Comprehensive linear and nonlinear heart rate variability normative data in children.

BACKGROUND: The autonomic nervous system (ANS) is critical in regulating involuntary bodily functions, including heart rate. Heart rate variability (HRV) reflects the complex interplay between the ANS and humoral factors, making it a valuable noninvasive tool for assessing autonomic function. While HRV has been extensively studied in adults, normative data for HRV in children, primarily based on long-term rhythm recordings, are limited. OBJECTIVE: This study aimed to establish comprehensive normative data for HRV in children. METHODS: In this retrospective study, we examined 24-h Holter monitors of children aged 1 day to 18 years, divided into six age groups, at Nemours Children's Health in Orlando, Florida, spanning the years 2013-2023. HRV analysis encompassed time-domain, frequency-domain, and nonlinear indices. RESULTS: Holter data for a total of 247 patients in six age groups were included. An age-related uptrend was observed in all time- and frequency-domain variables except the normalized unit of low-frequency power. Entropy analysis revealed contradictory results among different entropy techniques. Sample and approximate entropy analyses were consistent and showed less complexity and more predictability of HRV with decreasing heart rate, while Shannon entropy analysis showed the opposite. Fractal detrended fluctuation analysis exhibited significant decreases across the age groups, suggestive of diminishing self-similarity of HRV patterns. CONCLUSION: Control of heart rate and HRV is a highly complex process and requires further study for a better understanding. It seems that no single parameter can fully elucidate the entire process. A combination of time-domain, frequency-domain, and nonlinear indices may be necessary to explain HRV behavior in the growing body.

STRIvE-02: A First-in-Human Phase I Study of Systemically Administered B7-H3 Chimeric Antigen Receptor T Cells for Patients With Relapsed/Refractory Solid Tumors.

PURPOSE: B7-H3 is an immunoregulatory protein overexpressed by many pediatric solid tumors with limited expression on critical organs, making it an attractive immunotherapy target. We present a first-in-human phase I clinical trial systemically administered B7-H3 chimeric antigen receptor (CAR) T cells for young patients with relapsed or refractory solid tumors. PATIENTS AND METHODS: Patients were enrolled onto a phase I trial to examine the safety of B7-H3-specific CARs at various dose levels (DLs) using a standard 3 + 3 dose escalation design. RESULTS: Sixteen patients (range, 11-24 years; median, 18.5 years) were enrolled, and nine were treated at DL1 (0.5 × 106 CAR T cells/kg; n = 3) or DL2 (1 × 106 CAR T cells/kg; n = 6). There were no first infusion dose-limiting toxicities. Maximum first-infusion circulating CAR T cells detected in the peripheral blood were 4.98 cells/µL (range, 0-4.98 cells/µL) with detection of CAR T cells colocalizing with tumor cells at the site of metastatic disease in one patient. Patients were eligible for subsequent infusions. An objective partial response by PERCIST criteria was observed 28 days after a second CAR T cell infusion in a patient who did not have an objective response after the first infusion. The second infusion demonstrated marked enhancement of CAR T cell expansion to 1,590 cells/µL and was accompanied by cytokine release syndrome and dose-limiting transaminitis. Detailed peripheral blood cytokine profiling revealed elevated IL-21 levels preinfusion 2 compared with infusion 1. CONCLUSION: B7-H3 CAR T cells are tolerable and demonstrate limited antitumor activity without acute on-target, off-tumor toxicity. High levels of CAR T cell expansion may be necessary to achieve objective responses, but undefined host and tumor microenvironment factors appear to be critical (ClinicalTrials.gov identifier: NCT04483778).

In-hospital course of patients with heart failure with improved ejection fraction in the DELIVER trial.

AIMS: Patients with heart failure (HF) with improved ejection fraction (HFimpEF) may face residual risks of clinical events that are comparable to those experienced by patients with HF whose left ventricular ejection fraction (LVEF) has consistently been above 40%. However, little is known about the clinical course of patients with HFimpEF during hospitalization for HF. METHODS AND RESULTS: DELIVER randomized patients with HF and LVEF >40% to dapagliflozin or placebo, including HFimpEF (LVEF previously ≤40%). We evaluated all HF hospitalizations adjudicated by the clinical endpoints committee with available data for determination of in-hospital course. Complicated hospitalization was defined as any hospitalization requiring intensive care unit stay, intravenous vasopressors/inotropes/vasodilators, invasive or non-invasive ventilation, mechanical fluid removal, ultrafiltration, or mechanical circulatory support. LVEF changes were extracted using a validated GPT-3.5, a large language model, via a secure private endpoint. Of the 6263 patients enrolled in DELIVER, 1151 (18%) had HFimpEF. During a median follow-up of 2.3 years, there were 224 total HF hospitalizations in 144 patients with HFimpEF and 985 in 603 patients with LVEF consistently >40%. Patients with HFimpEF experienced higher rates of complicated HF hospitalization as compared with patients with LVEF consistently >40% (39% vs. 27%; p < 0.001). Among those who experienced a first HF hospitalization, there was no significant difference in length of stay or in-hospital mortality between patients with HFimpEF versus LVEF consistently >40%. In a subset of participants who had at least one LVEF measurement available during HF hospitalization, 66% of those with HFimpEF and 29% of patients with LVEF consistently >40% experienced a reduction in their LVEF to ≤40% from the time of enrolment (p < 0.001). In the entire DELIVER cohort, dapagliflozin reduced total uncomplicated and complicated HF hospitalizations, irrespective of HFimpEF status (pinteraction ≥0.30). CONCLUSIONS: Among patients hospitalized for HF in DELIVER, those with HFimpEF experienced a more adverse in-hospital clinical course, necessitating higher resource utilization beyond standard diuretic therapy compared with patients with HF and LVEF consistently >40%, but had similar in-hospital mortality. Treatment benefits of dapagliflozin were not modified by hospitalization type.

Integrated evaluation of workplace exposures and biomarkers of bladder cancer among textile dyeing workers.

BACKGROUND: The textile industry is the second risk factor for bladder cancer, after smoking. Previous studies focused on the impact of exposure to high concentrations of bladder carcinogenic chemicals in the textile dyeing industry on the elevation of bladder cancer biomarkers. This study aimed to evaluate bladder carcinogenic air pollutants in a textile dyeing factory and investigate its role and the role of serum 25-hydroxyvitamin D (25-OH vit. D) on cancer bladder biomarkers in exposed workers. METHODS: A cross-sectional study was conducted. Particulate and vapor forms of polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs) were monitored in the printing, dyeing, and preparing sections of a textile factory. Bladder tumor antigen (BTA), nuclear matrix protein 22 (NMP-22), and 25-OH vit. D were estimated in all the exposed workers (147 exposed workers) and in workers not occupationally exposed to chemicals (130 unexposed workers). RESULTS: Aromatic bladder carcinogenic compounds were either in low concentrations or not detected in the air samples of working areas. BTA and NMP-22 of exposed workers were not significantly different from the unexposed. However, 25-OH vit. D was significantly lower in the exposed than unexposed workers. There was a significant inverse correlation between 25-OH vit. D and duration of exposure in exposed workers. CONCLUSION: The mean levels of PAHs and VOCs were within the safe standard levels in the working areas. The non-significant difference in BTA and NMP-22 between the exposed and unexposed groups suggests the presence of occupational exposures to safe levels of bladder carcinogenic aromatics, while the significantly lower 25-OH vit. D levels among the exposed than the unexposed groups could suggest the potential association of 25-OH vit. D with occupational exposures to low levels of PAHs and VOCs, and this association was found to be inversely correlated with the duration of exposures. Accordingly, more specific predictor tests must be applied for early diagnosis of bladder cancer among the exposed workers.

Genomic Diversity as a Key Conservation Criterion: Proof-of-Concept From Mammalian Whole-Genome Resequencing Data.

Many international, national, state, and local organizations prioritize the ranking of threatened and endangered species to help direct conservation efforts. For example, the International Union for Conservation of Nature (IUCN) assesses the Green Status of species and publishes the influential Red List of threatened species. Unfortunately, such conservation yardsticks do not explicitly consider genetic or genomic diversity (GD), even though GD is positively associated with contemporary evolutionary fitness, individual viability, and with future evolutionary potential. To test whether populations of genome sequences could help improve conservation assessments, we estimated GD metrics from 82 publicly available mammalian datasets and examined their statistical association with attributes related to conservation. We also considered intrinsic biological factors, including trophic level and body mass, that could impact GD and quantified their relative influences. Our results identify key population GD metrics that are both reflective and predictive of IUCN conservation categories. Specifically, our analyses revealed that Watterson's theta (the population mutation rate) and autozygosity (a product of inbreeding) are associated with the current Red List categorization, likely because demographic declines that lead to "listing" decisions also reduce levels of standing genetic variation. We argue that by virtue of this relationship, conservation organizations like IUCN could leverage emerging genome sequence data to help categorize Red List threat rankings (especially in otherwise data-deficient species) and/or enhance Green Status assessments to establish a baseline for future population monitoring. Thus, our paper (1) outlines the theoretical and empirical justification for a new GD-based assessment criterion, (2) provides a bioinformatic pipeline for estimating GD from population genomic data, and (3) suggests an analytical framework that can be used to measure baseline GD while providing quantitative GD context for consideration by conservation authorities.

Factors Associated with Take Home Naloxone Refusal among Emergency Department Patients Participating in an Opioid Overdose Prevention Program.

BACKGROUND: Increasing the equitable distribution of take home naloxone (THN) may result in reduced deaths from opioid overdose (OD). OBJECTIVES: The primary study objective is to describe the demographic and clinical characteristics of emergency department (ED) patients who decline THN. The findings of this descriptive study may generate new hypotheses for successful THN distribution. METHODS: Retrospective chart review using prospectively collected program evaluation data from a single urban EDs Health Education THN database and electronic health record. Characteristics of participants who refused versus accepted THN were compared using Chi-square testing for categorical variables and t-tests for continuous variables. A multivariate model was built to assess associations of statistical and clinically relevant characteristics with THN refusal. RESULTS: A total of 711 ED patients were offered THN of which 334 (46%) declined. In unadjusted analysis, with the independent variable being refusal of the THN offer, being currently on medication for opioid use disorder (MOUD) was associated with a greater odds of refusal (OR 1.9, 95%CI 1.3-2.6) while any drug related overdose (OR 0.6, 95%CI 0.4-0.8) or being given a prescription for buprenorphine in the ED (OR 0.2, 95%CI 0.1-0.9) were both associated with a lower odds of refusal. CONCLUSIONS: Demographic characteristics did not differ between those who accept versus refuse THN. Patients already receiving MOUD were more likely to refuse THN while those starting MOUD in the ED were less likely to refuse THN. Further studies are needed to determine the root causes of patients' declination of THN and develop targeted interventions to address these causes.

Effects of temperature on electrical impedance of biological tissues: ex-vivo measurements.

Bioelectrical impedance techniques have been useful in various applications, including body composition analysis, impedance plethysmography, impedance cardiography, lung ventilation, perfusion, and tissue characterization. Electrical impedance methods have also been useful in characterizing different foods like meat, fruits, and beverages. However, the temperature of tissue samples can change their dielectric properties, affecting their impedance. This research investigated the effects of temperature on the impedance of various biological tissues over the frequency range of 10 Hz to 5 MHz. Freshly excised animal tissues (lamb, cow, chicken), fish, fruits, and plants were considered as biological samples. The samples were placed in a test cell and submerged in a water bath heated by a hot plate to vary the temperature. Impedance measurements were conducted using a bioimpedance spectrometer in 2 °C steps within the temperature range of 20 °C to 50 °C. Impedance values decreased with increased temperature across all measurement frequencies for all biological samples. Curve fitting indicated that impedance decreased linearly with temperature, with a mean correlation coefficient of 0.972 for all samples. For all biological samples under investigation, the relative impedance change ranged from -0.58% to -2.27% per °C, with a mean and standard deviation of (-1.42±0.34) %/°C. On average, animal samples exhibited a higher relative temperature coefficient of -1.56% per °C (±0.41) across the frequency range, compared to -1.31% per °C (±0.26) for fruit and vegetable samples. Additionally, the relative temperature coefficient values were generally higher at lower frequencies than at higher frequencies. The findings of this research can be valuable for studies or biomedical applications involving variable tissue temperatures.

Role of oral hypoglycaemic drugs in preventing complication in non-alcoholic fatty liver disease with type 2 diabetes mellitus.

Objective: To determine the prevalence of non-alcoholic fatty liver disease, and the effect of oral hypoglycaemic drugs and lifestyle modifications in reducing fatty liver changes and liver enzymes in these patients. METHODS: The comparative, observational study was conducted at the Department of Pharmacology, Sohail University, Karachi, from October 2022 to October 2023, and comprised patients of either gender having elevated liver enzymes and ultrasound finding of fatty liver changes along with raised glycated haemoglobin, transaminases, total cholesterol and triglycerides. The participants were prescribed oral hypoglycaemic agents by endocrinologists. Those given empaglifazolin + metformin were in group A, empaglifazolin + linglaptin in group B, sitaglaptin + metformin in group C, metformin alone in group D and sitaglaptin alone in group E. Lifestyle modifications were advised in all the treatment groups, while control group F was only advised lifestyle modifications. The intervention lasted 3 months. Investigations included B-mode ultrasound liver, liver enzymes and glycated haemoglobin, which were done at baseline and after the intervention. Data was analysed using SPSS 25. RESULTS: Of 200 patients, 40 were males and 160 were females in ratio of 1:4. The overall mean age was 48±16 years. There were 154(77%) patients who had non-alcoholic fatty liver disease with type 2 diabetes mellitus, while 46(23%) had only fatty liver changes. There were 50(25%) patients in group A, 30(15%) in group B, 30(15%) in group C, 40(20%) in group D, 10(5%) in group E and 40(20%) in group F. Post-intervention improvement was noted in 48(24%) patients, with 20(41.7%) of them being in group A. Conclusion: The prevalence of non-alcoholic fatty liver disease with type 2 diabetes was high. Combination of empagliflozin + metformin along with lifestyle modifications was highly effective in reducing fatty changes and the level of liver enzymes.

Lipid metabolism reprogramming in renal cell carcinomas.

This study investigates the intricate mechanisms underlying the correlation between elevated consumption of harmful fats and the onset of kidney malignancies. The rise in global obesity rates has been accompanied by an increased prevalence of renal cancers, prompting an exploration into the molecular pathways and biological processes linking these phenomena. Through an extensive review of current literature and clinical studies, we identify potential key factors contributing to the carcinogenic influence of harmful fats on renal tissues. Our analysis highlights the role of adipose tissue-derived factors, inflammatory mediators, and lipid metabolism dysregulation in fostering a microenvironment conducive to renal tumorigenesis. Furthermore, we delve into the impact of harmful fats on signaling pathways associated with cell proliferation, apoptosis evasion, and angiogenesis within the renal parenchyma. This review underscores the importance of elucidating the molecular intricacies linking lipid metabolism and kidney malignancies, offering a foundation for future research and the development of targeted preventive and therapeutic interventions. The findings discussed herein contribute to our understanding of the complex relationship between lipid mediators and renal cancer, providing a basis for public health strategies aimed at mitigating the impact of harmful fats on kidney health.

Agenesis of third molar among the younger population of India born in twenty first century.

Objectives: The objective of this study was to find the prevalence of agenesis of third molar among the younger population of India. Materials and Methods: A cross-sectional study was conducted, and a younger population (13-21 years) born in the twenty-first century were included. Individuals who required an orthopantomogram, for any reason, were recruited in the study. Results: A total number of 850 orthopantomograms were studied, and 298 (35.05%) individuals showed the agenesis of at least 1 or more third molars. The most common pattern of agenesis was the missing of both maxillary third molars, followed by the agenesis of all third molars. The frequency of agenesis was 18 >28 >48 >38. The study showed a significant predilection in the maxilla as compared to the mandible. There was no statistically significant gender predilection for agenesis of third molar. Conclusion: The prevalence of third molar agenesis is increasing rapidly with time, with no significant gender predilection and changing trends of patterns of agenesis.

Analysis of cell cycle stage, replicated DNA, and chromatin-associated proteins using high-throughput flow cytometry.

Flow cytometry is a versatile tool used for cell sorting, DNA content imaging, and determining various cellular characteristics. With the possibility of high-throughput analyses, it combines convenient labelling techniques to serve rapid, quantitative, and qualitative workflows. The ease of sample preparation and the broad range of applications render flow cytometry a preferred approach for many scientific questions. Yet, we lack practical adaptations to fully harness the quantitative and high-throughput capabilities of most cytometers for many organisms. Here, we present simple and advanced protocols for the analysis of total DNA content, de novo DNA synthesis, and protein association to chromatin in budding yeast and human cells. Upon optimization of experimental conditions and choice of fluorescent dyes, up to four parameters can be measured simultaneously and quantitatively for each cell of a population in a multi-well plate format. Reducing sample numbers, plastic waste, costs per well, and hands-on time without compromising signal quality or single-cell accuracy are the main advantages of the presented protocols. In proof-of-principle experiments, we show that DNA content increase in S-phase correlates with de novo DNA synthesis and can be predicted by the presence of the replicative helicase MCM2-7 on genomic DNA.

Investigating underlying molecular mechanisms, signaling pathways, emerging therapeutic approaches in pancreatic cancer.

Pancreatic adenocarcinoma, a clinically challenging malignancy constitutes a significant contributor to cancer-related mortality, characterized by an inherently poor prognosis. This review aims to provide a comprehensive understanding of pancreatic adenocarcinoma by examining its multifaceted etiologies, including genetic mutations and environmental factors. The review explains the complex molecular mechanisms underlying its pathogenesis and summarizes current therapeutic strategies, including surgery, chemotherapy, and emerging modalities such as immunotherapy. Critical molecular pathways driving pancreatic cancer development, including KRAS, Notch, and Hedgehog, are discussed. Current therapeutic strategies, including surgery, chemotherapy, and radiation, are discussed, with an emphasis on their limitations, particularly in terms of postoperative relapse. Promising research areas, including liquid biopsies, personalized medicine, and gene editing, are explored, demonstrating the significant potential for enhancing diagnosis and treatment. While immunotherapy presents promising prospects, it faces challenges related to immune evasion mechanisms. Emerging research directions, encompassing liquid biopsies, personalized medicine, CRISPR/Cas9 genome editing, and computational intelligence applications, hold promise for refining diagnostic approaches and therapeutic interventions. By integrating insights from genetic, molecular, and clinical research, innovative strategies that improve patient outcomes can be developed. Ongoing research in these emerging fields holds significant promise for advancing the diagnosis and treatment of this formidable malignancy.

Dosimetric effect of collimator rotation on intensity modulated radiotherapy and volumetric modulated arc therapy for rectal cancer radiotherapy.

INTRODUCTION: Intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) are the main radiotherapy techniques for treating and managing rectal cancer. Collimator rotation is one of the crucial parameters in radiotherapy planning, and its alteration can cause dosimetric variations. This study assessed the effect of collimator rotation on the dosimetric results of various IMRT and VMAT plans for rectal cancer. MATERIALS AND METHODS: Computed tomography (CT) images of 20 male patients with rectal cancer were utilized for IMRT and VMAT treatment planning with various collimator angles. Nine different IMRT techniques (5, 7, and 9 coplanar fields with collimator angles of 0°, 45°, and 90°) and six different VMAT techniques (1 and 2 full coplanar arcs with collimator angles of 0°, 45°, and 90°) were planned for each patient. The dosimetric results of various treatment techniques for target tissue (conformity index [CI] and homogeneity index [HI]) and organs at risk (OARs) sparing (parameters obtained from OARs dose-volume histograms [DVH]) as well as radiobiological findings were analyzed and compared. RESULTS: The 7-fields IMRT technique demonstrated lower bladder doses (V40Gy, V45Gy), unaffected by collimator rotation. The 9-fields IMRT and 2-arcs VMAT (excluding the 90-degree collimator) had the lowest V35Gy and V45Gy. A 90-degree collimator rotation in 2-arcs VMAT significantly increased small bowel and bladder V45Gy, femoral head doses, and HI values. Radiobiologically, the 90-degree rotation had adverse effects on small bowel NTCP (normal tissue complication probability). No superiority was found for a 45-degree collimator rotation over 0 or 30 degrees in VMAT techniques. CONCLUSION: Collimator rotation had minimal impact on dosimetric parameters in IMRT planning but is significant in VMAT techniques. A 90-degree rotation in VMAT, particularly in a 2-full arc technique, adversely affects PTV homogeneity index, bladder dose, and small bowel NTCP. Other evaluated collimator angles did not significantly affect VMAT dosimetrical or radiobiological outcomes.

Elucidating the effect of levothyroxine and triiodothyronine on methylglyoxal derived stress.

PURPOSE: Methylglyoxal (MG) is the most potent precursor during the formation of the advanced glycation end products (AGEs). MG-dependent glycative stress contributes to pathogenesis of diabetes, age-related disorders, and cancer. There is a great need to study the reduction process of glycative stress for effective management of metabolic disorders. From natural compounds to synthetic drugs, each element contributes to the reduction of glycative stress. Previously, it was established that the lowering of uric acid, low-density lipoprotein cholesterol, and urine albumin excretion rate, as well as reducing total oxidative stress, were all achieved more effectively with a levothyroxine regimen. Still, there is no such study found that supports the MG-dependent glycative stress reduction with thyroid hormone compound. Our study aims to investigate the effects of T3 and T4 on MG-dependent glycative stress. METHODS: The antiglycation effect was assayed through NBT assay, DNPH assay, ELISA, and fluorescence spectrophotometer. The intracellular reduction in reactive oxygen species (ROS) has been estimated through confocal microscopy. RESULTS: The results revealed an effective reduction in the formation of AGEs adducts and intracellular ROS formation. CONCLUSION: The investigation concludes AGEs formation was suppressed using these compounds, although in vivo and rigorous clinical trials are required in order to verify these findings.

Crosstalk between gut microbiota and host immune system and its response to traumatic injury.

Millions of microorganisms make up the complex microbial ecosystem found in the human gut. The immune system's interaction with the gut microbiota is essential for preventing inflammation and maintaining intestinal homeostasis. Numerous metabolic products that can cross-talk between immune cells and the gut epithelium are metabolized by the gut microbiota. Traumatic injury elicits a great and multifaceted immune response in the minutes after the initial offense, containing simultaneous pro- and anti-inflammatory responses. The development of innovative therapies that improve patient outcomes depends on the gut microbiota and immunological responses to trauma. The altered makeup of gut microbes, or gut dysbiosis, can also dysregulate immunological responses, resulting in inflammation. Major human diseases may become more common as a result of chronic dysbiosis and the translocation of bacteria and the products of their metabolism beyond the mucosal barrier. In this review, we briefly summarize the interactions between the gut microbiota and the immune system and human disease and their therapeutic probiotic formulations. We also discuss the immune response to traumatic injury.

Determinants of clinical response to injection laryngoplasty in unilateral vocal fold paralysis: a systematic review and meta-analysis.

BACKGROUND: Unilateral vocal fold paralysis (UVFP) significantly impairs vocal function, affecting patients' quality of life. Injection laryngoplasty, a primary treatment modality for UVFP, varies in effectiveness based on the material used, injection volume, and procedural nuances. This study aims to systematically analyze how these factors influence treatment outcomes to optimize intervention strategies. MATERIALS AND METHODS: We conducted a comprehensive meta-analysis and meta-regression using data extracted from 82 studies identified through a robust literature search on databases including PubMed, Scopus, and Web of Science, up to February 13, 2024. Eligible studies were single-armed observational or experimental that reported pre- and post-operative data on UVFP patients undergoing their first injection laryngoplasty. The primary outcomes analyzed included maximum phonation time, harmonics-to-noise ratio, fundamental frequency, jitter, shimmer, and subjective voice measures such as the Voice Handicap Index and GRBAS scale components. RESULTS: The meta-analysis revealed significant improvements in maximum phonation time (MPT) and harmonics-to-noise ratio (HNR) post-injection, with variability in outcomes influenced by injection material and procedural techniques. Meta-regression identified the injection volume and the timing of the procedure as significant predictors of MPT and HNR outcomes, respectively. Materials such as polydimethylsiloxane (PDMS) and autologous fat significantly improved MPT and reduced the grade of dysphonia and roughness, respectively. The type of injection material, volume, and approach were crucial in reducing symptoms of voice handicap and enhancing the overall vocal quality. CONCLUSIONS: Injection laryngoplasty significantly improves vocal outcomes in UVFP patients. The choice of injection material, volume, and timing of the intervention plays pivotal roles in determining the effectiveness of the procedure. Tailored treatment approaches based on these factors are recommended to enhance therapeutic efficacy and patient satisfaction.