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Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in ELANE, the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony-stimulating factor (G-CSF) is a first-line treatment of ELANE-mutant (ELANEmut) SCN. However, some ELANEmut patients, including patients with ELANE start codon mutations, do not respond to G-CSF. Here, through directed granulopoiesis of gene-edited isogenic normal and patient-derived iPSCs, we demonstrate that ELANE start codon mutations suffice to induce G-CSF-resistant granulocytic precursor cell death and refractory SCN. ELANE start codon-mutated neutrophil precursors express predominantly nuclear N-terminally truncated alternate NE. Unlike G-CSF-sensitive ELANE mutations that induce endoplasmic reticulum and unfolded protein response stress, we found that the mutation of the ELANE translation initiation codon resulted in NE aggregates and activated proapoptotic aggrephagy, as determined by downregulated BAG1 expression, decreased BAG1/BAG3 ratio, NE colocalization with BAG3, and localized expression of autophagic LC3B. We found that SERF1, an RNA-chaperone protein, known to localize in misfolded protein aggregates in neurodegenerative diseases, was highly upregulated and interacted with cytoplasmic NE of mutant neutrophil precursors. Silencing of SERF1 enhanced survival and differentiation of iPSC-derived neutrophil precursors, restoring their responsiveness to G-CSF. These observations provide a mechanistic insight into G-CSF-resistant ELANEmut SCN, revealing targets for therapeutic intervention.

Inflammasomes are protein complexes that mediate innate immune responses whose dysregulation has been linked to a spectrum of acute and chronic human conditions, which dictates therapeutic development that is aligned with disease variability. We designed a scalable, physiologic high-content imaging assay in human PBMCs that we analyzed using a combination of machine-learning and cell biology methods. This resulted in a set of biologically interpretable readouts that can resolve a spectrum of cellular states associated with inflammasome activation and inhibition. These methods were applied to a phenotypic screen that surfaced mechanistically distinct inflammasome inhibitors from an annotated 12,000 compound library. A set of over 100 inhibitors, including an array of Raf-pathway inhibitors, were validated in downstream functional assays. This approach demonstrates how complementary machine learning-based methods can be used to generate profiles of cellular states associated with different stages of complex biological pathways and yield compound and target discovery., Competing Interests: All authors were employees of Spring Discovery at the time of this study and have an equity interest in Spring Discovery., (© 2024 The Author(s).)

Liquid porosimetry experiments reveal a peculiar trend of the intrusion pressure of water in hydrophobic Cu 2 (3,3',5,5'-tetraethyl-4,4'-bipyrazolate) MOF. At lower temperature (T) range, the intrusion pressure (P i ) increases with T. For higher T values, P i  first reaches a maximum and then decreases. This is at odds with the Young-Laplace law, which for systems showing a continuous decrease of contact angle with T predicts a corresponding reduction of the intrusion pressure. Though the Young-Laplace law is not expected to provide quantitative predictions at the subnanoscale of Cu 2 (tebpz) pores, the physical intuition suggests that to a reduction of their hydrophobicity corresponds a reduction of the P i . Molecular dynamics simulations and sychrothron experiments allowed to clarify the mechanism of the peculiar trend of P i with T. At increasing temperatures the vapor density within the MOF' pores grows significantly, bringing the corresponding partial pressure to ≈5 MPa. This pressure, which is consistent with the shift of P i observed in liquid porosimetry, represents a threshold to be overcame before intrusion takes place. Beyond some value of temperature, the phenomenon of reduction of hydrophobicity (and water surface tension) dominated over the opposite effect of increase of vapor pressure and P i inverts its trend with T., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Although the Caribbean's Small Island Developing States (SIDS) minimally contribute to global greenhouse gas emissions, they face disproportionate climate risks and are particularly susceptible to systemic economic threats posed by climate change and subsequent increases in climate variability. Historically, strategic programs and investments have sought to develop more robust and adaptive engineered systems to absorb climate threats. However, such initiatives are limited and under-resourced in the SIDS' context. This article reviews existing climate strategies in the Caribbean and then critically examines current gaps and barriers relating to climate impact knowledge, needs, and implementation. This examination can assist Caribbean SIDS leadership to identify opportunities to transition from a vulnerability-reducing mindset to one of resilience and transformative adaptation to improve long-term economic outlooks, social welfare, and environmental stewardship despite recurring and escalating climate risks. Integr Environ Assess Manag 2024;20:1237-1255. © 2023 SETAC., (© 2023 SETAC.)

Oncologists use molecular prediction/pharmacogenomics to improve Rx of cancer. Voltaire now wrong.

Understanding modifiable prenatal and early life causal determinants of food allergy is important for the prevention of the disease. Randomized clinical trials studying environmental and dietary determinants of food allergy may not always be feasible. Identifying risk/protective factors for early-life food allergy often relies on observational studies, which may be affected by confounding bias. The directed acyclic graph (DAG) is a causal diagram useful to guide causal inference from observational epidemiological research. To date, research on food allergy has made little use of this promising method. We performed a literature review of existing evidence with a systematic search, synthesized 32 known risk/protective factors, and constructed a comprehensive DAG for early-life food allergy development. We present an easy-to-use online tool for researchers to re-construct, amend, and modify the DAG along with a user's guide to minimize confounding bias. We estimated that adjustment strategies in 57% of previous observational studies on modifiable factors of childhood food allergy could be improved if the researchers determined their adjustment sets by DAG. Future researchers who are interested in the causal inference of food allergy development in early life can apply the DAG to identify covariates that should and should not be controlled in observational studies., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The surface of Titan, Saturn's icy moon, is believed to be composed of various molecular minerals with a great diversity in structure and composition. Under the surface conditions, 93 K and 1.45 atm, most small molecules solidify and form minerals, including acetylene and ammonia. These two compounds can not only form single-component solids but also a 1:1 binary cocrystal that exhibits intriguing rotor phase behavior. This cocrystal is a putative mineral on Titan and other planetary bodies such as comets. In addition, the structure of the cocrystal is relevant to fundamental science as it can help better understand the emergence of rotor phases. Here, we present a detailed vibrational neutron spectroscopic study supported by a neutron powder diffraction study on the cocrystal and the single-phase solids. The experimentally observed spectral bands were assigned based on theoretical calculations. The established spectra-properties correlations for the cocrystal corroborate the observed properties. To the best of our knowledge, this study presents the first example of the application of neutron vibrational spectroscopy in studying Titan-relevant organic minerals.

Gallium-68-labeled FAPI-46 has recently been proposed as a novel positron emission tomography imaging probe to diagnose and monitor a wide variety of cancers. Promising results from several ongoing clinical trials have led to a soaring demand for this radiotracer. Typical [ 68 Ga]Ga-FAPI-46 labeling protocols do not cope with multiple generator elutions, leaving radiopharmacies unable to scale-up the production and meet the demand. Here, we propose a robust and efficient automated radiosynthesis of [ 68 Ga]Ga-FAPI-46 on the Trasis miniAllinOne synthesizer, featuring a prepurification step which allows multiple generator elutions and ensures compatibility with a wide range of gallium-68 generators. Our approach was to optimize the prepurification step by first testing five different cationic cartridge chemistries. Only the strong cationic exchange (SCX) cartridges tested had sufficient affinities for quantitative trapping of >99.9%, while the weak cationics did not exceed 50%. Packaging, rinsing, or flowing of the selected SCX cartridges was not noticeable, but improvements in fluidics managed to save time. Based on our previous development experience of [ 68 Ga]Ga-FAPI-46, radiolabeling optimization was also carried out at different temperatures during 10 min. At temperatures above 100°C, radiochemical yield (RCY) > 80% was achieved without significantly increasing the chemical impurities (<5.5 μg mL -1 ). The optimized sequence was reproducibly conducted with three different brands of widely used generators (RCY >88%). A comparison with radiosyntheses carried out without prepurification steps was also conclusive in terms of RCY, radiochemical yield, and chemical purity. Finally, high-activity tests using elutions from three generators were also successful for these parameters. [ 68 Ga]Ga-FAPI-46 was consistently obtained in good radiochemical yields (>89%, n = 3 ), and the final product quality was compliant with internal specifications based on European Pharmacopoeia. This process is suitable for GMP production and allows scaling-up of routine productions, higher throughput, and, ultimately, better patient care., Competing Interests: Authors SD, CV, and TG were employed by Trasis. FV was employed by SOFIE iTheranostics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Paty, Degueldre, Provost, Schmitt, Trump, Fouque, Vriamont, Valla, Gendron and Madar.)

Introduction: Sacral neuromodulation (SNM) and onabotulinumtoxinA (BoNTA) injection are third-line therapies for overactive bladder (OAB). Although the efficacy of each third-line treatment has been well established in clinical trials, there is far less information about performing one third-line therapy after the other. Our aim is thus to investigate the outcomes of post-SNM BoNTA and post-BoNTA SNM as "second" third-line treatments., Methods: We retrospectively reviewed all OAB patients who had both SNM and BoNTA between 2013 and 2022. The primary endpoint was the response rates (>50% improvements) of the second third-line treatments. Secondary endpoints were the proportion of the patients who achieved total dry, the duration of treatments of patients who had significant responses, and risk factors that are associated with treatment response or duration of treatments., Results: A total of 172 patients had two third-line therapies. There were 104 patients who had post-SNM BoNTA and 68 patients who had post-BoNTA SNM. In the post-SNM BoNTA group, 62.5% (65/104) had significant responses after BoNTA treatment. In the post-BoNTA SNM group, 61.8% (44/68) had significant responses after SNM treatment. The proportions of patients who became dry were 21.2% and 23.5%, respectively. In the post-SNM BoNTA group, spinal pathology is associated with a lower probability of a significant response (48.9% vs. 73.7%, p-value = 0.0105)., Conclusions: BoNTA or SNM remains a viable option for refractory OAB after patients fail from one another. Spinal pathology is associated with a poorer response of post-SNM BoNTA., (© 2024 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Although coveted in applications, few materials expand when subject to compression or contract under decompression, i.e., exhibit negative compressibility. A key step to achieve such counterintuitive behaviour is the destabilisations of (meta)stable equilibria of the constituents. Here, we propose a simple strategy to obtain negative compressibility exploiting capillary forces both to precompress the elastic material and to release such precompression by a threshold phenomenon - the reversible formation of a bubble in a hydrophobic flexible cavity. We demonstrate that the solid part of such metastable elastocapillary systems displays negative compressibility across different scales: hydrophobic microporous materials, proteins, and millimetre-sized laminae. This concept is applicable to fields such as porous materials, biomolecules, sensors and may be easily extended to create unexpected material susceptibilities., (© 2024. The Author(s).)

Rationale: Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes in patients with cystic fibrosis (CF). However, ETI effects on impaired mucosal homeostasis and host defense at the molecular and cellular levels in the airways of patients with CF remain unknown. Objectives: To investigate effects of ETI on the transcriptome of nasal epithelial and immune cells from children with CF at the single-cell level. Methods: Nasal swabs from 13 children with CF and at least one F508del allele aged 6 to 11 years were collected at baseline and 3 months after initiation of ETI, subjected to single-cell RNA sequencing, and compared with swabs from 12 age-matched healthy children. Measurements and Main Results: Proportions of CFTR -positive cells were decreased in epithelial basal, club, and goblet cells, but not in ionocytes, from children with CF at baseline and were restored by ETI therapy to nearly healthy levels. Single-cell transcriptomics revealed an impaired IFN signaling and reduced expression of major histocompatibility complex classes I and II encoding genes in epithelial cells of children with CF at baseline, which was partially restored by ETI. In addition, ETI therapy markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. Conclusions: Pharmacological improvement of CFTR function improves innate mucosal immunity and reduces immune cell inflammatory responses in the upper airways of children with CF at the single-cell level, highlighting the potential to restore epithelial homeostasis and host defense in CF airways by early initiation of ETI therapy.

Fluids under extreme confinement show characteristics significantly different from those of their bulk counterpart. This work focuses on water confined within the complex cavities of highly hydrophobic metal-organic frameworks (MOFs) at high pressures. A combination of high-pressure intrusion-extrusion experiments with molecular dynamic simulations and synchrotron data reveals that supercritical transition for MOF-confined water takes place at a much lower temperature than in bulk water, ∼250 K below the reference values. This large shifting of the critical temperature ( T c ) is attributed to the very large density of confined water vapor in the peculiar geometry and chemistry of the cavities of Cu 2 tebpz (tebpz = 3,3',5,5'-tetraethyl-4,4'-bipyrazolate) hydrophobic MOF. This is the first time the shift of T c is investigated for water confined within highly hydrophobic nanoporous materials, which explains why such a large reduction of the critical temperature was never reported before, neither experimentally nor computationally.

Background: Allergic Asthma is a disease presenting various endotypes and no current therapies act curative but alleviate disease symptoms. Dietary interventions are gaining increasing importance in regulating immune responses. Furthermore, short chain fatty acids (SFCA), as the main products of dietary fiber's fermentation by the gut bacteria, ameliorate the pathogenesis and disease burden of different illnesses including asthma. Nevertheless, the connection and crosstalk between the gut and lung is poorly understood., Objective: In this work, the role of high fiber diet on the development of allergic asthma at baseline and after exacerbation of disease induced by respiratory viruses was investigated., Methods: Hereby, SCFA in serum of asthmatic and non-asthmatic pre-school children before and after airway disease symptoms were analyzed. Moreover, the effect of high fiber diet in vivo in a murine model of house dust mite extract (HDM) induced allergic asthma and in the end in isolated lung and spleen cells infected ex vivo with Rhinovirus was analyzed., Results: In this study, a decrease of the SCFA 3-Hydroxybutyric acid in serum of asthmatic children after symptomatic episodes at convalescent visit as compared to asthmatic and control children at baseline visit was observed. In experimental asthma, in mice fed with high fiber diet, a reduced lung GATA3 + Th2 type mediated inflammation, mucus production and collagen deposition and expression of Fc epsilon receptor Ia (FcεRIa) in eosinophils was observed. By contrast, the CD8+ memory effector T cells were induced in the lungs of asthmatic mice fed with high fiber diet. Then, total lung cells from these asthmatic mice fed with either standard food or with fiber rich food were infected with RV ex vivo . Here, RV1b mRNA was found significantly reduced in the lung cells derived from fiber rich food fed mice as compared to those derived from standard food fed asthmatic mice. Looking for the mechanism, an increase in CD8+ T cells in RV infected spleen cells derived from fiber rich fed asthmatic mice, was observed., Conclusion: Convalescent preschool asthmatic children after a symptomatic episode have less serum ß-Hydroxybutyric acid as compared to control and asthmatic children at baseline visit. Fiber rich diet associated with anti-inflammatory effects as well as anti-allergic effects by decreasing Type 2 and IgE mediated immune responses and inducing CD8+ memory effector T cells in a murine model of allergic asthma. Finally, ex vivo infection with Rhinovirus (RV) of total lung cells from asthmatic mice fed with fiber rich food led to a decreased RV load as compared to mice fed with standard food. Moreover, spleen cells derived from asthmatic mice fed with fiber rich food induced CD8+ T cells after ex vivo infection with RV., Clinical Implications: Dietary interventions with increased content in natural fibers like pectins would ameliorate asthma exacerbations. Moreover, respiratory infection in asthma downregulated SCFA in the gut contributing to asthma exacerbations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Schenzel, Geiger, Nendel, Yang, Krammer, Leberle, Brunst, Trump, Mittler, Rauh, Geppert, Tausche, Hohenberger, Rieker, Schieweck, Zundler and Finotto.)

Flexible nanoporous materials are of great interest for applications in many fields such as sensors, catalysis, material separation, and energy storage. Of these, metal-organic frameworks (MOFs) are the most explored thus far. However, tuning their flexibility for a particular application remains challenging. In this work, we explore the effect of the exogenous property of crystallite size on the flexibility of the ZIF-8 MOF. By subjecting hydrophobic ZIF-8 to hydrostatic compression with water, the flexibility of its empty framework and the giant negative compressibility it experiences during water intrusion were recorded via in operando synchrotron irradiation. It was observed that as the crystallite size is reduced to the nanoscale, both flexibility and the negative compressibility of the framework are reduced by ∼25% and ∼15%, respectively. These results pave the way for exogenous tuning of flexibility in MOFs without altering their chemistries.

Background: Inflammatory processes have been suggested as a culprit of vascular damage in pediatric hypertension. We aimed to investigate transcriptional changes of immune modulators and determine their association with office blood pressure in adolescents who were not diagnosed with hypertension at the time of the study visit., Methods: Office blood pressure measurements and blood samples were taken from adolescents of 2 German birth cohorts, GINIplus (The German Infant Study on the Influence of Nutrition Intervention Plus Air Pollution and Genetics on Allergy Development; discovery cohort, n=1219) and LISA (Influences of Lifestyle-related factors on the Immune System and the Development of Allergies in Childhood; validation cohort, n=809), during the 15-year follow-up visit and categorized based on the European Society of Hypertension Guideline. Hs-CRP (high-sensitivity C-reactive protein) and expression of 51 genes encoding cytokines/receptors and transcription factors were analyzed., Results: The prevalence of elevated systolic blood pressure (overweight/obese) was 14.0% (5.1%) and 16.4% (5.2%) in the discovery and validation cohorts, respectively. An enhanced cytotoxic ( GZMB, PRF1, IL2RB ) and proinflammatory ( FOS, IL1B , hs-CRP) immune profile was observed in association with the hypertension class in both cohorts. Expression of hs-CRP and IL1B was driven by overweight with IL1B being identified as a mediator between body mass index and elevated systolic blood pressure (adj.β/95% CI, 0.01/0.0002-0.02). The association of GZMB (adjusted odds ratio/95% CI, 1.67/1.26-2.21; P =0.0004) and PRF1 (adjusted odds ratio/95% CI, 1.70/1.26-2.29; P =0.0005) in the hypertension class remained significant in normal-weight individuals without parental predisposition. These effects were confirmed in LISA., Conclusions: Adolescent hypertension is not limited to known risk groups. As adolescents in the hypertension class show an inflammatory profile similar to that of established hypertension in adults, blood pressure monitoring at a young age is critical to ensure early intervention and prevention of adverse sequelae., Competing Interests: Disclosures None.

A proposed low-energy alternative to the separation of alkanes from alkenes by energy-intensive cryogenic distillation is separation by porous adsorbents. Unfortunately, most adsorbents preferentially take up the desired, high-value major component alkene, requiring frequent regeneration. Adsorbents with inverse selectivity for the minor component alkane would enable the direct production of purified, reagent-grade alkene, greatly reducing global energy consumption. However, such materials are exceedingly rare, especially for propane/propylene separation. Here, we report that through adaptive and spontaneous pore size and shape adaptation to optimize an ensemble of weak noncovalent interactions, the structurally responsive metal-organic framework CdIF-13 ( sod -Cd(benzimidazolate) 2 ) exhibits inverse selectivity for propane over propylene with record-setting separation performance under industrially relevant temperature, pressure, and mixture conditions. Powder synchrotron X-ray diffraction measurements combined with first-principles calculations yield atomic-scale insight and reveal the induced fit mechanism of adsorbate-specific pore adaptation and ensemble interactions between ligands and adsorbates. Dynamic column breakthrough measurements confirm that CdIF-13 displays selectivity under mixed-component conditions of varying ratios, with a record measured selectivity factor of α ≈ 3 at 95:5 propylene:propane at 298 K and 1 bar. When sequenced with a low-cost rigid adsorbent, we demonstrated the direct purification of propylene under ambient conditions. This combined atomic-level structural characterization and performance testing firmly establishes how cooperatively flexible materials can be capable of unprecedented separation factors.

The aryl hydrocarbon receptor (AHR) signaling pathway is a complex regulatory network that plays a critical role in various biological processes, including cellular metabolism, development, and immune responses. The complexity of AHR signaling arises from multiple factors, including the diverse ligands that activate the receptor, the expression level of AHR itself, and its interaction with the AHR nuclear translocator (ARNT). Additionally, the AHR crosstalks with the AHR repressor (AHRR) or other transcription factors and signaling pathways and it can also mediate non-genomic effects. Finally, posttranslational modifications of the AHR and its interaction partners, epigenetic regulation of AHR and its target genes, as well as AHR-mediated induction of enzymes that degrade AHR-activating ligands may contribute to the context-specificity of AHR activation. Understanding the complexity of AHR signaling is crucial for deciphering its physiological and pathological roles and developing therapeutic strategies targeting this pathway. Ongoing research continues to unravel the intricacies of AHR signaling, shedding light on the regulatory mechanisms controlling its diverse functions., Competing Interests: Declaration of Competing Interest ST and CO are founders and CO is managing director of cAHRmeleon Bioscience GmbH. Authors of this manuscript have patents on AHR inhibitors in cancer (WO2013034685, CO); A method to multiplex tryptophan and its metabolites (WO2017072368, CO); A transcriptional signature to determine AHR activity (WO2020201825, ST, CO); Interleukin-4-induced gene 1 (IL4I1) as a biomarker (WO2020208190, ST, MTP, CO); Interleukin-4-induced gene 1 (IL4I1) and its metabolites as biomarkers for cancer (WO2021116357, ST, CO)., (Copyright © 2023. Published by Elsevier Inc.)

Introduction and Hypothesis: Sacral neuromodulation (SNM) is a commonly performed procedure for various conditions. Infection rates range as high as 10% and often require operative explantation with resultant increased cost and morbidity. Pouches impregnated with antibiotic have been utilized in cardiovascular procedures with decreasing infectious complications. TYRX is an antibiotic pouch utilizing minocycline and rifampin manufactured by Medtronic. The objective of this study is to investigate the utility of antimicrobial pouches for patients undergoing SNM., Methods: We retrospectively analyzed our patients undergoing SNM using an antimicrobial pouch and compared them with a historic cohort. Additional variables of interest included post-operative infection, diagnosis of diabetes, weight, and revision case or virgin implant., Results: A total of 170 cases were identified, ranging from March 2017 to November 2022. Overall infection rate was 2.9% with 0 in the antimicrobial pouch cohort (0%) versus 5 in the historic cohort (5.5%; p = 0.04). Groups were similar in terms of body habitus. The group receiving an antimicrobial pouch was noted to be older with a higher percentage of female patients. 85 patients received an antimicrobial pouch and 85 did not. Of the infections, 4 occurred in revision cases (6.9%) and 1 in a virgin implant (0.9%; p = 0.03). No difference was noted in infection rate with regard to a diagnosis of diabetes or body habitus., Conclusion: The use of antimicrobial pouches in SNM is associated with a decreased rate of infectious complications. Revision cases displayed a higher rate of infectious complications., (© 2023. The International Urogynecological Association.)

During the first 500 million years of cosmic history, the first stars and galaxies formed, seeding the Universe with heavy elements and eventually reionizing the intergalactic medium 1-3 . Observations with the James Webb Space Telescope (JWST) have uncovered a surprisingly high abundance of candidates for early star-forming galaxies, with distances (redshifts, z), estimated from multiband photometry, as large as z ≈ 16, far beyond pre-JWST limits 4-9 . Although such photometric redshifts are generally robust, they can suffer from degeneracies and occasionally catastrophic errors. Spectroscopic measurements are required to validate these sources and to reliably quantify physical properties that can constrain galaxy formation models and cosmology 10 . Here we present JWST spectroscopy that confirms redshifts for two very luminous galaxies with z > 11, and also demonstrates that another candidate with suggested z ≈ 16 instead has z = 4.9, with an unusual combination of nebular line emission and dust reddening that mimics the colours expected for much more distant objects. These results reinforce evidence for the early, rapid formation of remarkably luminous galaxies while also highlighting the necessity of spectroscopic verification. The large abundance of bright, early galaxies may indicate shortcomings in current galaxy formation models or deviations from physical properties (such as the stellar initial mass function) that are generally believed to hold at later times., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

While the link between exposure to high levels of ambient particulate matter (PM) and increased incidences of respiratory and cardiovascular diseases is widely recognized, recent epidemiological studies have shown that low PM concentrations are equally associated with adverse health effects. As DNA methylation is one of the main mechanisms by which cells regulate and stabilize gene expression, changes in the methylome could constitute early indicators of dysregulated signaling pathways. So far, little is known about PM-associated DNA methylation changes in the upper airways, the first point of contact between airborne pollutants and the human body. Here, we focused on cells of the upper respiratory tract and assessed their genome-wide DNA methylation pattern to explore exposure-associated early regulatory changes. Using a mobile epidemiological laboratory, nasal lavage samples were collected from a cohort of 60 adults that lived in districts with records of low (Simmerath) or moderate (Stuttgart) PM 10 levels in Germany. PM 10 concentrations were verified by particle measurements on the days of the sample collection and genome-wide DNA methylation was determined by enzymatic methyl sequencing at single-base resolution. We identified 231 differentially methylated regions (DMRs) between moderately and lowly PM 10 exposed individuals. A high proportion of DMRs overlapped with regulatory elements, and DMR target genes were involved in pathways regulating cellular redox homeostasis and immune response. In addition, we found distinct changes in DNA methylation of the HOXA gene cluster whose methylation levels have previously been linked to air pollution exposure but also to carcinogenesis in several instances. The findings of this study suggest that regulatory changes in upper airway cells occur at PM 10 levels below current European thresholds, some of which may be involved in the development of air pollution-related diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Hydrophobic flexible zeolitic imidazole frameworks (ZIFs) represent reference microporous materials in the area of mechanical energy storage, conversion, and dissipation via non-wetting liquid intrusion-extrusion cycle. However, some of them exhibit drawbacks such as lack of stability, high intrusion pressure, or low intrusion volume that make them non-ideal materials to consider as candidates for real applications. In this work, we face these limitations by exploiting the hybrid ZIF concept. Concretely, a bimetallic SOD-like ZIF consisting of Co and Zn ions was synthesized and compared with Co-ZIF (ZIF-67) and Zn-ZIF (ZIF-8) showing for the first time that the hybrid ZIF combines the good stability of ZIF-8 with the higher water intrusion volume of ZIF-67. Moreover, it is shown that the hybrid-ZIF approach can be used to tune the intrusion/extrusion pressure, which is crucial for technological applications., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

In the last 20 years, the field of biotechnology has made significant progress and attracted substantial investments, leading to different paths of technological modernization among nations. As a result, there is now an international divide in the commercial and intellectual capabilities of biotechnology, and the implications of this divergence are not well understood. This raises important questions about why global actors are motivated to participate in biotechnology modernization, the challenges they face in achieving their goals, and the possible future direction of global biotechnology development. Using the framework of prospect theory, this paper explores the role of risk culture as a fundamental factor contributing to this divergence. It aims to assess the risks and benefits associated with the early adoption of biotechnology and the regulatory frameworks that shape the development and acceptance of biotechnological innovations. By doing so, it provides valuable insights into the future of biotechnology development and its potential impact on the global landscape., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Trump, Cummings, Loschin, Keisler, Wells and Linkov.)

Zeolitic Imidazolate Frameworks (ZIF) find application in storage and dissipation of mechanical energy. Their distinctive properties linked to their (sub)nanometer size and hydrophobicity allow for water intrusion only under high hydrostatic pressure. Here we focus on the popular ZIF-8 material investigating the intrusion mechanism in its nanoscale cages, which is the key to its rational exploitation in target applications. In this work, we used a joint experimental/theoretical approach combining in operando synchrotron experiments during high-pressure intrusion experiments, molecular dynamics simulations, and stochastic models to reveal that water intrusion into ZIF-8 occurs by a cascade filling of connected cages rather than a condensation process as previously assumed. The reported results allowed us to establish structure/function relations in this prototypical microporous material, representing an important step to devise design rules to synthesize porous media.

Objective: To assess the demographics, neurologic manifestations, comorbidities, and treatment of patients with seronegative primary Sjögren's syndrome (pSS)., Patients and Methods: We conducted a retrospective chart review on patients with seronegative pSS evaluated by a neurologist at the University of Utah Health between January 2010 and October 2018. The diagnosis was based on characteristic symptoms, positive minor salivary gland biopsy according to the American-European Consensus Group 2002 criteria, and seronegative antibody status., Results: Of 45 patients who met the study criteria, 42 (93.3%) were Caucasian, and 38 (84.4%) were female. The patients' mean age at diagnosis was 47.8 ± 12.6 (range 13-71) years. Paresthesia, numbness and dizziness, and headache were noted in 40 (88.9%), 39 (86.7%), and 36 patients (80.0%), respectively. Thirty-four patients underwent brain magnetic resonance imaging. Of these, 18 (52.9%) showed scattered nonspecific periventricular and subcortical cerebral white matter T2/fluid-attenuated inversion recovery hyperintense foci. Twenty-nine patients (64.4%) presented to the neurology clinic prior to pSS diagnosis, and the median delay in diagnosis from the first neurology clinic visit was 5 (interquartile ranges 2.0-20.5) months. Migraine and depression were the most common comorbidities in 31 patients (68.9%). Thirty-six patients received at least one immunotherapy, and 39 were on at least one medication for neuropathic pain., Conclusion: Patients often display various nonspecific neurological symptoms. Clinicians should express a high degree of skepticism regarding seronegative pSS and consider minor salivary gland biopsy to avoid delaying diagnosis, as undertreatment can affect patients' quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hoshina, Wong, Galli, Bacharach, Klein, Lebiedz-Odrobina, Rose, Trump, Hull, Greenlee and Clardy.)

Background: Childhood asthma is a result of a complex interaction of genetic and environmental components causing epigenetic and immune dysregulation, airway inflammation and impaired lung function. Although different microarray based EWAS studies have been conducted, the impact of epigenetic regulation in asthma development is still widely unknown. We have therefore applied unbiased whole genome bisulfite sequencing (WGBS) to characterize global DNA-methylation profiles of asthmatic children compared to healthy controls., Methods: Peripheral blood samples of 40 asthmatic and 42 control children aged 5-15 years from three birth cohorts were sequenced together with paired cord blood samples. Identified differentially methylated regions (DMRs) were categorized in genotype-associated, cell-type-dependent, or prenatally primed. Network analysis and subsequent natural language processing of DMR-associated genes was complemented by targeted analysis of functional translation of epigenetic regulation on the transcriptional and protein level., Results: In total, 158 DMRs were identified in asthmatic children compared to controls of which 37% were related to the eosinophil content. A global hypomethylation was identified affecting predominantly enhancer regions and regulating key immune genes such as IL4, IL5RA, and EPX. These DMRs were confirmed in n = 267 samples and could be linked to aberrant gene expression. Out of the 158 DMRs identified in the established phenotype, 56 were perturbed already at birth and linked, at least in part, to prenatal influences such as tobacco smoke exposure or phthalate exposure., Conclusion: This is the first epigenetic study based on whole genome sequencing to identify marked dysregulation of enhancer regions as a hallmark of childhood asthma., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

"Modest doubt is call'd the beacon of the wise."-William Shakespeare, Troilus and Cressida. Although the character Hector warns his fellow Trojans with this line not to engage in war against the Greeks, Shakespeare's works are replete with characters who do not incorporate modest doubt, or any consideration of uncertainty, in their risk decisions. Perhaps Shakespeare was simply a keen observer of human nature. Although risk science has developed tremendously over the last five decades (and scientific inquiry over five centuries), the human mind still frequently defaults to conviction about certain beliefs, absent sufficient scientific evidence-which has effects not just on individual lives, but on policy decisions that affect many. This perspective provides background on the Shakespearean quote in its literary and historical context. Then, as this quote is the theme of the 2023 Society for Risk Analysis Annual Meeting, we describe how "modest doubt"-incorporating the notion of uncertainty into risk analysis for individual and policy decisions-is still the "beacon of the wise" today., (© 2023 The Authors. Risk Analysis published by Wiley Periodicals LLC on behalf of Society for Risk Analysis.)

Osteosarcoma is the most common bone sarcoma and is typically found in the distal femur, proximal tibia, and proximal humerus. While several factors are known to influence survival, less is known regarding the influence of primary tumor location. This study describes the clinical features and prognosis of mandibular osteosarcoma. The SEER database was utilized to identify cases of mandibular osteosarcoma diagnosed between 2004 and 2015. Sex, age, grade, histological subtype, tumor size, tumor extension, presence of metastasis at diagnosis, and therapeutic intervention were determined. Osteosarcomas originating from other sites were assessed for comparison. There were 164 cases of mandibular osteosarcoma identified, representing 5.5% of all surveyed osteosarcomas. The 2-, 5-, and 10-year overall survival rates were 79.9%, 65.6% and 58.5%, respectively. Survival was worse for patients with older age, larger tumor size, metastatic disease, and absence of surgical resection. Compared to other sites, mandibular osteosarcomas were significantly smaller tumors and were far less likely to metastasize. Mandibular osteosarcoma manifested at an older age than the more common extremity osteosarcomas and presented with smaller tumors. Rates of metastasis of jaw osteosarcoma were much lower than osteosarcoma found in the extremities, while mortality rates were comparable., (Copyright © 2022 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Neoplasms of the lungs are the leading cause of cancer incidence and mortality worldwide. Although immunotherapy has increased the overall survival of patients with lung cancer, there is the need to improve this treatment. At this regard, blood lipid levels are thought to be linked to cancer risk and thus a preventive intervention through regulation of the nutrition of patients with lung cancer is gaining much attention. In this study, we therefore asked about the contribution of serum lipids and cholesterol cellular metabolism in lung cancer development and progression. We measured different serum lipids and analyzed cholesterol synthesis enzymes 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) and acetyl-coenzyme A cholesterol acetyltransferase 1 (ACAT1) as well as the cholesterol cellular export protein ATP-binding cassette (ABC) A-1 mRNA by quantitative PCR (qPCR) in the control and tumoral regions of post-surgery lung tissues to analyze the accumulation of cholesterol in cancer cells in a cohort of patients with lung adenocarcinoma (LUAD). We found that triglycerides in serum directly correlated with the body mass index (BMI) in patients with LUAD. By contrast, we found that high-density lipoprotein (HDL) cholesterol inversely correlated with the BMI, C-reactive protein (CRP) and overall survival and total cholesterol inversely correlated with the tumor diameter, serum CRP and overall survival in these LUAD patients. Functionally, the role of cholesterol is indispensable for the growth and development of normal animal cells where it is tightly regulated. Excess of cellular cholesterol regulated by HMGCR is converted to cholesteryl esters by the enzyme ACAT1 and exported extracellularly by the cholesterol transporter ABCA1. Here we found HMGCR and ACAT1 upregulated and ABCA1 downregulated in the lung's tumoral region of our LUAD cohort, indicating cholesterol dysregulated cellular export in lung tumor cells., (© 2023. The Author(s).)

Background: Transesophageal echocardiograms (TEEs) performed during transcatheter structural cardiac interventions may result in greater complications than those performed in the nonoperative setting or even those performed during cardiac surgery. However, there are limited data on complications associated with TEE during these procedures. We evaluated the prevalence of major complications among these patients in the United States., Methods: A retrospective cohort study was conducted using an electronic health record database (TriNetX Research Network) from large academic medical centers across the United States for patients undergoing TEE during transcatheter structural interventions from January 2012 to January 2022. Using the American Society of Echocardiography-endorsed International Statistical Classification of Diseases and Related Health Problems Clinical Modifications (10th edition) codes, patients undergoing TEE during a transcatheter structural cardiac intervention, including transaortic, mitral or tricuspid valve repair, left atrial appendage occlusion, atrial septal defect closure, patent foramen ovale closure, and paravalvular leak repair, were identified. The primary outcome was major complications within 72 hours of the procedure (composite of bleeding and esophageal and upper respiratory tract injury). The secondary aim was the frequency of major complications, death, or cardiac arrest within 72 hours in patients who completed intraoperative TEE during surgical valve replacement., Results: Among 12,043 adult patients (mean age, 74 years old; 42% female) undergoing TEE for transcatheter structural cardiac interventions, 429 (3.6%) patients had a major complication. Complication frequency was higher in patients on anticoagulation or antiplatelet therapy compared with those not on therapy (3.9% vs 0.5%; risk ratio [RR] = 8.09, P < .001). Compared with those patients <65 years of age, patients ≥65 years of age had a higher frequency of major complications (3.9% vs 2.2%; RR = 1.75, P < .001). Complication frequency was similar among male and female patients (3.5% vs 3.7%; RR = 0.96, P = .67). Among 28,848 patients who completed surgical valve replacement with TEE guidance, 728 (2.5%) experienced a major complication., Conclusions: This study found that more than 3% of patients undergoing TEE during transcatheter structural cardiac interventions have a major complication, which is more common among those on anticoagulant or antiplatelet therapy or who are elderly. With a shift of poor surgical candidates to less invasive percutaneous procedures, the future of TEE-guided procedures relies on comprehensive risk discussion and updating practices beyond conventional methods to minimize risk for TEE-related complications., (Copyright © 2023 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Thermal polymorphism in the alkali-metal salts incorporating the icosohedral monocarba-hydridoborate anion, CB 11 H 12 - , results in intriguing dynamical properties leading to superionic conductivity for the lightest alkali-metal analogues, LiCB 11 H 12 and NaCB 11 H 12 . As such, these two have been the focus of most recent CB 11 H 12 - related studies, with less attention paid to the heavier alkali-metal salts, such as CsCB 11 H 12 . Nonetheless, it is of fundamental importance to compare the nature of the structural arrangements and interactions across the entire alkali-metal series. Thermal polymorphism in CsCB 11 H 12 was investigated using a combination of techniques: X-ray powder diffraction; differential scanning calorimetry; Raman, infrared, and neutron spectroscopies; and ab initio calculations. The unexpected temperature-dependent structural behavior of anhydrous CsCB 11 H 12 can be potentially justified assuming the existence of two polymorphs with similar free energies at room temperature: ( i ) a previously reported, ordered R 3 polymorph stabilized upon drying and transforming first to R 3 c symmetry near 313 K and then to a similarly packed but disordered I 43 d polymorph near 353 K and ( ii ) a disordered Fm 3 polymorph that initially appears from the disordered I 43 d polymorph near 513 K along with another disordered high-temperature P 6 3 mc polymorph. Quasielastic neutron scattering results indicate that the CB 11 H 12 - anions in the disordered phase at 560 K are undergoing isotropic rotational diffusion, with a jump correlation frequency [1.19(9) × 10 11 s -1 ] in line with those for the lighter-metal analogues.

Introduction and Hypothesis: Overactive bladder (OAB) affects up to 43% of women. Treatment ranges from lifestyle modification to invasive therapies. Nearly 75% of patients report using the internet to gain health information creating a need for interpretable, online resources. This study is aimed at evaluating the readability of online resources for OAB treatment in the US population., Methods: Google and Bing were queried regarding "sacral neuromodulation," "peripheral tibial nerve stimulation (PTNS)," and "bladder botox." The first 20 results from each search engine were assessed, representing over 90% of accessed search results. Websites were categorized as institutional/reference, commercial, nonprofit, or personal. The Gunning fog (GF), Simple Measure of Gobbledygook (SMOG), and Dale-Chall (DC) validated readability scores were used to assess results., Results: Sacral neuromodulation yielded 27 eligible results. The associated mean readability scores correlated with levels of college senior (GF), high school junior (SMOG), and college level (DC). PTNS yielded 31 eligible results. The associated mean readability scores correlated with levels of college senior (GF), high school senior (SMOG), and college level (DC). Bladder botox yielded 17 eligible results. The associated mean readability scores correlated with levels of college sophomore (GF), high school junior (SMOG), and college level (DC). There was no difference between the therapies regarding readability. Sixty-one percent of websites were institutional/reference, 24% were commercial, 13% were nonprofit, and 2% were personal., Conclusions: High levels of reading comprehension are required by the general US population to understand OAB information obtained through the internet. These findings highlight a need for simplification of online resources pertaining to OAB., (© 2022. The International Urogynecological Association.)

Prostate cancer patients routinely undergo surveillance for recurrence using prostate-specific antigen (PSA). While PSA's benefit in screening is controversial, its use for detecting recurrence in patients with history of prostate cancer is pivotal. Rising PSAs with the newly advanced prostate-specific membrane antigen positron emission tomography (PSMA PET) can help localize the location of recurrences for better excision and management. Here, we present a 55-year-old with prostate cancer, with initially undetectable postprostatectomy PSA levels, who later presented with a PSA of 3.47 ng/mL. PSMA PET showed isolated uptake in an abdominal wall mass. Pelvic lymphadenectomy and abdominal wall mass excision were performed, confirming a single metastasis in an abdominal wall lymph node. Metastasectomy led to a dramatic drop in PSA to 0.10 ng/mL both postoperatively and on long-term follow-up. Our case illustrates the potential benefit of metastasis-directed therapy in delayed oligometastasis following definitive management of prostate cancer., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Andrew Williams et al.)

The field of biotechnology has produced a wide variety of materials and products which are rapidly entering the commercial marketplace. While many developments promise revolutionary benefits, some of them pose uncertain or largely untested risks and may spur debate, consternation, and outrage from individuals and groups who may be affected by their development and use. In this paper we show that the success of any advanced genetic development and usage requires that the creators establish technical soundness, ensure safety and security, and transparently represent the product's ethical, legal, and social implications (ELSI). We further identify how failures to address ELSI can manifest as significant roadblocks to product acceptance and adoption and advocate for use of the "safety-by-design" governance philosophy. This approach requires addressing risk and ELSI needs early and often in the technology development process to support innovation while providing security and safety for workers, the public, and the broader environment. This paper identifies and evaluates major ELSI challenges and perspectives to suggest a methodology for implementing safety-by-design in a manner consistent with local institutions and politics. We anticipate the need for safety-by-design approach to grow and permeate biotechnology governance structures as the field expands in scientific and technological complexity, increases in public attention and prominence, and further impacts human health and the environment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Trump, Cummings, Klasa, Galaitsi and Linkov.)

Background: Sjögren syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and diminished secretory function of the salivary glands. Dexamethasone (DEX) resolves dry mouth and lymphocytic infiltration; however, this treatment is difficult to maintain because of multiple adverse effects (eg, osteoporosis and skin thinning); likewise, aspirin-triggered resolvin D1 (AT-RvD1) increases saliva secretion but cannot eliminate lymphocytic infiltration. Previous studies showed that a combination of low-dose DEX with AT-RvD1 before disease onset prevents SS-like features in a mouse model; however, this is not clinically practical because there are no reliable indicators of SS before disease onset. Therefore, the authors applied the combined treatment at disease onset to show its efficacy and comparative lack of adverse effects, so that it may reasonably be maintained over a patient's lifetime., Methods: NOD/ShiLtJ mice were treated with ethanol (vehicle control), high-dose DEX alone, AT-RvD1 alone, or a combination of low-dose DEX with AT-RvD1 at disease onset for 8 weeks. Then saliva flow rates were measured, and submandibular glands were harvested for histologic analyses., Results: A combined treatment of low-dose DEX with AT-RvD1 significantly decreased mast cell degranulation and lymphocytic infiltration, increased saliva secretion, and restored apical aquaporin-5 expression in submandibular glands of NOD/ShiLtJ mice., Conclusions: Low-dose DEX combined with AT-RvD1 reduces the severity of SS-like manifestation and prevents the development of advanced and potentially irreversible damage, all in a form that can reasonably be administered indefinitely without the need to cease treatment because of secondary effects.

Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest.

Asthma is a chronic airway disease whose exacerbations are often triggered by rhinovirus infection. TGF-β1 induces rhinovirus replication in infected cells. Moreover, TGF-β1 is a pleiotropic mediator that is produced by many immune cells in the latent, inactive form bound to the latency-associated peptide (LAP) and to the transmembrane protein glycoprotein A repetitions predominant (GARP). In this study we wanted to investigate the effect of rhinovirus infection on the TGF-β secretion and the downstream signaling via TGF-βRI/RII in peripheral blood mononuclear cells from control and asthmatic patients after rhinovirus infection ex vivo. Here, we found a significant upregulation of TGF-βRII in untouched PBMCs of asthmatics as well as a suppression of TGF-β release in the rhinovirus-infected PBMC condition. Moreover, consistent with an effect of TGF-β on Tregs, PBMCs infected with RV induced Tregs, and TGF-βRII directly correlated with RV1b mRNA. Finally, we found via flow cytometry that NK cells expressed less GARP surface-bound TGF-β, while cytokine-producing NK bright cells were induced. In summary, we show that rhinovirus infection inhibits TGF-β release in PBMCs, which results in the activation of both Treg and NK cells.

Large predators often are believed to cause declines in hunter harvests of ungulates due to direct competition for prey with hunters. In Alberta, predators of elk (Cervus elaphus), including grizzly bear (Ursus arctos), cougar (Puma concolor), and wolf (Canis lupus), have increased in recent years. We used trend analysis replicated by Wildlife Management Unit (WMU) to examine regional trends in elk harvest and hunter success. Over a 26-yr period, average harvest of elk increased by 5.46% per year for unrestricted bull and by 6.64% per year for limited-quota seasons. Also, over the same time frame, average hunter success increased by 0.2% per year for unrestricted bull and by 0.3% per year for limited-quota seasons, but no trend was detected in hunter effort (P>0.05). Our results show that increasing large-predator populations do not necessarily reduce hunter harvest of elk, and we only found evidence for this in Alberta's mountain WMUs where predation on elk calves has reduced recruitment. Furthermore, data indicate that Alberta's elk harvest management has been sustainable, i.e., hunting has continued while populations of elk have increased throughout most of the province. Wildlife agencies can justify commitments to long-term population monitoring because data allow adaptive management and can inform stakeholders on the status of populations., Competing Interests: The authors have declared that no competing interests exist.

Angiomyolipoma (AML) is a benign renal tumor usually found incidentally. Rarely, AML can present with renal colic due to urinary tract obstruction. Prior cases of obstructing AML have been presented and managed successfully with surgical removal. Selective angioembolization has emerged as an alternative management strategy for AML, but no documented cases have been presented for this strategy in the setting of obstruction. Here, we present a case of obstructing AML treated with selective angioembolization with subsequent resolution of obstruction., (© 2022 The Authors.)

As the effects of climate change become more visible, extreme weather events are becoming more common. The effects of flooding on health are understood but the long-term impact on the well-being of those affected need to be considered. This mixed methods secondary analysis of a cross-sectional survey examined the extent to which being flooded in the past is associated with ongoing concerns about flooding. Survey data were collected from residents in Hull 11 years after the initial flooding event. Respondents were asked about the floods in 2007 and their current level of concern about flooding. Ordinal logistic regression explored the effect of age and tenancy status as predictors of current concern. Textual data were analyzed using thematic content analysis. Responses were received from 457 households, of whom 202 (48%) were affected by flooding in 2007. A fifth of respondents were very concerned about future flooding. Those who were not flooded were significantly less concerned about the risk of future flooding (U = 33391.0, z = 5.89, p < 0.001). Those who reported negative health and wellbeing effects from the floods were significantly more concerned about future flooding than those whose health was not affected (U = 7830.5, z = 4.43, p < 0.001). Whilst some residents were reassured by the introduction of new flood alleviation schemes, others did not feel these were adequate, and worried about the impact of climate change. The financial and emotional impacts of the floods still resonated with families 11 years after the event, with many fearing they would not cope if it happened again. Despite the 2007 floods in Hull happening over a decade ago, many of those affected continue to experience high levels of anxiety when storms are forecast. Residents feel powerless to protect themselves, and many remain unconvinced by the presence of new flood alleviation schemes. However, with the ongoing threat of climate change, it may be that other residents are unrealistic in their expectation to be 'protected' from flood events. Therefore, public health agencies need to be able to mobilize organizations to come together to pro-actively support families affected by flooding, to ensure those in need do not fall through the gaps of public healthcare delivery., Competing Interests: The authors have declared that no competing interests exist.

We present a case of severe acute variceal bleeding in an ileal conduit stoma successfully managed with trans -hepatic trans -portal selective angioembolization as a lifesaving measure. Despite repeated transfusions, the patient's hemoglobin continued to be unstable. The patient underwent transhepatic embolization of ileal stoma varicose veins. Angioembolization was followed up with excision of ileal conduit stoma and creation of cutaneous ureterostomy for definitive treatment management of hemorrhage. In conclusion, trans -hepatic trans -portal embolization is an effective option for management of severe acute variceal bleeding in an ileal conduit stoma as a lifesaving measure and can be followed by excision of the conduit., Competing Interests: None of the contributing authors have any conflict of interest, including specific financial interests or relationships and affiliations relevant to the subject matter or materials discussed in the manuscript., (© 2022 The Authors. Published by Elsevier Inc.)

Background: The COVID-19 pandemic has a significant impact on economy. Decisions regarding the reopening of businesses should account for infection risks., Objective: This paper describes a novel model for COVID-19 infection risks and policy evaluations., Methods: The model combines the best principles of the agent-based, microexposure, and probabilistic modeling approaches. It takes into account specifics of a workplace, mask efficiency, and daily routines of employees, but does not require specific inter-agent rules for simulations. Likewise, it does not require knowledge of microscopic disease related parameters. Instead, the risk of infection is aggregated into the probability of infection, which depends on the duration and distance of every contact. The probability of infection at the end of a workday is found using rigorous probabilistic rules. Unlike previous models, this approach requires only a few reference data points for calibration, which are more easily collected via empirical studies., Results: The application of the model is demonstrated for a typical office environment and for a real-world case., Conclusion: The proposed model allows for effective risk assessment and policy evaluation when there are large uncertainties about the disease, making it particularly suitable for COVID-19 risk assessments., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Competing Interests: Dr Vines discloses relationships with Teleflex Medical, the Rice Foundation, and Theravance Biopharma. Dr Scott discloses relationships Teleflex and Aerogen. Dr Kaur discloses a relationship with the American Association of Respiratory Care. Dr Trump discloses a relationship with Fisher and Paykel. Ms Jackson discloses a relationship with Fisher & Paykel. Dr Li discloses relationships with Fisher & Paykel Healthcare, Heyer, Aerogen, the Rice Foundation, the American Association for Respiratory Care, and also serves as Section Editor for Respiratory Care. The other authors have no conflict of interest to disclose.

Background: High flow nasal cannula (HFNC) use reduces work of breathing and improves oxygenation for patients with hypoxemic respiratory failure. Limited prior work has explored protocolized use of HFNC for trauma patients outside the Intensive Care Unit (ICU). The purpose of this study is to describe and evaluate use of HFNC for patients with rib fractures when therapy was standard of care on all floors of the hospital., Methods: In 2018, the study hospital expanded use of HFNC (AIRVO; Fisher Paykel, Auckland, NZ) to all floors of the hospital, making it available in the ICU, Emergency Department (ED), and on general inpatient floors. The study group included adult patients with three or more rib fractures who received HFNC at any location in the hospital (Phase 2: January 2018-December 2019). The study group was compared to a historical control group when HFNC was available only in the ICU (Phase 1: March 2013-July 2015). Patients were excluded from the study if they received invasive mechanical ventilation prior to HFNC. Primary outcomes were mechanical ventilation rates, ICU days, length of hospitalization, and mortality., Results: During the study period, 63 patients received HFNC, with 35% of patients (n = 22) receiving the duration of therapy outside the ICU. When compared to the control group (N = 63), there were no significant differences in total hospital days (9 vs. 9, p=.64), mechanical ventilation (19% vs. 13%, p=.47), or mortality (3% vs. 5%, p = 1.00). Twenty-seven percent of patients (n = 17) in the study group avoided the ICU during hospitalization., Conclusions: Findings suggest that HFNC therapy can be safely initiated and managed on all hospital floors for patients with multiple rib fractures. Making the therapy available outside the ICU may reduce healthcare resource use without adversely affecting patient outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 (ELF5) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47-9.63; p-value < 5.0 × 10 -6 ) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2., (© 2022. The Author(s).)

Introduction: Clinically node-positive non-metastatic bladder cancer (cN+) has been the target of several studies aiming to establish a standard of care for this population. Limited studies have shown a survival benefit for various multimodal therapy approaches. The role of radiation therapy has not been well established. Our study aims to study the trends of the reported treatment options offered to patients with cN+ bladder cancer in a national database and to evaluate the effect of various treatments, including radiation, on survival., Methods: The National Cancer Database (NCDB) was used to identify cN+ bladder cancer patients who received chemotherapy alone or in combination with radical cystectomy (RC) or radiotherapy. 3,481 patients were included and divided into 4 groups: chemotherapy only, chemotherapy and RC, chemotherapy and radiation therapy, and chemotherapy, RC, and radiation therapy. Demographic data was compared using ANOVA for continuous variables, and Chi-square for categorical variables. Multivariable analysis was done to compare groups using a multinomial logistic regression model. Kaplan-Meier test was used for survival analysis and Cox-Regression was used for multivariable survival analysis., Results: Patients undergoing RC were significantly younger ( P <0.001). There was a significant difference between the groups regarding racial distribution, facility-type and insurance status. There was no difference in gender, Charlson\Deyo score, financial or educational status. Patients who underwent combination therapy with chemotherapy and RC were found to have the longest median survival time at 27 months. Multivariable analysis showed that final treatment, age, sex, Charlson\Deyo comorbidity score, TNM edition and facility-type were significant survival predictors. Race, insurance and financial status failed to maintain significance. There was no survival difference between the chemotherapy group and chemo-radiotherapy group., Conclusions: The combination of surgery and chemotherapy achieves statistically significant superior survival in cN+ bladder cancer. Adding radiotherapy to chemotherapy did not improve survival in this group of patients., Abbreviations: (cN+): Clinically node-positive non-metastatic, (MIBC): Muscle invasive bladder cancer, (NCDB): National Cancer Database, (NAC): Neoadjuvant chemotherapy, (RC): Radical Cystectomy., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.