Search

OBJECTIVES:. Cardiogenic shock (CS) is associated with high mortality. Patients treated for CS mostly require heparin therapy, which may be associated with complications such as heparin-induced thrombocytopenia (HIT). HIT represents a serious condition associated with platelet decline and increased hypercoagulability and remains a poorly researched field in intensive care medicine. Primary purpose of this study was to: 1) determine HIT prevalence in CS, 2) assess the performance of common diagnostic tests for the workup of HIT, and 3) compare outcomes in CS patients with excluded and confirmed HIT. DESIGN:. Retrospective dual-center study including adult patients 18 years old or older with diagnosed CS and suspected HIT from January 2010 to November 2022. SETTING:. Cardiac ICU at the Ludwig-Maximilians University hospital in Munich and the university hospital of Bonn. PATIENTS AND INTERVENTIONS:. In this retrospective analysis, adult patients with diagnosed CS and suspected HIT were included. Differences in baseline characteristics, mortality, neurologic and safety outcomes between patients with excluded and confirmed HIT were evaluated. MEASUREMENTS AND MAIN RESULTS:. In cases of suspected HIT, positive screening antibodies were detected in 159 of 2808 patients (5.7%). HIT was confirmed via positive functional assay in 57 of 2808 patients, corresponding to a prevalence rate of 2.0%. The positive predictive value for anti-platelet factor 4/heparin screening antibodies was 35.8%. Total in-hospital mortality (58.8% vs. 57.9%; p > 0.999), 1-month mortality (47.1% vs. 43.9%; p = 0.781), and 12-month mortality (58.8% vs. 59.6%; p > 0.999) were similar between patients with excluded and confirmed HIT, respectively. Furthermore, no significant difference in neurologic outcome among survivors was found between groups (Cerebral Performance Category [CPC] score 1: 8.8% vs. 8.8%; p > 0.999 and CPC 2: 7.8% vs. 12.3%; p = 0.485). CONCLUSIONS:. HIT was a rare complication in CS patients treated with unfractionated heparin and was not associated with increased mortality. Also, HIT confirmation was not associated with worse neurologic outcome in survivors. Future studies should aim at developing more precise, standardized, and cost-effective strategies to diagnose HIT and prevent complications.

Background: MRI (magnetic resonance imaging) represents the diagnostic image modality of choice in several conditions. With an increasing number of patients requiring MRI for diagnostic purposes, the issue of safety in patients with cardiac implantable electronic devices (CIED) undergoing this imaging modality will play an ever more important role. The purpose of this study was to assess the safety and device function following MRI in an unrestricted real-world cohort of patients with a wide array of cardiac devices. Methods: We conducted a retrospective single-center study including 1010 MRI studies conducted in adult patients (≥18 years) with an implanted CIED treated in the University Hospital of Munich (LMU) between July 2012 and March 2024. Patients with non-MR conditionally labeled leads, abandoned or epicardial leads, as well as lead fragments, were included for analysis. Results: Across a total of 1010 MRIs (920 total MR-conditional device generators) performed in patients with an implanted CIED, there were no deaths, reports of discomfort, palpitations, heating, or ventricular arrythmias in the 24 h following MRI. Only 2/1010 MRIs were followed by a reported atrial arrhythmia within 24 h, both in patients with an MR-conditional pacemaker (PM) device without an abandoned lead. No significant changes in device function following MRI from baseline were observed across all included CIEDs. Lastly, no instances of severe malfunction, such as generator failure, loss of capture, electrical reset, or inappropriate inhibition of pacing, were found in post-MRI interrogation reports across all MRI studies. Conclusions: Based on the analysis of 1010 MRIs undergone by patients with CIEDs, following standardized device interrogation, manufacturer-advised device programming, monitoring of vital function, and manufacturer-advised reprogramming, MRI can be performed safely and without adverse events or changes in device function.

Critical care cardiology (CCC) in the modern era is shaped by a multitude of innovative treatment options and an increasingly complex, ageing patient population. Generating high-quality evidence for novel interventions and devices in an intensive care setting is exceptionally challenging. As a result, formulating the best possible therapeutic approach continues to rely predominantly on expert opinion and local standard operating procedures. Fostering the full potential of CCC and the maturation of the next generation of decision-makers in this field calls for an updated training concept, that encompasses the extensive knowledge and skills required to care for critically ill cardiac patients while remaining adaptable to the trainee’s individual career planning and existing educational programs. In the present manuscript, we suggest a standardized training phase in preparation of the first ICU rotation, propose a modular CCC core curriculum, and outline how training components could be conceptualized within three sub-specialization tracks for aspiring cardiac intensivists.

Abstract Glucocorticoid receptor (GR) is a transcription factor that plays a crucial role in cancer biology. In this study, we utilized an in silico‐designed GR activity signature to demonstrate that GR relates to the proliferative capacity of numerous primary cancer types. In breast cancer, the GR activity status determines luminal subtype identity and has implications for patient outcomes. We reveal that GR engages with estrogen receptor (ER), leading to redistribution of ER on the chromatin. Notably, GR activation leads to upregulation of the ZBTB16 gene, encoding for a transcriptional repressor, which controls growth in ER‐positive breast cancer and associates with prognosis in luminal A patients. In relation to ZBTB16's repressive nature, GR activation leads to epigenetic remodeling and loss of histone acetylation at sites proximal to cancer‐driving genes. Based on these findings, epigenetic inhibitors reduce viability of ER‐positive breast cancer cells that display absence of GR activity. Our findings provide insights into how GR controls ER‐positive breast cancer growth and may have implications for patients' prognostication and provide novel therapeutic candidates for breast cancer treatment.

Abstract Cells within the tumour microenvironment (TME) can impact tumour development and influence treatment response. Computational approaches have been developed to deconvolve the TME from bulk RNA-seq. Using scRNA-seq profiling from breast tumours we simulate thousands of bulk mixtures, representing tumour purities and cell lineages, to compare the performance of nine TME deconvolution methods (BayesPrism, Scaden, CIBERSORTx, MuSiC, DWLS, hspe, CPM, Bisque, and EPIC). Some methods are more robust in deconvolving mixtures with high tumour purity levels. Most methods tend to mis-predict normal epithelial for cancer epithelial as tumour purity increases, a finding that is validated in two independent datasets. The breast cancer molecular subtype influences this mis-prediction. BayesPrism and DWLS have the lowest combined numbers of false positives and false negatives, and have the best performance when deconvolving granular immune lineages. Our findings highlight the need for more single-cell characterisation of rarer cell types, and suggest that tumour cell compositions should be considered when deconvolving the TME.

While transcriptomics have enhanced our understanding for cancer, spatial transcriptomics enable the characterisation of cellular interactions. Here, the authors integrate single cell data with spatial information for HER2 + tumours and develop tools for the prediction of interactions between tumour-infiltrating cells.

Abstract Background Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC through unknown mechanisms. Methods Here, we have defined unique molecular insights into the function of ID4 in BLBC and the related disease high-grade serous ovarian cancer (HGSOC), by combining RIME proteomic analysis, ChIP-seq mapping of genomic binding sites and RNA-seq. Results These studies reveal novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage. Analysis of clinical samples demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair deficiency. Conclusions These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOC.

Summary: Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.

Subtypes of cancer associated fibroblasts can both promote and suppress tumorigenesis. Here, the authors investigate how p53 status in pancreatic cancer cells affects their interaction with cancer associated fibroblasts, and report perlecan as a mediator of the pro-metastatic environment.

Single cell RNA sequencing generates short reads from one end of a template, providing incomplete transcript coverage and limiting identification of diverse sequences such as antigen receptors. Here the authors combine long read nanopore sequencing with short read profiling of barcoded libraries to generate full-length antigen receptor sequences.

Summary: Inhibitor of differentiation (ID) proteins dimerize with basic HLH (bHLH) transcription factors, repressing transcription of lineage-specification genes across diverse cellular lineages. ID4 is a key regulator of mammary stem cells; however, the mechanism by which it achieves this is unclear. Here, we show that ID4 has a cell autonomous role in preventing myoepithelial differentiation of basal cells in mammary organoids and in vivo. ID4 positively regulates proliferative genes and negatively regulates genes involved in myoepithelial function. Mass spectrometry reveals that ID4 interacts with the bHLH protein HEB, which binds to E-box motifs in regulatory elements of basal developmental genes involved in extracellular matrix and the contractile cytoskeleton. We conclude that high ID4 expression in mammary basal stem cells antagonizes HEB transcriptional activity, preventing myoepithelial differentiation and allowing for appropriate tissue morphogenesis. Downregulation of ID4 during pregnancy modulates gene regulated by HEB, promoting specialization of basal cells into myoepithelial cells.

Stromal cell recruitment, activation and crosstalk with cancer cells is poorly understood. Here, the authors demonstrate that cancer cell-derived Hedgehog ligand triggers stromal remodeling that in turn induces a cancer-stem-cell like, drug-resistant phenotype of nearby cancer cells while treatment with smoothened inhibitors reverses these phenotypes.

ObjectiveThis retrospective study aimed to address acceptance and long-term adherence to Continuous Positive Airway Pressure (CPAP) treatment among non-responder patients to ImThera THN system who initially declined this therapy.Material and methodsWe employed a structured outpatient approach to communicate THN study results, categorize initial CPAP nonadherence reasons, and encourage CPAP trials through tailored appointments. Recorded follow-ups addressed individual concerns, providing medical guidance and acknowledging person-specific challenges. Adherence data were collected using CPAP hour meters at predetermined intervals, following Belgium's social security stipulations.ResultsBetween July 2014 and October 2016, eleven participants, including one woman, with prior CPAP experience (average 2 months) were enrolled. Initial non-adherence was linked to ENT or psychological factors. Ten patients agreed to CPAP trials, where interventions included changing CPAP brand, pressure adjustments, mask changes, and additional measures like cognitive-behavioral therapy and nasal spray. After 1 year, mean adherence was 6.3 ± 2 h/day, and average CPAP usage duration was 8.67 ± 2.13 years. As of November 2023, eight out of eleven patients were still actively using CPAPConclusionIn this investigation, we challenged the concept of CPAP non-adherence, highlighting evolving adherence and the significance of continuous monitoring and personalized interventions. Our findings underscore ongoing patient education, multidisciplinary support, and dynamic intervention adaptation for enhanced adherence in challenging patient populations. The results provide insights applicable to non-adherent patients with obstructive sleep apnea, emphasizing the importance of individualized care and sustained engagement for improved CPAP acceptance.

The cyclization of cis-2-(2-azidophenyl)-1-benzyl-3-ethoxycarbonylaziridines and trans-2-(2-azidophenyl)-3-nitrocyclopropane-1,1-dicarboxylates yielded the respective aziridino[2,3-c]quinolin-2-ones and cyclopropa[c]quinolin-2-ones. Ring-opening of the aziridine-fused species under silica gel catalysis provided 3-aminoquinolin-2-ones whereas the ring-expansion of the cyclopropane-fused derivatives by the action of sodium hydride gave 1-benzazepin-2-ones, in both cases in a regioselective manner. A computational study using DFT methods revealed that the mechanism for the transformation of cyclopropa[c]quinolin-2-ones into 1-benzazepin-2-ones involves the initial deprotonation step of its amide function followed by two pericyclic events: a 6π-electrocyclic ring opening and a subsequent [1,5]-H shift. Keywords: Aziridino[2,3-c]quinolin-2-ones, Cyclopropa[c]quinolin-2-ones, 3-aminoquinolin-2-ones, Benzazepin-2-ones, 6π-electrocyclic ring opening, [1,5]-H shift

We aim to establish a rough first prospect on the potential of certain biorelevant solvents (water, ammonia, and methane) being present in liquid form inside the uppermost few meters of several modeled rocky and icy surfaces of hypothetical bodies orbiting active galactic nuclei (AGNs) and investigate under which constraints this might occur. For this, we adjust and average X-ray spectra from a sample of 20 Type-1 Seyfert galaxies to calculate the mean snowline of the sample used. We then vary the hypothetical body’s orbit between 10% and 100% of the snowline radius and calculate a sub-surface attenuation within four different model surface compositions for each. We then use this as a continuous source term for a thermal model. Example bodies are systematically investigated with sizes between 1/30 and 20 earth radii, with further variations also considered (such as possible bound rotation), to end up with a perspective of solvent phases under a wide slew of different conditions. We find that liquid solvents are possible under a multitude of parameters, with temperature being the main constraint to liquid water whereas body size and pressure are the main constraint to liquid methane and ammonia.

Obstructive sleep apnoea syndrome (OSAS) is a highly prevalent chronic respiratory disorder with prevalence among adult males of ≥10%. The most common daytime symptom associated with OSAS is excessive sleepiness, which in more severe manifestations can result in sleepiness at the wheel while driving and probably contributes to the substantial increase in accident risk among patients with OSAS. Fortunately, current evidence indicates that successful therapy of OSAS, particularly with continuous positive airway pressure, can bring the accident risk down to levels similar to an equivalent general population. The recognition of the increased driving accident risk in OSAS prompted the Transport and Mobility Directorate of the European Commission to establish a working group on this topic in 2012, which ultimately led to a revision of Annex III of the EU Driving Licence Directive, which is subject to mandatory implementation by European Union member states by December 2015. This directive specifies that patients with moderate or severe OSAS associated with significant daytime sleepiness should be prohibited from driving until effective therapy is established. These new regulations are designed to balance the legitimate objective of public safety with not penalising OSAS patients who are complying with effective therapy. Successful implementation of regulations on driving in OSAS patients must also include measures to educate relevant stakeholders including patients, medical personnel, traffic police and employers in the transport industry. The key objective is to encourage patients with possible OSAS to seek diagnosis and treatment and not to inhibit OSAS patients from coming forward.