations. Single peptide reactivities were identified using ELISPOT and extended flow cytometric analysis of markers associated with T cell fitness or dysfunction was performed to phenotypically characterize the cNeT, TIL and REP-TIL. Analysis of the immune cell composition showed that cNeT, TIL and REP-TIL have similar CD3+ T cell content (median cNeT 90.2%, TIL 87.3%, REP-TIL 95%, n=6) and are composed of CD4+ and CD8+ T cells (median CD4:CD8 ratio- cNeT 11.1, TIL 2.03 and REP-TIL 4.7, n=6). cNeT showed superior clonal neoantigen specificity compared to TIL or REP-TIL. The proportion of CD3+ T cells responding to clonal neoantigen rechallenge was increased in cNeT (median 24.3%) compared to TIL (median 0.6%) and REP-TIL (median 1.8%) (n=5). The VELOSTM process incorporating the PELEUSTM platform for prediction of clonal neoantigens generates T cell products enriched for clonal neoantigen reactivities and superior phenotypic characteristics compared to conventional TIL. The VELOSTM process is currently being used to manufacture cNeT for two first-in-human studies including NSCLC and melanoma patients (NCT04032847, NCT03997474). Ethical approval: The samples for the study were collected under an ethically approved protocol (NCT03517917). Citation Format: Eleni Kotsiou, Tie Zheng Hou, Joseph Robinson, Sonal Varsani, Theres Oakes, Pablo D. Becker, Shreenal Patel, Jennine Mootien, Andrew Craig, Jane Robertson, Edward Samuel, James Reading, Lyra Del Rosario, Andrew Haynes, Samra Turajlic, Farah Islam, David Lawrence, Mariam Jamal-Hanjani, Martin Foster, Sergio A. Quezada, Katy Newton. Next generation clonal neoantigen targeting T cells, generated using the PELEUSTM bioinformatics platform and the VELOSTM manufacturing method show superior reactivity and phenotypic characteristics than classical TIL products [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 875.

Este trabalho apresenta uma análise da obra Capitães da Areia, de Jorge Amado, abordando a constituição social do sujeito e sua conformação política dentro de um contexto ficcional. A partir da observação das dificuldades enfrentadas pelo personagem Pedro Bala, tendo-o como personagem principal desta pesquisa, analisa-se sua trajetória ao longo do enredo no contexto sociocultural a que este estava inserido.  O trabalho foi realizado por meio de pesquisa do tipo revisão bibliográfica, com a seleção de textos relacionados ao contexto e a obra em si. Foram lidos textos de José Murilo de Carvalho (2015), Karl Marx (1998), entre outros, pois estes se aproximam direta e indiretamente dos temas estruturantes abordados na trama.  A estrutura da pesquisa foi desenvolvida a fim de propor uma reflexão, trazendo à tona questões sociais ainda bem evidentes em nossa atual sociedade. Por fim, vimos Pedro Bala tornando-se um militante que representou um grupo que estava à margem da sociedade, dando voz, questionando e lutando por direitos que todos os cidadãos devem ter em uma sociedade, dando demonstração que a construção do sujeito é histórica e não determinada previamente.

U rimskom pravu gotovo da i nemamo izvore koji pažnju posvećuju direktno tijelu umrle osobe. Tijelo kao takvo nije bilo zaštićeno. Pokojnik se štitio, prvenstveno, kroz zaštitu groba, koji je smatran stvari posvećenoj kultu pokojnika – diis manibus relictae. Unatoč tome, detaljnija analiza pravnih izvora jasno afirmira tezu o postojanju pravila iz sfere pogrebnog prava, kojima je regulirano konstituiranje određenih ograničenih prava u vezi s tijelom umrle osobe, a usko povezanih s odlučivanjem o načinu obavljanja pogreba, kremacije, prijenosa tijela, izgradnji nadgrobnog spomenika i slično. Autor smatra kako se ostvarivanje ovih prava u prvom redu vrši po volji umrlog, a u slučaju kada je nije iskazao, na vršenje se pozivaju bračni drug i nužni nasljednici. Nasljednici se pozivaju onim redom kojim bi ih i po rimskom pravu pozivali na nasljedstvo, neovisno o tome jesu li išta iz imovine umrlog naslijedili. Opstojnost predstavljene koncepcije ispitana je i u okviru kanonskog prava, ali i europskog prava u doba kodificiranja privatnog prava tijekom 19.. i na početku 20. stoljeća. Imajući u vidu da ne postoje jedinstveni stavovi o ovim pitanjima, autor posebnu pozornost posvećuje pravnoj kulturi Austrijskog građanskog zakonika, ostavljajući mogućnost da se pravne praznine riješe u duhu rimske pravne tradicije.

Infection with the new corona virus (SARS-CoV-2) was first registered in December 2019 in China, and then later spread rapidly to the rest of the world. On December 31, 2019, the World Health Organization (WHO) informed the public for the first time about causes of pneumonnia of unknown origin, in the city of Wuhan (Hubei Province, China), in people who were epidemiologically linked to a seafood and wet animal whole sale local market in Wuhan. Coronavrus disease, called COVID-19 (Corona virus disease 2019), after China quickly spread to most countries in the wold, and the WHO on March 11, 2020 declared a pandmic with this virus. SARS-CoV-2, has a high level of sequential similarities to the SARS-CoV-1 and uses the same receptors when it enters the human body (angiotensin-converting enzyme 2/ACE2). COVID-19 is respiratry infection that is primarily transmitted via respiratry droplets. Typical symptoms of COVID-19 infection can be very moderate (infected can be even asymptomatic) to very severe, with severe respiratory symptoms (bilateral severe pneumonia), septic schock, and fatal outcome. Numeous unknows regarding the biological, epidemilogical adn clinical characteristics of COVID-19, still exist, and make it impossible to predict with certainty the further course of the current pandemic. COVID-19 is primarily a disease of the respiratory system, but SARS-CoV-2, in a number of patients also penetrates the CNS, and apparently could be responsible for fatal outcome in some cases. The entrry of the virus into the brain can lead to neurological and psychiatric manifestationss, which are not uncommon, including headache, paresthesia, myalgia, impaired consciousnessm, confusion or delirum and cerebrovascular diseases. SARS-CoV-2 positive individuals should be evaluated in a timely manner for neurological and psychiatic symptoms because tretament of infection-related neurological and psychiatric complications is an important factor in better prognosis of severe COVID-19 patients.From the current point of view, it seems that in COVID-19 survivors, in the coming years and decades, the inflammatory systemic process and/or the inflammatory process of the brain could trigger long-term mechanisms that generally lead to an increase of neurological and neurodegenerative disorders. Psychosocial consequences as well as consequences for mental health are also significant, both for the general population and especially for health workers of all profiles. COVID-19 pandemia is associtaed with negative psychosocial consequences, including depressive symptoms, anxiety, anger and stress, sleep disorders, simpotms of posttrauamtic stres disorder, social isolation, loneliness and stigmatization.

Presents case reports of two psychiatric patients who suddenly deteriorated and burned in a severe psychiatric condition due to the circumstances they faced due to the COVID-19 pandemic, which required urgent admission and intensive psychiatric treatment. In the first case report, pandemic and restrictive measures were the predisposing factors for suicide attempt of the patient who is the war veteran with diagnosed complex PTSD, while the precipitating factors for the suicide attempt were impaired physician-patient communication, fear of losing a job and existential issues. There is a need to raise awareness in society that rising unemployment is associated with an increased number of suicides, as well as responsible and balanced media coverage of the COVID-19 pandemic. In the second case report, our patient with bipolar disorder got into relapse of disease with psychotic symptoms during the pandemic of COVID-19 after changes the work structure and after she illegally visited her son who was self-isolated after returning to B&H from abroad, with no self-protected equipment. Overall, both case studies illustrate the psychological potential that the crisis caused by the COVID-19 pandemic has on at-risk groups of psychiatric patients. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

: Understanding the role of religious communities in Croatia and Bosnia and Her-zegovina’s post-Communist societies is very important for grasping the nature and history of democratic development in these two countries. A close investigation reveals that the relationship between the political and religious elites is cruci-al, but also subject to change given the shifting nature of social developments. Three stages in this relationship can be observed. The first phase started with the collapse of Yugoslavia and Communism in 1991-1992 and lasted until the early 2000s. This was a formative stage for the new societies, and religion played a key role in the national homogenisation and construction of new identities. The second phase, which started in the early 2000s and lasted most of the decade, was a period of relative economic prosperity, with a weakening of the nationalist political elites’ sway, and consequently a weakening of the role of the religious organisations. The third phase, which started with the financial crisis of 2008 and is still ongoing, is marked by a renewed populist and rightist agenda in politics, which has also resulted in a strengthening of the public role of organised religion in both countries.

BACKGROUND Occurrence of symptoms of fear and depression among general population during the outbreak of COVID-19 seems to present an emerging problem worldwide. The aim of this study was to examine levels of fear and depressive symptoms in association with COVID-19 outbreak and to assess other contributing factors in the population of Bosnia and Herzegovina. SUBJECTS AND METHODS Link to an anonymous questionnaire, mainly based on The Fear of COVID-19 Scale (Ahorsu et al. 2020) and two-item and nine-item Patient Health Questionnaires (PHQs) (Maurer et al. 2018) (background information, fear assessment and information regarding depression) was distributed online to general population of Bosnia and Herzegovina. RESULTS Out of 1201 respondents, 217 (18.0%) reported experiencing fear and 341 (28.4%) reported having symptoms of depression during COVID-19 outbreak. The mean age of the subjects was 30.57±11.26. Being older (OR=1.044; 95% CI 1.031-1.057; p<0.001) and having moderate to severe depressive symptoms (OR=1.093; 95% CI 1.067-1.120; p<0.001) were independent significant predictors for developing fear; living in rural environment (OR=0.551; 95% Cl 0.325-0.935; p=0.0027) significantly decreased the risk of developing fear; being female (OR=1.750; 95% CI 1.242-2.466; p=0.001), unemployed (OR=1.557; 95% CI 1.040-2.330; p=0.032) or student (OR=1.943; 95% CI 1.450-2.604; p<0.001) were independent significant predictors for developing moderate to severe depressive symptoms in association with COVID-19. Mann Whitney U-test showed that being older was statistically associated with fear (p<0.001) and being younger was statistically associated with depressive symptoms (p<0.001). CONCLUSIONS In conclusion, based on our findings, fear and depressive symptoms in general population of Bosnia and Herzegovina during the outbreak of COVID-19 were present in 18.06% (fear) and 28.39% (depression) of subjects and it was statistically associated with age, gender, occupation, living environment and may present a secondary uprising problem connected to outbreak of COVID-19.

Background and aim Striving for harmonisation of specialty training and excellence of care in rheumatology, the European League Against Rheumatism (EULAR) established a task force to develop points to consider (PtCs) for the assessment of competences during rheumatology specialty training. Methods A systematic literature review on the performance of methods for the assessment of competences in rheumatology specialty training was conducted. This was followed by focus groups in five selected countries to gather information on assessment practices and priorities. Combining the collected evidence with expert opinion, the PtCs were formulated by the multidisciplinary task force, including rheumatologists, medical educationalists, and people with rheumatic and musculoskeletal diseases. The level of agreement (LoA) for each PtC was anonymously voted online. Results Four overarching principles and 10 PtCs were formulated. The overarching principles highlighted the importance of assessments being closely linked to the rheumatology training programme and protecting sufficient time and resources to ensure effective implementation. In the PtCs, two were related to overall assessment strategy (PtCs 1 and 5); three focused on formative assessment and portfolio (PtCs 2–4); three focused on the assessment of knowledge, skills or professionalism (PtCs 6–8); one focused on trainees at risk of failure (PtC 9); and one focused on training the trainers (PtC 10). The LoA (0–10) ranged from 8.75 to 9.9. Conclusion These EULAR PtCs provide European guidance on assessment methods throughout rheumatology training programmes. These can be used to benchmark current practices and to develop future strategies, thereby fostering continuous improvement in rheumatology learning and, ultimately, in patient care.

People suffering from hearing impairment often have difficulties participating in conversations in so-called cocktail party scenarios where multiple individuals are simultaneously talking. Although advanced algorithms exist to suppress background noise in these situations, a hearing device also needs information about which speaker a user actually aims to attend to. The voice of the correct (attended) speaker can then be enhanced through this information, and all other speakers can be treated as background noise. Recent neuroscientific advances have shown that it is possible to determine the focus of auditory attention through noninvasive neurorecording techniques, such as electroencephalography (EEG). Based on these insights, a multitude of auditory attention decoding (AAD) algorithms has been proposed, which could, combined with appropriate speaker separation algorithms and miniaturized EEG sensors, lead to so-called neurosteered hearing devices. In this article, we provide a broad review and a statistically grounded comparative study of EEG-based AAD algorithms and address the main signal processing challenges in this field.

Parkinson`s disease (PD) is a progressive neurodegenerative disorder involving dopaminergic neurons from the substantia nigra. The loss of dopaminergic neurons results in decreased dopamine (DA) release in the striatum and thus impaired motor functions. DA is one of the key neurotransmitters monitored for the diagnosis, and during the progression and treatment of PD. Therefore, sensitive and selective DA detection methods are of high clinical relevance. In this study, a new microfluidic device utilized for electrochemical DA detection is reported. The microfluidic sensing device operates in the range of 0.1 - 1000 nM DA requiring only ~ 2.4 µL sample volume, which corresponds to detectable 240 amol of DA. Using this sensor, we were able to monitor the changes in DA levels in cerebrospinal fluid (CSF) and plasma of a mouse model of PD and following the treatment of drug L-3,4-dihydroxyphenylalanine (L-DOPA), which reversed the parkinsonian symptoms in PD mice.