The Listening Network and Cochlear Implant Benefits in Hearing-Impaired Adults

Older adults with mild or no hearing loss make more errors and expend more effort listening to speech. Cochlear implants (CI) restore hearing to deaf patients but with limited fidelity. We hypothesized that patient-reported hearing and health-related quality of life in CI patients may similarly vary according to age. Speech Spatial Qualities (SSQ) of hearing scale and Health Utilities Index Mark III (HUI) questionnaires were administered to 543 unilaterally implanted adults across Europe, South Africa, and South America. Data were acquired before surgery and at 1, 2, and 3 years post-surgery. Data were analyzed using linear mixed models with visit, age group (18–34, 35–44, 45–54, 55–64, and 65+), and side of implant as main factors and adjusted for other covariates. Tinnitus and dizziness prevalence did not vary with age, but older groups had more preoperative hearing. Preoperatively and postoperatively, SSQ scores were significantly higher (¿0.75–0.82) for those aged <45 compared with those 55+. However, gains in SSQ scores were equivalent across age groups, although postoperative SSQ scores were higher in right-ear implanted subjects. All age groups benefited equally in terms of HUI gain (0.18), with no decrease in scores with age. Overall, younger adults appeared to cope better with a degraded hearing before and after CI, leading to better subjective hearing performance.

Me, My Girls, and the Ideal Hotel: Segmenting Motivations of the Girlfriend Getaway Market Using Fuzzy C-Medoids for Fuzzy Data.

Segmenting the motivation of travelers using the push and pull framework remains ubiquitous in tourism. This study segments the girlfriend getaway (GGA) market on motivation (push) and accommodation (pull) attributes and identifies relationships between these factors. Using a relatively novel clustering algorithm, the Fuzzy C-Medoids clustering for fuzzy data (FCM-FD), on a sample of 749 women travelers, three segments (Socializers, Enjoyers, and Rejoicers) are uncovered. The results of a multinomial fractional model show relationships between the clusters of motivation and accommodation attributes as well as sociodemographic characteristics. The research highlights the importance of using a gendered perspective in applying well established motivation models such as the push and pull framework. The findings have implications for both destination and accommodation management

Haemogenic Gastruloids Recapitulate Developmental Haematopoiesis and Provide an Ontogeny-Relevant Context to Dissect the Origins of Infant Leukemia

Meeting abstract presented at the 64th ASH Annual Meeting and Exposition, New Orleans, LA, USA, 10-13 Dec 2022..Modelling of developmental hematopoiesis has historically been challenging due to the inability to produce hematopoietic stem cells (HSC) and recapitulate microenvironment interactions ex vivo. Gastruloids are 3D aggregates of embryonic stem (ES) cells which display developmentally-specific spatial and temporal organization that recapitulate gastrulation. We adapted the gastruloid protocol to introduce hematopoietic signalling cues, and generated an in vitro model of embryonic hematopoiesis that sequentially recapitulates the formation of hemogenic endothelium, hematopoietic progenitors, and pre-HSC, over a culture period of 216 hours. Flow cytometry analysis detected the presence of c-Kit+ endothelium at 120h, followed by emergence of CD41+ hematopoietic progenitors at 144h, and the appearance of CD45+ cells from 192h. CD45+ cells were observed in small clusters adjoining endothelium-lined structures, reminiscent of developmental hemogenic-to-endothelial transition and intra-aortic clusters. Single-cell RNA sequencing revealed specification of pre-definitive and definitive waves of embryonic hematopoiesis, aligning 144h-CD41+ cells with erythro-myeloid progenitors (EMP), and late CD45+ with lympho-myeloid progenitors and pre-HSC, altogether supporting the hemogenic gastruloid as a model that is temporally and topographically congruous with the embryo. The close recapitulation of developmental ontogeny led us to explore hemogenic gastruloids to understand cell and stage-specific susceptibility to forms of Acute Myeloid Leukaemia exclusively observed in infants. The chromosomal translocation t(7;12)(q36;p13), characterized by the ectopic overexpression of the MNX1 gene, is found in up to one third of infant AML cases, but has been challenging to model using conventional strategies, largely due to the inability of MNX1 to transform adult hematopoietic cells. The age-selectivity of t(7;12) has been proposed to reflect a transient developmental window for a target cell of origin absent in adult life, but its nature is yet to be defined. In order to identify the context of MNX1-driven leukemogenesis, we produced hemogenic gastruloids using lentiviral-transduced mouse ES cells in which we overexpressed MNX1 as a proxy of t(7;12). Although MNX1 did not interfere with ES cell pluripotent cultures, it primed incipient hemogenic programmes and promoted hemogenic gastruloid formation. Critically, expression of MNX1 resulted in transformation of gastruloid-derived hematopoietic cells, as assessed by serial colony-forming cell replating, with expansion of a phenotypic myeloid cell, a phenomenon not observed in adult tissues. Detailed analysis of the cellular composition of MNX1-overexpressing hemogenic gastruloids revealed a significant effect in the output of CD41+ and c-Kit+ populations at 144h, but no effect in CD45+ cells at 192-216h, suggesting that the target of MNX1 lies within the EMP stage, an observation supported by single-cell RNA-seq analysis of MNX1 vs control gastruloids. Systematic comparison of the temporal transcriptional profiles of hemogenic gastruloids, MNX1-overexpressing gastruloids, and t(7;12) patients, pinpoints the target cell of MNX1 at the HE-to-EMP transition. In summary, we propose a novel model of embryonic hematopoiesis capable of capturing developmentally-relevant cellularity and topography of the early hematopoietic microenvironment, with the ability to mechanistically elucidate developmental associations of infant leukemia

Matrix metalloproteinases in human melanoma cell lines and xenografts: increased expression of activated matrix metalloproteinase-2 (MMP-2) correlates with melanoma progression

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tumour progression and metastasis. In this study, we investigated the in vitro and in vivo expression patterns of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1 and TIMP-2 mRNA and protein in a previously described human melanoma xenograft model. This model consists of eight human melanoma cell lines with different metastatic behaviour after subcutaneous (s.c.) injection into nude mice. MMP-1 mRNA was detectable in all cell lines by reverse transcription polymerase chain reaction (RT-PCR), but the expression was too low to be detected by Northern blot analysis. No MMP-1 protein could be found using Western blotting. MMP-2 mRNA and protein were present in all cell lines, with the highest expression of both latent and active MMP-2 in the highest metastatic cell lines MV3 and BLM. MMP-3 mRNA was expressed in MV3 and BLM, and in the non-metastatic cell line 530, whereas MMP-3 protein was detectable only in MV3 and BLM. None of the melanoma cell lines expressed MMP-9. TIMP-1 and TIMP-2 mRNA and protein, finally, were present in all cell lines. A correlation between TIMP expression level and metastatic capacity of cell lines, however, was lacking. MMP and TIMP mRNA and protein expression levels were also studied in s.c. xenograft lesions derived from a selection of these cell lines. RT-PCR analysis revealed that MMP-1 mRNA was present in MV3 and BLM xenografts, and to a lesser extent in 530. Positive staining for MMP-1 protein was found in xenograft lesions derived from both low and high metastatic cell lines, indicating an in vivo up-regulation of MMP-1. MMP-2 mRNA was detectable only in xenografts derived from the highly metastatic cell lines 1F6m, MV3 and BLM. In agreement with the in vitro results, the highest levels of both latent and activated MMP-2 protein were observed in MV3 and BLM xenografts. With the exception of MMP-9 mRNA expression in 530 xenografts, MMP-3, MMP-9, and TIMP-1 mRNA and protein were not detectable in any xenograft, indicating a down-regulated expression of MMP-3 and TIMP-1 in vivo. TIMP-2 mRNA and protein were present in all xenografts; interestingly, the strongest immunoreactivity of tumour cells was found at the border of necrotic areas. Our study demonstrates that of all tested components of the matrix metalloproteinase system, only expression of activated MMP-2 correlates with increased malignancy in our melanoma xenograft model, corroborating an important role of MMP-2 in human melanoma invasion and metastasis. © 1999 Cancer Research Campaig

Challenges and satisfaction in Cardiothoracic Surgery Residency Programmes: insights from a Europe-wide survey.

OBJECTIVES: The increasing complexity of surgical patients and working time constraints represent challenges for training. In this study, the European Association for Cardio-Thoracic Surgery Residents' Committee aimed to evaluate satisfaction with current training programmes across Europe. METHODS: We conducted an online survey between October 2018 and April 2019, completed by a total of 219 participants from 24 countries. RESULTS: The average respondent was in the fourth or fifth year of training, mostly on a cardiac surgery pathway. Most trainees follow a 5-6-year programme, with a compulsory final certification exam, but no regular skills evaluation. Only a minority are expected to take the examination by the European Board of Cardiothoracic Surgery. Participants work on average 61.0 ± 13.1 h per week, including 27.1 ± 20.2 on-call. In total, only 19.7% confirmed the implementation of the European Working Time Directive, with 42.0% being unaware that European regulations existed. Having designated time for research was reported by 13.0%, despite 47.0% having a postgraduate degree. On average, respondents rated their satisfaction 7.9 out of 10, although 56.2% of participants were not satisfied with their training opportunities. We found an association between trainee satisfaction and regular skills evaluation, first operator experience and protected research time. CONCLUSIONS: On average, residents are satisfied with their training, despite significant disparities in the quality and structure of cardiothoracic surgery training across Europe. Areas for potential improvement include increasing structured feedback, research time integration and better working hours compliance. The development of European guidelines on training standards may support this

Imaging and impact of myocardial fibrosis in aortic stenosis

Aortic stenosis is characterized both by progressive valve narrowing and the left ventricular remodeling response that ensues. The only effective treatment is aortic valve replacement, which is usually recommended in patients with severe stenosis and evidence of left ventricular decompensation. At present, left ventricular decompensation is most frequently identified by the development of typical symptoms or a marked reduction in left ventricular ejection fraction <50%. However, there is growing interest in using the assessment of myocardial fibrosis as an earlier and more objective marker of left ventricular decompensation, particularly in asymptomatic patients, where guidelines currently rely on non- randomized data and expert consensus. Myocardial fibrosis has major functional consequences, is the key pathological process driving left ventricular decompensation, and can be divided into 2 categories. Replacement fibrosis is irreversible and identified using late gadolinium enhancement on cardiac magnetic resonance, while diffuse fibrosis occurs earlier, is potentially reversible, and can be quantified with cardiac magnetic resonance T1 mapping techniques. There is a substantial body of observational data in this field, but there is now a need for randomized clinical trials of myocardial imaging in aortic stenosis to optimize patient management. This review will discuss the role that myocardial fibrosis plays in aortic stenosis, how it can be imaged, and how these approaches might be used to track myocardial health and improve the timing of aortic valve replacement

The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance

Targeting 2-Oxoglutarate-Dependent oxygenases in Acute Myeloid Leukaemia

Haematopoiesis is a life-long process of blood cell production that occurs through strictly regulated self-renewal, proliferation, and differentiation of haematopoietic stem cells (HSCs) in hypoxic microenvironment of the bone marrow niche. Accumulation of clonal mutations, that give mutated haematopoietic stem and progenitor cells (HSPCs) proliferative advantage, and subsequent acquisition of driver mutations lead to development of Acute Myeloid Leukaemia (AML)-initiating leukaemic stem cells (LSCs). Standard chemotherapies efficiently target AML blasts; however, they frequently fail to eradicate the chemotherapy resistant LSCs, leading to disease relapse. Thus, exposing biological vulnerabilities of LSCs is of great therapeutic interest. 2-oxoglutarate (2OG)-dependent oxygenases (2OGXs) are superfamily of enzymes involved in numerous important biological processes including hypoxia sensing, epigenetic regulation, or cellular metabolism. Moreover, the function of 2OGXs is controlled by tricarboxylic acid (TCA) cycle metabolites. However, the role of many 2OGXs and their metabolic regulation in normal haematopoiesis and leukemogenesis is poorly understood. This thesis shows that member of 2OGXs, Jumonji domain-containing protein 6 (JMJD6), is a critical regulator of HSCs during steady-state haematopoiesis, upon haematopoietic injury, and serial transplantation. JMJD6 controls the HSC function by suppressing the oxidative phosphorylation (OXPHOS) which prevents aberrant production of toxic reactive oxygen species (ROS). Moreover, this thesis reveals that JMJD6 is not required for leukaemic transformation, LSCs development, and AML propagation in models that involve the histone lysine methyltransferase 2A (KMT2A aka MLL) rearrangement. This thesis also finds that stabilisation of Hypoxia Inducible Factor (HIF-) through pharmacological inhibition of Prolyl Hydroxylase Domains (PHDs) is a promising therapeutic strategy to target LSCs in AML, without serious adverse effects. Furthermore, PHD inhibition significantly potentiates the efficacy of B-Cell Lymphoma (BCL-2) inhibitor venetoclax. Lastly, this thesis shows that Diroxymel fumarate (DRF) potently targets AML in vitro, and substantially increases the efficacy of venetoclax in vivo; proposing the utilisation of fumarate esters for AML treatment

Tissue Engineered Materials in Cardiovascular Surgery: The Surgeon's Perspective

In cardiovascular surgery, reconstruction and replacement of cardiac and vascular structures are routinely performed. Prosthetic or biological materials traditionally used for this purpose cannot be considered ideal substitutes as they have limited durability and no growth or regeneration potential