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Dietary Advanced Glycation End Products and Cardiovascular-Kidney-Metabolic Complications.
No full textCardiovascular-kidney-metabolic (CKM) syndrome is a new term indicating a health condition that emphasizes the interconnection of diabetes (type 2 diabetes [T2D]), insulin resistance (IR), CKD, and cardiovascular disease; the pathogenic links between these conditions seem to start with IR/T2D. The incidence and prevalence of this condition are increasing in parallel with the contemporary Western culture consumption of ultra-processed foods. Thermic processing of food increases the formation of pro-oxidant and proinflammatory advanced glycation end products (AGEs), which are partially absorbed into the body increasing the body pool of AGEs, which eventually produces chronic tissue injury, including IR. In this article, we review the literature and present experimental and human data supporting the hypothesis that AGEs in food are major contributory factors to toxicity of ultra-processed foods. We postulate that although hyperglycemia accompanying the diabetic state increases endogenous AGE production, ingestion of these compounds in food may also initiate oxidative stress that eventually causes IR and T2D. Several small clinical trials have studied the effect of dietary AGE intake restriction over variable periods of time, and most of them have demonstrated significant reduction not only in circulating markers of AGEs but also in markers of inflammation and oxidative stress in healthy as well as in CKM subjects. An AGE-restricted diet has also been shown to improve markers of IR. Final proof of a therapeutic role for the low AGE diet will require large, prospective, and randomized clinical trials, which may be challenging to accomplish. We believe, however, that current available data make it reasonable and prudent to advise limitation of dietary AGEs in the general population as well as in CKM patients. Importantly, the simple changes in culinary techniques suggested here can markedly affect AGE content in food and be incorporated as meal patterns consistent with most currently available recommendations promoting CKM health
Nasal and systemic immune responses correlate with viral shedding after influenza challenge in people with complex preexisting immunity.
No full textEach year in the United States, ~50% of adults ≥18 years old are vaccinated against influenza viruses, with protective efficacy averaging 40.5% over the past 20 years. To model annual seasonal influenza, a cohort of 74 adults, who were unscreened for preexisting A/H1N1 immunity and half of whom were recently immunized with licensed QIV (mean of 64 days), were challenged with A/H1N1 influenza virus. Transcriptomic, proteomic, and VDJ repertoire analyses were performed on nasal and peripheral blood samples from participants to identify nasal mucosal and systemic immune responses that correlated with viral shedding and immune correlates of protection. Viral-shedding participants showed increased T cell, but not B cell, VDJ diversity with expansion of low-frequency B cell clones postchallenge, including broadly neutralizing motifs. Nonshedding participants demonstrated decreased clonality and increased richness of B and T cell VDJ clones, increased preinoculation nasal mucosal immune gene and serum protein expression, and increased ex vivo peripheral blood mononuclear cell responses. Nasal mucosal responses in participants shedding virus for 2 or more days showed higher early viral loads and exhibited stronger induction of antiviral responses compared with those in participants who shed virus for 1 day. Last, participants with a single day of viral shedding were three times more likely to be female. These data shed light on the complex immune responses in the nasal mucosa and the periphery after influenza vaccination and infection, which will be critical for next-generation vaccine development
Cardiovascular, kidney, and metabolic health: an actionable vision for heart failure prevention.
No full textThe substantial and growing prevalence of heart failure, which remains the leading cause of preventable hospitalisation worldwide, has brought heart failure prevention into sharp focus. Although this condition has historically been characterised by impaired cardiac function, mounting evidence has underscored its complex and multisystem pathobiology. Epidemiological studies have indicated that other forms of cardiovascular disease, along with kidney and metabolic dysfunction, frequently and increasingly contribute to heart failure onset. Clinical trials have additionally demonstrated the power of several new pharmacotherapies to simultaneously modify cardiovascular, kidney, and metabolic (CKM) health. This convergence of epidemiology and therapy highlights deeply interconnected mechanisms of disease, identifying CKM diseases-and their pathophysiological and sociostructural antecedents-as important but often under-recognised targets for heart failure prevention. Herein, we illustrate that positioning heart failure prevention within the broader context of CKM health provides an actionable framework for patients, health-care professionals, health systems, communities, and policy makers
Trimodal Single-Cell Gene Regulatory Networks Reveal Principles of Stemness Loss and Cell Fate Acquisition in Human Hematopoiesis.
No full textHematopoiesis requires the coordinated loss of stemness and acquisition of lineage identity, yet the regulatory logic and principles underlying these transitions has remained elusive. Single-cell studies suggest that hematopoietic stem and progenitor cells progress along continuous trajectories, but this view conflicts with the existence of discrete, functionally validated populations. Here, we establish the first dynamic, enhancer-based gene regulatory networks (eGRNs) that resolve the molecular programs underlying early human hematopoietic fate decisions. Built on a high-resolution trimodal framework generated with TEA-seq, these networks integrate simultaneously measured transcription factor abundance, enhancer and promoter accessibility, and gene expression within single-cell trajectories anchored to immunophenotypically defined populations. Our framework reveals that stemness loss and lineage acquisition are temporally and mechanistically uncoupled: stemness programs decline gradually through reduced TF abundance long before chromatin closure, whereas lineage identity emerges stepwise through enhancer reconfiguration and activation of lineage-defining eGRNs. This process generates discrete regulatory states that align with immunophenotypically defined populations. Together, these findings reconcile continuous and discrete models of hematopoiesis and establish eGRNs as a powerful framework for defining cell types by their regulatory logic. In addition, we provide an interactive web-based resource to facilitate further investigation of eGRNs and trajectories during early human hematopoiesis
Radiomics Combined with Transcriptomics Improves Prediction of Breast Cancer Recurrence, Molecular Subtype and Grade.
No full textNoninvasive therapeutic ultrasound to increase perfusion in chronic limb-threatening ischemia: An early feasibility study.
No full textBackground: Preclinical studies have demonstrated that therapeutic ultrasound (TUS) increases perfusion in peripheral artery disease (PAD). This pilot study assessed the safety and effectiveness of a noninvasive TUS device in patients with advanced PAD.
Methods: A phased array of TUS transducers was fabricated on a wearable sleeve, designed to sonicate the posterior and anterior tibial arteries (and their collaterals) at the calf level. Twelve patients with PAD (Rutherford classes 3-5) were enrolled in a single-arm study in which they underwent 30-40 daily 90-minute TUS sessions to the diseased limb. Changes in pedal flow and tissue oxygenation (StO2) were measured by laser speckle and spatial frequency domain imaging, respectively. A subset of five patients underwent evaluation by laser Doppler, transcutaneous oximetry (TcPO2), and quality of life questionnaires (Vascular Quality of Life Questionnaire [VascuQoL] and the Walking Impairment Questionnaire [WIQ]).
Results: Eleven out of 12 enrolled patients completed the study. During 90-minute TUS sessions pedal flow improved by 180% (p \u3c 0.001) on laser speckle imaging, and 18% (p = 0.12) on laser Doppler. Tissue oxygenation improved by 18% (p = 0.43) on TcPO2 and by 6% (p = 0.097) on StO2. After all sessions, tissue oxygenation improved by 17% (p = 0.020) on StO2, without significant changes in laser Doppler (+39%, p = 0.41) or TcPO2 (-3%, p = 0.70), which was largely in the normal range (56 ± 15 mmHg) at baseline. VascuQoL improved by 2.4 points (14%, p = 0.080) and WIQ improved by 8.2 points (11%, p = 0.053).
Conclusions: TUS for patients with symptomatic PAD was safe and well tolerated. Most metrics of tissue perfusion and oxygenation improved, but future sham-controlled studies are needed and planned
Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for the Role of Surgery for Patients With Functioning Pituitary Adenomas.
No full textBACKGROUND AND OBJECTIVES: With the recent improvements in surgery, along with our ability to manage many pituitary tumors medically, the exact role of surgery for the treatment of functioning pituitary adenomas (PA) remains unclear. The purpose of this evidence-based clinical practice guideline was to determine the role of surgery in the treatment of functioning PA.
METHODS: A systematic review of the literature was performed using the National Library of Medicine/PubMed database and Embase for studies relevant to the role of surgery in the treatment of patients with functioning PA. Clinical studies evaluating the role of trans-sphenoidal surgery vs medical management, endoscopic techniques vs microsurgery, the benefit of the use of adjunct surgical techniques to patient outcome, and the role of second surgery were selected for review.
RESULTS: The literature search yielded 7073 abstracts. Of these, 60 studies met inclusion criteria, and evidence-based guidelines were formulated on the use of surgical resection compared with medical management, the use of endoscopic techniques and/or other surgical adjunct techniques, and the benefit of reoperation for recurrent tumors compared with medical treatment and/or radiation.
CONCLUSION: Class III evidence suggests a benefit to surgery over medical management for growth hormone-secreting adenomas without evidence to support a benefit to pretreatment with a somatostatin analog before surgery. Class III evidence suggests a benefit to medical management over surgery in the treatment of patients with prolactinomas at primary diagnosis. There are insufficient data to support the benefit of endoscopic surgery compared with microscopic surgery, with or without additional adjuvant surgical techniques, for extent of surgical resection, hormone remission, length of stay, or complication rate, in the treatment of functional PA. There is a suggestion, however, that the endoscopic technique may be superior to the microscopic technique, for a shorter operative time and for extent of surgical resection and hormone remission rates for noninvasive pituitary macroadenomas. Similarly, there are insufficient data to support the use of reoperation for recurrent tumor compared with radiation and/or medical treatment
Correction: CITEViz: interactively classify cell populations in CITE-Seq via a flow cytometry-like gating workflow using R-Shiny.
No full textThe Atypical Presentation and Delayed Timing of Anastomotic Leak in Patients Who Undergo Cytoreducation and Hyperthermic Intraperitoneal Chemotherapy.
No full textIntroduction: Anastomotic leak (AL) can be a disproportionately devastating complication following cytoreductive surgery (CRS)/hyperthermic intraperitoneal chemotherapy (HIPEC) due to its effect on both perioperative and oncologic outcomes. Anecdotally, patients who underwent CRS/HIPEC present in an atypically fashion compared to those who undergo non-CRS/HIPEC gastrointestinal surgery, but this has never been rigorously studied.
Methods: The records for all consecutive patients who underwent CRS/HIPEC with curative intent from prospectively maintained databases at two high-volume centers were retrospectively reviewed. Those who experienced AL were identified and dichotomized into early (
Results: On median postoperative day (POD) 15, 6.1% of patients experienced AL . Demographics, disease histology, risk factors for AL, receipt of neoadjuvant therapy, and extent of surgery were well-balanced. A higher proportion of small bowel anastomoses leaked in
Conclusions: Patients who experience AL after CRS/HIPEC often present in an atypical manner compared to those who undergo non-CRS/HIPEC gastrointestinal surgery. These findings are important to any practitioner who encounters CRS/HIPEC patients given that early recognition of AL is crucial to mitigating subsequent sequelae that can negatively impact both short-term perioperative and long-term oncologic outcomes in this uniquely challenging population