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Heart Failure Assessment Using Multiparameter Polar Representations and Deep Learning.
Heart failure refers to the inability of the heart to pump enough amount of blood to the body. Nearly 7 million people die every year because of its complications. Current gold-standard screening techniques through echocardiography do not incorporate information about the circadian rhythm of the heart and clinical information of patients. In this vein, we propose a novel approach to integrate 24-hour heart rate variability (HRV) features and patient profile information in a single multi-parameter and color-coded polar representation. The proposed approach was validated by training a deep learning model from 7,575 generated images to predict heart failure groups, i.e., preserved, mid-range, and reduced left ventricular ejection fraction. The developed model had overall accuracy, sensitivity, and specificity of 93%, 88%, and 95%, respectively. Moreover, it had a high area under the receiver operating characteristics curve (AUROC) of 0.88 and an area under the precision-recalled curve (AUPR) of 0.79. The novel approach proposed in this study suggests a new protocol for assessing cardiovascular diseases to act as a complementary tool to echocardiography as it provides insights on the circadian rhythm of the heart and can be potentially personalized according to patient clinical profile information.Clinical relevance- Implementing polar representations with deep learning in clinical settings to supplement echocardiography leverages continuous monitoring of the heart's circadian rhythm and personalized cardiovascular medicine while reducing the burden on medical practitioners.
Recognition of Pediatric Congenital Heart Diseases by Using Phonocardiogram Signals and Transformer-Based Neural Networks.
The phonocardiogram (PCG) or heart sound auscultation is a low-cost and non-invasive method to diagnose Congenital Heart Disease (CHD). However, recognizing CHD in the pediatric population based on heart sounds is difficult because it requires high medical training and skills. Also, the dependency of PCG signal quality on sensor location and developing heart in children are challenging. This study proposed a deep learning model that classifies unprocessed or raw PCG signals to diagnose CHD using a one-dimensional Convolution Neural Network (1D-CNN) with an attention transformer. The model was built on the raw PCG data of 484 patients. The results showed that the attention transformer model had a good balance of accuracy of 0.923, a sensitivity of 0.973, and a specificity of 0.833. The Receiver Operating Characteristic (ROC) plot generated an Area Under Curve (AUC) value of 0.964, and the F1-score was 0.939. The suggested model could provide quick and appropriate real-time remote diagnosis application in classifying PCG of CHD from non-CHD subjects.Clinical Relevance- The suggested methodology can be utilized to analyze PCG signals more quickly and affordably for rural doctors as a first screening tool before sending the cases to experts.
Emotional Climate Recognition in Conversations using Peers' Speech-based Bispectral Features and Affect Dynamics.
Emotion recognition in conversations using artificial intelligence (AI) has recently gained a lot of attention, as it can provide additional emotion cues that can be correlated with human social behavior. An extension towards an AI-based emotional climate (EC) recognition, i.e., the recognition of the joint emotional atmosphere dynamically created and perceived by the peers throughout a conversation, is proposed here. In our approach, namely MLBispeC (Machine Learning Based Bispectral Classification), the peers' speech signals during their conversation are subjected to time-windowed bispectral analysis, allowing for feature extraction related to dynamic harmonics nonlinear interactions. In addition, peers' affect dynamics, derived from their same time-windowed emotion labeling, are combined to form an extended feature vector, inputted into two well-known machine learning classifiers (Support Vector Machine, K-Nearest Neighbor). MLBispeC was evaluated on the Interactive Emotional Dyadic Motion Capture (IEMOCAP) open access dataset, which contains 2D emotions, i.e., Arousal (A) and valence (V) that are divided into (low/high) classes. The experimental results have shown that MLBispeC outperforms previous state-of-the-art techniques, achieving an accuracy of 0.826A/0.754V, sensitivity of 0.864A/0.774V, and area under the curve (AUC) of 0.821A/0.799V. This demonstrates the effectiveness of MLBispeC to objectively recognize peers' EC during their conversation, allowing for insights into their emotional and social interactions.Clinical relevance-Unobtrusive, objective and dynamic recognition of the EC built during peers' conversation can scaffold effective assessment of patients with physiological, psychological, and mental diseases, at various age ranges (children, adults, and older adults).
C-Cell Hyperplasia and Cystic Papillary Thyroid Carcinoma in a Patient with Type 1B Pseudohypoparathyroidism and Hypercalcitoninaemia: Case Report and Review of the Literature.
Hypercalcitoninaemia has been described in patients with pseudohypoparathyroidism (PHP) type 1A and 1B. Elevated calcitonin levels are thought to result from impaired Gsα receptor signaling, leading to multiple hormone resistance. Evidence on the risk of medullary thyroid carcinoma (MTC) or C-cell hyperplasia in PHP patients with hypercalcitoninaemia is lacking. A 43-year-old Caucasian man was referred to our endocrinology clinic for chronic hypocalcemia associated with elevated serum parathormone levels and a single cystic thyroid nodule. The patient did not show skeletal deformities, and screening for concomitant hormone resistances was negative, except for the presence of elevated serum calcitonin levels. The workup led to a molecular diagnosis of sporadic PHP1B. Fine needle aspiration of the thyroid nodule was not diagnostic. The calcium stimulation test yielded an abnormal calcitonin response. Given the scarcity of data on the risk of thyroid malignancy in PHP and calcium stimulation test results, total thyroidectomy was performed. Histological examination revealed cystic papillary thyroid cancer in a background of diffuse C-cell hyperplasia. To our knowledge, we are the first to describe a rare form of thyroid cancer combined with C-cell hyperplasia in a patient with PHP and hypercalcitoninaemia. In the present case, a mere receptor resistance might not fully explain the elevated calcitonin levels, suggesting that hypercalcitoninaemia should be carefully evaluated in PHP patients, especially in the case of concomitant thyroid nodules. Further studies on larger cohorts are needed to elucidate this topic.
Patient-reported symptoms and diagnostic journey in Multiple Myeloma
Introduction: Late presentation of multiple myeloma (MM) heightens the risk of complication risks, including end-organ damage. This study aimed to: 1) detail the diagnostic journey of MM patients, encompassing symptoms, initial diagnoses, and healthcare professionals met; 2) establish the median duration from symptom onset to MM diagnosis; and 3) examine factors linked to timely MM diagnosis within 12 weeks. Methods: A total of 300 adults self-reporting MM were analysed from the Rare and Undiagnosed Diseases cohort Study (RUDY). The RUDY study is a web-based platform, where participants provide dynamic consent and self-report their MM diagnosis and information about their diagnostic journey. This includes the estimated date of initial potential first symptoms, descriptions of these symptoms, the healthcare professionals they consulted, and other diagnoses received before the MM diagnosis. Descriptive statistics, combinatorial analyses and logistic regression analyses were used to describe and examine the diagnostic journey of individuals with MM. Results: Overall, 52% of the participants reported other diagnoses before MM diagnosis, with musculoskeletal disorders (47.8%), such as osteoporosis, costochondritis, or muscle strains, being the most common. The most prevalent initial reported symptom was back pain/vertebral fractures (47%), followed by chest/shoulder pain, including rib pain and fractures (20%), and fatigue/tiredness (19.7%). 40% of participants were diagnosed by direct referral from primary care to haematology without seeing other healthcare professionals whilst 60% consulted additional specialists before diagnosis. The median time from symptom onset to MM diagnosis was 4 months (IQR 2-10 months, range 0-172). Seeing an Allied Healthcare Professional such as a physiotherapist, chiropractor or an osteopath (OR = 0.25, 95% CI [0.12, 0.47], p <0.001), experiencing infection symptoms (OR = 0.32, 95% CI [0.13, 0.76], p = 0.013), and having chest or shoulder pain (OR = 0.45, 95% CI [0.23, 0.86], p = 0.020) were associated with a lower likelihood of being diagnosed with MM within 12 weeks. Older age (OR = 1.04, 95% CI [1.02, 1.07], p = 0.001) was associated with a higher likelihood of diagnosis within 12 weeks. Discussion: Developing resources for allied health professionals may improve early recognition of MM.
Adult stem cell activity in naked mole rats for long-term tissue maintenance.
The naked mole rat (NMR), Heterocephalus glaber, the longest-living rodent, provides a unique opportunity to explore how evolution has shaped adult stem cell (ASC) activity and tissue function with increasing lifespan. Using cumulative BrdU labelling and a quantitative imaging approach to track intestinal ASCs (Lgr5+) in their native in vivo state, we find an expanded pool of Lgr5+ cells in NMRs, and these cells specifically at the crypt base (Lgr5+CBC) exhibit slower division rates compared to those in short-lived mice but have a similar turnover as human LGR5+CBC cells. Instead of entering quiescence (G0), NMR Lgr5+CBC cells reduce their division rates by prolonging arrest in the G1 and/or G2 phases of the cell cycle. Moreover, we also observe a higher proportion of differentiated cells in NMRs that confer enhanced protection and function to the intestinal mucosa which is able to detect any chemical imbalance in the luminal environment efficiently, triggering a robust pro-apoptotic, anti-proliferative response within the stem/progenitor cell zone.
Microenvironmental control of stem cell fate in intestinal homeostasis and disease.
The conventional model of intestinal epithelial architecture describes a unidirectional tissue organizational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt-luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. Evidence is accumulating to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment including paracrine, mesenchymal, and endogenous epithelial morphogen gradients. Recent research suggests that in intestinal homeostasis, stem cells transit reversibly between states of variable competence in the niche. Furthermore, selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Importantly, it has been recently shown that this disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. This paper reviews the exciting developments in the study of stem cell dynamics in homeostasis, intestinal regeneration, and carcinogenesis, and explores the implications for human disease and cancer therapies.
ERK and AKT signaling drive MED1 overexpression in prostate cancer in association with elevated proliferation and tumorigenicity.
MED1 is a key coactivator of the androgen receptor (AR) and other signal-activated transcription factors. Whereas MED1 is overexpressed in prostate cancer cell lines and is thought to coactivate distinct target genes involved in cell-cycle progression and castration-resistant growth, the underlying mechanisms by which MED1 becomes overexpressed and its oncogenic role in clinical prostate cancer have remained unclear. Here, we report that MED1 is overexpressed in the epithelium of clinically localized human prostate cancer patients, which correlated with elevated cellular proliferation. In a Nkx3.1:Pten mutant mouse model of prostate cancer that recapitulates the human disease, MED1 protein levels were markedly elevated in the epithelium of both invasive and castration-resistant adenocarcinoma prostate tissues. Mechanistic evidence showed that hyperactivated ERK and/or AKT signaling pathways promoted MED1 overexpression in prostate cancer cells. Notably, ectopic MED1 overexpression in prostate cancer xenografts significantly promoted tumor growth in nude mice. Furthermore, MED1 expression in prostate cancer cells promoted the expression of a number of novel genes involved in inflammation, cell proliferation, and survival. Together, these findings suggest that elevated MED1 is a critical molecular event associated with prostate oncogenesis.
Modeling prostate cancer in mice: something old, something new, something premalignant, something metastatic.
More than 15 years ago, the first generation of genetically engineered mouse (GEM) models of prostate cancer was introduced. These transgenic models utilized prostate-specific promoters to express SV40 oncogenes specifically in prostate epithelium. Since the description of these initial models, there have been a plethora of GEM models of prostate cancer representing various perturbations of oncogenes or tumor suppressors, either alone or in combination. This review describes these GEM models, focusing on their relevance for human prostate cancer and highlighting their strengths and limitations, as well as opportunities for the future.
Isolation of ORCTL3 in a novel genetic screen for tumor-specific apoptosis inducers.
We have established a systematic high-throughput screen for genes that cause cell death specifically in transformed tumor cells. In a first round of screening, cDNAs that induce apoptosis in a transformed human cell line are detected. Positive genes are subsequently tested in a synthetic lethal screen in normal cells versus their isogenic counterparts that have been transformed by a particular oncogene. In this way, the organic cation transporter-like 3 (ORCTL3) gene was found to be inactive in normal rat kidney (NRK) cells, but to induce apoptosis in NRK cells transformed by oncogenic H-ras. ORCTL3 also causes cell death in v-src-transformed cells and in various human tumor cell lines but not in normal cells or untransformed cell lines. Although ORCTL3 is a member of the organic cation transporter gene family, our data indicate that this gene induces apoptosis independently of its putative transporter activity. Rather, various lines of evidence suggest that ORCTL3 brings about apoptosis by an endoplasmic reticulum stress-mediated mechanism. Finally, we detected ORCTL3 to be downregulated in human kidney tumors.
Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche.
Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.