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Abstract The diagnosis of lymphomas is challenging due to their diverse histological presentations and clinical manifestations. There is a need for inexpensive tools that require minimal expertise and are accessible for routine laboratories. Contrastingly, current conventional diagnostic methods are often found only in specialized environments. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy offers a nondestructive and user-friendly approach in the analysis of a wide range of samples. In this paper, we determined whether the technique coupled with machine learning can detect and differentiate lymphoma within lymphoid tissue samples. Tissue sections from 295 individuals diagnosed with lymphoma and 389 individuals without the disease were analyzed using ATR-FTIR spectroscopy. The resulting spectral dataset was split using a 70:30 train-test split. Partial least Squares Discriminant Analysis (PLS-DA) models were trained to distinguish non-malignant lymphoid tissue from lymphoma samples and to differentiate between subtypes. On the training set (n = 478), significant spectral differences were mainly identified in the 1800–900 cm–1 region, attributed to fundamental biochemical constituents like proteins, lipids, carbohydrates, and nucleic acids. On the independent test set (n = 206), the trained PLS-DA model achieved a promising AUC of 0.882 (95% CI: 0.881–0.884) in the differentiation between lymphoma and non-malignant lymphoid tissue. In addition, comparative analyses revealed spectral distinctions and notable clustering between the different lymphoma subtypes. This study provides valuable insights into the application of ATR-FTIR spectroscopy and machine learning in the field of lymphoma diagnosis as a non-destructive, rapid and inexpensive tool with the potential to be easily implemented in non-specialized laboratories.

Abstract Until recently, treatment options for patients diagnosed with Acute Myeloid Leukemia (AML) were limited and predominantly relied on various combinations, dosages, or schedules of traditional chemotherapeutic agents. Patients with advanced age, relapsed/refractory disease or comorbidities were often left without effective treatment options. Novel advances in the understanding of leukemogenesis at the molecular and genetic levels, alongside recent progress in drug development, have resulted in the emergence of novel therapeutic agents and strategies for AML patients. Among these innovations, the receptor tyrosine kinase AXL has been established as a promising therapeutic target for AML. AXL is a key regulator of several cellular functions, including epithelial-to-mesenchymal transition in tumor cells, immune regulation, apoptosis, angiogenesis and the development of chemoresistance. Clinical studies of AXL inhibitors, as single agents and in combination therapy, have demonstrated promising efficacy in treating AML. Additionally, novel AXL-targeted therapies, such as AXL-specific antibodies or antibody fragments, present potential solutions to overcome the limitations associated with traditional small-molecule AXL inhibitors or multikinase inhibitors. This review provides a comprehensive overview of the structure and biological functions of AXL under normal physiological conditions, including its role in immune regulation. We also summarize AXL’s involvement in cancer, with a specific emphasis on its role in the pathogenesis of AML, its contribution to immune evasion and drug resistance. Moreover, we discuss the AXL inhibitors currently undergoing (pre)clinical evaluation for the treatment of AML.

Abstract CAR T cells are widely applied for relapsed hematological cancer patients. With six approved cell therapies, for Multiple Myeloma and other B-cell malignancies, new insights emerge. Profound evidence shows that patients who fail CAR T-cell therapy have, aside from antigen escape, a more glycolytic and weakened metabolism in their CAR T cells, accompanied by a short lifespan. Recent advances show that CAR T cells can be metabolically engineered towards oxidative phosphorylation, which increases their longevity via epigenetic and phenotypical changes. In this review we elucidate various strategies to rewire their metabolism, including the design of the CAR construct, co-stimulus choice, genetic modifications of metabolic genes, and pharmacological interventions. We discuss their potential to enhance CAR T-cell functioning and persistence through memory imprinting, thereby improving outcomes. Furthermore, we link the pharmacological treatments with their anti-cancer properties in hematological malignancies to ultimately suggest novel combination strategies.

Abstract Multiple Myeloma (MM), a cancer of terminally differentiated plasma cells, is the second most prevalent hematological malignancy and is incurable due to the inevitable development of drug resistance. Intense protein synthesis is a distinctive trait of MM cells, supporting the massive production of clonal immunoglobulins or free light chains. The mammalian target of rapamycin (mTOR) kinase is appreciated as a master regulator of vital cellular processes, including regulation of metabolism and protein synthesis, and can be found in two multiprotein complexes, mTORC1 and mTORC2. Dysregulation of these complexes is implicated in several types of cancer, including MM. Since mTOR has been shown to be aberrantly activated in a large portion of MM patients and to play a role in stimulating MM cell survival and resistance to several existing therapies, understanding the regulation and functions of the mTOR complexes is vital for the development of more effective therapeutic strategies. This review provides a general overview of the mTOR pathway, discussing key discoveries and recent insights related to the structure and regulation of mTOR complexes. Additionally, we highlight findings on the mechanisms by which mTOR is involved in protein synthesis and delve into mTOR-mediated processes occurring in MM. Finally, we summarize the progress and current challenges of drugs targeting mTOR complexes in MM.

IntroductionThe pathogenesis of Attention-Deficit Hyperactivity Disorder (ADHD) is thought to be multifactorial, with a potential role for the bidirectional communication between the gut microbiome and brain development and function. Since the “golden-standard” medication therapy with methylphenidate (MPH) is linked to multiple adverse effects, there is a need for alternative treatment options such as dietary polyphenols. These secondary plant metabolites exert antioxidant and anti-inflammatory effects, but much less is known about their impact on the gut microbiota. Since polyphenols are believed to modulate gut microbial composition, interventions might be advantageous in ADHD therapy. Therefore, intervention studies with polyphenols in ADHD therapy investigating the gut microbial composition are highly relevant.MethodsBesides the primary research questions addressed previously, this study explored a potential prebiotic effect of the polyphenol-rich French Maritime Pine Bark Extract (PBE) compared to MPH and a placebo in pediatric ADHD patients by studying their impact on the gut microbiota via amplicon sequencing of the full length 16S rRNA gene ribosomal subunit (V1-V9).ResultsOne interesting finding was the high relative abundance of Bifidobacteria among all patients in our study cohort. Moreover, our study has identified that treatment (placebo, MPH and PBE) explains 3.94% of the variation in distribution of microbial taxa (adjusted p-value of 0.011).DiscussionOur small sample size (placebo: n = 10; PBE: n = 13 and MPH: n = 14) did not allow to observe clear prebiotic effects in the patients treated with PBE. Notwithstanding this limitation, subtle changes were noticeable and some limited compositional changes could be observed.Clinical Trial Registrationdoi: 10.1186/S13063-017-1879-6

Abstract Background 5’ untranslated regions (5’UTRs) are essential modulators of protein translation. Predicting the impact of 5’UTR variants is challenging and rarely performed in routine diagnostics. Here, we present a combined approach of a comprehensive prioritization strategy and functional assays to evaluate 5’UTR variation in two large cohorts of patients with inherited retinal diseases (IRDs). Methods We performed an isoform-level re-analysis of retinal RNA-seq data to identify the protein-coding transcripts of 378 IRD genes with highest expression in retina. We evaluated the coverage of their 5’UTRs by different whole exome sequencing (WES) kits. The selected 5’UTRs were analyzed in whole genome sequencing (WGS) and WES data from IRD sub-cohorts from the 100,000 Genomes Project (n = 2397 WGS) and an in-house database (n = 1682 WES), respectively. Identified variants were annotated for 5’UTR-relevant features and classified into seven categories based on their predicted functional consequence. We developed a variant prioritization strategy by integrating population frequency, specific criteria for each category, and family and phenotypic data. A selection of candidate variants underwent functional validation using diverse approaches. Results Isoform-level re-quantification of retinal gene expression revealed 76 IRD genes with a non-canonical retina-enriched isoform, of which 20 display a fully distinct 5’UTR compared to that of their canonical isoform. Depending on the probe design, 3–20% of IRD genes have 5’UTRs fully captured by WES. After analyzing these regions in both cohorts, we prioritized 11 (likely) pathogenic variants in 10 genes (ARL3, MERTK, NDP, NMNAT1, NPHP4, PAX6, PRPF31, PRPF4, RDH12, RD3), of which 7 were novel. Functional analyses further supported the pathogenicity of three variants. Mis-splicing was demonstrated for the PRPF31:c.-9+1G>T variant. The MERTK:c.-125G>A variant, overlapping a transcriptional start site, was shown to significantly reduce both luciferase mRNA levels and activity. The RDH12:c.-123C>T variant was found in cis with the hypomorphic RDH12:c.701G>A (p.Arg234His) variant in 11 patients. This 5’UTR variant, predicted to introduce an upstream open reading frame, was shown to result in reduced RDH12 protein but unaltered mRNA levels. Conclusions This study demonstrates the importance of 5’UTR variants implicated in IRDs and provides a systematic approach for 5’UTR annotation and validation that is applicable to other inherited diseases.

Abstract Acute Myeloid Leukemia (AML) is a heterogeneous disease with limited treatment options and a high demand for novel targeted therapies. Since myeloid-related protein S100A9 is abundantly expressed in AML, we aimed to unravel the therapeutic impact and underlying mechanisms of targeting both intracellular and extracellular S100A9 protein in AML cell lines and primary patient samples. S100A9 silencing in AML cell lines resulted in increased apoptosis and reduced AML cell viability and proliferation. These therapeutic effects were associated with a decrease in mTOR and endoplasmic reticulum stress signaling. Comparable results on AML cell proliferation and mTOR signaling could be observed using the clinically available S100A9 inhibitor tasquinimod. Interestingly, while siRNA-mediated targeting of S100A9 affected both extracellular acidification and mitochondrial metabolism, tasquinimod only affected the mitochondrial function of AML cells. Finally, we found that S100A9-targeting approaches could significantly increase venetoclax sensitivity in AML cells, which was associated with a downregulation of BCL-2 and c-MYC in the combination group compared to single agent therapy. This study identifies S100A9 as a novel molecular target to treat AML and supports the therapeutic evaluation of tasquinimod in venetoclax-based regimens for AML patients.

Abstract Objectives Different materials have been used for capping the pulp after exposure during caries removal in permanent teeth. The purpose of this study was to collate and analyze all pertinent evidence from randomized controlled trials (RCTs) on different materials used in patients undergoing pulpotomy or direct pulp capping in carious teeth. Materials and Methods Trials comparing two or more capping agents used for direct pulp capping (DPC) or pulpotomy were considered eligible. An electronic search of four databases and two clinical trial registries was carried out up to February 28, 2021 using a search strategy properly adapted to the PICO framework. Screening, data extraction, and risk of bias (RoB) assessment of primary studies were performed in duplicate and independently. The primary outcome was clinical and radiological success; secondary outcomes included continued root formation, tooth discoloration, and dentin bridge formation. Results 21 RCTs were included in the study. The RoB assessment indicated a moderate risk among the studies. Due to significant clinical and statistical heterogeneity among the studies, performing network meta‐analysis (NMA) was not possible. An ad hoc subgroup analysis revealed strong evidence of a higher success of DPC with Mineral Trioxide Aggregate (MTA) compared to calcium hydroxide (CH) (odds ratio [OR] = 3.10, 95% confidence interval [CI]: 1.66−5.79). MTA performed better than CH in pulp capping (both DPC and pulpotomy) of mature compared to immature teeth (OR = 3.34, 95% CI: 1.81−6.17). The GRADE assessment revealed moderate strength of evidence for DPC and mature teeth, and low to very low strength of evidence for the remaining subgroups. Conclusions Considerable clinical and statistical heterogeneity among the trials did not allow NMA. The ad hoc subgroup analysis indicated that the clinical and radiographic success of MTA was higher than that of CH but only in mature teeth and DPC cases where the strength of evidence was moderate. PROSPERO Registration: number CRD42020127239.

En pocas palabras, el objetivo de la coronariografía diagnóstica es diferenciar el origen del dolor torácico de un paciente entre 1 de 4 endotipos: a) estenosis epicárdica; b) espasmo coronario; c) enfermedad microvascular coronaria (EMC); y d) igualmente importante, dolor torácico no coronario. Resulta imperativo señalar que este último es un diagnóstico por descarte y, por lo tanto, no puede confirmarse sin realizar una valoración formal de los demás mecanismos implicados (figura 1). A pesar de esta verdad palmaria, la interpretación de la mayoría de las coronariografías se limita a la mera «observación» de un «sombragrama». Un abordaje con un bajo rendimiento diagnóstico, ya que el 40% de los pacientes no presentan estenosis epicárdicas significativas, una entidad conocida como angina sin enfermedad coronaria obstructiva (ANOCA)1. A pe­sar de la presencia de angina típica o de la evidencia de isquemia durante las pruebas no invasivas, estos pacientes suelen quedar descartados sin más sin un diagnóstico formal. Figura 1. Se debe realizar un cateterismo con coronariografía a los pacientes que presentan dolor torácico intenso, recurrente y debilitante y, cuando sea necesario, pruebas de la función coronaria para averiguar el mecanismo desencadenante del dolor. El dolor torácico de origen no coronario es un diagnóstico...

Simply stated, the goal of diagnostic coronary angiography is to distinguish the cause of a patient’s chest pain from 1 of 4 endotypes: a) epicardial stenosis; b) coronary spasm; c) coronary microvascular disease (CMD); and d) —equally important—noncoronary chest pain. Crucially, the latter is a diagnosis of exclusion and consequently cannot be confirmed without formal assessment of the other mechanisms (figure 1). Despite this truism, the interpretation of most coronary angiograms is limited to simple “eyeballing” of an epicardial “shadowgram”. This approach has a low diagnostic yield with 40% of patients found to have no significant epicardial stenoses—an entity known as angina with no obstructive coronary arteries (ANOCA).1 Despite the presence of typical angina or evidence of ischemia during noninvasive testing, these patients, are frequently nonchalantly dismissed without a formal diagnosis. Figure 1. Patients with compelling, recurring, and debilitating chest pain should undergo catheterization with coronary angiography and—when needed—coronary function testing to unravel the mechanism of their pain. Noncoronary chest pain is a diagnosis of exclusion and consequently can only be confirmed if the 3 other mechanisms have been assessed. FFR, fractional flow reserve; PPG, pullback pressure gradient. This very large group of patients is heterogeneous, and establishing the underlying cause of...

Abstract Background LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency disease (PID) characterized by a regulatory T cell defect resulting in immune dysregulation and autoimmunity. We present two siblings born to consanguineous parents of North African descent with LRBA deficiency and central nervous system (CNS) manifestations. As no concise overview of these manifestations is available in literature, we compared our patient’s presentation with a reviewed synthesis of the available literature. Case presentations The younger brother presented with enteropathy at age 1.5 years, and subsequently developed Evans syndrome and diabetes mellitus. These autoimmune manifestations led to the genetic diagnosis of LRBA deficiency through whole exome sequencing with PID gene panel. At 11 years old, he had two tonic–clonic seizures. Brain MRI showed multiple FLAIR-hyperintense lesions and a T2-hyperintense lesion of the cervical medulla. His sister presented with immune cytopenia at age 9 years, and developed diffuse lymphadenopathy and interstitial lung disease. Genetic testing confirmed the same mutation as her brother. At age 13 years, a brain MRI showed multiple T2-FLAIR-hyperintense lesions. She received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) 3 months later. Follow-up MRI showed regression of these lesions. Conclusions Neurological disease is documented in up to 25% of patients with LRBA deficiency. Manifestations range from cerebral granulomas to acute disseminating encephalomyelitis, but detailed descriptions of neurological and imaging phenotypes are lacking. LRBA deficiency amongst other PIDs should be part of the differential diagnosis in patients with inflammatory brain lesions. We strongly advocate for a more detailed description of CNS manifestations in patients with LRBA deficiency, when possible with MR imaging. This will aid clinical decision concerning both anti-infectious and anti-inflammatory therapy and in considering the indication for allo-HSCT.

Background Following percutaneous coronary intervention (PCI), optical coherence tomography provides prognosis information. The pullback pressure gradient is a novel index that discriminates focal from diffuse coronary artery disease based on fractional flow reserve pullbacks. We sought to investigate the association between coronary artery disease patterns, defined by coronary physiology, and optical coherence tomography after stent implantation in stable patients undergoing PCI. Methods and Results This multicenter, prospective, single‐arm study was conducted in 5 countries (NCT03782688). Subjects underwent motorized fractional flow reserve pullbacks evaluation followed by optical coherence tomography‐guided PCI. Post‐PCI optical coherence tomography minimum stent area, stent expansion, and the presence of suboptimal findings such as incomplete stent apposition, stent edge dissection, and irregular tissue protrusion were compared between patients with focal versus diffuse disease. Overall, 102 patients (105 vessels) were included. Fractional flow reserve before PCI was 0.65±0.14, pullback pressure gradient was 0.66±0.14, and post‐PCI fractional flow reserve was 0.88±0.06. The mean minimum stent area was 5.69±1.99 mm2 and was significantly larger in vessels with focal disease (6.18±2.12 mm2 versus 5.19±1.72 mm2, P=0.01). After PCI, incomplete stent apposition, stent edge dissection, and irregular tissue protrusion were observed in 27.6%, 10.5%, and 51.4% of the cases, respectively. Vessels with focal disease at baseline had a lower prevalence of incomplete stent apposition (11.3% versus 44.2%, P=0.002) and more irregular tissue protrusion (69.8% versus 32.7%, P

ABSTRACT Wolbachia are a genus of insect endosymbiotic bacteria which includes strains wMel and wAlbB that are being utilized as a biocontrol tool to reduce the incidence of Aedes aegypti-transmitted viral diseases like dengue. However, the precise mechanisms underpinning the antiviral activity of these Wolbachia strains are not well defined. Here, we generated a panel of Ae. aegypti-derived cell lines infected with antiviral strains wMel and wAlbB or the non-antiviral Wolbachia strain wPip to understand host cell morphological changes specifically induced by antiviral strains. Antiviral strains were frequently found to be entirely wrapped by the host endoplasmic reticulum (ER) membrane, while wPip bacteria clustered separately in the host cell cytoplasm. ER-derived lipid droplets (LDs) increased in volume in wMel- and wAlbB-infected cell lines and mosquito tissues compared to cells infected with wPip or Wolbachia-free controls. Inhibition of fatty acid synthase (required for triacylglycerol biosynthesis) reduced LD formation and significantly restored ER-associated dengue virus replication in cells occupied by wMel. Together, this suggests that antiviral Wolbachia strains may specifically alter the lipid composition of the ER to preclude the establishment of dengue virus (DENV) replication complexes. Defining Wolbachia’s antiviral mechanisms will support the application and longevity of this effective biocontrol tool that is already being used at scale.IMPORTANCEAedes aegypti transmits a range of important human pathogenic viruses like dengue. However, infection of Ae. aegypti with the insect endosymbiotic bacterium, Wolbachia, reduces the risk of mosquito to human viral transmission. Wolbachia is being utilized at field sites across more than 13 countries to reduce the incidence of viruses like dengue, but it is not well understood how Wolbachia induces its antiviral effects. To examine this at the subcellular level, we compared how different strains of Wolbachia with varying antiviral strengths associate with and modify host cell structures. Strongly antiviral strains were found to specifically associate with the host endoplasmic reticulum and induce striking impacts on host cell lipid droplets. Inhibiting Wolbachia-induced lipid redistribution partially restored dengue virus replication demonstrating this is a contributing role for Wolbachia's antiviral activity. These findings provide new insights into how antiviral Wolbachia strains associate with and modify Ae. aegypti host cells.

Background: The Apfel simplified risk score includes four risk factors: female sex, non-smoking status, postoperative nausea and vomiting or motion sickness history, and postoperative opioid use. The score is calculated preoperatively, so postoperative opioid use must be predicted. We aimed to determine whether anaesthetists can predict patients' postoperative opioid use and dose. Methods: Specialist anaesthetists from eight hospitals preoperatively predicted opioid use and dose in the post-anaesthesia care unit (PACU) and for the first 24 h postoperatively, which was compared with actual opioid use and dose. Opioid doses were converted to oral morphine equivalents (MEQ). Correlations between predicted and actual opioid use and dose were analysed with Spearman's rho and linear regression. Results: A total of 487 anaesthetist–patient pairs were included. Anaesthetists overpredicted opioid use (398 [82%] predicted vs 251 [52%] actual patients requiring opioids in the PACU; 396 [81%] predicted vs 291 [60%] actual in the first 24 h) (Spearman's rho [95% confidence interval] 0.24 [0.16–0.33], P

The role of coronary CT angiography for the diagnosis and risk stratification of coronary artery disease is well established. However, its potential beyond the diagnostic phase remains to be determined. The current review focuses on the insights that coronary CT angiography can provide when planning and performing percutaneous coronary interventions. We describe a novel approach incorporating anatomical and functional pre-procedural planning enhanced by artificial intelligence, computational physiology and online 3D CT guidance for percutaneous coronary interventions. This strategy allows the individualisation of patient selection, optimisation of the revascularisation strategy and effective use of resources.

BackgroundImmunotherapeutic targets in multiple myeloma (MM) have variable expression height and are partly expressed in subfractions of patients only. With increasing numbers of available compounds, strategies for appropriate choice of targets (combinations) are warranted. Simultaneously, risk assessment is advisable as patient’s life expectancy varies between months and decades.MethodsWe first assess feasibility of RNA-sequencing in a multicenter trial (GMMG-MM5, n=604 patients). Next, we use a clinical routine cohort of untreated symptomatic myeloma patients undergoing autologous stem cell transplantation (n=535, median follow-up (FU) 64 months) to perform RNA-sequencing, gene expression profiling (GEP), and iFISH by ten-probe panel on CD138-purified malignant plasma cells. We subsequently compare target expression to plasma cell precursors, MGUS (n=59), asymptomatic (n=142) and relapsed (n=69) myeloma patients, myeloma cell lines (n=26), and between longitudinal samples (MM vs. relapsed MM). Data are validated using the independent MMRF CoMMpass-cohort (n=767, FU 31 months).ResultsRNA-sequencing is feasible in 90.8% of patients (GMMG-MM5). Actionable immune-oncological targets (n=19) can be divided in those expressed in all normal and >99% of MM-patients (CD38, SLAMF7, BCMA, GPRC5D, FCRH5, TACI, CD74, CD44, CD37, CD79B), those with expression loss in subfractions of MM-patients (BAFF-R [81.3%], CD19 [57.9%], CD20 [82.8%], CD22 [28.4%]), aberrantly expressed in MM (NY-ESO1/2 [12%], MUC1 [12.7%], CD30 [4.9%], mutated BRAF V600E/K [2.1%]), and resistance-conveying target-mutations e.g., against part but not all BCMA-directed treatments. Risk is assessable regarding proliferation, translated GEP- (UAMS70-, SKY92-, RS-score) and de novo (LfM-HRS) defined risk scores. LfM-HRS delineates three groups of 40%, 38%, and 22% of patients with 5-year and 12-year survival rates of 84% (49%), 67% (18%), and 32% (0%). R-ISS and RNA-sequencing identify partially overlapping patient populations, with R-ISS missing, e.g., 30% (22/72) of highly proliferative myeloma.ConclusionRNA-sequencing based assessment of risk and targets for first choice treatment is possible in clinical routine.

Abstract Global catch rates of sharks and rays from artisanal fisheries are underreported, leading to a lack of data on population status. This forms a major barrier to developing effective management plans, such is the case in Central and West Africa. Over 3 years, we undertook the first systematic quantitative assessment of sharks and rays landed by an artisanal fishery in the Republic of the Congo. During 507 sampling days (mean 14 surveys per month), we recorded 73,268 individuals. These comprised 42 species, of which 81% are considered at an elevated risk of extinction. Landings were dominated by immature individuals, especially for species of conservation concern. Presence of species thought to have largely disappeared from the region such as the African wedgefish (Rhynchobatus luebberti) and smoothback angelshark (Squatina oculata) suggest Congolese waters are a potential stronghold for these species—warranting increased protection. We identified seasonality of catch within years, but not across years. Both inter‐ and intra‐annual trends varied by species, signifying annual fluctuations in catch of each species but consistent catch of all species year‐on‐year. Analysis showed increased catch between the short‐wet and the long‐wet, and the long‐dry seasons (January–February and August–September). Lowest catch was shown to occur during the short‐wet and the short‐dry seasons (October–December), which may provide an opportunity for seasonal closures or gear restrictions.

The introduction of the Metaverse and the rise of social virtual reality platforms such as VRChat has led to increased communication and collaboration in virtual reality. As interactions in social virtual reality take place through avatars, the behaviour, and in particular the eye gaze of an avatar can have an impact on the user experience. However, it is still unclear which features of the user experience are most influenced. Therefore, this study used data from 44 female participants to investigate how avatar gaze behaviour (static eyes vs. real-time tracked eyes) affects their perceived quality of communication and the amount of one-sided eye contact participants make during a communicative or collaborative task in virtual reality. In addition, the study investigated the mediating role of perceived avatar “uncanniness” (i.e., the finding that humanoid objects that imperfectly resemble real people evoke feelings of discomfort) in this relationship and the moderation effect of two multi-user scenarios (collaboration vs. communication). The results showed that uncanniness directly affected the perceived quality of communication. However, it did not significantly mediate the relationship between avatar eye gaze behaviour and the quality of communication or the amount of one-sided eye contact. Finally, there were no significant differences in user experience between the two scenarios. From this, we can conclude that the uncanniness of an avatar being interacted with in VR is not enough to hinder communication and collaboration in an immersive medium. And even if an avatar is perceived as uncanny, normative communication cues such as eye contact are still present. Notably, due to sample availability, the results of this study are based on a female-only sample. Thus, future research can benefit from exploring the outlined effects in a more gender-balanced sample.

Abstract Background Obesity in adolescents is a growing public health issue. Bariatric surgery is an effective, yet controversial treatment option for adolescents. The moral acceptability of this procedure by health-care professionals as well as the general public can be influenced by its portrayal in the news media. Our objective was to analyze how newspaper articles portrayed adolescent bariatric surgery, with attention to the language used and moral arguments made. Methods Using an inductive thematic analysis approach, we analyzed 26 UK and 12 US newspaper articles (2014–2022) on adolescent bariatric surgery for implicit or explicit moral evaluations and use of normative language. Coding was performed after immersive reading, assisted by NVivo. Themes were identified and refined iteratively through consecutive auditing cycles to enrich the depth and rigor of our analysis. Results The major themes identified related to (1) defining the burden of adolescent obesity, (2) sparking moral outrage, (3) sensation-seeking, and (4) raising ethical issues. The articles employed moral language, specifically non-neutral and negative discourse regarding surgery. Blame was attributed to adolescents or their parents. Sensationalist wording often reinforced the normative content, drawing the attention of the reader and contributing to stigmatization of adolescents with severe obesity as lacking will power and being lazy. Further moral issues that stood out were the challenges in obtaining an informed consent, and the unequal access to surgery for socially disadvantaged groups. Conclusions Our findings provide insights into how adolescent bariatric surgery is represented in the print news media. Despite frequent citing of experts and studies on the efficacy, safety and unmet need for bariatric surgery, obesity and surgery in adolescents are often stigmatized and sensationalized, with (prospective) patients depicted as looking for an easy way out in the form of a solution brought by others (health systems, society, tax payers). This may increase the stigma surrounding adolescent obesity, and therefore limit the acceptability of specific treatments such as bariatric surgery.

Abstract The extracellular 373‐kDa PehA heme peroxidase of Pseudomonas putida KT2440 has two enzymatic domains which depend on heme cofactor for their peroxidase activity. A null pehA mutant was generated to examine the impact of PehA in rhizosphere colonization competence and the induction of plant systemic resistance (ISR). This mutant was not markedly hampered in colonization efficiency. However, increase in pehA dosage enhanced colonization fitness about 30 fold in the root and 900 fold in the root apex. In vitro assays with purified His‐tagged enzymatic domains of PehA indicated that heme‐dependent peroxidase activity was required for the enhancement of root tip colonization. Evaluation of live/dead cells confirmed that overexpression of pehA had a positive effect on bacterial cell viability. Following root colonization of rice plants by KT2440 strain, the incidence of rice blast caused by Magnaporthe oryzae was reduced by 65% and the severity of this disease was also diminished in comparison to non‐treated plants. An increase in the pehA dosage was also beneficial for the control of rice blast as compared with gene inactivation. The results suggest that PehA helps P. putida to cope with the plant‐imposed oxidative stress leading to enhanced colonization ability and concomitant ISR‐elicitation.

Background Cardiac death or myocardial infarction still occurs in patients undergoing contemporary percutaneous coronary intervention (PCI). We aimed to identify adverse clinical and vessel characteristics related to hard outcomes after PCI and to investigate their individual and combined prognostic implications. Methods and Results From an individual patient data meta‐analysis of 17 cohorts of patients who underwent post‐PCI fractional flow reserve measurement after drug‐eluting stent implantation, 2081 patients with available clinical and vessel characteristics were analyzed. The primary outcome was cardiac death or target‐vessel myocardial infarction at 2 years. The mean age of patients was 64.2±10.2 years, and the mean angiographic percent diameter stenosis was 63.9%±14.3%. Among 11 clinical and 8 vessel features, 4 adverse clinical characteristics (age ≥65 years, diabetes, chronic kidney disease, and left ventricular ejection fraction

BackgroundInfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is clinically diverse, and children have a low risk of developing severe coronavirus disease 2019 (COVID-19). However, children with chronic diseases have a potentially increased risk.MethodsWe performed a prospective surveillance study with longitudinal serum SARS-CoV-2 anti-nucleocapsid antibody quantification and questionnaires in pediatric tertiary care patients during the first waves of the COVID-19 pandemic (November 2020–September 2021). The results were compared with those of healthy children and adults from the same geographic area.ResultsWe obtained 525 samples from 362 patients (M/F ratio of 1.3:1; median age of 11.1 years) comprising children with immune-suppressive or immune-modulating drugs (32.9%), inborn errors of immunity (23.5%), type 1 diabetes mellitus (15.2%), and rheumatic diseases (11.9%). A total of 51 (9.7%) samples were seropositive among 37/351 children (10.5%). Seropositivity increased from 5.8% in November–December 2020 to 21.6% in July–September 2021. Compared with adults, a longitudinal analysis revealed reduced seroprevalence but similar kinetics as in children from the same country. Demographic or social variables and disease characteristics did not correlate with seropositivity. Being obese and household contact with COVID-19-infected individuals significantly increased the odds of infection. The majority of seropositive patients had mild symptoms (21/37). One-third were asymptomatic and/or unaware of having COVID-19 (10/37). Four patients (4/37) needed hospitalization, with good clinical outcomes.ConclusionsAlthough harboring a chronic disease, we observed a low SARS-CoV-2 incidence in a cohort of pediatric tertiary care patients, comparable with healthy children during the first year of the pandemic. Infection was mostly associated with mild symptoms.

Multiple myeloma (MM) is the second most prevalent hematologic malignancy and is incurable because of the inevitable development of drug resistance. Methionine adenosyltransferase 2α (MAT2A) is the primary producer of the methyl donor S-adenosylmethionine (SAM) and several studies have documented MAT2A deregulation in different solid cancers. As the role of MAT2A in MM has not been investigated yet, the aim of this study was to clarify the potential role and underlying molecular mechanisms of MAT2A in MM, exploring new therapeutic options to overcome drug resistance. By analyzing publicly available gene expression profiling data, MAT2A was found to be more highly expressed in patient-derived myeloma cells than in normal bone marrow plasma cells. The expression of MAT2A correlated with an unfavorable prognosis in relapsed patients. MAT2A inhibition in MM cells led to a reduction in intracellular SAM levels, which resulted in impaired cell viability and proliferation, and induction of apoptosis. Further mechanistic investigation demonstrated that MAT2A inhibition inactivated the mTOR-4EBP1 pathway, accompanied by a decrease in protein synthesis. MAT2A targeting in vivo with the small molecule compound FIDAS-5 was able to significantly reduce tumor burden in the 5TGM1 model. Finally, we found that MAT2A inhibition can synergistically enhance the anti-MM effect of the standard-of-care agent bortezomib on both MM cell lines and primary human CD138+ MM cells. In summary, we demonstrate that MAT2A inhibition reduces MM cell proliferation and survival by inhibiting mTOR-mediated protein synthesis. Moreover, our findings suggest that the MAT2A inhibitor FIDAS-5 could be a novel compound to improve bortezomib-based treatment of MM.

A decoction of Rhizophora mucronata Lam. mangrove bark is used as an antidiabetic treatment in Asia. Kombucha tea is a fermented beverage, which is also claimed to be antidiabetic. In this work, the potency of R. mucronata leaves as α-glucosidase inhibitor was studied to assess whether it could be a suitable alternative to the use of R. mucronata bark. α-glucosidase inhibitory activities were determined for three extracts prepared from R. mucronata leaves, being the unfermented tea of R. mucronata leaves, the fermented kombucha tea and an 80% methanolic extract of the residual R. mucronata leaves. Flavonoid glycosides were identified in tea powder, kombucha tea and in the crude methanolic extract. Both the unfermented tea and the kombucha tea after 7 days of fermentation inhibited α-glucosidase with IC50 values of 0.12 ± 0.02 mg/mL and 0.09 ± 0.04 mg/mL, respectively. The methanolic extract showed a stronger α-glucosidase inhibitory activity compared to the kombucha tea and tea powder with an IC50 value of 0.0435 ± 0.0007 mg/mL. Acarbose, used as a positive control, inhibited α-glucosidase with an IC50 value of 2.4 ± 0.2 mg/mL. It was found that the three types of preparations of R. mucronata all were potent α-glucosidase inhibitors.

The emergence of artificial intelligence and machine learning (ML) has revolutionized the landscape of clinical medicine, offering opportunities to improve medical practice and research. This narrative review explores the current status and prospects of applying ML to chronic kidney disease (CKD). ML, at the intersection of statistics and computer science, enables computers to derive insights from extensive datasets, thereby presenting an interesting landscape for constructing statistical models and improving data interpretation. The integration of ML into clinical algorithms aims to increase efficiency and promote its adoption as a standard approach to data interpretation in nephrology. As the field of ML continues to evolve, collaboration between clinicians and data scientists is essential for defining data-sharing and usage policies, ultimately contributing to the advancement of precision diagnostics and personalized medicine in the context of CKD.

Continuous Thermodilution is a novel method of quantifying coronary flow (Q) in mL/min. To account for variability of Q within the cardiac cycle, the trace is smoothened with a 2 s moving average filter. This can sometimes be ineffective due to significant heart rate variability, ventricular extrasystoles, and deep inspiration, resulting in a fluctuating temperature trace and ambiguity in the location of the “steady state”. This study aims to assess whether a longer moving average filter would smoothen any fluctuations within the continuous thermodilution traces resulting in improved interpretability and reproducibility on a test–retest basis. Patients with ANOCA underwent repeat continuous thermodilution measurements. Analysis of traces were performed at averages of 10, 15, and 20 s to determine the maximum acceptable average. The maximum acceptable average was subsequently applied as a moving average filter and the traces were re-analysed to assess the practical consequences of a longer moving average. Reproducibility was then assessed and compared to a 2 s moving average. Of the averages tested, only 10 s met the criteria for acceptance. When the data was reanalysed with a 10 s moving average filter, there was no significant improvement in reproducibility, however, it resulted in a 12% diagnostic mismatch. Applying a longer moving average filter to continuous thermodilution data does not improve reproducibility. Furthermore, it results in a loss of fidelity on the traces, and a 12% diagnostic mismatch. Overall, current practice should be maintained.

Objectives: We aimed to determine the association between newborn bacterial colonization and infant respiratory morbidity in the first 6 months of life. Methods: This prospective study included healthy newborn infants. Nasopharyngeal swabs performed within 72 hours of delivery were analyzed using polymerase chain reaction. We assessed cumulative respiratory morbidity of infants at 6 months. Results: A total of 426 mother-infant pairs were recruited. In 53.3% (n = 225) of newborns, Streptococcus pneumoniae (46%) and Staphylococcus aureus (7.3%) were isolated. None had Haemophilus influenzae nor Moraxella catarrhalis. At the age of 6 months, 50.7% of infants had experienced respiratory symptoms, 25% had unscheduled doctor visits, and 10% were treated with nebulizers. Colonization with S. pneumoniae was associated with reduced risk of any respiratory symptom (adjusted odds ratio [aOR] 0.39, 95% confidence interval [CI] 0.16, 0.50), unscheduled doctor visits (aOR 0.35; 95% CI 0.18, 0.67), and nebulizer treatment (aOR 0.23, 95% CI 0.07, 0.72) at 6 months. Pregnancy-induced hypertension was also associated with increased need for nebulizer treatment (aOR 9.11, 95% CI 1.43, 58.1). Conclusion: Colonization of the newborn respiratory tract occurred in 53% of infants. S. pneumoniae was the most common organism, and this was associated with a reduced risk for respiratory morbidity at 6 months of life.

Abstract Cancer cells are well-known for their capacity to adapt their metabolism to their increasing energy demands which is necessary for tumor progression. This is no different for Multiple Myeloma (MM), a hematological cancer which develops in the bone marrow (BM), whereby the malignant plasma cells accumulate and impair normal BM functions. It has become clear that the hypoxic BM environment contributes to metabolic rewiring of the MM cells, including changes in metabolite levels, increased/decreased activity of metabolic enzymes and metabolic shifts. These adaptations will lead to a pro-tumoral environment stimulating MM growth and drug resistance In this review, we discuss the identified metabolic changes in MM and the BM microenvironment and summarize how these identified changes have been targeted (by inhibitors, genetic approaches or deprivation studies) in order to block MM progression and survival.

Abstract Background Most studies examining survival of neonates with congenital diaphragmatic hernia (CDH) are in high-income countries. We aimed to describe the management, survival to hospital discharge rate, and factors associated with survival of neonates with unilateral CDH in a middle-income country. Methods We retrospectively reviewed the medical notes of neonates with unilateral CDH admitted to a pediatric intensive care unit (PICU) in a tertiary referral center over a 15-year period, from 2003–2017. We described the newborns’ respiratory care pathways and then compared baseline demographic, hemodynamic, and respiratory indicators between survivors and non-survivors. The primary outcome measure was survival to hospital discharge. Results Altogether, 120 neonates were included with 43.3% (52/120) diagnosed antenatally. Stabilization occurred in 38.3% (46/120) with conventional ventilation, 13.3% (16/120) with high-frequency intermittent positive-pressure ventilation, and 22.5% (27/120) with high frequency oscillatory ventilation. Surgical repair was possible in 75.0% (90/120). The overall 30-day survival was 70.8% (85/120) and survival to hospital discharge was 66.7% (80/120). Survival to hospital discharge tended to improve over time (p > 0.05), from 56.0% to 69.5% before and after, respectively, a service reorganization. For those neonates who could be stabilized and operated on, 90.9% (80/88) survived to hospital discharge. The commonest post-operative complication was infection, occurring in 43.3%. The median survivor length of stay was 32.5 (interquartile range 18.8–58.0) days. Multiple logistic regression modelling showed vaginal delivery (odds ratio [OR] = 4.8; 95% confidence interval [CI] [1.1–21.67]; p = 0.041), Apgar score $$\ge$$ ≥ 7 at 5 min (OR = 6.7; 95% CI [1.2–36.3]; p = 0.028), and fraction of inspired oxygen (FiO2)

BackgroundThe increasing number of infections caused by Escherichia coli resistant to clinically important antibiotics is a global concern for human and animal health. High overall levels of extended-spectrum beta-lactamase (ESBL)-producing and ciprofloxacin-resistant (ciproR) Escherichia coli in livestock are reported in Belgium. This cross-sectional study aimed to genotypically characterize and trace ESBL-and ciproR-E. coli of Belgian food-producing animals.MethodsA total of 798 fecal samples were collected in a stratified-random sampling design from Belgian broilers and sows. Consequently, 77 ESBL-E. coli and 84 ciproR-E. coli were sequenced using Illumina MiSeq. Minimum inhibitory concentration (MIC) for fluoroquinolones and cephalosporins were determined. Molecular in silico typing, resistance and virulence gene determination, and plasmid identification was performed. Scaffolds harboring ESBL or plasmid-mediated quinolone resistance (PMQR) genes were analyzed to detect mobile genetic elements (MGEs) and plasmid origins. Core genome allelic distances were used to determine genetic relationships among isolates.ResultsA variety of E. coli sequence types (ST) (n = 63), resistance genes and virulence profiles was detected. ST10 was the most frequently encountered ST (8.1%, n = 13). The pandemic multidrug-resistant clone ST131 was not detected. Most farms harbored more than one ESBL type, with blaCTX-M-1 (41.6% of ESBL-E. coli) being the most prevalent and blaCTX M-15 (n = 3) being the least prevalent. PMQR genes (15.5%, n = 13) played a limited role in the occurrence of ciproR-E. coli. More importantly, sequential acquisition of mutations in quinolone resistance-determining regions (QRDR) of gyrA and parC led to increasing MICs for fluoroquinolones. GyrA S83L, D87N and ParC S80I mutations were strongly associated with high-level fluoroquinolone resistance. Genetically related isolates identified within the farms or among different farms highlight transmission of resistant E. coli or the presence of a common reservoir. IncI1-I(alpha) replicon type plasmids carried different ESBL genes (blaCTX-M-1, blaCTX-M-32 and blaTEM-52C). In addition, the detection of plasmid replicons with associated insertion sequence (IS) elements and ESBL/PMQR genes in different farms and among several STs (e.g., IncI1-I(alpha)/IncX3) underline that plasmid transmission could be another important contributor to transmission of resistance in these farms.ConclusionOur findings reveal a multifaceted narrative of transmission pathways. These findings could be relevant in understanding and battling the problem of antibiotic resistance in farms.

Abstract Background Multiple myeloma (MM) remains an incurable cancer despite advances in therapy. Therefore, the search for new targets is still essential to uncover potential treatment strategies. Metabolic changes, induced by the hypoxic bone marrow, contribute to both MM cell survival and drug resistance. Pyrroline-5-carboxylate reductase 1 and 2 (PYCR1 and PYCR2) are two mitochondrial enzymes that facilitate the last step in the glutamine-to-proline conversion. Overexpression of PYCR1 is involved in progression of several cancers, however, its’ role in hematological cancers is unknown. In this study, we investigated whether PYCR affects MM viability, proliferation and response to bortezomib. Methods Correlation of PYCR1/2 with overall survival was investigated in the MMRF CoMMpass trial (653 patients). OPM-2 and RPMI-8226 MM cell lines were used to perform in vitro experiments. RPMI-8226 cells were supplemented with 13C-glutamine for 48 h in both normoxia and hypoxia (

Background Angiographic parameters can facilitate the risk stratification of coronary lesions but remain insufficient in the prediction of future myocardial infarction (MI).AIMS We compared the ability of humans, angiographic parameters and deep learning (DL) to predict the lesion that would be responsible for a future MI in a population of patients with non-significant CAD at baseline.Methods We retrospectively included patients who underwent invasive coronary angiography (ICA) for MI, in whom a previous angiogram had been performed within 5 years. The ability of human visual assessment, diameter stenosis, area stenosis, quantitative flow ratio (QFR) and DL to predict the future culprit lesion (FCL) was compared.Results In total, 746 cropped ICA images of FCL and non-culprit lesions (NCL) were analysed. Predictive models for each modality were developed in a training set before validation in a test set. DL exhibited the best predictive performance with an area under the curve of 0.81, compared with diameter stenosis (0.62, p=0.04), area stenosis (0.58, p=0.05) and QFR (0.67, p=0.13). DL exhibited a significant net reclassification improvement (NRI) compared with area stenosis (0.75, p=0.03) and QFR (0.95, p=0.01), and a positive nonsignificant NRI when compared with diameter stenosis. Among all models, DL demonstrated the highest accuracy (0.78) followed by QFR (0.70) and area stenosis (0.68). Predictions based on human visual assessment and diameter stenosis had the lowest accuracy (0.58).Conclusion In this feasibility study, DL outperformed human visual assessment and established angiographic parameters in the prediction of FCLs. Larger studies are now required to confirm this finding.

Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies.Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases.Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.

Background Immunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells. S100A9 was previously identified as a key regulator of myeloid cell accumulation and suppressive activity. Tasquinimod, a small molecule inhibitor of S100A9, is currently in a phase Ib/IIa clinical trial in MM patients (NCT04405167). We aimed to gain more insights into its mechanisms of action both on the myeloma cells and the immune microenvironment.Methods We analyzed the effects of tasquinimod on MM cell viability, cell proliferation and downstream signaling pathways in vitro using RNA sequencing, real-time PCR, western blot analysis and multiparameter flow cytometry. Myeloid cells and T cells were cocultured at different ratios to assess tasquinimod-mediated immunomodulatory effects. The in vivo impact on immune cells (myeloid cell subsets, macrophages, dendritic cells), tumor load, survival and bone disease were elucidated using immunocompetent 5TMM models.Results Tasquinimod treatment significantly decreased myeloma cell proliferation and colony formation in vitro, associated with an inhibition of c-MYC and increased p27 expression. Tasquinimod-mediated targeting of the myeloid cell population resulted in increased T cell proliferation and functionality in vitro. Notably, short-term tasquinimod therapy of 5TMM mice significantly increased the total CD11b+ cells and shifted this population toward a more immunostimulatory state, which resulted in less myeloid-mediated immunosuppression and increased T cell activation ex vivo. Tasquinimod significantly reduced the tumor load and increased the trabecular bone volume, which resulted in prolonged overall survival of MM-bearing mice in vivo.Conclusion Our study provides novel insights in the dual therapeutic effects of the immunomodulator tasquinimod and fosters its evaluation in combination therapy trials for MM patients.

There is increasing attention given to the concept of trustworthiness for artificial intelligence and robotics. However, trust is highly context-dependent, varies among cultures, and requires reflection on others’ trustworthiness, appraising whether there is enough evidence to conclude that these agents deserve to be trusted. Moreover, little research exists on what happens when too much trust is placed in robots and autonomous systems. Conceptual clarity and a shared framework for approaching overtrust are missing. In this contribution, we offer an overview of pressing topics in the context of overtrust and robots and autonomous systems. Our review mobilizes insights solicited from in-depth conversations from a multidisciplinary workshop on the subject of trust in human–robot interaction (HRI), held at a leading robotics conference in 2020. A broad range of participants brought in their expertise, allowing the formulation of a forward-looking research agenda on overtrust and automation biases in robotics and autonomous systems. Key points include the need for multidisciplinary understandings that are situated in an eco-system perspective, the consideration of adjacent concepts such as deception and anthropomorphization, a connection to ongoing legal discussions through the topic of liability, and a socially embedded understanding of overtrust in education and literacy matters. The article integrates diverse literature and provides a ground for common understanding for overtrust in the context of HRI.

Background Coronary artery disease (CAD) patterns play an essential role in the decision‐making process about revascularization. The pullback pressure gradient (PPG) quantifies CAD patterns as either focal or diffuse based on fractional flow reserve (FFR) pullbacks. The objective of this study was to evaluate the impact of CAD patterns on acute percutaneous coronary intervention (PCI) results considered surrogates of clinical outcomes. Methods and Results This was a prospective, multicenter study of patients with hemodynamically significant CAD undergoing PCI. Motorized FFR pullbacks and optical coherence tomography (OCT) were performed before and after PCI. Post‐PCI FFR >0.90 was considered an optimal result. Focal disease was defined as PPG >0.73 (highest PPG tertile). Overall, 113 patients (116 vessels) were included. Patients with focal disease were younger than those with diffuse CAD (61.4±9.9 versus 65.1±8.7 years, P=0.042). PCI in vessels with high PPG (focal CAD) resulted in higher post‐PCI FFR (0.91±0.07 in the focal group versus 0.86±0.05 in the diffuse group, P

The success of immunotherapeutic approaches in hematological cancers is partially hampered by the presence of an immunosuppressive microenvironment. Myeloid-derived suppressor cells (MDSC) are key components of this suppressive environment and are frequently associated with tumor cell survival and drug resistance. Based on their morphology and phenotype, MDSC are commonly subdivided into polymorphonuclear MDSC (PMN-MDSC or G-MDSC) and monocytic MDSC (M-MDSC), both characterized by their immunosuppressive function. The phenotype, function and prognostic value of MDSC in hematological cancers has been intensively studied; however, the therapeutic targeting of this cell population remains challenging and needs further investigation. In this review, we will summarize the prognostic value of MDSC and the different attempts to target MDSC (or subtypes of MDSC) in hematological cancers. We will discuss the benefits, challenges and opportunities of using MDSC-targeting approaches, aiming to enhance anti-tumor immune responses of currently used cellular and non-cellular immunotherapies.

Background Deferring revascularization in patients with nonsignificant stenoses based on fractional flow reserve (FFR) is associated with favorable clinical outcomes up to 15 years. Whether this holds true in patients with reduced left ventricular ejection fraction is unclear. We aimed to investigate whether FFR provides adjunctive clinical benefit compared with coronary angiography in deferring revascularization of patients with intermediate coronary stenoses and reduced left ventricular ejection fraction. Methods and Results Consecutive patients with reduced left ventricular ejection fraction (≤50%) undergoing coronary angiography between 2002 and 2010 were screened. We included patients with at least 1 intermediate coronary stenosis (diameter stenosis ≥40%) in whom revascularization was deferred based either on angiography plus FFR (FFR guided) or angiography alone (angiography guided). The primary end point was the cumulative incidence of all‐cause death at 10 years. The secondary end point (incidence of major adverse cardiovascular and cerebrovascular events) was a composite of all‐cause death, myocardial infarction, any revascularization, and stroke. A total of 840 patients were included (206 in the FFR‐guided group and 634 in the angiography‐guided group). Median follow‐up was 7 years (interquartile range, 3.22–11.08 years). After 1:1 propensity‐score matching, baseline characteristics between the 2 groups were similar. All‐cause death was significantly lower in the FFR‐guided group compared with the angiography‐guided group (94 [45.6%] versus 119 [57.8%]; hazard ratio [HR], 0.65 [95% CI, 0.49–0.85]; P

Objectives: To evaluate the effect of French Maritime Pine Bark Extract (PBE; Pycnogenol®) on immune, oxidative stress and neurochemical biomarkers in paediatric Attention-Deficit Hyperactivity Disorder (ADHD) as compared to methylphenidate (MPH) and placebo. Results: Paediatric ADHD patients (n = 88, 70 % male, mean age 10.1 years) were randomised (placebo (n = 30), PBE (n = 32) and MPH (n = 26)) receiving 20 mg/day if

Objectives: Determine the effect of French Maritime Pine Bark Extract (PBE; Pycnogenol®) on Attention-Deficit Hyperactivity Disorder (ADHD) behaviour and co-morbid physical/psychiatric symptoms, compared to placebo and the medicine MPH, and to assess its tolerability. Behaviour (measured by the ADHD-Rating Scale (ADHD-RS) and Social-Emotional Questionnaire (SEQ)) and physical complaints were evaluated in weeks 5 and 10. Results: Eighty-eight paediatric ADHD patients (70 % male, mean age 10.1 years) were randomised to placebo (n = 30), PBE (n = 32) or MPH (n = 26). Teachers reported significant improvement of total and hyperactivity/impulsivity ADHD-RS scores by PBE and MPH after 10 weeks compared to placebo. MPH also improved inattention. SEQ ratings support ADHD-RS results. Adverse effects were reported five times more frequently for MPH than for PBE. Conclusions: PBE appears a good alternative for MPH in paediatric ADHD and especially in the primary school environment, a fortiori when considering its almost complete lack of adverse effects.

Uromodulin, also known as Tamm-Horsfall protein, represents the predominant urinary protein in healthy individuals. Over the years, studies have revealed compelling associations between urinary and serum concentrations of uromodulin and various parameters, encompassing kidney function, graft survival, cardiovascular disease, glucose metabolism, and overall mortality. Consequently, there has been a growing interest in uromodulin as a novel and effective biomarker with potential applications in diverse clinical settings. Reduced urinary uromodulin levels have been linked to an elevated risk of acute kidney injury (AKI) following cardiac surgery. In the context of chronic kidney disease (CKD) of different etiologies, urinary uromodulin levels tend to decrease significantly and are strongly correlated with variations in estimated glomerular filtration rate. The presence of uromodulin in the serum, attributable to basolateral epithelial cell leakage in the thick ascending limb, has been observed. This serum uromodulin level is closely associated with kidney function and histological severity, suggesting its potential as a biomarker capable of reflecting disease severity across a spectrum of kidney disorders. The UMOD gene has emerged as a prominent locus linked to kidney function parameters and CKD risk within the general population. Extensive research in multiple disciplines has underscored the biological significance of the top UMOD gene variants, which have also been associated with hypertension and kidney stones, thus highlighting the diverse and significant impact of uromodulin on kidney-related conditions. UMOD gene mutations are implicated in uromodulin-associated kidney disease, while polymorphisms in the UMOD gene show a significant association with CKD. In conclusion, uromodulin holds great promise as an informative biomarker, providing valuable insights into kidney function and disease progression in various clinical scenarios. The identification of UMOD gene variants further strengthens its relevance as a potential target for better understanding kidney-related pathologies and devising novel therapeutic strategies. Future investigations into the roles of uromodulin and regulatory mechanisms are likely to yield even more profound implications for kidney disease diagnosis, risk assessment, and management.

Background: The DynamX Novolimus-Eluting Coronary Bioadaptor System (DynamX® Bioadaptor) has uncaging elements that disengage after the resorption of the polymer coating, aiming to restore vessel function in the treated segment and to avoid long-term adverse outcomes associated with the permanent caging of the coronary artery seen with conventional stenting. Methods: This prospective, multicenter, single-arm first-in-human study enrolled 50 patients in Belgium and Italy who were treated with the DynamX Bioadaptor. Eligible patients had de novo lesions in coronary arteries measuring between 2.5 and 3.5 mm in diameter and ≤24 mm in length. Clinical follow-up was performed up to 36 months. This analysis includes the intention-to-treat population and is based on data available. The preclinical studies include optical coherence tomography (OCT) analyses of 5 DynamX Bioadaptors implanted in 3 mini Yucatan pigs (at 3, 12 and 24 months), and assessment of smooth muscle cell gene expression profile in 8 pigs of which each was implanted with the DynamX Bioadaptor and the Xience drug-eluting stent. To assess the gene expression profile by quantitative real-time polymerase chain reaction, animals were sacrificed at 3, 6, 9 and 12 months. Results: Target lesion failure at 36 months was 8.7% (4/46), consisting of one clinically-driven target lesion revascularization and 3 cardiac deaths (all site-reported to be unrelated to the device or procedure). There were no additional target vessel revascularization and no definite or probable scaffold thrombosis. Preclinical data confirmed late lumen enlargement (from 7.02 ± 1.31 mm2 at baseline to 8.46 ± 1.31 mm2 at 24 months) and identified an increased expression of contractile genes around 9 months compared to a conventional drug-eluting stent. Conclusions: The DynamX Bioadaptor demonstrated very good 36-month clinical outcomes, highlighted by the absence of target-vessel myocardial infarction and definite or probable device thrombosis, and only one target lesion revascularization up to 36 months. These data are supported by preclinical studies that showed late lumen enlargement by OCT and an increased expression of contractile genes around 9 months compared to conventional drug-eluting stents, indicating faster vessel healing. Larger clinical studies are necessary to compare outcomes against contemporary drug-eluting stents. Clinical Trial Registration: https://clinicaltrials.gov/: NCT03429894.

Assessing coronary physiology after stent implantation facilitates the optimisation of percutaneous coronary intervention (PCI). Coronary artery disease (CAD) patterns can be characterised by the pullback pressure gradient (PPG) index. The impact of focal vs. diffuse disease on physiology-guided incremental optimisation strategy (PIOS) is unknown. This is a sub-study of the TARGET-FFR randomized clinical trial (NCT03259815). The study protocol directed that optimisation be attempted for patients in the PIOS arm when post-PCI FFR was n = 61 PIOS and 53 controls) with both pre-PCI fractional flow reserve (FFR) pullbacks and post-PCI FFR were included. A PPG ≥ 0.74 defined focal CAD. The PPG correlated significantly with post-PCI FFR (r = 0.43; 95% CI 0.26 to 0.57; p-value < 0.001) and normalised delta FFR (r = 0.49; 95% CI 0.34 to 0.62; p-value < 0.001). PIOS was more frequently applied to vessels with diffuse CAD (6% focal vs. 42% diffuse; p-value = 0.006). In patients randomized to PIOS, those with focal disease achieved higher post-PCI FFR than patients with diffuse CAD (0.93 ± 0.05 vs. 0.83 ± 0.07, p < 0.001). There was a significant interaction between CAD patterns and the randomisation arm for post-PCI FFR (p-value for interaction = 0.004). Physiology-guided stent optimisation was applied more frequently to vessels with diffuse disease; however, patients with focal CAD at baseline achieved higher post-PCI FFR.

Drug resistance (DR) of cancer cells leading to relapse is a huge problem nowadays to achieve long-lasting cures for cancer patients. This also holds true for the incurable hematological malignancy multiple myeloma (MM), which is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Although new treatment approaches combining immunomodulatory drugs, corticosteroids, proteasome inhibitors, alkylating agents, and monoclonal antibodies have significantly improved median life expectancy, MM remains incurable due to the development of DR, with the underlying mechanisms remaining largely ill-defined. It is well-known that MM is a heterogeneous disease, encompassing both genetic and epigenetic aberrations. In normal circumstances, epigenetic modifications, including DNA methylation and posttranslational histone modifications, play an important role in proper chromatin structure and transcriptional regulation. However, in MM, numerous epigenetic defects or so-called ‘epimutations’ have been observed and this especially at the level of DNA methylation. These include genome-wide DNA hypomethylation, locus specific hypermethylation and somatic mutations, copy number variations and/or deregulated expression patterns in DNA methylation modifiers and regulators. The aberrant DNA methylation patterns lead to reduced gene expression of tumor suppressor genes, genomic instability, DR, disease progression, and high-risk disease. In addition, the frequency of somatic mutations in the DNA methylation modifiers seems increased in relapsed patients, again suggesting a role in DR and relapse. In this review, we discuss the recent advances in understanding the involvement of aberrant DNA methylation patterns and/or DNA methylation modifiers in MM development, progression, and relapse. In addition, we discuss their involvement in MM cell plasticity, driving myeloma cells to a cancer stem cell state characterized by a more immature and drug-resistant phenotype. Finally, we briefly touch upon the potential of DNA methyltransferase inhibitors to prevent relapse after treatment with the current standard of care agents and/or new, promising (immuno) therapies.

Abstract Multiple myeloma (MM) is a heterogeneous haematological disease that remains clinically challenging. Increased activity of the epigenetic silencer EZH2 is a common feature in patients with poor prognosis. Previous findings have demonstrated that metabolic profiles can be sensitive markers for response to treatment in cancer. While EZH2 inhibition (EZH2i) has proven efficient in inducing cell death in a number of human MM cell lines, we hereby identified a subset of cell lines that despite a global loss of H3K27me3, remains viable after EZH2i. By coupling liquid chromatography-mass spectrometry with gene and miRNA expression profiling, we found that sensitivity to EZH2i correlated with distinct metabolic signatures resulting from a dysregulation of genes involved in methionine cycling. Specifically, EZH2i resulted in a miRNA-mediated downregulation of methionine cycling-associated genes in responsive cells. This induced metabolite accumulation and DNA damage, leading to G2 arrest and apoptosis. Altogether, we unveiled that sensitivity to EZH2i in human MM cell lines is associated with a specific metabolic and gene expression profile post-treatment.

Abstract Repetitive hypoxia seen in obstructive sleep apnoea syndrome (OSAS) may affect bone metabolism increasing the risk for secondary osteoporosis. This study investigates the association between OSAS in children and secondary osteoporosis. This cross-sectional study included 150 children aged 10–17 years: 86 with OSAS and 64 with no OSAS. OSAS was confirmed by polysomnography. Quantitative ultrasound (QUS) of calcaneum measuring speed of sound (SoS) and broadband ultrasound attenuation (BUA) were collected. Other parameters collected including bone profile, vitamin D levels, physical activity scoring and dietary calcium intake. Majority were male and Malay ethnicity. OSAS children were mostly obese (84%) and 57% had moderate to severe OSAS. Most had lower physical activities scores. Mean (SD) phosphate and Alkaline phosphatase were lower in OSA children compared to controls: PO4, p = 0.039 and ALP, p

Abstract Background We investigated the association of insulin resistance (IR) with coronary plaque morphology and the risk of cardiovascular events in patients enrolled in the Providing Regional Observations to Study Predictors of Events in Coronary Tree (PROSPECT) study. Methods Patients with acute coronary syndromes (ACS) were divided based on DM status. Non-DM patients were further stratified according to homeostasis-model-assessment IR (HOMA-IR) index as insulin sensitive (IS; HOMA-IR ≤ 2), likely-IR (LIR; 2

Abstract We describe both phenotype and pathogenesis in two male siblings with typical retinitis pigmentosa (RP) and the potentially X-linked RP (XLRP) carrier phenotype in their mother. Two affected sons, two unaffected daughters, and their mother underwent detailed ophthalmological assessments including Goldmann perimetry, color vision testing, multimodal imaging and ISCEV-standard electroretinography. Genetic testing consisted of targeted next-generation sequencing (NGS) of known XLRP genes and whole exome sequencing (WES) of known inherited retinal disease genes (RetNet-WES). Variant validation and segregation analysis were performed by Sanger sequencing. The mutational load of the RHO variant in the mother was assessed in DNA from leucocytes, buccal cells and hair follicles using targeted NGS. Both affected sons showed signs of classical RP, while the mother displayed patches of hyperautofluorescence on blue light autofluorescence imaging and regional, intraretinal, spicular pigmentation, reminiscent of a carrier phenotype of XLRP. XLRP testing was negative. RetNet-WES testing revealed RHO variant c.404G > C p.(Arg135Pro) in a mosaic state (21% of the reads) in the mother and in a heterozygous state in both sons. Targeted NGQSS of the RHO variant in different maternal tissues showed a mutation load between 25.06% and 41.72%. We report for the first time that somatic mosaicism of RHO variant c.404G > C p.(Arg135Pro) mimics the phenotype of a female carrier of XLRP, in combination with heterozygosity for the variant in the two affected sons.