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Nature Medicine Oct 2023Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical... (Review)
Review
Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
Topics: Humans; Precision Medicine; Consensus; Diabetes Mellitus; Evidence-Based Medicine
PubMed: 37794253
DOI: 10.1038/s41591-023-02502-5 -
International Journal of Molecular... May 2023Adipose tissue (AT) can be classified into two different types: (i) white adipose tissue (WAT), which represents the largest amount of total AT, and has the main... (Review)
Review
Adipose tissue (AT) can be classified into two different types: (i) white adipose tissue (WAT), which represents the largest amount of total AT, and has the main function of storing fatty acids for energy needs and (ii) brown adipose tissue (BAT), rich in mitochondria and specialized in thermogenesis. Many exogenous stimuli, e.g., cold, exercise or pharmacological/nutraceutical tools, promote the phenotypic change of WAT to a beige phenotype (BeAT), with intermediate characteristics between BAT and WAT; this process is called "browning". The modulation of AT differentiation towards WAT or BAT, and the phenotypic switch to BeAT, seem to be crucial steps to limit weight gain. Polyphenols are emerging as compounds able to induce browning and thermogenesis processes, potentially via activation of sirtuins. SIRT1 (the most investigated sirtuin) activates a factor involved in mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), which, through peroxisome proliferator-activated receptor γ (PPAR-γ) modulation, induces typical genes of BAT and inhibits genes of WAT during the transdifferentiation process in white adipocytes. This review article aims to summarize the current evidence, from pre-clinical studies to clinical trials, on the ability of polyphenols to promote the browning process, with a specific focus on the potential role of sirtuins in the pharmacological/nutraceutical effects of natural compounds.
Topics: Humans; Sirtuins; Polyphenols; PPAR gamma; Obesity; Adipose Tissue, White; Adipose Tissue, Brown; Thermogenesis
PubMed: 37298226
DOI: 10.3390/ijms24119276 -
Blood Advances Sep 2023Although allogeneic hematopoietic cell transplant (allo-HCT) is curative for high-risk pediatric acute myeloid leukemia (AML), disease relapse remains the primary cause...
Although allogeneic hematopoietic cell transplant (allo-HCT) is curative for high-risk pediatric acute myeloid leukemia (AML), disease relapse remains the primary cause of posttransplant mortality. To identify pressures imposed by allo-HCT on AML cells that escape the graft-versus-leukemia effect, we evaluated immune signatures at diagnosis and posttransplant relapse in bone marrow samples from 4 pediatric patients using a multimodal single-cell proteogenomic approach. Downregulation of major histocompatibility complex class II expression was most profound in progenitor-like blasts and accompanied by correlative changes in transcriptional regulation. Dysfunction of activated natural killer cells and CD8+ T-cell subsets at relapse was evidenced by the loss of response to interferon gamma, tumor necrosis factor α signaling via NF-κB, and interleukin-2/STAT5 signaling. Clonotype analysis of posttransplant relapse samples revealed an expansion of dysfunctional T cells and enrichment of T-regulatory and T-helper cells. Using novel computational methods, our results illustrate a diverse immune-related transcriptional signature in posttransplant relapses not previously reported in pediatric AML.
Topics: Humans; Child; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Transplantation, Homologous; Histocompatibility Antigens Class II; Recurrence
PubMed: 37327118
DOI: 10.1182/bloodadvances.2022009468 -
Sports Medicine - Open Apr 2024Ultra-endurance events are gaining popularity in multiple exercise disciplines, including cycling. With increasing numbers of ultra-cycling events, aspects influencing... (Review)
Review
BACKGROUND
Ultra-endurance events are gaining popularity in multiple exercise disciplines, including cycling. With increasing numbers of ultra-cycling events, aspects influencing participation and performance are of interest to the cycling community.
MAIN BODY
The aim of this narrative review was, therefore, to assess the types of races offered, the characteristics of the cyclists, the fluid and energy balance during the race, the body mass changes after the race, and the parameters that may enhance performance based on existing literature. A literature search was conducted in PubMed, Scopus, and Google Scholar using the search terms 'ultracycling', 'ultra cycling', 'ultra-cycling', 'ultra-endurance biking', 'ultra-bikers' and 'prolonged cycling'. The search yielded 948 results, of which 111 were relevant for this review. The studies were classified according to their research focus and the results were summarized. The results demonstrated changes in physiological parameters, immunological and oxidative processes, as well as in fluid and energy balance. While the individual race with the most published studies was the Race Across America, most races were conducted in Europe, and a trend for an increase in European participants in international races was observed. Performance seems to be affected by characteristics such as age and sex but not by anthropometric parameters such as skin fold thickness. The optimum age for the top performance was around 40 years. Most participants in ultra-cycling events were male, but the number of female athletes has been increasing over the past years. Female athletes are understudied due to their later entry and less prominent participation in ultra-cycling races. A post-race energy deficit after ultra-cycling events was observed.
CONCLUSION
Future studies need to investigate the causes for the observed optimum race age around 40 years of age as well as the optimum nutritional supply to close the observed energy gap under consideration of the individual race lengths and conditions. Another research gap to be filled by future studies is the development of strategies to tackle inflammatory processes during the race that may persist in the post-race period.
PubMed: 38679655
DOI: 10.1186/s40798-024-00715-7 -
Proceedings of the National Academy of... Dec 2023Idiopathic normal pressure hydrocephalus (iNPH) is an enigmatic neurological disorder that develops after age 60 and is characterized by gait difficulty, dementia, and...
Idiopathic normal pressure hydrocephalus (iNPH) is an enigmatic neurological disorder that develops after age 60 and is characterized by gait difficulty, dementia, and incontinence. Recently, we reported that heterozygous deletions may cause iNPH. Here, we identify mutations affecting nine additional genes (, ) that are statistically enriched among iNPH patients. The encoded proteins are all highly expressed in choroid plexus and ependymal cells, and most have been associated with cilia. Damaging mutations in , which encodes an adenylate kinase, were detected in 9.6% of iNPH patients. Mice homozygous for an iNPH-associated mutation displayed normal cilia structure and number, but decreased cilia motility and beat frequency, communicating hydrocephalus, and balance impairment. +/- mice displayed normal brain development and behavior until early adulthood, but subsequently developed communicating hydrocephalus. Together, our findings suggest that heterozygous mutations that impair ventricular epithelial function may contribute to iNPH.
Topics: Humans; Mice; Animals; Adult; Middle Aged; Hydrocephalus, Normal Pressure; Hydrocephalus; Brain; Choroid Plexus; Mutation; Proteins
PubMed: 38100419
DOI: 10.1073/pnas.2300681120 -
Nature Communications Oct 2023Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic...
Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic models that inform disease management in the clinic. Tumor only sequencing assays are limited in their ability to identify definitive somatic variants, which can lead to ambiguity in clinical reporting and patient management. Here, we describe the MSK-IMPACT Heme cohort, a comprehensive data set of somatic alterations from paired tumor and normal DNA using a hybridization capture-based next generation sequencing platform. We highlight patterns of mutations, copy number alterations, and mutation signatures in a broad set of myeloid and lymphoid neoplasms. We also demonstrate the power of appropriate matching to make definitive somatic calls, including in patients who have undergone allogeneic stem cell transplant. We expect that this resource will further spur research into the pathobiology and clinical utility of clinical sequencing for patients with hematologic neoplasms.
Topics: Humans; Neoplasms; Hematologic Neoplasms; Mutation; High-Throughput Nucleotide Sequencing; DNA
PubMed: 37898613
DOI: 10.1038/s41467-023-42585-9 -
Medical Engineering & Physics Jun 2023Direct measurement of cardiac pressure-volume (PV) relationships is the gold standard for assessment of ventricular hemodynamics, but few innovations have been made to...
Direct measurement of cardiac pressure-volume (PV) relationships is the gold standard for assessment of ventricular hemodynamics, but few innovations have been made to "multi-beat" PV analysis beyond traditional signal processing. The Prony method solves the signal recovery problem with a series of dampened exponentials or sinusoids. It achieves this by extracting the amplitude, frequency, dampening, and phase of each component. Since its inception, application of the Prony method to biologic and medical signal has demonstrated a relative degree of success, as a series of dampened complex sinusoids easily generalizes to multifaceted physiological processes. In cardiovascular physiology, the Prony analysis has been used to determine fatal arrythmia from electrocardiogram signals. However, application of the Prony method to simple left ventricular function based on pressure and volume analysis is absent. We have developed a new pipeline for analysis of pressure volume signals recorded from the left ventricle. We propose fitting pressure-volume data from cardiac catheterization to the Prony method for pole extraction and quantification of the transfer function. We implemented the Prony algorithm using open-source Python packages and analyzed the pressure and volume signals before and after severe hemorrhagic shock, and after resuscitation with stored blood. Each animal (n = 6 per group) underwent a 50% hemorrhage to induce hypovolemic shock, which was maintained for 30 min, and resuscitated with 3-week-old stored RBCs until 90% baseline blood pressure was achieved. Pressure-volume catheterization data used for Prony analysis were 1 s in length, sampled at 1000 Hz, and acquired at the time of hypovolemic shock, 15 and 30 min after induction of hypovolemic shock, and 10, 30, and 60 min after volume resuscitation. We next assessed the complex poles from both pressure and volume waveforms. To quantify deviation from the unit circle, which represents deviation from a Fourier series, we counted the number of poles at least 0.2 radial units away from it. We found a significant decrease in the number of poles after shock (p = 0.0072 vs. baseline) and after resuscitation (p = 0.0091 vs. baseline). No differences were observed in this metric pre and post volume resuscitation (p = 0.2956). We next found a composite transfer function using the Prony fits between the pressure and volume waveforms and found differences in both the magnitude and phase Bode plots at baseline, during shock, and after resuscitation. In summary, our implementation of the Prony analysis shows meaningful physiologic differences after shock and resuscitation and allows for future applications to broader physiological and pathophysiological conditions.
Topics: Animals; Heart Ventricles; Shock, Hemorrhagic; Hemodynamics; Resuscitation; Ventricular Function, Left
PubMed: 37230699
DOI: 10.1016/j.medengphy.2023.103987 -
Journal of Nuclear Cardiology :... Jun 2023This work investigated the impact of different cardiac gating methods on the assessment of cardiac function by FDG-PET in a cross-validation PET/MR study.
BACKGROUND
This work investigated the impact of different cardiac gating methods on the assessment of cardiac function by FDG-PET in a cross-validation PET/MR study.
METHODS AND RESULTS
MR- and PET-based left ventricular end-diastolic, end-systolic volumes, and ejection fraction (EDV, ESV, and EF) were delineated in 30 patients with a PET/MR examination. Cardiac PET imaging was performed using three ECG gating methods: fixed number of gates per beat (STD), STD with a beat acceptance window (STD-BR), and fixed gate duration (FW). High MR-PET correlations were found in all the values. ESVs correlated better than EDVs and EFs: Pearson's r coefficient [0.92, 0.92, 0.92] in ESV vs [0.75, 0.81, 0.80] in EDV and [0.79, 0.91, 0.87] in EF, for each method [STD, STD-BR, FW]. Biases with respect to MRI for all the evaluated PET methods were less than 13% in EDV, 5% in ESV, and 14% in EF, but with wide limits of agreements, in the range (59-68)% in EDV, (65-70)% in ESV, and (49-71)% in EF. STD showed the strongest disagreement, while there were no marked differences between STD-BR and FW.
CONCLUSION
Based on these findings, PET- and MR-based cardiac function parameters were highly correlated but in substantial disagreement with variabilities introduced by the selected PET ECG gating method. The most significant differences were associated with the ECG gating method susceptible to highly irregular beats, while similar performance was observed in the methods using uniform adjustment of gates width per beat with the beat acceptance window, and fixed gate width along all the beats. Thus, strict quality controls of R peak detection are needed to minimize its impact on the function assessment.
Topics: Humans; Electrocardiography; Magnetic Resonance Imaging; Positron-Emission Tomography; Reproducibility of Results; Stroke Volume; Ventricular Function, Left
PubMed: 36180767
DOI: 10.1007/s12350-022-03105-2 -
Europace : European Pacing,... Nov 2023The aim of our study was to analyse the response to short-coupled atrial extrastimuli to identify areas of hidden slow conduction (HSC) and their relationship with the...
AIMS
The aim of our study was to analyse the response to short-coupled atrial extrastimuli to identify areas of hidden slow conduction (HSC) and their relationship with the atrial fibrillation (AF) phenotype.
METHODS AND RESULTS
Twenty consecutive patients with paroxysmal AF and persistent AF (10:10) underwent the first pulmonary vein isolation procedure. Triple short-coupled extrastimuli were delivered in sinus rhythm (SR), and the evoked response was analysed: sites exhibiting double or highly fragmented electrograms (EGM) were defined as positive for HSC (HSC+). The delta of the duration of the bipolar EGM was analysed, and bipolar EGM duration maps were built. High-density maps were acquired using a multipolar catheter during AF, SR, and paced rhythm. Spatial co-localization of HSC+ and complex fractionated atrial EGMs (CFAE) during AF was evaluated. Persistent AF showed a higher number and percentage of HSC+ than paroxysmal AF (13.9% vs. 3.3%, P < 0.001). The delta of EGM duration was 53 ± 22 ms for HSC+ compared with 13 ± 11 (10) ms in sites with negative HSC (HSC-) (P < 0.001). The number and density of HSC+ were lower than CFAE during AF (19 vs. 56 per map, P < 0.001). The reproducibility and distribution of HSC+ in repeated maps were superior to CFAE (P = 0.19 vs. P < 0.001). Sites with negative and positive responses showed a similar bipolar voltage in the preceding sinus beat (1.65 ± 1.34 and 1.48 ± 1.47 mV, P = 0.12).
CONCLUSION
Functional mapping identifies more discrete and reproducible abnormal substrates than mapping during AF. The HSC+ sites in response to triple extrastimuli are more frequent in persistent AF than in paroxysmal AF.
Topics: Humans; Atrial Fibrillation; Reproducibility of Results; Electrophysiologic Techniques, Cardiac; Heart Rate; Heart Atria; Catheter Ablation
PubMed: 37961921
DOI: 10.1093/europace/euad246