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Was ist neu? Epidemiologie In einer aktuellen epidemiologischen Arbeit zeigt sich ein seit 2013 rückläufiger Trend von Clostridioides-difficile-Infektionen (CDI) in Deutschland, zusammen mit einer Abnahme des Anteils hypervirulenter Ribotypen (vor allem RT 027 und RT 078). Dennoch bleibt die Krankheitslast hoch und insbesondere ältere und vorerkrankte Patientinnen und Patienten sind häufig betroffen. Aktuelle US-amerikanische Daten zeigen, dass bei älteren Patientinnen und Patienten insbesondere CDI-Rezidive, assoziierte psychiatrische Diagnosen wie Depressionen sowie Folgeerkrankungen wie Sepsis eine hohe Krankheitslast für Betroffene darstellen. Mikrobiologie Neue Studien liefern Erkenntnisse zum Zusammenspiel von C. difficile mit anderen Darmpathogenen; so scheinen Koinfektionen mit Enterokokken zu einer erhöhten Virulenz von C. difficile beizutragen. Neue europäische Therapieleitlinie Nach der 2021 aktualisierten ESCMID-Leitlinie ist Fidaxomicin aufgrund des geringeren Rezidivrisikos Mittel der ersten Wahl für erstmalig auftretende und rezidivierende CDI. Metronidazol dagegen sollte nur dann zum Einsatz kommen, wenn weder Fidaxomicin noch Vancomycin zur Verfügung stehen. Die fäkale Mikrobiota-Transplantation (FMT) hat sich im Rahmen eines individuellen Heilversuchs zur Behandlung mehrfach rezidivierender CDI etabliert; allerdings wurden die regulatorischen Auflagen dafür im Zuge der Corona-Pandemie weiter verschärft. Auch bei refraktär verlaufender fulminanter CDI kann die FMT als Alternative zur chirurgischen Intervention erwogen werden. Weitere Behandlungsmöglichkeiten Mit dem Small-Molecule-Antibiotikum Ridinilazol könnte in Zukunft neben Fidaxomicin ein weiteres CDI-Antibiotikum mit schmalem Wirkspektrum und kaum enteraler Resorption zur Verfügung stehen. Die orale Mikrobiota-Therapie mittels aufgereinigter Firmicutes-Sporen (SER-109) zeigte in einer aktuellen Phase-III-Studie vielversprechende Ergebnisse und könnte in Zukunft durch die Anwendung in oralen Kapseln eine unkomplizierte Alternative zur FMT darstellen. Toxoid-Impfstoff Die Hoffnungen auf einen gut wirksamen Toxoid-Impfstoff zur Primär- und Sekundärprävention von CDI haben sich in der CLOVER-Studie leider nicht erfüllt.

Despite routine use of DNA-hypomethylating agents (HMAs) in AML/MDS therapy, their mechanisms of action are not yet unraveled. Pleiotropic effects of HMAs include global methylome and transcriptome changes. We asked whether in blasts and T-cells from AML patients HMA-induced in vivo demethylation and remethylation occur randomly or non-randomly, and whether gene demethylation is associated with gene induction. Peripheral blood AML blasts from patients receiving decitabine (20 mg/m2 day 1–5) were serially isolated for methylome analyses (days 0, 8 and 15, n = 28) and methylome-plus-transcriptome analyses (days 0 and 8, n = 23), respectively. T-cells were isolated for methylome analyses (days 0 and 8; n = 16). We noted massive, non-random demethylation at day 8, which was variable between patients. In contrast, T-cells disclosed a thousand-fold lesser, random demethylation, indicating selectivity of the demethylation for the malignant blasts. The integrative analysis of DNA demethylation and transcript induction revealed 87 genes displaying a significant inverse correlation, e.g. the tumor suppressor gene IFI27, whose derepression was validated in two AML cell lines. These results support HMA-induced, non-random early in vivo demethylation events in AML blasts associated with gene induction. Larger patient cohorts are needed to determine whether a demethylation signature may be predictive for response to this treatment.

PURPOSE Hydroxyurea (HY) is a reference treatment of advanced myeloproliferative neoplasms. We conducted a randomized phase III trial comparing decitabine (DAC) and HY in advanced myeloproliferative chronic myelomonocytic leukemias (CMML). PATIENTS AND METHODS Newly diagnosed myeloproliferative CMML patients with advanced disease were randomly assigned 1:1 to intravenous DAC (20 mg/m2/d days 1-5) or HY (1-4 g/d) in 28-day cycles. The primary end point was event-free survival (EFS), events being death and acute myelomonocytic leukemia (AML) transformation or progression. RESULTS One-hundred seventy patients received DAC (n = 84) or HY (n = 86). Median age was 72 and 74 years, and median WBC count 32.5 × 109/L and 31.2 × 109/L in the DAC and HY arms, respectively. Thirty-three percent of DAC and 31% of HY patients had CMML-2. Patients received a median of five DAC and six HY cycles. With a median follow-up of 17.5 months, median EFS was 12.1 months in the DAC arm and 10.3 months in the HY arm (hazard ratio [HR], 0.83; 95% CI, 0.59 to 1.16; P = .27). There was no significant interaction between treatment effect and blast or platelet count, anemia, CMML Prognostic Scoring System, Groupe Francophone des Myelodysplasies, or CMML Prognostic Scoring System–mol risk. Fifty-three (63%) DAC patients achieved a response compared with 30 (35%) HY patients ( P = .0004). Median duration of response was similar in both arms (DAC, 16.3 months; HY, 17.4 months; P = .90). Median overall survival was 18.4 months in the DAC arm and 21.9 months in the HY arm ( P = .67). Compared with HY, DAC significantly reduced the risk of CMML progression or transformation to acute myelomonocytic leukemia (cause-specific HR, 0.62; 95% CI, 0.41 to 0.94; P = .005) at the expense of death without progression or transformation (cause-specific HR, 1.55; 95% CI, 0.82 to 2.9; P = .04). CONCLUSION Compared with HY, frontline treatment with DAC did not improve EFS in patients with advanced myeloproliferative CMML (ClinicalTrials.gov identifier: NCT02214407 ).

Nosocomial wound infections are a dreaded complication in patients with burns. However, access to the necessary microbiological diagnostics is impaired in low-resource settings. This prospective observational cohort study aimed to describe the bacterial pathogens, resistance profiles and clinical outcomes of patients with wound infections admitted to the largest specialized unit for burns and plastic surgery in Uganda. Blood and wound swab cultures were taken for bacterial species identification and antibiotic susceptibility testing. A total of 140 patients (female: n = 62, 44.3%) with a median age of 26 (IQR 7–35) years were included between October 2020 and April 2022, of which the majority (n = 101, 72.2%) had burn wounds (72.3% Grade 2b, 14.9% Grade 3). Gram-negative Enterobacterales, Pseudomonas spp. and Acinetobacter spp. were most commonly isolated from wound swabs and nearly all isolates were multidrug resistant with very limited treatment options. While the clinical outcome was favorable in 21 (15%) study participants, the majority were left with disabilities (minor: n = 41, 29.3%, moderate: n = 52, 37%, major: n = 14 (10%)). Twelve (8.6%) study participants died, mostly of Gram-negative sepsis. Our findings highlight the urgent need for routine access to microbiological diagnostics to improve patient care and local surveillance efforts on antimicrobial resistance.

We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR], 0.55; P < .001); both in younger (HR, 0.59; P < .001) and older patients (HR, 0.42; P < .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P < .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.

ZUSAMMENFASSUNG2019 wurden 1,4 Milliarden internationale Reisen gezählt, wobei Deutschland zu den reisefreudigsten Nationen zählt. Kinder stellen in der Reisemedizin eine vulnerable Gruppe mit speziellem Beratungsbedarf dar. Eine qualifizierte reisemedizinische Beratung mindestens 4–6 Wochen vor einer Reise kann Gesundheitsrisiken bei Kindern und Eltern minimieren. Neben der Empfehlung einer adäquaten Auslandskrankenversicherung muss der aktuelle Impfstatus erhoben und komplettiert und ggf. um spezifische Reiseimpfungen ergänzt werden. Weitere Beratungsinhalte zielen auf Verhaltensmaßnahmen (z. B. Nahrungsmittelhygiene, Sonnenschutz), auf den Insektenschutz (Expositionsprophylaxe) sowie auf die Malariaprophylaxe in Risikogebieten. Der betreuende Kinderarzt sollte die wichtigsten Reise- und Tropenerkrankungen in Grundzügen kennen. Viele reiseassoziierte Infektionskrankheiten wie Durchfälle oder Hauterkrankungen können kompetent vom Kinderarzt behandelt werden. Im Zweifelsfall ist frühzeitig Kontakt mit einem reise- oder tropenmedizinischen Zentrum aufzunehmen. Eine potenziell fatale Malaria-Erkrankung muss bei passender Reiseanamnese sowie Fieber oder sonstigen unklaren Symptomen als Differenzialdiagnose immer in Betracht gezogen werden.

Understanding SARS-CoV-2 breakthrough infections in vaccinated healthcare workers is of key importance in mitigating the effects of the COVID-19 pandemic in healthcare facilities. An observational prospective cohort study was conducted in vaccinated employees with acute SARS-CoV-2 infection between October 2021 and February 2022. Serological and molecular testing was performed to determine SARS-CoV-2 viral load, lineage, antibody levels, and neutralizing antibody titers. A total of 571 (9.7%) employees experienced SARS-CoV-2 breakthrough infections during the enrolment period, of which 81 were included. The majority (n = 79, 97.5%) were symptomatic and most (n = 75, 92.6%) showed Ct values < 30 in RT-PCR assays. Twenty-four (30%) remained PCR-positive for > 15 days. Neutralizing antibody titers were strongest for the wildtype, intermediate for Delta, and lowest for Omicron variants. Omicron infections occurred at higher anti-RBD-IgG serum levels (p = 0.00001) and showed a trend for higher viral loads (p = 0.14, median Ct difference 4.3, 95% CI [−2.5–10.5]). For both variants, viral loads were significantly higher in participants with lower anti-RBD-IgG serum levels (p = 0.02). In conclusion, while the clinical course of infection with both the Omicron and Delta variants was predominantly mild to moderate in our study population, waning immune response over time and prolonged viral shedding were observed.

Background Alveolar echinococcosis (AE) is an endemic parasitic zoonosis in Germany. In most cases, the liver is the primary organ affected. Case presentation A 59-year old female patient presented with increasing exertional dyspnea and unintentional weight loss. A computed tomography (CT) scan showed a left-sided chylous pleural effusion and multiple intrahepatic masses with infiltration of the diaphragm and the pleura. The findings were initially misinterpreted as hepatocellular carcinoma (HCC) with infiltrating growth. Liver biopsy of one of the masses showed no evidence of malignancy, but an amorphous necrosis of unclear origin. HCC was further ruled out by magnetic resonance imaging (MRI). However, MRI findings were highly suspicious for hepatothoracic dissemination and complications due to AE. Typical histologic findings in a repeated and more specific examination of the liver tissue and a positive serology for echinococcosis confirmed the diagnosis of AE. As the hepatic and pulmonary manifestations were considered inoperable in a curative matter, an anti-parasitic treatment with albendazole was initiated. A video-assisted thoracoscopic surgery (VATS) with removal of the chylous effusion as well as a talc pleurodesis was performed to relieve the patient from dyspnea. Two months later, the patient was asymptomatic and a positron emission tomography (PET)-CT-scan with [18 F] fluoro-2-deoxy-d-glucose (FDG) showed a remarkable diminution of the hepatic manifestation. Conclusions This case demonstrates a rare presentation of alveolar echinococcosis with a focus on pulmonary symptoms, emphasizing the importance of evaluation for pulmonary involvement in patients with AE and respiratory symptoms.

Wilms’ tumor 1 (WT1) protein is highly immunogenic and overexpressed in acute myeloid leukemia (AML), consequently ranked as a promising target for novel immunotherapeutic strategies. Here we report our experience of a phase I/II clinical trial (NCT01051063) of a vaccination strategy based on WT1 recombinant protein (WT1-A10) together with vaccine adjuvant AS01B in five elderly AML patients (median age 69 years, range 63–75) receiving a total of 62 vaccinations (median 18, range 3–20) after standard chemotherapy. Clinical benefit was observed in three patients: one patient achieved measurable residual disease clearance during WT1 vaccination therapy, another patient maintained long-term molecular remission over 59 months after the first vaccination cycle. Interestingly, in one case, we observed a complete clonal switch at AML relapse with loss of WT1 expression, proposing suppression of the original AML clone by WT1-based vaccination therapy. Detected humoral and cellular CD4+ T cell immune responses point to efficient immune stimulation post-vaccination, complementing hints for induced conventional T cell infiltration into the bone marrow and a shift from senescent/exhausted to a more activated T cell profile. Overall, the vaccinations with WT1 recombinant protein had an acceptable safety profile and were thus well tolerated.To conclude, our data provide evidence of potential clinical efficacy of WT1 protein-based vaccination therapy in AML patients, warranting further investigations.

ZUSAMMENFASSUNGIn den Jahren 2020 und 2021 kam es zu einer Aufeinanderfolge ungewöhnlich verlaufender Infektionen bei Lastkraftwagenfahrern, die in unserer Klinik behandelt wurden. Anhand von 5 Fallvignetten wird herausgearbeitet, dass Lastkraftwagenfahrer ein erhöhtes Risiko für potenziell schwer verlaufende Infektionskrankheiten durch individuelle und berufsbedingte Risikofaktoren sowie erschwerten Zugang zu medizinischer Versorgung aufweisen. Im professionellen Kontakt mit Patienten dieser Berufsgruppe ist daher besondere Aufmerksamkeit geboten.

Background Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. Methods In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. Findings From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). Interpretation When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. Funding US National Institutes of Health.

Purpose: Histone deacetylase inhibitors (HDACi) are being studied in clinical trials with the aim to induce cellular differentiation, growth arrest, and apoptosis of tumor cells. Recent reports suggest that the multidrug resistance-1 (MDR1) gene is regulated by epigenetic mechanisms. To investigate whether additional drug transporters are regulated by HDACi and how this affects cytotoxicity, acute myeloid leukemia (AML) cells were examined.Experimental Design: AML cells were cultured in the presence of phenylbutyrate, valproate, suberoylanilide hydroxamic acid, or trichostatin A and analyzed for drug transporter expression and function as well as sensitivity to anticancer drugs.Results:MDR1, breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins (MRP) 7 and 8 were induced in a dose- and time-dependent manner as shown by semiquantitative PCR. The pattern of gene induction was cell line specific. Phenylbutyrate induced P-glycoprotein and BCRP expression and the efflux of drugs as determined with labeled substrates. KG-1a cells treated with phenylbutyrate developed resistance to daunorubicin, mitoxantrone, etoposide, vinblastine, paclitaxel, topotecan, gemcitabine, and 5-fluorouracil; as a result drug-induced apoptosis was impaired. Chromatin immunoprecipitation revealed the hyperacetylation of histone proteins in the promoter regions of MDR1, BCRP, and MRP8 on valproate treatment. Furthermore, an alternative MRP8 promoter was induced by HDACi treatment.Conclusions: Exposure of AML cells to HDACi induces a drug resistance phenotype broader than the “classic multidrug resistance,” which might negatively affect treatment effectiveness.

Supplementary Data from Histone Deacetylase Inhibitors Induce a Very Broad, Pleiotropic Anticancer Drug Resistance Phenotype in Acute Myeloid Leukemia Cells by Modulation of Multiple ABC Transporter Genes

Supplementary Information: Supplementary Figures 1-11, Supplementary Figure Legends, Supplementary Tables 1-4

Hypomethylating agents (HMA) have become the backbone of nonintensive acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) treatment, also by virtue of their activity in patients with adverse genetics, for example, monosomal karyotypes, often with losses on chromosome 7, 5, or 17. No comparable activity is observed with cytarabine, a cytidine analogue without DNA-hypomethylating properties. As evidence exists for compounding hypermethylation and gene silencing of hemizygous tumor suppressor genes (TSG), we thus hypothesized that this effect may preferentially be reversed by the HMAs decitabine and azacitidine. An unbiased RNA-sequencing approach was developed to interrogate decitabine-induced transcriptome changes in AML cell lines with or without a deletion of chromosomes 7q, 5q or 17p. HMA treatment preferentially upregulated several hemizygous TSG in this genomic region, significantly derepressing endogenous retrovirus (ERV)3–1, with promoter demethylation, enhanced chromatin accessibility, and increased H3K4me3 levels. Decitabine globally reactivated multiple transposable elements, with activation of the dsRNA sensor RIG-I and interferon regulatory factor (IRF)7. Induction of ERV3–1 and RIG-I mRNA was also observed during decitabine treatment in vivo in serially sorted peripheral blood AML blasts. In patient-derived monosomal karyotype AML murine xenografts, decitabine treatment resulted in superior survival rates compared with cytarabine. Collectively, these data demonstrate preferential gene derepression and ERV reactivation in AML with chromosomal deletions, providing a mechanistic explanation that supports the clinical observation of superiority of HMA over cytarabine in this difficult-to-treat patient group.Significance:These findings unravel the molecular mechanism underlying the intriguing clinical activity of HMAs in AML/MDS patients with chromosome 7 deletions and other monosomal karyotypes.See related commentary by O'Hagan et al., p. 813

Supplementary Table 1 from Epigenetic Modification of CCAAT/Enhancer Binding Protein α Expression in Acute Myeloid Leukemia

SUMMARYThe majority of mitochondrial precursor proteins are imported through the Tom40 β-barrel channel of the translocase of the outer membrane (TOM). The sorting and assembly machinery (SAM) is essential for β-barrel membrane protein insertion into the outer membrane and thus required for the assembly of the TOM complex. Here we demonstrate that the a-helical outer membrane protein Mco6 forms a complex with the mitochondrial distribution and morphology protein Mdm10 as part of the SAM machinery. Moreover, Mco6 also interacts with the subunit Mim1 of the mitochondrial import complex (MIM), which is itself required for the biogenesis of a-helical outer membrane proteins.MCO6andMDM10display a negative genetic interaction and aMCO6-MDM10yeast double mutant contains reduced levels of TOM complex. Cells lacking Mco6 affect the levels of Mdm10 and MIM-subunits associated with assembly defects of the TOM complex. Thus, this work reveals a role of the SAMMco6complex for the biogenesis of the mitochondrial outer membrane.

Not available.

SMITH Science Day 2022, Aachen, Germany, 23 Nov 2022 - 23 Nov 2022; German Medical Science GMS Publishing House (2023). doi:10.3205/22SMITH01, Published by German Medical Science GMS Publishing House

Vaccination is considered one of the most important achievements of modern medicine and has saved millions of lives. As a result, the age-old fear of severe or fatal infectious diseases has largely been forgotten in society; however, the pandemic triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shows how quickly this fear can return. Also, many people have reservations about medical measures, especially if they are directed against vague dangers. Paradoxically, the success of vaccinations jeopardizes the acceptance. To counteract this development, this article provides information on basic vaccination principles, legal frameworks and components of vaccines. It explains the most important categories, goals, core elements of vaccination programs and the most important recommendations of the Standing Committee on Vaccination at the Robert Koch Institute (STIKO). It explains the current state of knowledge with respect to required resources, assessment of vaccine reactions, complication management and possible vaccine damage.

Treatment of myelodysplastic syndromes includes the administration of the hypomethylating agent decitabine. An early platelet response in decitabine-treated myelodysplastic syndrome patients is a predictor of overall survival. The effect of decitabine on megakaryocytes and the bone marrow, however, is understudied. We show that an early platelet increment was not detectable in healthy mice during decitabine treatment. Analyses of bone marrow sections revealed vessels with dilated lumina, decreased cellularity, but increased number of red blood cells and the presence of (pro)platelet-like particles. Taken together, decitabine treatment of healthy mice does not induce an early platelet increment, but affects the bone marrow.

In our study, we aimed to explore the profile of the high-risk subgroup of suicide attempters that used a violent means compared to suicide attempters that chose a non-violent suicide means. Therefore, we recruited a sample of inpatients with recent suicide attempts in three psychiatric hospitals in Thuringia, Germany. We used a structured clinical interview to assess the psychiatric diagnoses, sociodemographic data, and characteristics of the suicide attempt. Furthermore, we used several validated clinical questionnaires to measure suicidal ideations, suicide intent, depression severity, hopelessness, impulsivity, aggression, anger expression, and childhood trauma. We compared 41 individuals using violent means to 59 using non-violent means with univariate and multivariate statistical analyses. We found significantly (corrected for multiple comparisons) higher levels of impulsivity-related sensation-seeking in violent suicide attempters in univariate and multivariate analyses, and additionally in anger expression directed inward at an uncorrected statistical threshold. Besides that, there were no significant differences between the two groups. We assume that underlying neurocognitive mechanisms, such as impaired decision-making processes and/or differences in risk/loss assessment, could explain the higher levels of questionnaire-based sensation-seeking in subjects who use violent suicide means. Further research is needed, including neuroimaging and biochemical techniques, to gain more insight into the mechanisms underlying the choice of a suicidal means.

International audience; This study investigated the potential for the development of novel perceptual experiences through sustained training with a sensory augmentation device. We developed (1) a new geomagnetic sensory augmentation device, the NaviEar, and (2) a battery of tests for automaticity in the use of the device. The NaviEar translates head direction toward north into continuous sound according to a “wind coding” principle. To facilitate automatization of use, its design is informed by considerations of the embodiment of spatial orientation and multi-sensory integration, and it uses a sensory coding scheme derived from means for auditory perception of wind direction that is common in sailing because it is easy to understand and use. The test battery assesses different effects of automaticity (interference, rigidity of responses, and dynamic integration) assuming that automaticity is a necessary criterion to show the emergence of perceptual feel, that is, an augmented experience with perceptual phenomenal quality. We measured performance in simple training tasks, administered the tests for automaticity, and assessed subjective reports through a questionnaire. Results suggest that the NaviEar is easy and comfortable to use and has a potential for applications in real-world situations. Despite high usability, however, a 5-day training with the NaviEar did not reach levels of automaticity that are indicative of perceptual feel. We propose that the test battery for automaticity may be used as a benchmark test for iterative research on perceptual experiences in sensory augmentation and sensory substitution.

BackgroundDelay in diagnosing sepsis results in potentially preventable deaths. Mainly due to their complexity or limited applicability, machine learning (ML) models to predict sepsis have not yet become part of clinical routines. For this reason, we created a ML model that only requires complete blood count (CBC) diagnostics.MethodsNon-intensive care unit (non-ICU) data from a German tertiary care centre were collected from January 2014 to December 2021. Patient age, sex, and CBC parameters (haemoglobin, platelets, mean corpuscular volume, white and red blood cells) were utilised to train a boosted random forest, which predicts sepsis with ICU admission. Two external validations were conducted using data from another German tertiary care centre and the Medical Information Mart for Intensive Care IV database (MIMIC-IV). Using the subset of laboratory orders also including procalcitonin (PCT), an analogous model was trained with PCT as an additional feature.FindingsAfter exclusion, 1,381,358 laboratory requests (2016 from sepsis cases) were available. The derived CBC model shows an area under the receiver operating characteristic (AUROC) of 0.872 (95% CI, 0.857–0.887) for predicting sepsis. External validations show AUROCs of 0.805 (95% CI, 0.787–0.824) and 0.845 (95% CI, 0.837–0.852) for MIMIC-IV. The model including PCT revealed a significantly higher performance (AUROC: 0.857; 95% CI, 0.836–0.877) than PCT alone (AUROC: 0.790; 95% CI, 0.759–0.821; pInterpretationOur results demonstrate that routine CBC results could significantly improve diagnosis of sepsis when combined with ML. The CBC model can facilitate early sepsis prediction in non-ICU patients with high robustness in external validations. Its implementation in clinical decision support systems has strong potential to provide an essential time advantage and increase patient safety.FundingThe study was part of the AMPEL project (www.ampel.care), which is co-financed through public funds according to the budget decided by the Saxon State Parliament under the RL eHealthSax 2017/18 grant number 100331796.

The Excel-file provides the data accompanying our study "Can perception be extended to a “feel of north”? Tests of automaticity with the NaviEar" published in Adaptive Behaviour. If you look for the code of the NaviEar App, it may be found on GitHub: https://github.com/christophWit/NaviEar The Excel features 10 sheets with data. 1. Participants: Specification of participant sample; columns: participant ID (pp), sex (female, male), age, and the date of the first experimental day (dd, mm, yyyy). 2. Wrd2Pnt: Data from training task Word-to-Pointing; columns: participant ID (pp), measurement type (training or roated-signal test), reference orientation (RefOri; 0 = North), testing day (day), date (yyyy mm dd) & time (hh mm ss), session number (ss), trial number (trial), subversion (vers, 1 = off, 2 = on), tazi = test azimuth, razi = response azimuth, dazi = difference between test and response (razi - tazi),rt= response time,sub_1, sub_2,sub_3 = subjective ratings of familiarity, orientation, and loudness. 3. Snd2Pnt: Data from training task Sound-to-Pointing; format as Wrd2Pnt. 4. Snd2Wrd: Data from training task Sound-to-Word; format as Wrd2Pnt, except subversions (vers): 1 = delay, 2 = cue-on, 3 = on. 5. AngDff: Data from training task Angle-Difference; format as Wrd2Pnt, except tazi1 = first test azimuth, tazi2 = second test azimuth; dazi_dir = difference between both test azimuths (tazi2 - tazi1), including direction; dazi = absolute difference between test, i.e., without direction of difference; razi = responded azimuth difference between the two tests. 6. DisDetect: Data from Distortion Detection test; columns: participant ID (pp), session (ss), path (cf. Figure S3 in Supplementary Material), distortion (dist), 0 = no distortion, negative = distortion to the right, positive = distortion to the left, 1 = weak distortion (difficult), 2 = strong distortion (easy), distAmpli = distortion amplitude (in degree azimuth: 40 deg = weak, 70 deg = strong), distCentre, distWidth = parameters to localise distortion (centre and spread), rsp = response (0 = no, not distorted; 1 = yes, distorted). 7. Veering: Data from Veering test; columns: nr = trial number; path = path in Table S1 of the Supplementary Material; unlike in the other paths, there were no turns in the straight veering path (turn = 0), bias, bias_dir, & bias_lbl = indicate the type of bias: 0 = unbiased, negative = biased to the right, positive = biased to the left, missing value = no NaviEar; |bias| = 80 indicates the strength of bias in azimuth degree; start_ori = start orientation, target_ori target orientation (is the same as start orientation because the veering path does not have any turn), rsp_ori = response orientation, dff_ori = difference between target and response orientation, rsp_dst = distance from a straight line. 8. Interference: Data from Automatic interference test; columns: format as for Veering Test, except that path indicates the path as in Table S1 and turn the sum of 90 deg turns with direction (negative = right, positive = left); the target orientation (target_ori) is the sum of start orientation + turns (taking the direction of turns, i.e., the sign, into consideration). 9. PostExpQuest: Ratings from post experimental questionnaire (cf. Table S2 of Supplementary Material). 10. QualitativeData: Unconstrained text entries (comments) in postexperimental questionnaire (cf. Table S2 and Table S12).

Myelodysplasic Syndromes (MDS) are diseases occurring mainly in the elderly population. Although hematopoietic stem cell transplantation is the only hope for cure, a majority of the patients suffering from MDS are too old or frail for intensive treatment regimens such as intensive chemotherapy and transplantation. The gold standard for those patients is currently treatment with hypomethylating agents, although real life data could not reproduce the overall survival rates reported for the pivotal azacitidine phase III study. MDS treatment is often inspired by treatment for acute myeloid leukemia (AML). The new gold standard for elderly and frail patients not able to undergo intensive treatment regimens in AML is the combination of hypomethylating agents with venetoclax, a BCL-2 inhibitor that also showed excellent treatment outcomes in other hematological malignancies. In this review, we explain the rationale for the use of venetoclax in hematological malignancies, study outcomes available so far and the current knowledge of its use in MDS. This article is protected by copyright. All rights reserved.

BACKGROUND: The SARS-CoV-2 pandemic is a worldwide challenge. The CRIT-CoV-U pilot study generated a urinary proteomic biomarker consisting of 50 peptides (COV50), which predicted death and disease progression from SARS-CoV-2. After the interim analysis presented for the German Government, here, we aimed to analyse the full dataset to consolidate the findings and propose potential clinical applications of this biomarker. METHODS: CRIT-CoV-U was a prospective multicentre cohort study. In eight European countries (Austria, France, Germany, Greece, North Macedonia, Poland, Spain, and Sweden), 1012 adults with PCR-confirmed COVID-19 were followed up for death and progression along the 8-point WHO scale. Capillary electrophoresis coupled with mass spectrometry was used for urinary proteomic profiling. Statistical methods included logistic regression and receiver operating characteristic curve analysis with a comparison of the area under curve (AUC) between nested models. Hospitalisation costs were derived from the care facility corresponding with the Markov chain probability of reaching WHO scores ranging from 3 to 8 and flat-rate hospitalisation costs adjusted for the gross per capita domestic product of each country. FINDINGS: From June 30 to Nov 19, 2020, 228 participants were recruited, and from April 30, 2020, to April 14, 2021, 784 participants were recruited, resulting in a total of 1012 participants. The entry WHO scores were 1-3 in 445 (44%) participants, 4-5 in 529 (52%) participants, and 6 in 38 (4%) participants; and of all participants, 119 died and 271 had disease progression. The odds ratio (OR) associated with COV50 in all 1012 participants for death was 2·44 (95% CI 2·05-2·92) unadjusted and 1·67 (1·34-2·07) when adjusted for sex, age, BMI, comorbidities, and baseline WHO score; and for disease progression, the OR was 1·79 (1·60-2·01) when unadjusted and 1·63 (1·41-1·91) when adjusted (p

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with high potential of metastases and therapeutic resistance. Although genetic mutations drive PDAC initiation, they alone do not explain its aggressive nature. Epigenetic mechanisms, including aberrant DNA methylation and histone modifications, significantly contribute to inter- and intratumoral heterogeneity, disease progression and metastasis. Thus, increased understanding of the epigenetic landscape in PDAC could offer new potential biomarkers and tailored therapeutic approaches. In this review, we shed light on the role of epigenetic modifications in PDAC biology and on the potential clinical applications of epigenetic biomarkers in liquid biopsy. In addition, we provide an overview of clinical trials assessing epigenetically targeted treatments alone or in combination with other anticancer therapies to improve outcomes of patients with PDAC.