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Background Pediatric hypertension is linked to environmental factors like neighborhood noise disrupting sleep, which is crucial for health. The specific interaction between noise and sleep health in causing hypertension still needs to be explored. Methods and Results We analyzed data from 3320 participants of the ABCD (Adolescent Brain Cognitive Development) study, recruited across 21 US cities and monitored from 2018 to 2020 through 2020 to 2022. Participants with complete data on Fitbit‐tracked sleep, blood pressure, height, neighborhood noise, and covariates (biological sex, race and ethnicity, pubertal stage, waist circumference) were included. Hypertension was defined as average blood pressure ≥95th percentile for age, sex, and height. Sleep health was categorized on the basis of daily duration: healthy (9–12 hours), moderately healthy (±1 hour from optimal), and low (≥1 hour deviation). Noise exposure was measured as median nighttime anthropogenic noise levels by zip code. The incidence of hypertension increased from 1.7% (95% CI, 1.4–2.1) in 2018 to 2020 to 2.9% (95% CI, 2.4–3.6) in 2020 to 2022. Adolescents with healthier sleep had a lower risk of developing hypertension (relative risk, 0.63 [95% CI, 0.25–0.82]), while no significant effects were found for neighborhood noise alone or in combination with sleep health. Conclusions Adequate sleep significantly reduces the risk of hypertension in adolescents, independent of environmental noise exposure. These findings underscore the importance of promoting good sleep hygiene among youth to mitigate hypertension risk.

Abstract Background Dupilumab, omalizumab, and mepolizumab are the three biologics currently approved for use in CRSwNP in Canada. Despite evidence of efficacy, their cost-effectiveness, which is a key factor influencing prescribing patterns, has not yet been compared to each other. Methods A cost-effectiveness model using quality-adjusted life years (QALYs) was constructed using a Decision Tree Markov analysis. A third-party healthcare payer perspective and a 10-year time horizon was used. A willingness-to-pay (WTP) threshold of 50,000 Canadian dollars (CAD) per QALY was used to determine cost-effectiveness. Dupilumab, omalizumab, and mepolizumab were each compared to each other. Results Omalizumab was the most cost-effective biologic using current estimates of cost and efficacy in CRSwNP. Using omalizumab as a baseline, dupilumab had an ICER of $235,305/QALY. Mepolizumab was dominated by omalizumab and dupilumab at the current drug prices and estimates of efficacy. Sensitivity analyses determined that when increasing the WTP threshold to $150,000/QALY, dupilumab became cost-effective compared to omalizumab in 22.5% of simulation scenarios. Additionally, altering dosing frequency had a significant effect on cost-effectiveness. Conclusion When comparing the relative cost-effectiveness of biologics in recalcitrant CRSwNP, omalizumab currently appears to be the most cost-effective option. Future reductions in drug prices, adjustments to currently approved dosing regimens, better patient selection, and improvements in sinus surgery outcomes will challenge the current cost-effectiveness models and necessitate reassessment as treatments for CRSwNP continue to evolve.

Pushing the resolution limit to the nanoscale is a critical challenge for applying the reflective Fourier ptychographic microscopy (FPM) to metrologies for characterization of nanoscale features. Characterization of opaque nanoscale samples using reflective FPM requires chiefly a light source with shorter wavelength to obtain nanoscale resolution, as state-of-the-art device sizes have become sub-100 nm or deep sub-wavelength. We report a reflective deep ultraviolet (DUV) FPM featured by an aperture scanning illumination based on the epi-illumination scheme for accommodating a 193 nm excimer laser source and a high numerical aperture (NA) catadioptric objective lens. The illumination system enables robust control of high-NA angular illumination and optimal energy fluence for FPM imaging and prevention of damage to the sample and optical components. The implemented reflective DUV FPM demonstrated image reconstruction of multiline targets with a minimum linewidth of 80 nm with an average contrast six times higher than conventional DUV microscopy.

Abstract Fibroblast growth factor 23 (FGF23) is a bone-derived endocrine hormone that regulates phosphate and vitamin D metabolism. In models of FGF23 excess, renal deoxyribonuclease 1 (Dnase1) mRNA expression is downregulated. Dnase-1 is an endonuclease which binds monomeric actin. We investigated whether FGF23 suppresses renal Dnase-1 expression to facilitate endocytic retrieval of renal sodium dependent phosphate co-transporters (NaPi-IIa/c) from the brush border membrane by promoting actin polymerization. We showed that wild type mice on low phosphate diet and Fgf23 −/− mice with hyperphosphatemia have increased renal Dnase1 mRNA expression while in Hyp mice with FGF23 excess and hypophosphatemia, Dnase1 mRNA expression is decreased. Administration of FGF23 in wild type and Fgf23 −/− mice lowered Dnase1 expression. Taken together, our data shows that Dnase1 is regulated by FGF23. In 6-week-old Dnase1 −/− mice, plasma phosphate and renal NaPi-IIa protein were significantly lower compared to wild-type mice. However, these changes were transient, normalized by 12 weeks of age and had no impact on bone morphology. Adaptation to low and high phosphate diet were similar in Dnase1 −/− and Dnase1 +/+ mice, and loss of Dnase1 gene expression did not rescue hyperphosphatemia in Fgf23 −/− mice. We conclude that Dnase-1 does not mediate FGF23-induced inhibition of renal tubular phosphate reabsorption.

Radiation (RT) and chemoradiation therapy (CRT) play an essential role in head and neck cancer treatment. However, both cause numerous side effects in the oral cavity, paranasal sinuses, and pharynx, having deleterious consequences on patients’ quality of life. Concomitant with significant advances in radiation oncology, much attention has turned to understanding the role of the microbiome in the pathogenesis of treatment-induced tissue toxicity, to ultimately explore microbiome manipulation as a therapeutic intervention. This review sought to discuss current publications investigating the impact of RT and CRT-induced changes on the head and neck microbiome, using culture-independent molecular methods, and propose opportunities for future directions. Based on 13 studies derived from a MEDLINE, EMBASE, and Web of Science search on November 7, 2021, use of molecular methods has uncovered various phyla and genera in the head and neck microbiome, particularly the oral microbiome, not previously known using culture-based methods. However, limited research has investigated the impact of RT/CRT on subsites other than the oral cavity and none of the studies aimed to examine the relationship between the head and neck microbiome and treatment effectiveness. Findings from this review provide helpful insights on our current understanding of treatment-induced oral mucositis, dental plaque, and caries formation and highlight the need for future research to examine the effect of RT/CRT on the sinonasal and oropharyngeal microbiome. In addition, future research should use larger cohorts, examine the impact of the microbiome on treatment response, and study the effect of manipulating the microbiome to overcome therapy resistance.

Summary: Sparse manipulation of neuron excitability during free behavior is critical for identifying neural substrates of behavior. Genetic tools for precise neuronal manipulation exist in the fruit fly, Drosophila melanogaster, but behavioral tools are still lacking to identify potentially subtle phenotypes only detectible using high-throughput and high spatiotemporal resolution. We developed three assay components that can be used modularly to study natural and optogenetically induced behaviors. FlyGate automatically releases flies one at a time into an assay. FlyDetect tracks flies in real time, is robust to severe occlusions, and can be used to track appendages, such as the head. GlobeDisplay is a spherical projection system covering the fly’s visual receptive field with a single projector. We demonstrate the utility of these components in an integrated system, FlyPEZ, by comprehensively modeling the input-output function for directional looming-evoked escape takeoffs and describing a millisecond-timescale phenotype from genetic silencing of a single visual projection neuron type. : Williamson et al. developed a high-throughput device to automatically isolate individual flies and record their behavior with high-speed video. They demonstrate the system’s utility for studying the Drosophila brain using modern genetic tools by discovering behavioral phenotypes that result from manipulation of small groups of neurons. Keywords: neuroscience, Drosophila, behavior, neural substrates, high throughput, neural circuits, high-speed video, visual stimulation, neural activation, escape, machine vision

Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and vitamin D metabolism. In patients with acute kidney injury (AKI), FGF23 levels rise rapidly after onset of AKI and are associated with AKI progression and increased mortality. In mouse models of AKI, excessive rise in FGF23 levels is accompanied by a moderate increase in FGF23 expression in bone. We examined the folic acid-induced AKI (FA-AKI) mouse model to determine whether other organs contribute to the increase in plasma FGF23 and assessed the vitamin D axis as a possible trigger for increased Fgf23 gene expression. Twenty-four hours after initiation of FA-AKI, plasma intact FGF23 and 1,25(OH)2D were increased and kidney function declined. FA-treated mice developed renal inflammation as shown by increased Tnf and Tgfb mRNA expression. Fgf23 mRNA expression was 5- to 15-fold upregulated in thymus, spleen and heart of FA-treated mice, respectively, but only 2-fold in bone. Ectopic renal Fgf23 mRNA expression was also detected in FA-AKI mice. Plasma FGF23 and Fgf23 mRNA expression in thymus, spleen, heart, and bone strongly correlated with renal Tnf mRNA expression. Furthermore, Vdr mRNA expression was upregulated in spleen, thymus and heart and strongly correlated with Fgf23 mRNA expression in the same organ. In conclusion, the rapid rise in plasma FGF23 in FA-AKI mice is accompanied by increased Fgf23 mRNA expression in multiple organs and increased Vdr expression in extra osseous tissues together with increased plasma 1,25(OH)2D and inflammation may trigger the rise in FGF23 in FA-AKI.

Objectives: Identify whether identification of S. aureus on conventional culture is a predictor of success or failure after ESS followed by budesonide nasal irrigations (BUD) in chronic rhinosinusitis (CRS) patients at high risk of recurrence.Methodology: Prospective clinical trial including 116 patients from a tertiary care center at high-risk of disease recurrence following ESS+BUD. Blood samples, microbial swabs, and SNSS/SNOT-22 were taken on the day of surgery (Visit-1) and 4 months postoperatively (Visit-2). Outcomes were evaluated using symptoms and mucosal status as assessed by the Lund-Kennedy endoscopic score.Results: Seventy-five patients (69.4%) attained SNOT-22 MCID or higher. (Mean = 33.4, range 9–75). Objective documentation of recurrence of disease, as defined by combined endoscopic/symptomatic criteria, was noted in 58/116 patients (50%). Revision surgery was associated with a significantly higher rate of disease recurrence (60.0 vs. 28.0%; p < 0.001). Culture for Staphylococcus aureus was associated with disease recurrence, preoperatively and at 4 months post-surgery (p = 0.020; p < 0.001). This was restricted to post-operative cultures in the revision group (10.0 vs. 48.8%; p < 0.001). Other factors associated with poor outcome included intolerance to non-steroidal anti-inflammatory drugs (NSAID) (p = 0.036). Significantly higher Lund-Kennedy scores in the recurrence groups despite similar symptom intensity, emphasizing the importance of considering objective outcome in addition to patient-reported ones.Conclusion: Patients undergoing revision ESS are at high risk of disease recurrence, even when budesonide irrigations are used post operatively. Presence of S. aureus on culture pre-operatively or at 4 months post-ESS is associated with a negative outcome. This suggests that S. aureus negatively influences outcome, possibly via a number of mechanisms, including interactions with the (i) immune system, (ii) regeneration and repair of the sinus epithelium, or (iii) via interference with the sinus microbiome. This suggests that S. aureus may be a simple and inexpensive biomarker for disease severity and indicates a clear need to better appreciate S. aureus on how it contributes mechanistically to disease development and persistence in order to develop targeted therapeutic strategies.

CD4+ Foxp3+ regulatory T cells (Tregs) are an essential component of immune homeostasis. Modulation of Treg function has been proposed as a means of treating autoimmune conditions and preventing rejection of organ transplants, although achieving this goal will require a detailed understanding of Treg signaling pathways. Signaling within Tregs is known to differ considerably from that observed in other T cell subsets. Of note, Tregs are the only cell type known to constitutively express CD25, the main ligand-binding subunit of the IL-2 receptor. The PI(3)K/Akt/mTOR cascade constitutes a major signaling pathway downstream of IL-2 and is closely tied to cellular metabolism. Due to increasing recognition of the links between cellular fuel usage and immune cell function, the interplay between IL-2 signaling and Treg metabolism represents an important space for exploration and a potential approach for immunomodulation. Here, we discuss how IL-2 may affect Treg metabolism via PI(3)K signaling, as well as the effects of altered metabolism on Treg lineage stability and suppressor function.

To survive, animals must convert sensory information into appropriate behaviours1,2. Vision is a common sense for locating ethologically relevant stimuli and guiding motor responses3-5. How circuitry converts object location in retinal coordinates to movement direction in body coordinates remains largely unknown. Here we show through behaviour, physiology, anatomy and connectomics in Drosophila that visuomotor transformation occurs by conversion of topographic maps formed by the dendrites of feature-detecting visual projection neurons (VPNs)6,7 into synaptic weight gradients of VPN outputs onto central brain neurons. We demonstrate how this gradient motif transforms the anteroposterior location of a visual looming stimulus into the fly's directional escape. Specifically, we discover that two neurons postsynaptic to a looming-responsive VPN type promote opposite takeoff directions. Opposite synaptic weight gradients onto these neurons from looming VPNs in different visual field regions convert localized looming threats into correctly oriented escapes. For a second looming-responsive VPN type, we demonstrate graded responses along the dorsoventral axis. We show that this synaptic gradient motif generalizes across all 20 primary VPN cell types and most often arises without VPN axon topography. Synaptic gradients may thus be a general mechanism for conveying spatial features of sensory information into directed motor outputs.

The chest X-ray lung cancer screening program of Mayo Lung Project (MLP) yielded mixed results of improved lung case survival but no improvement in lung cancer mortality. This paper analyzes the smoking patterns of study participants in order to examine possible behavioral ramifications of periodic lung cancer screening. Using a longitudinal difference-of-difference model, we compared the smoking behavior, in terms of current smoker status among all subjects and the intensity of smoking among those continuing smokers, between those who received periodic lung cancer screening and those who received usual-care. In both arms of this lung cancer screening trial, there was a sizable decline in cigarette smoking one year after participants received baseline prevalence screening. There was no significant difference in current smoker status between the intervention group receiving periodic Xray screening and the control group receiving usual care. While we detect that the continuing smokers in the intervention group smoked more than their counterparts in the control group, the magnitude of the difference is not sufficient to explain a substantial difference in lung cancer incidence between the two groups. Our study shows that periodic lung screening in MLP did not decrease smoking behavior beyond the observed decline following the initial prevalence screening conducted at baseline for both the intervention and control groups. Our results also indicate, paradoxically, that participants assigned to the intervention group smoked more cigarettes per day on average than those in the control group. Lung cancer screening programs need additional cessation components to sustain the abstinence effect typically observed following initial lung screening.

Highly localized deposition of ECRH/ECCD is particularly suited for MHD control, in particular when combined with real-time beam orientation and power control capabilities. The powerful (4.5MW) and flexible (7 steerable launcher) EC system on TCV has recently been complemented by an equally flexible digital real-time control system with the aim of developing and testing integrated MHD control methods [1]. Sawtooth pacing is one such method [2]. The crash time of stabilized sawteeth can be precisely controled by removing the EC power at a given time after the last sawtooth crash, causing the crash to occur at a short and reproducible time thereafter. This control strategy is combined with efficient neoclassical tearing mode (NTM) preemption by depositing power at the mode rational surfaces only during a short time synchronized with the island-seeding sawtooth crash. If an NTM appears nevertheless, full power is applied to stabilize the mode. The real-time steerable launchers have also been employed to stabilize fully saturated NTMs and to investigate the precise requirements for deposition localization for full island stabilization. Finally, though ELM dynamics is markedly different, recent results show that ELM pacing is possible using a similar control technique as used for sawtooth pacing. In this case, edge EC power is removed after each ELM, and is reapplied after a programmable time interval. The ELM period can be real-time controlled by adjusting the length of this interval. While the overall trend conforms to the increase of ELM frequency with increasing power, this technique provides a means to significantly regularize the ELM cycle.

Drug Outreach, Promoting Awareness (DOPA) is an undergraduate outreach program for local high school students designed to convey the neurobiological basis, risks, and addictive potential of commonly abused drugs. Here we describe DOPA and evaluate the program, including its impact on high school student attitudes about drug harm risk and addiction. Undergraduate neuroscience students versed in the neurobiology, physiology, and policy of drugs are trained in active learning methods, enabling them to create engaging and interactive classroom-based educational materials. Survey results showed that participation in DOPA increased high school student perceptions of the addictive potential and harm risk of drugs, which studies have shown to be inversely correlated with drug-taking. High school students also responded positively to the interactive nature of the program. These findings demonstrate how extensively trained undergraduates who are close peers to high school students can effectively lead science outreach initiatives and shift adolescent attitudes about drugs.

We define an analogue of the classical Mellin transform for vector‐valued weakly holomorphic cusp forms for SL(2,Z)$SL(2,\mathbb {Z})$ and prove a converse theorem for such forms in terms of the new transform. As applications we get converse theorems for scalar valued weakly holomorphic forms for SL(2,Z)$SL(2,\mathbb {Z})$ as well as Γ0(p)$\Gamma _0(p)$ for primes p$p$. [ABSTRACT FROM AUTHOR]

The article explores regional discrimination as a quasiform of racial discrimination and compares anti-discrimination laws in the U.S. and United Kingdom (UK), as well as international human rights law and Chinese laws' protection against regional discrimination. Topics discussed include lack of protection in the U.S., absence of protection in the UK, emerging international academic focus on classism, overlap between race, class and region, and potential of disparate impact claims as remedy.

Prior to the coronavirus pandemic, tourism stakeholders were actively addressing sustainability, environmental conservation, and local community involvement challenges. Learning from the pandemic, tourism planning and development anchored not only on sustainability but also on safety, resilience, and risk reduction considerations. While success in developing sustainable destinations is an outcome of efficient and effective governance, tourism governance requires cooperation and interaction among its value-chain members through engagement strategies. Using the principles of sustainability, stakeholder participation, and safe travels, we redesigned existing frameworks to explain how tourism stakeholders can enhance destination governance by repositioning governance from the destination to the value chain. We propose a synchronized value chain arising from stakeholder collaboration to reinforce visitor's confidence toward travel thereby creating a sustainable, safe, and resilient post-pandemic tourism industry. [ABSTRACT FROM AUTHOR]