Waterpipe Tobacco Brands and Flavors Sold Online in the USA.

INTRODUCTION: Flavor additives are commonly used in combustible tobacco products to mask harshness and increase appeal. However, research on the availability of flavored waterpipe tobacco (WT) is lacking, yet is important to support implementation of policies. METHODS: We completed a comprehensive online search in 2020 to identify WT brands and flavors sold online in the USA. We conducted a descriptive content analysis categorizing flavors as explicit (i.e., clear taste/flavor) or concept (i.e., no clear taste/flavor); and coded for 23 flavor descriptors (e.g., fruit, mint/menthol, tobacco). Flavor names were double-coded and discrepancies were resolved by a third coder. RESULTS: We identified 66 WT brands with 118 product lines (i.e., sub-brands). We found 2953 flavors, including 1871 unique flavors. Brands averaged 45 flavors (range: 1-183). Almost three quarters (73.5%, n = 2171) used explicit flavor names and 26.5% (n = 782) used concept flavor names. Concept flavors varied widely, and included names such as 1001 Nights and California Dream. The most common flavor descriptors were fruit (54.1%) and mint/menthol (12.5%). Tobacco was rarely (0.2%) used as a flavor descriptor. Flavor descriptors also included location (10.7%), color (11.1%), candy (6.3%), cool/ice (5.3%), and alcohol (5.5%). CONCLUSIONS: WT is available in 1871 unique flavors, likely contributing to product appeal and use. Like other tobacco products, fruit and mint/menthol are common flavors. Given the significant health consequences associated with WT smoking and the role of flavors in product use, regulatory action specifically targeting WT flavors is urgently needed.

KAP1/TRIM28 - antiviral and proviral protagonist of herpesvirus biology.

Dysregulation of the constitutive heterochromatin machinery (HCM) that silences pericentromeric regions and endogenous retroviral elements in the human genome has consequences for aging and cancer. By recruiting epigenetic regulators, Krüppel-associated box (KRAB)-associated protein 1 (KAP1/TRIM28/TIF1ß) is integral to the function of the HCM. Epigenetically silencing DNA genomes of incoming herpesviruses to enforce latency, KAP1 and HCM also serve in an antiviral capacity. In addition to gene silencing, newer reports highlight KAP1's ability to directly activate cellular gene transcription. Here, we discuss the many facets of KAP1, including recent findings that unexpectedly connect KAP1 to the inflammasome, reveal KAP1 cleavage as a novel mode of regulation, and argue for a pro-herpesviral KAP1 function that ensures transition from transcription to replication of the herpesvirus genome.

A comparative evaluation of ChatGPT 3.5 and ChatGPT 4 in responses to selected genetics questions.

OBJECTIVES: To evaluate the efficacy of ChatGPT 4 (GPT-4) in delivering genetic information about BRCA1, HFE, and MLH1, building on previous findings with ChatGPT 3.5 (GPT-3.5). To focus on assessing the utility, limitations, and ethical implications of using ChatGPT in medical settings. MATERIALS AND METHODS: A structured survey was developed to assess GPT-4's clinical value. An expert panel of genetic counselors and clinical geneticists evaluated GPT-4's responses to these questions. We also performed comparative analysis with GPT-3.5, utilizing descriptive statistics and using Prism 9 for data analysis. RESULTS: The findings indicate improved accuracy in GPT-4 over GPT-3.5 (P < .0001). However, notable errors in accuracy remained. The relevance of responses varied in GPT-4, but was generally favorable, with a mean in the "somewhat agree" range. There was no difference in performance by disease category. The 7-question subset of the Bot Usability Scale (BUS-15) showed no statistically significant difference between the groups but trended lower in the GPT-4 version. DISCUSSION AND CONCLUSION: The study underscores GPT-4's potential role in genetic education, showing notable progress yet facing challenges like outdated information and the necessity of ongoing refinement. Our results, while showing promise, emphasizes the importance of balancing technological innovation with ethical responsibility in healthcare information delivery.

Piximi - An Images to Discovery web tool for bioimages and beyond.

Deep learning has greatly accelerated research in biological image analysis yet it often requires programming skills and specialized tool installation. Here we present Piximi, a modern, no-programming image analysis tool leveraging deep learning. Implemented as a web application at Piximi.app, Piximi requires no installation and can be accessed by any modern web browser. Its client-only architecture preserves the security of researcher data by running all computation locally. Piximi offers four core modules: a deep learning classifier, an image annotator, measurement modules, and pre-trained deep learning segmentation modules. Piximi is interoperable with existing tools and workflows by supporting import and export of common data and model formats. The intuitive researcher interface and easy access to Piximi allows biological researchers to obtain insights into images within just a few minutes. Piximi aims to bring deep learning-powered image analysis to a broader community by eliminating barriers to entry.

Influence of anatomical structure on antiscatter grid performance in 2D: application to x-ray angiography and a prototype 29:1 ratio grid.

OBJECTIVE: The use of uniform phantoms to assess the influence of X-ray scatter and antiscatter grids on X-ray angiography and fluoroscopy image quality disregards the influence of spatially variable X-ray attenuation of patients. The purpose of this work was to measure scatter to primary ratio (SPR) and antiscatter grid SNR improvement factor (KSNR) using experimental conditions which better mimic patient imaging conditions. APPROACH: Three adult-sized anthropomorphic phantoms were used. AP and lateral projection images of the thorax and abdomen were acquired with and without an antiscatter grid. Grids with ratio 15:1 and 29:1 (r15, r29) and X-ray fields of view 20, 25 (thorax) and 32, 42 cm (abdomen) were tested. Combined with a-priori measurements of grid scatter and primary transmission fractions, these images were used to calculate 2D SPR and KSNR maps. MAIN RESULTS: Results demonstrated that measurements by uniform phantom do not describe the complex 2D SPR and KSNR distributions associated with anthropomorphic phantoms. The regions of the images with the lowest primary X-ray intensity (greatest attenuation) had the highest SPR and the highest KSNR attributable to the grids. Considering all conditions, the 95th percentile of the SPR maps was in the range 42-185% greater than the median values and that of the KSNR maps was 4-20% higher than the median values. The combined influences of SID 120 vs. 107 cm and r29 vs. r15 grid resulted in KSNR in the range 1.05-1.49. SIGNIFICANCE: Performance of anti-scatter grids using anatomically complex phantoms highlights the substantial variation of SPR and KSNR within 2D images. Also, this work demonstrates the benefit of the prototype r29 grid for thoracic and abdominal angiography imaging conditions is substantial, especially for large patients and radiodense image regions.

Cellpose as a reliable method for single-cell segmentation of autofluorescence microscopy images.

Autofluorescence microscopy uses intrinsic sources of molecular contrast to provide cellular-level information without extrinsic labels. However, traditional cell segmentation tools are often optimized for high signal-to-noise ratio (SNR) images, such as fluorescently labeled cells, and unsurprisingly perform poorly on low SNR autofluorescence images. Therefore, new cell segmentation tools are needed for autofluorescence microscopy. Cellpose is a deep learning network that is generalizable across diverse cell microscopy images and automatically segments single cells to improve throughput and reduce inter-human biases. This study aims to validate Cellpose for autofluorescence imaging, specifically from multiphoton intensity images of NAD(P)H. Manually segmented nuclear masks of NAD(P)H images were used to train new Cellpose models. These models were applied to PANC-1 cells treated with metabolic inhibitors and patient-derived cancer organoids (across 9 patients) treated with chemotherapies. These datasets include co-registered fluorescence lifetime imaging microscopy (FLIM) of NAD(P)H and FAD, so fluorescence decay parameters and the optical redox ratio (ORR) were compared between masks generated by the new Cellpose model and manual segmentation. The Dice score between repeated manually segmented masks was significantly lower than that of repeated Cellpose masks (p<0.0001) indicating greater reproducibility between Cellpose masks. There was also a high correlation (R2>0.9) between Cellpose and manually segmented masks for the ORR, mean NAD(P)H lifetime, and mean FAD lifetime across 2D and 3D cell culture treatment conditions. Masks generated from Cellpose and manual segmentation also maintain similar means, variances, and effect sizes between treatments for the ORR and FLIM parameters. Overall, Cellpose provides a fast, reliable, reproducible, and accurate method to segment single cells in autofluorescence microscopy images such that functional changes in cells are accurately captured in both 2D and 3D culture.

CENP-E inhibition induces chromosomal instability and synergizes with diverse microtubule-targeting agents in breast cancer.

Drugs that perturb microtubules are commonly used to treat breast cancers of all subtypes in both early stage and metastatic disease, but they are only effective in approximately 50% of patients. High concentrations of microtubule-targeting agents can elicit mitotic arrest in cell culture models; however, recent evidence from primary and metastatic breast cancers revealed that they only accumulate at intratumoral levels capable of inducing abnormal multipolar mitotic spindles, not mitotic arrest. While maintenance of multipolar spindles can generate cytotoxic rates of chromosomal instability (CIN), focusing of aberrant multipolar spindles into normal bipolar spindles dramatically reduces CIN and confers resistance to microtubule poisons. Here, we showed that inhibition of the mitotic kinesin CENP-E overcomes resistance caused by focusing multipolar spindles. Clinically relevant microtubule-targeting agents used a mechanistically conserved pathway to induce multipolar spindles without requiring centrosome amplification. Focusing could occur at any point in mitosis, with earlier focusing conferring greater resistance to anti-microtubule agents. CENP-E inhibition increased CIN on focused spindles by generating chromosomes that remained misaligned at spindle poles during anaphase, which substantially increased death in the resulting daughter cells. CENP-E inhibition synergized with diverse, clinically relevant microtubule poisons to potentiate cell death in cell lines and suppress tumor growth in orthotopic tumor models. These results suggest that primary resistance to microtubule-targeting drugs can be overcome by simultaneous inhibition of CENP-E.

Sympathetic structural and electrophysiological remodeling in a rabbit model of reperfused myocardial infarction.

Chondroitin sulfate proteoglycans (CSPGs) inhibit sympathetic reinnervation in rodent hearts post myocardial infarction (MI), causing regional hypo-innervation that is associated with supersensitivity of ß-adrenergic receptors and increased arrhythmia susceptibility. To investigate the role of CSPGs and hypo-innervation in the heart of larger mammals, we used a rabbit model of reperfused MI and tested electrophysiological responses to sympathetic nerve stimulation (SNS). Innervated hearts from MI and sham rabbits were optically mapped using voltage and Ca 2+ -sensitive dyes. SNS was performed with electrical stimulation of the spinal cord and ß-adrenergic responsiveness was tested using isoproterenol. Sympathetic nerve density and CSPG expression were evaluated using immunohistochemistry. CSPGs were robustly expressed in the infarct and border zone of all MI hearts, and the presence of CSPGs was associated with reduced sympathetic nerve density in the infarct vs. remote region. Action potential duration (APD) dispersion and susceptibility to ventricular tachycardia/fibrillation (VT/VF) were increased with SNS in MI hearts but not in sham. SNS decreased APD 80 in MI but not sham hearts, while isoproterenol decreased APD 80 in both groups. Isoproterenol also shortened Ca 2+ transient duration (CaTD 80 ) in both groups but to a greater extent in MI hearts. Our data suggest sympathetic remodeling post-MI is similar between species, with CSPGs associated with sympathetic hypo-innervation. Despite a reduction in sympathetic nerve density, the infarct region of MI hearts remained responsive to both physiological SNS and isoproterenol, potentially through preserved or elevated ß-adrenergic responsiveness, which may underly increased APD dispersion and susceptibility for VT/VF. NEW & NOTEWORTHY: Here we show that CSPGs are present in the infarcts of rabbit hearts with reperfused MI, where they are associated with reduced sympathetic nerve density. Despite hypo-innervation, sympathetic responsiveness is maintained or enhanced in MI rabbit hearts, which also demonstrate increased APD dispersion and tendency for arrhythmias following sympathetic modulation. Together, this study indicates that the mechanisms of sympathetic remodeling post-MI are similar between species, with hypo-innervation likely associated with enhanced ß-adrenergic sensitivity.

Application of the solution-focused brief strategies via telephone for family caregivers of persons with dementia: the Alzheimer's Association National Helpline.

OBJECTIVES: Nearly 75% of persons living with dementia (PLWD) in the US live at home and are cared for by informal family members who have limited access to supportive and accessible services, indicating an increased need for these types of services (Alzheimer's Association, 2023). The Alzheimer's Association call centers offer free telephone care consultations, but it currently remains unclear which types of brief telephone support benefit caregivers. This study compares outcomes of participants who received traditional care consultation calls via the Alzheimer's Association National Helpline with care consultation calls from Helpline staff trained in Solution-Focused Brief Strategies (SFBS), a client-centered evidence- and resource-based approach. METHOD: Sequential callers were randomly assigned to the "traditional" or "SFBS" care consultation groups and were assessed at the time of call (baseline) and post-call (T1). The outcomes of interest were general self-efficacy (GSE), self-efficacy in managing emotions (PROMIS), caregiver mastery, therapeutic alliance, and goal setting. RESULTS: Of over 500 callers, callers receiving the SFBS scored higher on therapeutic alliance and goal-setting metrics, such as greater sense of collaboration on goals (effect size = 0.280, p = 0.0005, significant with Bonferroni correction), mutual agreement with care consultant on goals (effect size = 0.418, p < 0.0001, significant with Bonferroni correction), and believing the way the problem was resolved was correct (effect size = 0.286, p = 0.0007, significant with Bonferroni correction) than those receiving the traditional care consultation. Both groups reported improvements in the PROMIS measure, but there were no differences between groups. There were no significant differences in GSE or caregiver mastery scores between groups. CONCLUSION: This study provides evidence for the effectiveness of the integration of SFBS in dementia care consultation calls as part of telephone-based supportive services for dementia caregivers.

Optimizing automated detection of high frequency oscillations using visual markings does not improve SOZ localization.

OBJECTIVE: High frequency oscillations (HFOs) are a biomarker of the seizure onset zone (SOZ) and can be visually or automatically detected. In theory, one can optimize an automated algorithm's parameters to maximize SOZ localization accuracy; however, there is no consensus on whether or how this should be done. Therefore, we optimized an automated detector using visually identified HFOs and evaluated the impact on SOZ localization accuracy. METHODS: We detected HFOs in intracranial EEG from 20 patients with refractory epilepsy from two centers using (1) unoptimized automated detection, (2) visual identification, and (3) automated detection optimized to match visually detected HFOs. RESULTS: SOZ localization accuracy based on HFO rate was not significantly different between the three methods. Across patients, visually optimized detector settings varied, and no single set of settings produced universally accurate SOZ localization. Exploratory analysis suggests that, for many patients, detection settings exist that would improve SOZ localization. CONCLUSIONS: SOZ localization accuracy was similar for all three methods, was not improved by visually optimizing detector settings, and may benefit from patient-specific parameter optimization. SIGNIFICANCE: Visual HFO marking is laborious, and optimizing automated detection using visual markings does not improve localization accuracy. New patient-specific detector optimization methods are needed.

Affimer reagents as tool molecules to modulate platelet GPVI-ligand interactions and specifically bind GPVI dimer.

Glycoprotein (GP)VI plays a key role in collagen-induced platelet aggregation. Affimers are engineered binding protein alternatives to antibodies. We screened and characterized GPVI-binding Affimers as novel tools to probe GPVI function. Among the positive clones, M17, D22 and D18 bound GPVI with the highest affinities (KD in the nM range). These Affimers inhibited GPVI-CRP-XL/collagen interactions, CRP-XL/collagen induced platelet aggregation and D22 also inhibited in vitro thrombus formation on a collagen surface under flow. D18 bound GPVI dimer but not monomer. GPVI binding was increased for D18 but not M17/D22 upon platelet activation by CRP-XL and ADP. D22 but not M17/D18 displaced nanobody2 (Nb2) binding to GPVI, indicating similar epitopes for D22 with Nb2 but not for M17/D18. Mapping of binding sites revealed that D22 binds a site that overlaps with Nb2 on the D1-domain, while M17 targets a site on the D2-domain, overlapping in part with the glenzocimab binding site, a humanized GPVI antibody Fab-fragment. D18 targets a new region on the D2-domain. We found that D18 is a stable non-covalent dimer and forms a stable complex with dimeric GPVI with 1:1 stoichiometry. Taken together, our data demonstrate that Affimers modulate GPVI-ligand interactions and bind different sites on GPVI D1/D2-domains. D18 is dimer-specific and could be used as a tool to detect GPVI dimerization or clustering in platelets. A dimeric epitope regulating ligand binding was identified on the GPVI D2-domain, which could be used for the development of novel bivalent antithrombotic agents selectively targeting GPVI dimer on platelets.

A mouse model of TB-associated lung fibrosis reveals persistent inflammatory macrophage populations during treatment.

Post-TB lung disease (PTLD) causes a significant burden of global disease. Fibrosis is a central component of many clinical features of PTLD. To date, we have a limited understanding of the mechanisms of TB-associated fibrosis and how these mechanisms are similar to or dissimilar from other fibrotic lung pathologies. We have adapted a mouse model of TB infection to facilitate the mechanistic study of TB-associated lung fibrosis. We find that the morphologies of fibrosis that develop in the mouse model are similar to the morphologies of fibrosis observed in human tissue samples. Using Second Harmonic Generation (SHG) microscopy, we are able to quantify a major component of fibrosis, fibrillar collagen, over time and with treatment. Inflammatory macrophage subpopulations persist during treatment; matrix remodeling enzymes and inflammatory gene signatures remain elevated. Our mouse model suggests that there is a therapeutic window during which adjunctive therapies could change matrix remodeling or inflammatory drivers of tissue pathology to improve functional outcomes after treatment for TB infection.

Electrode Surface Area Impacts Measurement of High Frequency Oscillations in Human Intracranial EEG.

OBJECTIVE: High-frequency oscillations (HFOs) are a promising prognostic biomarker of surgical outcome in patients with epilepsy. Their rates of occurrence and morphology have been studied extensively using recordings from electrodes of various geometries. While electrode size is a potential confounding factor in HFO studies, it has largely been disregarded due to a lack of consistent evidence. Therefore, we designed an experiment to directly test the impact of electrode size on HFO measurement. METHODS: We first simulated HFO measurement using a lumped model of the electrode-tissue interaction. Then eight human subjects were each implanted with a high-density 8x8 grid of subdural electrodes. After implantation, the electrode sizes were altered using a technique recently developed by our group, enabling intracranial EEG recordings for three different electrode surface areas from a static brain location. HFOs were automatically detected in the data and their characteristics were calculated. RESULTS: The human subject measurements were consistent with the model. Specifically, HFO rate measured per area of tissue decreased significantly as electrode surface area increased. The smallest electrodes recorded more fast ripples than ripples. Amplitude of detected HFOs also decreased as electrode surface area increased, while duration and peak frequency were unaffected. CONCLUSION: These results suggest that HFO rates measured using electrodes of different surface areas cannot be compared directly. SIGNIFICANCE: This has significant implications for HFOs as a tool for surgical planning, particularly for individual patients implanted with electrodes of multiple sizes and comparisons of HFO rate made across patients and studies.

A role of epigenetic mechanisms in regulating female reproductive responses to temperature in a pest beetle.

Many species are threatened by climate change and must rapidly respond to survive in changing environments. Epigenetic modifications, such as DNA methylation, can facilitate plastic responses by regulating gene expression in response to environmental cues. Understanding epigenetic responses is therefore essential for predicting species' ability to rapidly adapt in the context of global environmental change. Here, we investigated the functional significance of different methylation-associated cellular processes on temperature-dependent life history in seed beetles, Callosobruchus maculatus Fabricius 1775 (Coleoptera: Bruchidae). We assessed changes under thermal stress in (1) DNA methyltransferase (Dnmt1 and Dnmt2) expression levels, (2) genome-wide methylation and (3) reproductive performance, with (2) and (3) following treatment with 3-aminobenzamide (3AB) and zebularine (Zeb) over two generations. These drugs are well-documented to alter DNA methylation across the tree of life. We found that Dnmt1 and Dnmt2 were expressed throughout the body in males and females, but were highly expressed in females compared with males and exhibited temperature dependence. However, whole-genome methylation did not significantly vary with temperature, and only marginally or inconclusively with drug treatment. Both 3AB and Zeb led to profound temperature-dependent shifts in female reproductive life history trade-off allocation, often increasing fitness compared with control beetles. Mismatch between magnitude of treatment effects on DNA methylation versus life history effects suggest potential of 3AB and Zeb to alter reproductive trade-offs via changes in DNA repair and recycling processes, rather than or in addition to (subtle) changes in DNA methylation. Together, our results suggest that epigenetic mechanisms relating to Dnmt expression, DNA repair and recycling pathways, and possibly DNA methylation, are strongly implicated in modulating insect life history trade-offs in response to temperature change.

Treatment planning for MR-guided SBRT of pancreatic tumors on a 1.5 T MR-Linac: A global consensus protocol.

Background and purpose: Treatment planning for MR-guided stereotactic body radiotherapy (SBRT) for pancreatic tumors can be challenging, leading to a wide variation of protocols and practices. This study aimed to harmonize treatment planning by developing a consensus planning protocol for MR-guided pancreas SBRT on a 1.5 T MR-Linac. Materials and methods: A consortium was founded of thirteen centers that treat pancreatic tumors on a 1.5 T MR-Linac. A phased planning exercise was conducted in which centers iteratively created treatment plans for two cases of pancreatic cancer. Each phase was followed by a meeting where the instructions for the next phase were determined. After three phases, a consensus protocol was reached. Results: In the benchmarking phase (phase I), substantial variation between the SBRT protocols became apparent (for example, the gross tumor volume (GTV) D99% ranged between 36.8 - 53.7 Gy for case 1, 22.6 - 35.5 Gy for case 2). The next phase involved planning according to the same basic dosimetric objectives, constraints, and planning margins (phase II), which led to a large degree of harmonization (GTV D99% range: 47.9-53.6 Gy for case 1, 33.9-36.6 Gy for case 2). In phase III, the final consensus protocol was formulated in a treatment planning system template and again used for treatment planning. This not only resulted in further dosimetric harmonization (GTV D99% range: 48.2-50.9 Gy for case 1, 33.5-36.0 Gy for case 2) but also in less variation of estimated treatment delivery times. Conclusion: A global consensus protocol has been developed for treatment planning for MR-guided pancreatic SBRT on a 1.5 T MR-Linac. Aside from harmonizing the large variation in the current clinical practice, this protocol can provide a starting point for centers that are planning to treat pancreatic tumors on MR-Linac systems.

Co-occurring Epilepsy and Attention-Deficit/Hyperactivity Disorder in a 6-Year-Old Boy.

CASE: "Andrew" is a 6-year-old, right-handed, cisgender boy who presents for neuropsychological testing to determine whether he meets criteria for attention-deficit/hyperactivity disorder (ADHD). Andrew's parents report that he is easily distracted, has poor concentration, and is unable to sustain attention for discrete periods of time. Andrew is the product of an uncomplicated pregnancy and delivery, and there were no reported concerns in the postnatal period. Andrew met all of his language and motor milestones on time. He was described as having an "easy" temperament in his infancy and toddler years. Difficulties with attention started in preschool in that Andrew was described as frequently "getting lost" in his play or the task he was working on. He was easy to redirect and responded to cues and reminders. Socially, Andrew was described as friendly but not always "picking up on social cues." Andrew's kindergarten teachers first noted that sometimes Andrew would "blank out" and appear to stare off, which was attributed to inattention. His teachers brought their concerns to Andrew's parents, and his parents began to observe Andrew more carefully and noted that these episodes also occurred at home daily. When queried, his parents reported that these episodes would last 4 to 5 seconds and Andrew would not respond to his name being called or to being physically touched. Andrew's medical history, and that of his immediate and extended family, is unremarkable. Routine hearing and vision screenings are also unremarkable. There are no reports of head injuries or concussions. Andrew's gait is stable, and there are no signs of motor weakness. There are no reports of sensory seeking or avoiding behaviors. There are no reports of witnessing or experiencing trauma; motor or vocal tics; or compulsions, ritualized behaviors, or restricted interests.Testing revealed high average verbal comprehension skills, average perceptual and fluid reasoning, and lower end of average working memory and processing speed. During testing, the examiner noted a rapid eye flutter, which Andrew did not see to recognize himself but did ask the examiner to repeat the previous question. Parent and teacher rating scales of emotional and behavioral functioning showed elevations in the areas of inattention and adaptability and 1 scale of executive functioning noted elevations in task monitoring but no other difficulties. Socially, Andrew is well liked by his peers, although he can present as "silly." He has many same-aged friends and enjoys group activities. His parents have been hesitant to get him involved in sports because he has been known to have these staring episodes right after competing in sporting events. He also tends to have them more often during the school week when he has less sleep, which his parents attribute to having a difficult time falling asleep at night. What would you do next?

Increased Heart Rate Fragmentation in Those with Williams-Beuren Syndrome Suggests Non-autonomic Mechanistic Contributors to Sudden Death Risk.

Williams-Beuren Syndrome (WBS) is a rare genetic condition caused by a chromosomal microdeletion at 7q11.23. It is a multi-system disorder characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis. Those with WBS are at increased risk of sudden death, but mechanisms underlying this remain poorly understood. We recently demonstrated autonomic abnormalities in those with WBS that are associated with increased susceptibility to arrhythmia and sudden cardiac death (SCD) risk. A recently introduced method for HRV analysis called 'heart rate fragmentation' (HRF) correlates with adverse cardiovascular events and death in studies where HRV failed to identify high-risk subjects. Some argue that HRF quantifies non-autonomic cardiovascular modulators. We, therefore, sought to apply HRF analysis to a WBS cohort to: 1) determine if those with WBS show differences in HRF compared to healthy controls and 2) determine if HRF correlates with traditional HRV measures in those with WBS. Similar to studies of those with CAD and atherosclerosis, we found significantly higher HRF in those with WBS compared to healthy controls. In general, HRF shows minimal correlation with traditional HRV metrics, suggesting that HRF may quantify some non-autonomic modulators of sudden death risk in those with WBS. We also introduce a new metric inspired by the HRF methodology, Significant Acute Rate Drop (SARD), which may permit vagal activity detection more directly. HRF and SARD increase the ability of non-invasive HRV measures to identify those at greatest risk for sudden cardiac death both in those with WBS as well as populations more broadly.

Our New Normal: Pediatric Nurse Residents' Experiences with Transition to Practice during the COVID-19 Pandemic.

This phenomenological qualitative study examined the lived experience of pediatric nurse residents' transition to practice during the COVID-19 pandemic. The purposive sample included nine pediatric nurses, participating in a nurse residency program, who entered the nursing profession during the first year of the pandemic. The setting was a free-standing, Magnet-recognized, pediatric academic medical center in the Northeastern U.S. Individual interviews were audio recorded and transcribed. Narratives were analyzed using a hermeneutic phenomenological approach. Five themes emerged from the data: Our New Normal; The Rules Keep Changing; I'm Not Ready for This (transition to practice); The Toll of COVID; and Shattered Family-Centered Care. Sub-themes emerged in The Toll of COVID theme: COVID and the Nursing Care Environment, Emotional Toll of COVID, Burnout: A Universal Truth, and The Pandemic within the Pandemic. The nurse residents' narratives uncovered the essence of their uncertainty, sorrow, growth, and resilience. Through the eyes of pediatric nurse residents, this study illuminated the experiences of these novices as they entered the nursing profession amid a pandemic.

Manual therapy and exercise effects on inflammatory cytokines: a narrative overview.

Background: Matching disease and treatment mechanisms is a goal of the Precision Medicine Initiative. Pro- and anti-inflammatory cytokines (e.g., Tumor Necrosis Factor-alpha, Transforming Growth Factor-beta, and Interleukin-2, 10, and 12) have gained a significant amount of interest in their potential role in persistent pain for musculoskeletal (MSK) conditions. Manual therapy (MT) and exercise are two guideline-recommended approaches for treating MSK conditions. The objective of this narrative overview was to investigate of the effects of MT and exercise on pro- and anti-inflammatory cytokines and determine the factors that lead to variability in results. Methods: Two reviewers evaluated the direction and variabilities of MT and exercise literature. A red, yellow, and green light scoring system was used to define consistencies. Results: Consistencies in responses were seen with acute and chronic exercise and both pro- and anti-inflammatory cytokines. Chronic exercise is associated with a consistent shift towards a more anti-inflammatory cytokine profile (Transforming Growth Factor-beta, and Interleukin-2 and 13, whereas acute bouts of intense exercise can transiently increase pro-inflammatory cytokine levels. The influence of MT on cytokines was less commonly studied and yielded more variable results. Conclusion: Variability in findings is likely related to the subject and their baseline condition or disease, when measurement occurs, and the exercise intensity, duration, and an individual's overall health and fitness.

Medicare Advantage Health Risk Assessments Contribute Up To $12 Billion Per Year To Risk-Adjusted Payments.

With Medicare Advantage (MA) enrollment surpassing 50 percent of Medicare beneficiaries, accurate risk-adjusted plan payment rates are essential. However, artificially exaggerated coding intensity, where plans seek to enhance measured health risk through the addition or inflation of diagnoses, may threaten payment rate integrity. One factor that may play a role in escalating coding intensity is health risk assessments (HRAs)-typically in-home reviews of enrollees' health status-that enable plans to capture information about their enrollees. In this study, we evaluated the impact of HRAs on Hierarchical Condition Categories (HCC) risk scores, variation in this impact across contracts, and the aggregate payment impact of HRAs, using 2019 MA encounter data. We found that 44.4 percent of MA beneficiaries had at least one HRA. Among those with at least one HRA, HCC scores increased by 12.8 percent, on average, as a result of HRAs. More than one in five enrollees had at least one additional HRA-captured diagnosis, which raised their HCC score. Potential scenarios restricting the risk-score impact of HRAs correspond with $4.5-$12.3 billion in reduced Medicare spending in 2020. Addressing increased coding intensity due to HRAs will improve the value of Medicare spending and ensure appropriate payment in the MA program.