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Abstract Background Knee osteoarthritis (KOA) presents a prevalent orthopedic condition causing substantial impairment in the quality of life and imposing a significant societal and economic burden. Mesenchymal stromal/stem cells (MSCs), known for their regenerative properties and immunomodulatory effects, have emerged as a promising therapeutic avenue in regenerative medicine. Despite MSCs' therapeutic potential, their precise mechanisms of action in KOA remain underexplored. Methods Conducted as a randomized, open-label clinical trial, 20 patients will be enrolled, with 10 in the intervention group and 10 in the control group. The primary focus will be to explore the molecular mechanisms associated with MSC therapy. Biomarkers and gene expressions related to cartilage metabolism, inflammation, immune modulation, and pain in the synovial fluid, blood, and tissue samples will be analyzed. Patients will undergo pre- and post-treatment evaluations using patient-reported outcome measures (PROMs) and comprehensive clinical assessments. Discussion This is an exploratory study with the goal to provide comprehensive insights into the therapeutic effects of MSCs on a molecular level, potentially paving the way for optimized and more effective MSC-based therapies in the management of KOA, as well as furthering the development of novel treatment strategies. Trial registration ClinicalTrials.gov, NCT06078059. Registered on 5 October 2023.

Protein- and peptide-based proton-conducting biomaterials have been touted as particularly promising for bioelectronics applications because of their advantageous chemical and physical characteristics, typically excellent biocompatibilities, and readily understood electrical properties. Within this context, our laboratory has previously discovered and systematically investigated bulk proton conduction for a unique family of cephalopod structural proteins called reflectins. Herein, we leverage a combination of experimental and computational methodologies to investigate the bulk electrical properties of hierarchically nanostructured films self-assembled from a previously reported truncated reflectin variant. Our findings indicate that the truncated reflectin variant exhibits protonic conductivities and associated figures of merit on par with those reported for both full-length reflectins and other proteinaceous proton-conducting materials. The combined studies enhance current understanding of reflectins’ functional properties within the framework of bioengineering and bioelectronics applications and may ultimately facilitate the development of other protein- and peptide-based conductive biomaterials.

IntroductionPsychiatric comorbidities have proven a consistent challenge. Recent approaches emphasize the need to move away from categorical descriptions of symptom clusters towards a dimensional view of mental disorders. From the perspective of phenomenological psychopathology, this shift is not enough, as a more detailed understanding of patients’ lived experience is necessary as well. One phenomenology-informed approach suggests that we can better understand the nature of psychiatric disorders through personalized network models, a comprehensive description of a person’s lifeworld in the form of salient nodes and the relationships between them. We present a detailed case study of a patient with multiple comorbidities, maladaptive coping mechanisms, and adverse childhood experiences.MethodsThe case was followed for a period of two years, during which we collected multiple streams of data, ranging from phenomenological interviews, neuropsychological assessments, language analysis, and semi-structured interviews (Examination of Anomalous Self Experience and Examination of Anomalous World Experience). We analytically constructed a personalized network model of his lifeworld.ResultsWe identified an experiential category “the crisis of objectivity” as the core psychopathological theme of his lifeworld. It refers to his persistent mistrust towards any information that he obtains that he appraises as originating in his subjectivity. We can developmentally trace the crisis of objectivity to his adverse childhood experience, as well as him experiencing a psychotic episode in earnest. He developed various maladaptive coping mechanisms in order to compensate for his psychotic symptoms. Interestingly, we found correspondence between his subjective reports and other sources of data.DiscussionHernan exhibits difficulties in multiple Research Domain Criteria constructs. While we can say that social sensorimotor, positive valence, and negative valence systems dysfunctions are likely associated with primary deficit (originating in his adverse childhood experience), his cognitive symptoms may be tied to his maladaptive coping mechanisms (although, they might be related to his primary disorder as well).

Sofoklejeva Antigona ima bogato in edinstveno, več kot stoletno zgodovino uprizarjanja na slovenskih poklicnih odrih. Začela se je z neuspelo predstavo pod taktirko Hinka Nučiča na odru ljubljanske Drame leta 1912 in nadaljevala s priljubljeno postavitvijo Frana Lipaha v istem gledališču na predvečer druge svetovne vojne. Po vojni je primat pri uprizarjanju te tragedije prevzelo Slovensko ljudsko gledališče Celje (tedaj se je imenovalo Mestno gledališče Celje); vse do leta 2013 je bilo celo edino slovensko poklicno gledališče, ki jo je uprizarjalo, prvič leta 1956 (r. Herbert Grün), nato še leta 1973 (r. Franci Križaj), nazadnje pa leta 2011 (r. Anđelka Nikolić). Glavni razlog za to nenavadno odsotnost Sofoklejeve Antigone na drugih slovenskih poklicnih odrih je bila najverjetneje izjemna priljubljenost Smoletove drame z istim naslovom, ki je bila v tem času uprizorjena kar osemkrat, še dodatno pa so Sofokleja izrivale tudi (redkejše) uprizoritve drugih modernih Antigon (Dušan Jovanović, Miro Gavran, Janusz Głowacki). Zadnje desetletje je vendarle prineslo preporod zanimanja za Sofoklejevo različico (in obenem tudi zaton zanimanja za uprizarjanje Smoleta, kar pritrjuje naši spekulaciji o njunem programskem konkuriranju). Po kritiško dobro sprejeti celjski uprizoritvi v režiji Anđelke Nikolić, sta bili leta 2013 prvič na sporedu dve uprizoritvi, prva v Mestnem gledališču ljubljanskem (bralna uprizoritev, r. Ira Ratej) in druga v Lutkovnem gledališču Ljubljana (r. Marko Čeh). Nazadnje, leta 2017, pa se je Antigona v udarnem slogu končno vrnila tudi v ljubljansko Dramo (r. Eduard Miler).

Abstract Disordered protein sequences can exhibit different binding modes, ranging from well-ordered folding-upon-binding to highly dynamic fuzzy binding. The primary function of the intrinsically disordered region of the antitoxin HigA2 from Vibrio cholerae is to neutralize HigB2 toxin through ultra-high-affinity folding-upon-binding interaction. Here, we show that the same intrinsically disordered region can also mediate fuzzy interactions with its operator DNA and, through interplay with the folded helix-turn-helix domain, regulates transcription from the higBA2 operon. NMR, SAXS, ITC and in vivo experiments converge towards a consistent picture where a specific set of residues in the intrinsically disordered region mediate electrostatic and hydrophobic interactions while “hovering” over the DNA operator. Sensitivity of the intrinsically disordered region to scrambling the sequence, position-specific contacts and absence of redundant, multivalent interactions, point towards a more specific type of fuzzy binding. Our work demonstrates how a bacterial regulator achieves dual functionality by utilizing two distinct interaction modes within the same disordered sequence.

Extracellular nanoparticles (EPs) are a subject of increasing interest for their biological role as mediators in cell–cell communication; however, their harvesting and assessment from bodily fluids are challenging, as processing can significantly affect samples. With the aim of minimizing processing artifacts, we assessed the number density (n) and hydrodynamic diameter (Dh) of EPs directly in diluted plasma and blood using the following recently developed technique: interferometric light microscopy (ILM). We analyzed 613 blood and plasma samples from human patients with inflammatory bowel disease (IBD), collected in trisodium citrate and ethylenediaminetetraacetic acid (EDTA) anticoagulants, and 163 blood and plasma samples from canine patients with brachycephalic obstructive airway syndrome (BOAS). We found a highly statistically significant correlation between n in the plasma and n in the blood only in the human (i.e., but not canine) blood samples, between the samples with trisodium citrate and EDTA, and between the respective Dh for both species (all p < 10−3). In the human plasma, the average was 139 ± 31 nm; in the human blood, was 158 ± 11 nm; in the canine plasma, was 155 ± 32 nm; and in the canine blood, was 171 ± 33 nm. The differences within species were statistically significant (p < 10−2), with sufficient statistical power (P > 0.8). For , we found no statistically significant differences between the human plasma and blood samples or between the samples with trisodium citrate and EDTA. Our results prove that measuring n and Dh of EPs in minimally processed fresh blood and in diluted fresh plasma by means of ILM is feasible for large populations of samples.

In the second half of the 1980s, Tine Hribar developed a distinctive interpretation of Sophocles’s Antigone, which he presented in 1991 in the monograph Tragična etika svetosti (The tragical ethics of sacredness). Here he developed an original concept of the sacred, on which he built an ethical system that has become – particularly through its determined defense of the so-called sanctity of the dead – a cornerstone of the Slovene reconciliation project. This paper deals with some of the fundamental problems that stem from Hribar’s enigmatic definition of the sacred as “the world itself in itself,” showing that, in the conclusions Hribar draws from that definition, the clear distinction between being and life is lost. The central aporia of the Tragična etika svetosti is also closely intertwined with other problematic dimensions of the work that are analysed in the paper: the unfounded appropriation of the ethical characteristics of traditions from which he distances himself in principle; the unreflecting distinction between being and action in relation to the sacred; and not least, the unexplained oscillation between vitalism and Antigone’s ideal of self sacrifice.

Background Biomaterials augmented with Bone Marrow Aspirate Concentrate (BMAC) are becoming increasingly utilized in the cartilage treatment. However, the potential role of cellular parameters in the intraoperatively applied BMAC have yet to be elucidated. Purpose (A) To evaluate clinical outcomes and safety of a combined single-step approach with scaffolds (fibrin glues, collagen gels, collagen-hydroxyapatite membrane) and filtered Bone Marrow Aspirate (fBMA) for the treatment of osteochondral lesions of the talus (OLTs). (B) To identify significant factors for postoperative improvements, considering cellular parameters as potential predictors. Methods All the patients operated on due to OLTs by the combination above were selected from the hospital registry database (35 pts, years 16–55, and minimally 1 year follow-up). Treatment outcomes were followed clinically with Patient-reported outcome measures (PROMs), and by pursuing serious adverse events (SAE) and graft failures (GF). Cellular parameters of the injected fBMA were determined. Pre- and postoperative PROMs values were compared to evaluate postoperative improvements. Multivariable regression models were applied to identify potential factors (demographics, medical history, joint and lesion characteristics, scaffold type, surgical and cellular parameters) that predict the treatment outcomes. Results At the mean follow-up of 32.2 (12.5) months, all Foot and Ankle Outcome Score (FAOS) and European Quality of Life in Five Dimensions Three-Level (EQ-5D-3 L) values improved significantly. 4 (11%) SAE (3 arthrofibrosis, one hardware removal), and 3 (9%) GF occurred. Female gender and concomitant procedures were the main negative predictors for postoperative outcomes. The number of fibroblast colony forming units (CFU-F) or their proportion among total nucleated cells (CFU-F/TNC) were positively correlated with the improvements of some PROMs. Conclusions Scaffolds augmented with fBMA proved as an adequate and safe approach for OLTs treatment. Cellular parameters seem to influence the treatment outcomes, thus further attention should be given to the intraoperatively applied products. Level of evidence Level IV.

Theoretical simulations of dispersed solid particle behaviour inside a scrubbing pool within the bubble rise region are presented. The goal is to evaluate the decontamination factor of the particles during the pool scrubbing process. The basic phenomena of pool scrubbing are described. The setup used for the simulation validation is presented. Then, the boundary and initial conditions of the PECA experiments, which were performed at CIEMAT (Madrid, Spain) and were used for simulations, are presented. The subgrid model for decontamination through transfer of particles from gas bubbles to the surrounding liquid is described. The calculation results are evaluated and compared with the part of the PECA experimental results to which the proposed modelling is applicable.

Background and Objectives: The subcutaneous (SC) formulation of vedolizumab has proven to be effective for the maintenance of remission after intravenous induction. Little is known about the efficacy of switching from intravenous maintenance treatment to SC. We aimed to assess the real-world efficacy of switching to SC treatment and to assess the impact of a baseline treatment regimen. Materials and Methods: In this observational cohort study, adult patients with inflammatory bowel disease who were switched to SC vedolizumab maintenance treatment were enrolled. Patients after intravenous induction and patients who switched from intravenous maintenance treatment (every 8 weeks or every 4 weeks) were included. The SC vedolizumab dosing was 108 mg every 2 weeks, regardless of the previous regimen. The clinical, biochemical, and endoscopic disease activity parameters and vedolizumab serum concentrations at the time of the switch and at the follow-up were assessed. Results: In total, 135 patients (38% Crohn’s disease, 62% ulcerative colitis) were switched to SC vedolizumab treatment. The median time to the first follow-up (FU) was 14.5 weeks (IQR 12–26), and the median time to the second FU was 40 weeks (IQR 36–52). Nine patients (7%) discontinued SC vedolizumab treatment, with two-thirds of them discontinuing due to active disease. In all dosing regimens, there were no significant changes in the clinical scores and CRP at the baseline and first and second FUs. Clinical and biochemical remission appeared to be maintained irrespective of the previous dosing regimen. Conclusions: The results of this real-world study suggest that the maintenance of clinical and biomarker remission can be achieved in patients who switched from intravenous to SC vedolizumab. The baseline vedolizumab dosing regimen (every 4 weeks versus every 8 weeks) did not have an impact on outcomes.

The Black Notebooks [Schwarze Hefte] are personal notebooks that Heidegger wrote from the beginning of the 1930s to the end of the war. The first notebook has been lost, but transcripts of the next fourteen, which originated in the decade 1931–1941, were published in 2014 in three consecutive volumes of the philosopher’s Gesamtausgabe (more recently, further notebooks up to 1970 have been published). Their publication triggered a new wave of public polemics about his Nazism and anti-Semitism. This paper evaluates Heidegger’s multistage and multilayered relationship to Judaism and National Socialism, and the most prominent modern interpretations of that relationship, especially in light of the Black Notebooks. Among such readings, some of the most profound and lucid are those of the editor of the German edition of the Notebooks, Peter Trawny, and the Spanish philosopher Jesus Adrian Escudero. Many early reactions to the first publication of the notebooks were characterized by a combative outrage that was not supported by serious study and understanding of the material in question. This paper studies the reasons why that initial, sensationalist reaction stimulated precisely the opposite effect from what might be expected: Instead of jeopardizing Heidegger’s well-established place in the Western philosophical canon, the controversies of 2014 triggered a kind of renaissance of interest in his life and work.

This paper deals with the more than century-long history of staging Sophocles’s Antigone on Slovenian professional stages. After the first, awkward attempt by Hinko Nučič in the Drama Ljubljana (1912), the impression was saved by the very well received second production directed by Fran Lipah (1939). The reception of Antigone in the wider Yugoslavia in the first decade after the war was marked by a highly successful production in Belgrade (1950), directed by Tomislav Tanhofer and Miroslav Belović. Also, the key to the further development of the (ambivalent) Slovenian relationship with the myth of Antigone – in its dramatic and theatrical as well as its philosophical reception – was the literary adoption of the myth among Slovenian emigrés to Argentina dealing with the trauma of the post-war massacres. The third Slovenian production, and the first post-war one, directed by Herbert Grün at the Celje City Theatre (1956), was carefully thought out in dramaturgic and aesthetic terms. However, the result on the stage left critics with mixed impressions. Then followed the rise and supremacy of Dominik Smole’s Antigone (1960). With a little help from its “peers,” the other contemporary Antigones, it managed in an intriguing way to oust Sophocles’s tragedy of the same name from Slovenian professional stages for half a century, with one important exception: until 2013, the Celje City Theatre remained the only theatre to stage it in the post-war period. It was staged for the second time in 1973 with the production by Franci Križaj, which got middling reviews – Križaj, incidentally, also directed the first and fifth stagings of Smole’s Antigone – and for the third time in 2011, in the critically well-received interpretation of the Serbian director Anđelka Nikolić, which was characterised by its aesthetically anachronistic and genre-fluid approach to the original.

Sofoklejeva Antigona ima bogato in edinstveno, več kot stoletno zgodovino uprizarjanja na slovenskih poklicnih odrih. Začela se je z neuspelo predstavo pod taktirko Hinka Nučiča na odru ljubljanske Drame leta 1912 in nadaljevala s priljubljeno postavitvijo Frana Lipaha v istem gledališču na predvečer druge svetovne vojne. Po vojni je primat pri uprizarjanju te tragedije prevzelo Slovensko ljudsko gledališče Celje (tedaj se je imenovalo Mestno gledališče Celje); vse do leta 2013 je bilo celo edino slovensko poklicno gledališče, ki jo je uprizarjalo, prvič leta 1956 (r. Herbert Grün), nato še leta 1973 (r. Franci Križaj), nazadnje pa leta 2011 (r. Anđelka Nikolić). Glavni razlog za to nenavadno odsotnost Sofoklejeve Antigone na drugih slovenskih poklicnih odrih je bila najverjetneje izjemna priljubljenost Smoletove drame z istim naslovom, ki je bila v tem času uprizorjena kar osemkrat, še dodatno pa so Sofokleja izrivale tudi (redkejše) uprizoritve drugih modernih Antigon (Dušan Jovanović, Miro Gavran, Janusz Głowacki). Zadnje desetletje je vendarle prineslo preporod zanimanja za Sofoklejevo različico (in obenem tudi zaton zanimanja za uprizarjanje Smoleta, kar pritrjuje naši spekulaciji o njunem programskem konkuriranju). Po kritiško dobro sprejeti celjski uprizoritvi v režiji Anđelke Nikolić, sta bili leta 2013 prvič na sporedu dve uprizoritvi, prva v Mestnem gledališču ljubljanskem (bralna uprizoritev, r. Ira Ratej) in druga v Lutkovnem gledališču Ljubljana (r. Marko Čeh). Nazadnje, leta 2017, pa se je Antigona v udarnem slogu končno vrnila tudi v ljubljansko Dramo (r. Eduard Miler). Članek pregledno obravnava vse naštete uprizoritve in jih ovrednoti s pomočjo sočasne kritiške ter poznejše gledališkozgodovinske recepcije.

Martin Heidegger je svoje branje Sofoklove Antigone razgrnil v dveh znamenitih sklopih predavanj na Univerzi v Freiburgu; prvi sklop, ki ga je študentom predstavil leta 1935, je osemnajst let pozneje s popravki in dopolnitvami objavil v knjigi Uvod v metafiziko (Einführung in die Metaphysik); drugega, ki ga je naslovil Hölderlinova himna »Ister« (Hölderlins Hymne »Der Ister«), je lahko leta 1942, sredi vojne vihre, podal le v okrnjeni različici, v natisnjeni celoti pa je svetovni javnosti postal dostopen šele leta 1984. Članek preučuje razloge, zakaj je razkritje Heideggerjeve druge obravnave Antigone – ki s prvo vzpostavlja intriganten interpretativni kontrast – odigralo ključno vlogo v osrednjem filozofskem projektu Tineta Hribarja in s tem v širši slovenski recepciji mita o Antigoni od druge polovice osemdesetih let do danes.

Research Question (RQ): What is the role of organisational commitment in health, especially in the context of other work-related psychosocial factors (optimism, empowerment, stressful working conditions, job insecurity, and satisfactory payment). Purpose: The aim of the paper is to examine the role of organisational commitment in employee’s health. Method: An ISSP survey on a subsample of 589 workers in Slovenia was statistically analysed, using 1) a bivariate Pearson correlation test;2) a hierarchical multivariate linear regression to compare two models, where to see the role of organisational commitment, health was predicted by work-related psychosocial factors in a model with and in a model without organisational commitment, and 3) structural equation modelling to understand interrelations amongst analysed concepts. Results The results shows all analysed factors contribute to health, but not all directly. Health was found to be directly related to stressful working conditions, optimism, and affective organisational commitment. The latter was found to mediate the effects of stressful working conditions, satisfactory payment and optimism on health. Organisation: The results have a significant impact on a more detailed review of the factors that contribute to better working conditions for healthier employees When employees are committed, they not only stay in the organisation, but they are also healthier and consequently perform better, thus benefits could be seen for employers and employees. It is useful for managers to have knowledge of psychological empowerment, job satisfaction, and organizational commitment, as they can utilize these elements to motivate, develop, and manage employees. Society: As working population is the one that represent the main active population in society, it is important to generate working conditions for healthier workforce. Understanding the role of organisational commitment, and other work-related psychosocial factors for health could benefit not only for organisations and employees, but for other society members, that rely on working population, as well. Originality: The study statistically examines the conceptual research model, where it does not stop on bivariate correlations, or model with one dependent variable, as found in many other studies, but explore inner correlations among factors, thus provide more detailed insight to the relations among organisational commitment, employee’s health and work-related psychosocial factors (optimism, empowerment, stressful working conditions, job insecurity, and satisfactory payment). With our findings we contribute to the discussion on a constructive and future oriented approach to provide working conditions that would lead to committed and healthier workforce. We suggest that policy makers and human resource managers in organisations create working conditions that are focused on improving health. By doing so, affective organisational commitment should be one of the top priorities. Limitations/further research: The study was cross-sectional. Our sample was limited to employees in Slovenia. Our study was limited by the scope of secondary data available; health predictors were selected in accordance with theory and available indicators in the existing survey; limited to main factors: health, organisational commitment and work-related psychosocial factors (optimism, empowerment, stressful working conditions, job insecurity, and satisfactory payment). Future research could focus also on other health related factors (such as genetics, certain lifestyles, the environment, and susceptibility to diseases), include longitudinal approach and compare different geographical contexts.

The authors present and discuss the results of a nation-wide survey on food safety knowledge among professional food handlers in Slovenia. The data were collected via a telephone survey using a well-established questionnaire adapted to the Slovenian context. Altogether, 601 respondents from hotels, restaurants, catering, and confectionery units completed the questionnaire. To assess food safety knowledge among food handlers in both general and specific domains, three indexes (a General Knowledge Index, a Personal Knowledge Index, and a Temperature Knowledge Index) were created. Among them, the Temperature Knowledge Index revealed the largest gaps in knowledge. An insufficient transfer of food safety knowledge from managers and chefs to assistant chefs and kitchen assistants in establishments where more persons handle food was evident, while a course titled “Hygiene Minimum” of standardised training from the past still significantly contributes to food safety knowledge. The results suggest a need for improvement in the current system of food safety training courses for professional food handlers in Slovenia. The human factor in the food supply chain still has a significant role in ensuring food safety culture, and therefore must become a more important part of the food safety management system.

Background and Objectives: The main drawback of lipofilling is fat transplant volume loss, which makes long-term results unreliable. This study’s aim was to assess the influence of an adipose-derived stromal vascular fraction (SVF) on volume retention in large-volume fat grafts. Materials and Methods: A murine model was used for the in vivo evaluation of fat-graft volume changes over 6 months. We used 28 immunocompromised nude NU(NCr)-Foxn1nu mice and human fat tissue as a liposuction by-product. Part of the fat tissue was used for SVF preparation. We created a fat transplant without SVF (SVF-) and with SVF (SVF+) groups. Large-volume grafts were injected above the sacrum and scapula in the same animal. Volume loss was evaluated using three-dimensional optical scanning at 14 days (T1), 3 months (T2), and 6 months (T3) after transplantation. Scans were processed with Artec Studio software to obtain stereolithography files. The volumes were calculated in RapidForm software 2006. Results: The highest volume loss was observed above the scapula at T3 (SVF- 85%; SVF+ 75%). There was a significant difference in volume between SVF-/SVF+ for grafts above the sacrum at T2, with lower loss in SVF+, and the significance became stronger at T3. The difference in volume loss was also significant above the scapula between SVF-/SVF+ at T3. Conclusions: Although we found a beneficial effect of SVF on the long-term survival of large-volume fat tissue transplants, volume loss due to other contributing factors was high.

Recommendations for the dental treatment of patients with head and neck cancer (HNC) in Slovenia treated with radiation follow the recommendations and guidelines of the Royal College of Surgeons of England created in association with the British Society for Disability and Oral Health, the Recommendations for the treatment of patients with head and neck cancer in Slovenia and at the same time consider the existing capabilities of the Slovenian health care system. The recommendations aim to prevent or reduce complications in the oral cavity due to radiation therapy. They define the dental care before, during and after radiation therapy at all three levels of dental care, which ensures the timeliness and accessibility of dental care. The recommendations represent a unified opinion of all stakeholders in the field of dental treatment of HNC patients in the country.

Povezava med mitom o Antigoni in slovenskimi povojnimi izvensodnimi poboji, ki jo je odmevno opredelil Tine Hribar v filozofskih in političnih spisih iz druge polovice osemdesetih let, se v kontekstu slovenske literarne zgodovine in komparativistike najpogosteje pojavlja v interpretacijah Antigone Dominika Smoleta. Pričujoči članek, ki zasleduje stoletno slovensko recepcijo antigonskega mita med letoma 1875 in 1974 – od njegove prve pojavitve v slovenskem jeziku do prve eksplicitne upodobitve slovenskih konfliktov iz časa 2. svetovne vojne skozi njegovo prizmo –, pokaže, da je literarna povezava med tem mitom in osrednjo zgodovinsko travmo tega prostora bistveno širša od Smoletove slovite drame.

In postwar Western culture, the myth of Antigone has been the subject of noted literary, literary-critical, dramatic, philosophical, and philological treatments, not least due to the strong influence of one of the key plays of the twentieth century, Jean Anouilh’s Antigone. The rich discussion of the myth has often dealt with its most famous formulation, Sophocles’ Antigone, but has paid less attention to the broader ancient context; the epic sources (the Iliad, Odyssey, Thebaid, and Oedipodea); the other tragic versions (Aeschylus’s Seven Against Thebes and his lost Eleusinians; Euripides’s Suppliants, Phoenician Women, and Antigone, of which only a few short fragments have been preserved); and the responses of late antiquity. This paper analyses the basic features of this nearly thousand-year-long ancient tradition and shows how they connect in surprising ways – sometimes even more directly than Sophoclean tragedy does – with the main issues in some unique contemporary traditions of its reception (especially the Slovenian, Polish and Argentine ones): the question of burying the wartime (or postwar) dead and the ideal of reconciliation.

Članek opisuje mladost in šolanje Antona Sovreta, kasneje znamenitega klasičnega filologa in prevajalca. Rodil se je v kmečki družini v Šavni Peči, kjer je tudi odrastel. Njegov oče je bil po železniški nesreči invalidsko upokojen in družina se je preselila v Krško. Nižjo gimnazijo je Sovre opravil v Celju, višjo pa v Ljubljani. Sprva je študiral na Dunaju, kjer je bil tudi predsednik društva slovenskih študentov Slovenija; kasneje je študiral v Gradcu. Leta 1912 se je prijavil h klavzurnim izpitom, ki pa mu jih ni uspelo opraviti v celoti. Med prvo svetovno vojno se je poročil z Albino Schöner. Diplomiral je šele leta 1925 z diplomskimi izpiti na Univerzi v Ljubljani. Članek povzema tudi življenjske poti Sovretovih sedmih sorojencev, skupaj z vojaško službo vseh njegovih petih bratov med prvo svetovno vojno.

Splošni opomin (Admonitio generalis) je kapitular (frankovski zakonodajni odlok) Karla Velikega (vladal 768–814), ki je bil temeljni dokument njegovega programa kulturne prenove (renovatio). Kapitular je bil izdan 23. marca 789. Čeprav je v prvi vrsti ideološke narave, ni ostal le mrtva črka na papirju: še istega leta so ob njem izšli trije drugi kapitularji, ki so ga vsebinsko dopolnjevali (Duplex legationis edictum, Capitulare missorum, Breviarum missorum Aquitanicum). Kapitularje so frankovski vladarji sicer izdajali že prej, vendar še nikoli več kot dva v istem letu. Prav tako so se kmalu po izdaji Admonitio generalis v različnih delih kraljestva zvrstile sinode, ki pred tem v frankovskem kraljestvu niso bile tako pogoste. Na teh zborovanjih je bil program, začrtan v Admonitio generalis, konkretiziran in uveden v prakso.

Abstract Background A major bottleneck in drug delivery is the breakdown and degradation of the delivery system through the endosomal/lysosomal network of the host cell, hampering the correct delivery of the drug of interest. In nature, the bacterial pathogen Listeria monocytogenes has developed a strategy to secrete Listeriolysin O (LLO) toxin as a tool to escape the eukaryotic lysosomal system upon infection, allowing it to grow and proliferate unharmed inside the host cell. Results As a “proof of concept”, we present here the use of purified His-LLO H311A mutant protein and its conjugation on the surface of gold nanoparticles to promote the lysosomal escape of 40 nm-sized nanoparticles in mouse embryonic fibroblasts. Surface immobilization of LLO was achieved after specific functionalization of the nanoparticles with nitrile acetic acid, enabling the specific binding of histidine-tagged proteins. Conclusions Endosomal acidification leads to release of the LLO protein from the nanoparticle surface and its self-assembly into a 300 Å pore that perforates the endosomal/lysosomal membrane, enabling the escape of nanoparticles.

Priporočila za obravnavo rakov glave in vratu (RGV) v Sloveniji sledijo priporočilom in usmeritvam, povzetim v publikaciji neprofitne mreže 30 vodilnih severnoameriških inštitucij za obravnavo raka, National Comprehensive Cancer Network, in hkrati upoštevajo obstoječe zmožnosti slovenskega zdravstvenega sistema. Smernice predstavljajo poenoteno mnenje vseh štirih najpomembnejših deležnikov na področju obravnave rakov glave in vratu v državi: Klinike za otorinolaringologijo in cervikofacialno kirurgijo, Kliničnega oddelka za maksilofacialno in oralno kirurgijo ter Stomatološke klinike UKC Ljubljana, Klinike za otorinolaringologijo, cervikalno in maksilofacialno kirurgijo UKC Maribor ter Onkološkega inštituta Ljubljana.

Uvod: Oskrba pacientov je kompleksna in zahteva učinkovito sodelovanje različnih profilov zdravstvene in socialne oskrbe. Medpoklicno izobraževanje je lahko uspešen način izboljševanja medpoklicnega sodelovanja in oskrbe pacienta. Namen pregleda literature je bil preučiti vpliv medpoklicnega izobraževanja medicinskih sester na njihovo medpoklicno sodelovanje z drugimi profili v zdravstvu in identificirati morebitne merske instrumente za preučevanje tega vpliva. Metode: S sistematičnim pregledom literature so bili pregledani znanstveni članki, objavljeni med letoma 2011 in 2018, navedeni v bibliografskih bazah CINAHL, MEDLINE in PubMed Central. Proučevani so bili članki, ki so obravnavali zaposlene in študente zdravstvene nege, ki so se medpoklicno izobraževali in tudi sodelovali z drugimi profili zdravstvene in socialne oskrbe pacientov. Rezultati: Izmed 1277 identificiranih objav je bilo v končno analizo vključenih devet virov. Sedem raziskav je poročalo o tem, da je bilo po medpoklicnem izobraževanju medpoklicno sodelovanje boljše, večja sta bila tudi medsebojno spoštovanje vključenih in medpoklicna samozavest, izboljšano pa pozitivno mišljenje o vlogi soudeleženih poklicev pri zdravstveni oskrbi. Dve raziskavi sta nasprotno poročali, da medpoklicno izobraževanje ne vpliva na zgoraj navedene dejavnike. Ugotovljena je bila prisotnost različnih merskih instrumentov za ocenjevanje vpliva medpoklicnega izobraževanja na medpoklicno sodelovanje. Diskusija in zaključek: Rezultati potrjujejo smiselnost vpeljave medpoklicnega izobraževanja v redni del študijskih programov zdravstvene nege. V prihodnje bi bila potrebna obsežnejša longitudinalna raziskava, ki bi preučevala medpoklicno izobraževanje medicinskih sester in potrdila njegov vpliv na medpoklicno sodelovanje v praksi.

The article critically evaluates The Three Lives of Antigone, Slavoj Žižek’s first dramatic work. Žižek’s polemical rewriting of Sophocles’ tragedy is examined in the broader perspective of Žižek’s philosophy and other Antigones: those of Sophocles, Jean Anouilh, Bertolt Brecht and Dominik Smole. Slavoj Žižek has interpreted Sophocles’ Antigone in numerous philosophical works. In his earlier treatises, he mainly gave a cautious summary of Hegel’s, Heidegger’s and Lacan’s theses on Antigone; lately, however, Žižek’s attitude to Sophocles’ Antigone has grown decidedly negative. The main point in Žižek’s critique of Sophocles’ tragedy is that his Antigone is not an appropriate symbol of genuine social revolt. Based on this conviction, Žižek contrived his own version of Antigone with an alternative ending in which the choir carries out a revolution and condemns Antigone to death. It is argued in the article that Žižek’s dramatic project fails to convince. It is essentially a superficial apology for political violence, which can ultimately only be understood as a veiled defence of the political status quo.

Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.

Plant-derived nanovesicles (NVs) have attracted interest due to their anti-inflammatory, anticancer and antioxidative properties and their efficient uptake by human intestinal epithelial cells. Previously we showed that tomato (Solanum lycopersicum L.) fruit is one of the interesting plant resources from which NVs can be obtained at a high yield. In the course of the isolation of NVs from different batches of tomatoes, using the established differential ultracentrifugation or size-exclusion chromatography methods, we occasionally observed the co-isolation of viral particles. Density gradient ultracentrifugation (gUC), using sucrose or iodixanol gradient materials, turned out to be efficient in the separation of NVs from the viral particles. We applied cryogenic transmission electron microscopy (cryo-TEM), scanning electron microscopy (SEM) for the morphological assessment and LC–MS/MS-based proteomics for the protein identification of the gradient fractions. Cryo-TEM showed that a low-density gUC fraction was enriched in membrane-enclosed NVs, while the high-density fractions were rich in rod-shaped objects. Mass spectrometry–based proteomic analysis identified capsid proteins of tomato brown rugose fruit virus, tomato mosaic virus and tomato mottle mosaic virus. In another batch of tomatoes, we isolated tomato spotted wilt virus, potato virus Y and southern tomato virus in the vesicle sample. Our results show the frequent co-isolation of plant viruses with NVs and the utility of the combination of cryo-TEM, SEM and proteomics in the detection of possible viral contamination.

Despite their high potential, most of the clinically approved iron oxide (IO)-based contrast agents for magnetic resonance imaging (MRI) have been withdrawn from the market either due to safety issues or lack of sales. To address this challenge, erythrocyte membranes have been used to prepare IO-based T2 contrast agents with superior MRI properties and higher safety margin. A simple formulation procedure has been proposed, and the nanostructures’ morphology and physicochemical properties have been evaluated. We compared their performance in terms of contrast ability in MRI to the more clinically established magneto-liposomes and non-encapsulated nanoparticles (NPs). The encapsulation of 5-nm iron oxide nanoparticles (IO NPs) in the liposomes and erythrocyte membrane vesicles (EMVs) led to a significant improvement in their r2 relaxivity. r2 values increased to r2 = 188 ± 2 mM−1s−1 for magneto-liposomes and r2 = 269 ± 3 mM−1s−1 for magneto-erythrocyte membranes, compared to “free” IO NPs with (r2 = 12 ± 1 mM−1 s−1), measured at a 9.4 T MRI scanner. The superiority of magneto-erythrocyte membranes in terms of MRI contrast efficacy is clearly shown on T2-weighted MR images. Our study revealed the hemocompatibility of the developed contrast agents in the MRI-relevant concentration range.

The research was conducted with the aim to determine the relation among behavior in a working environment, the level of intellectual abilities, and success in practical training in adolescents with difficulties in mental development. The sample included 50 adolescents with difficulties in mental development, of both genders, 16-21 years of age (AM=18.48; SD=1.59), who attended Secondary vocational school in Belgrade. There were 16 (32%) participants with moderate intellectual disability (ID), 17 (34%) with mild ID, and 17 (34%) with borderline intellectual functioning (BIF). Data on participants' age, intellectual abilities, class and grade in practical training were taken from school records. Behavior in a working environment and vocational interests were assessed by Vocational Evaluation Questionnaire, applied in a form of interviews with occupational therapists. By applying the analysis of covariance and controlling the influence of the level of intellectual abilities, it was determined that the total score of Vocational Evaluation Questionnaire significantly influenced the grade in practical training (p≤0.000), due to the domains of social skills (p=0.012), communication (p=0.001) and working skills (p≤0.000). The results of Vocational Evaluation Questionnaire explained about 47% (η2part=0.471) of variance, while the level of intellectual functioning explained slightly under 10% (η2part=0.097). The obtained results indicate the need for continuous monitoring and evaluation of the vocational training process of young people with difficulties in mental development, for the purpose of profiling their working abilities more clearly.

The research aims to determine the relation between auditory attention and practical adaptive skills in persons with moderate intellectual disability (MIO). The sample included 66 persons with MID, 33 (50%) men and 33 (50%) women, between 17 and 54 years of age (AM=30.89; SD=9.637). Auditory attention was assessed by tasks testing auditory span (verbal and nonverbal) and maintaining auditory attention, which belong to the Protocol for Cognitive Abilities Assessment. Data on practical adaptive skills were obtained from standardized interviews with special educators, by applying Independent functioning and Physical development domains of the Adaptive Functioning Scale. The results of the assessed domains were grouped into the Personal independence factor, which represents the acquisition level of practical adaptive skills. Compared to the norms for the population of persons with intellectual disability, the standard scores mean value of the participants with MID in practical skills domain was above average. No statistically significant difference was determined between the participants' age and gender and their achievements in practical skills domain. The results of the participants with MID in tasks assessing auditory attention were extremely uneven. In tasks which assess attention range, the mean value of the achieved level/span of verbal attention was 1.8 (a bit under four stimuli in a row), and the span of nonverbal auditory attention did not reach the first level (two stimuli in a row). With regard to the achievements in maintaining attention task, the participants grouped into two categories, with more participants (53%) belonging to the category characterized by a complete failure in performing the task. By applying the analysis of variance, it was determined that verbal attention span was a statistically significant factor (p=0.033) of the personal independence factor, while nonverbal auditory span (p=0.028-0.003) and maintaining auditory attention (p=0.031-0.001) were statistically significant factors of practical skills in all assessed domains.

Pore-forming toxins act by forming oligomeric pores in lipid membranes. Here the authors report the crystal structure of the lysenin pore, providing insights into the assembly and function of the pore in addition to suggesting that its properties make lysenin potentially well-suited for nanopore sensing applications.

The sensitivity of two commercial metal oxide (MOx) sensors to ethylene is tested at different relative humidities. One sensor (MiCS-5914) is based on tungsten oxide, the other (MQ-3) on tin oxide. Both sensors were found to be sensitive to ethylene concentrations down to 10 ppm. Both sensors have significant response times; however, the tungsten sensor is the faster one. Sensor models are developed that predict the concentration of ethylene given the sensor output and the relative humidity. The MQ-3 sensor model achieves an accuracy of ±9.2 ppm and the MiCS-5914 sensor model predicts concentration to ±7.0 ppm. Both sensors are more accurate for concentrations below 50 ppm, achieving ±6.7 ppm (MQ-3) and 5.7 ppm (MiCS-5914).

A screen printed pH sensor was developed using a PANI layer as a proton sensitive material for the in-situ measurements of matrix cross-linking. The sensor showed a linear response in a broad pH range (3–10) and had an evident cross-talk to Cl− ions. Preliminary in-situ measurements showed a substantial signal change during the cross-linking process.

Listeria monocytogenes is a food and soil-borne pathogen that secretes a pore-forming toxin listeriolysin O (LLO) as its major virulence factor. We tested the effects of LLO on an intestinal epithelial cell line Caco-2 and compared them to an unrelated pore-forming toxin equinatoxin II (EqtII). Results showed that apical application of both toxins causes a significant drop in transepithelial electrical resistance (TEER), with higher LLO concentrations or prolonged exposure time needed to achieve the same magnitude of response than with EqtII. The drop in TEER was due to pore formation and coincided with rearrangement of claudin-1 within tight junctions and associated actin cytoskeleton; however, no significant increase in permeability to fluorescein or 3 kDa FITC-dextran was observed. Influx of calcium after pore formation affected the magnitude of the drop in TEER. Both toxins exhibit similar effects on epithelium morphology and physiology. Importantly, LLO action upon the membrane is much slower and results in compromised epithelium on a longer time scale at lower concentrations than EqtII. This could favor listerial invasion in hosts resistant to E-cadherin related infection.

A rapid advanced packaging concept, consisting of inkjet photopolymer printing and Ag nanoparticles printing, was investigated for the construction of a pressure sensor package. Acrylate-type 3D package housing with 7 through-holes was printed with a polyjet printer and the through-vias and connection pads were manufactured via Ag glue dispensing and inkjet printing of Ag nanoparticle ink. The flip-chip packaging concept was pursued for the electrical connection between the package and the pressure sensor dye.

Background: During the COVID-19 pandemic, many intensive care units (ICUs) halted research to focus on COVID-19-specific studies., Objective: To describe the conduct of an international randomized trial of stress ulcer prophylaxis (Re-Evaluating the Inhibition of Stress Erosions in the ICU [REVISE]) during the pandemic, addressing enrolment patterns, center engagement, informed consent processes, data collection, a COVID-specific substudy, patient transfers, and data monitoring., Methods: REVISE is a randomized trial among mechanically ventilated patients, comparing pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important upper gastrointestinal bleeding and the primary safety outcome of 90-day mortality. We documented protocol implementation status from March 11th 2020-August 30th 2022., Results: The Steering Committee did not change the scientific protocol. From the first enrolment on July 9th 2019 to March 10th 2020 (8 months preceding the pandemic), 267 patients were enrolled in 18 centers. From March 11th 2020-August 30th 2022 (30 months thereafter), 41 new centers joined; 59 were participating by August 30th 2022 which enrolled 2961 patients. During a total of 1235 enrolment-months in the pandemic phase, enrolment paused for 106 (8.6%) months in aggregate (median 3 months, interquartile range 2;6). Protocol implementation involved a shift from the a priori consent model pre-pandemic (188, 58.8%) to the consent to continue model (1615, 54.1%, p < 0.01). In one new center, an opt-out model was approved. The informed consent rate increased slightly (80.7% to 85.0%, p = 0.05). Telephone consent encounters increased (16.6% to 68.2%, p < 0.001). Surge capacity necessitated intra-institutional transfers; receiving centers continued protocol implementation whenever possible. We developed a nested COVID-19 substudy. The Methods Centers continued central statistical monitoring of trial metrics. Site monitoring was initially remote, then in-person when restrictions lifted., Conclusion: Protocol implementation adaptations during the pandemic included a shift in the consent model, a sustained high consent rate, and launch of a COVID-19 substudy. Recruitment increased as new centers joined, patient transfers were optimized, and monitoring methods were adapted., (© 2024. Crown.)

Proliferation of COVID-19 research underscored the need for improved awareness among investigators, research staff and bedside clinicians of the operational details of clinical studies. The objective was to describe the genesis, goals, participation, procedures, and outcomes of two research operations committees in an academic ICU during the COVID-19 pandemic., Design: Two-phase, single-center multistudy cohort., Setting: University-affiliated ICU in Hamilton, ON, Canada., Patients: Adult patients in the ICU, medical stepdown unit, or COVID-19 ward., Interventions: None., Measurements and Main Results: An interprofessional COVID Collaborative was convened at the pandemic onset within our department, to proactively coordinate studies, help navigate multiple authentic consent encounters by different research staff, and determine which studies would be suitable for coenrollment. From March 2020 to May 2021, five non-COVID trials continued, two were paused then restarted, and five were launched. Over 15 months, 161 patients were involved in 215 trial enrollments, 110 (51.1%) of which were into a COVID treatment trial. The overall informed consent rate (proportion agreed of those eligible and approached including a priori and deferred consent models) was 83% (215/259). The informed consent rate was lower for COVID-19 trials (110/142, 77.5%) than other trials (105/117, 89.7%; p = 0.01). Patients with COVID-19 were significantly more likely to be coenrolled in two or more studies (29/77, 37.7%) compared with other patients (13/84, 15.5%; p = 0.002). Review items for each new study were collated, refined, and evolved into a modifiable checklist template to set up each study for success. The COVID Collaborative expanded to a more formal Department of Critical Care Research Operations Committee in June 2021, supporting sustainable research operations during and beyond the pandemic., Conclusions: Structured coordination and increased communication about research operations among diverse research stakeholders cultivated a sense of shared purpose and enhanced the integrity of clinical research operations., Competing Interests: Dr Cook holds a Canada Research Chair from the Canadian Institutes for Health Research. Dr. Lewis holds the Constantine Douketis New Researcher Award from the Research Institute of St. Joseph’s Healthcare Hamilton. Dr. Kho holds a Canada Research Chair from the Canadian Institutes for Health Research. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Introduction: High prolactin (PRL) concentrations are found in laboratory test results of patients on majority of antipsychotic drugs. Prevalence rates and degrees of severity of hyperprolactinemia (HPRL) based on PRL concentration may depend on the presence of macroprolactin in the serum. The aim of the study was to investigate the difference between PRL concentrations before and after precipitation of macroprolactin and to examine if there were any changes in the categorization of HPRL between samples prior and after precipitation., Materials and Methods: Total of 98 female patients (median age 33; range 19-47 years) diagnosed with a psychotic disorder, proscribed antipsychotic drugs, and with HPRL were included. Total PRL concentration and PRL concentration after macroprolactin precipitation with polyethylene glycol (postPEG-PRL) were determined by the chemiluminometric method on the Beckman Coulter Access2 analyser., Results: Total PRL concentrations (median 1471; IQC: 1064-2016 mlU/L) and postPEG-PRL concentrations (median 1453; IQC: 979-1955 mlU/L) were significantly correlated using intraclass correlation coefficient for single measurements (mean estimation 0.96; 95%CI 0.93-0.97) and average measurement (mean estimation 0.98; 95%CI 0.96-0.99), and all investigated female patient had HPRL according to PRL and postPEG-PRL concentration. The median PRL recovery following PEG precipitation was 95; IQC: 90-100%. There was substantial agreement (kappa test = 0.859, 95% CI: 0.764-0.953) between the categories of HPRL severity based on total PRL concentrations and postPEG-PRL concentrations., Conclusion: The study demonstrated that HPRL was present in all subjects using the reference interval for total PRL concentration and postPEG-PRL concentration with no significant impact of macroprolactin presence in the serum on the categorization of patients according to severity of HPRL., Competing Interests: Potential conflict of interest None declared., (Croatian Society of Medical Biochemistry and Laboratory Medicine.)

In healthy human skin host defense molecules such as antimicrobial peptides (AMPs) contribute to skin immune homeostasis. In patients with the congenital disease ectodermal dysplasia (ED) skin integrity is disturbed and as a result patients have recurrent skin infections. The disease is characterized by developmental abnormalities of ectodermal derivatives and absent or reduced sweating. We hypothesized that ED patients have a reduced skin immune defense because of the reduced ability to sweat. Therefore, we performed a label-free quantitative proteome analysis of wash solution of human skin from ED patients or healthy individuals. A clear-cut difference between both cohorts could be observed in cellular processes related to immunity and host defense. In line with the extensive underrepresentation of proteins of the immune system, dermcidin, a sweat-derived AMP, was reduced in its abundance in the skin secretome of ED patients. In contrast, proteins involved in metabolic/catabolic and biosynthetic processes were enriched in the skin secretome of ED patients. In summary, our proteome profiling provides insights into the actual situation of healthy versus diseased skin. The systematic reduction in immune system and defense-related proteins may contribute to the high susceptibility of ED patients to skin infections and altered skin colonization.

Recent advances in mass spectrometry (MS) have led to increased applications of shotgun proteomics to the refinement of genome annotation. The typical "proteo-genomic" workflows rely on the mapping of peptide MS/MS spectra onto databases derived via six-frame translation of the genome sequence. These databases contain a large proportion of spurious protein sequences which make the statistical confidence of the resulting peptide spectrum matches difficult to assess. Here we performed a comprehensive analysis of the Escherichia coli proteome using LTQ-Orbitrap MS and mapped the corresponding MS/MS spectra onto a six-frame translation of the E. coli genome. We hypothesized that the protein-coding part of the E. coli genome approaches complete annotation and that the majority of six frame-specific (novel) peptide spectrum matches can be considered as false positive identifications. We confirm our hypothesis by showing that the posterior error probability distribution of novel hits is almost identical to that of reversed (decoy) hits; this enables us to estimate the sensitivity, specificity, accuracy, and false discovery rate in a typical bacterial proteo-genomic dataset. We use two complementary computational frameworks for processing and statistical assessment of MS/MS data: MaxQuant and Trans-Proteomic Pipeline. We show that MaxQuant achieves a more sensitive six-frame database search with an acceptable false discovery rate and is therefore well suited for global genome reannotation applications, whereas the Trans-Proteomic Pipeline achieves higher specificity and is well suited for high-confidence validation. The use of a small and well-annotated bacterial genome enables us to address genome coverage achieved in state-of-the-art bacterial proteomics: identified peptide sequences mapped to all expressed E. coli proteins but covered 31.7% of the protein-coding genome sequence. Our results show that false discovery rates can be substantially underestimated even in "simple" proteo-genomic experiments obtained by means of high-accuracy MS and point to the necessity of further improvements concerning the coverage of peptide sequences by MS-based methods.

Aim: To investigate genetic differences between Crohn's disease (CD) patients with a sustained remission vs relapsers after discontinuing infliximab while in corticosteroid-free remission., Methods: Forty-eight CD patients received infliximab and were in full corticosteroid-free clinical remission but then discontinued infliximab for reasons other than a loss of response, were identified by review of an electronic database and charts. Infliximab-associated remission was defined as corticosteroid-free plus normalization of clinical disease activity [CD activity index (CDAI) < 150] during follow-up visits based on physician global assessments. A CD relapse (loss of infliximab-induced remission) was clinically defined as a physician visit for symptoms of disease activity (CDAI > 220) and a therapeutic intervention with CD medication(s), or a hospitalization with complications related to active CD. Genetic analyses were performed on samples from 14 patients (n = 6 who had a sustained long term remission after stopping infliximab, n = 8 who rapidly relapsed after stopping infliximab). Nucleotide-binding oligomerization domain 2 (NOD2)/caspase activation recruitment domain 15 (CARD15) polymorphisms (R702W, G908R and L1007fs) and the inflammatory bowel disease 5 (IBD5) polymorphisms (IGR2060a1 and IGR3081a1) were analyzed in each group., Results: Five single nucleotide polymorphisms of IBD5 and NOD2/CARD15 genes were successfully analyzed for all 14 subjects. There was no significant increase in frequency of the NOD2/CARD15 polymorphisms (R702W, G908R and L1007fs) and the IBD5 polymorphisms (IGR2060a1 and IGR3081a1) in either group of patients; those whose disease relapsed rapidly or those who remained in sustained long term remission following the discontinuation of infliximab. Nearly a third of patients in full clinical remission who stopped infliximab for reasons other than loss of response remained in sustained clinical remission, while two-thirds relapsed rapidly. There was a marked difference in the duration of clinical remission following discontinuance of infliximab between the two groups. The patients who lost remission did so after 1.0 years ± 0.6 years, while those still in remission were at the time of this study, 8.1 years ± 2.6 years post-discontinuation of infliximab, P < 0.001. The 8 patients who had lost remission after discontinuing infliximab had a mean number of 5 infusions (range 3-7), with a mean treatment time of 7.2 mo (range 1.5 mo-15 mo). The mean duration of time from the last infusion of infliximab to the time of loss of remission was 382 d (range 20 d-701 d). The 6 patients who remained in remission after discontinuing infliximab had a mean number of 6 infusions (range 3-12), with a mean treatment duration of 12 mo (range 3.6 mo-32 mo) (P = 0.45 relative to those who lost remission)., Conclusion: There are no IBD5 or NOD2/CARD15 mutations that predict which patients might have sustained remission and which will relapse rapidly after stopping infliximab.

Objective: To determine whether the clinical efficacy and safety of infliximab in diverse clinical referral practices was similar to that seen in the randomized, controlled clinical trials., Methods: Data were gathered from a review of charts of 109 consecutive patients with inflammatory and/or fistulizing Crohn's disease who received infliximab infusions. Responses were recorded based on the physician's global clinical assessment and classified as complete, partial or nonresponse., Results: One hundred nine patients were treated with one to nine infusions of infliximab at a dose of 5 mg/kg and followed up for a median of 24 weeks (range one to 40 weeks). Fifty-four patients were treated for inflammatory disease, 38 for fistulizing disease and 17 for both. Clinical response occurred in 73% (17% complete response, 55% partial response). The clinical response rate did not vary relative to patient demographics, disease distribution, indication for infliximab, or the concomitant use of corticosteroids or immune modifiers. For those taking concomitant immune modifiers, the response rate was 75%. The median time to response was two weeks (range one to six weeks). The median duration of response was 12 weeks (range six to 88 weeks). Reduction or cessation of steroids was possible in 17 of 32 patients. Adverse events related to infliximab occurred in 7% of patients. These events were characterized as mild and did not require stoppage of infliximab therapy, except in one patient who had a treatable anaphylactic-like infusion reaction., Conclusions: The patient group in the present study realized significant clinical benefit, with minimal adverse effects, following treatment with infliximab. Clinical response rates paralleled those previously described in placebo controlled trials and retrospective clinical practice reviews. Nevertheless, the complete response rate (ie, remission) in this patient group was lower than that previously described.