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Competing Interests: The authors declare no conflict of interest.

Purpose: Asthma is affecting 4-5% of all adults (10% of children) in Germany, ≥ half are inadequately controlled. In 2019 up to 54 thousand patients suffered from severe uncontrolled asthma, 52% were treated/co-treated by pneumonologists. 45% of them had continuous oral corticosteroid (OCS)- and short-acting β2-agonist (SABA) overuse for ≥2 years. The aim of the current study was to analyze the main treatments, escalation schemes and the adherence to the GINA recommendations., Patients and Methods: Retrospective analysis in 2021 based on data from January to December 2019 in Germany, using the IQVIA™ LRx prescription database and the IQVIA™ Disease Analyzer database containing anonymized electronic medical records as the main data sources., Results: In 2019 25,200 patients with severe, uncontrolled asthma treated in a pneumonologist´s practice in Germany received GINA 3 (0,4%), GINA 4 (76%) or GINA 5 therapy (24%) during the study year compared to 59% GINA 5 therapy in the 5-10% (1,500-3,000) co-treated in a specialized outpatient department. In Pneumonologists` practices the most frequent choice in GINA 5 was OCS in 69% of patients (biologicals 37%, long-acting muscarinic antagonist (LAMA) 20%) compared to 66% biologicals, 55% OCS, and 25% LAMA in the outpatient department. 54,958 of 613,000 GINA 4/5 patients were treated with OCS, 9,725 even with doses above the so called "Cushing threshold" for prednisolone of 2700 mg/year. After introduction of a biological treatment, patients reduced their SABA prescriptions by 28%, OCS by 55%, and OCS overall exposure by 40%, one-third did not need OCS anymore., Conclusion: In 75% of patients with uncontrolled asthma for ≥2 years therapy was not escalated beyond GINA 4 or low dose OCS was used as the most frequent add-on treatment in GINA 5 contradictory to treatment recommendations. Use of biologics reduced on demand rescue medication and OCS use., Competing Interests: KCB and OS have no relevant competing interests to disclose for this work. SH is a GSK employee and shareholder. KM reports speaker and/ or advisory fees from AstraZeneca, Chiesi, GSK, Novartis, Sanofi. CN received honoraria and advisory board fees from GSK, Sanofi, AstraZeneca and Novartis. DS received honoraria for lectures and/or consultancy from AstraZeneca, Bayer, Berlin-Chemie, Boehringer, Sanofi, Chiesi, GSK, Janssen, Novartis, Pfizer. RL is an employee of IQVIA. IQVIA is a technology service provider that carried out the database studies within the scope of a commercial engagement with GSK. DK reports personal fees from GSK, AstraZeneca, Sanofi Aventis, and Novartis. JCV has lectured for and received honoraria from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Revotar, Sandoz-Hexal, Stallergens, TEVA, UCB/ Schwarz-Pharma, Zydus/Cadila and has participated in advisory boards for Avontec, ALK, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, LETI, MEDA, MSD, Mundipharma, Novartis, Regeneron, Revotar, Roche, Sanofi-Aventis, Sandoz-Hexal, TEVA, UCB/Schwarz-Pharma and has received research grants from Deutsche Forschungsgesellschaft, Land Mecklenburg-Vorpommern, GSK, MSD and is a full-time employee of the Universitätsmedizin Rostock. The authors report no other conflicts of interest in this work., (© 2024 Milger et al.)

Meropenem penetration into the cerebrospinal fluid (CSF) is subject to high interindividual variability resulting in uncertain target attainment in CSF. Recently, several authors recommended administering meropenem as a continuous infusion (CI) to optimize CSF exposure. This study aimed to compare the concentrations and pharmacokinetics of meropenem in CSF after intermittent infusion (II) and CI. This prospective, observational study (NCT04426383) included critically ill patients with external ventricular drains who received either II or CI of meropenem. Meropenem pharmacokinetics in plasma and CSF were characterized using population pharmacokinetic modeling (NONMEM 7.5). The developed model was used to compare the concentration-time profile and probability of target attainment (PTA) between II and CI. A total of 16 patients (8 CI, 8 II; samples: n plasma = 243, n CSF = 263) were recruited, with nine patients (5 CI, 4 II) suffering from cerebral and seven patients from extracerebral infections. A one-compartment model described the plasma concentrations adequately. Meropenem penetration into the CSF (partition coefficient (KP), c CSF /c plasma ) was generally low (6.0%), exhibiting substantial between-subject variability (coefficient of variation: 84.0%). There was no correlation between the infusion mode and KP, but interleukin (IL)-6 measured in CSF showed a strong positive correlation with KP ( P < 0.001). Dosing simulations revealed no relevant differences in CSF concentrations and PTA in CSF between CI and II. Our study did not demonstrate increased penetration rates or higher concentrations of meropenem in the CSF with CI compared with II., Clinical Trials: This study is registered with ClinicalTrials.gov as NCT04426383., Competing Interests: S.G.W. received research support from Boehringer Ingelheim and AqVida GmbH; consultancy fees from Medicine for Malaria Venture, Utility Therapeutics, and Merck KGaA; and speaker honoraria from GlaxoSmithKline. C.S. received speaker honoraria from CytoSorbents Europe GmbH. M.Z. received research support from CytoSorbents Europe GmbH, consulting fees from Gilead, and speaker honoraria from MSD. U.L. received consulting honoraria from CytoSorbents Europe GmbH and was part of an advisory board of Roche Diagnostics International Ltd. All other authors declare no conflict of interest.

Opioid withdrawal is a liability of chronic opioid use and misuse, impacting people who use prescription or illicit opioids. Hyperactive autonomic output underlies many of the aversive withdrawal symptoms that make it difficult to discontinue chronic opioid use. The locus coeruleus (LC) is an important autonomic centre within the brain with a poorly defined role in opioid withdrawal. We show here that pannexin-1 (Panx1) channels expressed on microglia critically modulate LC activity during opioid withdrawal. Within the LC, we found that spinally projecting tyrosine hydroxylase (TH)-positive neurons (LC spinal ) are hyperexcitable during morphine withdrawal, elevating cerebrospinal fluid (CSF) levels of norepinephrine. Pharmacological and chemogenetic silencing of LC spinal neurons or genetic ablation of Panx1 in microglia blunted CSF NE release, reduced LC neuron hyperexcitability, and concomitantly decreased opioid withdrawal behaviours in mice. Using probenecid as an initial lead compound, we designed a compound (EG-2184) with greater potency in blocking Panx1. Treatment with EG-2184 significantly reduced both the physical signs and conditioned place aversion caused by opioid withdrawal in mice, as well as suppressed cue-induced reinstatement of opioid seeking in rats. Together, these findings demonstrate that microglial Panx1 channels modulate LC noradrenergic circuitry during opioid withdrawal and reinstatement. Blocking Panx1 to dampen LC hyperexcitability may therefore provide a therapeutic strategy for alleviating the physical and aversive components of opioid withdrawal., (© 2024. The Author(s).)

Current food systems fail to provide equity, sustainability, and positive health outcomes, thus underscoring the critical need for their transformation. Intervening in food environments holds substantial promise for contributing to this much-needed transformation. Despite scholars and practitioners often recognizing the necessity for bottom-up approaches, there is a dearth of empirical investigations evaluating the potential of these approaches to contribute to food system transformations in low- and middle-income countries (LMICs). Our study aimed to address this research gap, providing a unique perspective in this regard. Drawing on evidence from two co-creation case studies conducted with small-scale informal fruit and vegetable vendors and poor consumers in Vietnam and Nigeria from January 2020 to December 2021, we explored the relevance of bottom-up community-engaged co-creation processes in intervening within LMICs' food retail environments. Employing a mixed-methods approach that includes quantitative surveys, qualitative interviews, participatory workshops, and focus group discussions, we demonstrated that bottom-up co-creation processes involving marginalized socioeconomic groups can generate retail-level innovations that are tailored to informal retail contexts, whereas remaining aligned with established top-down theories and literature pertaining to food environments and healthy diets. We provided empirical evidence highlighting how both vendors and consumers respond positively to the co-created innovations. Expanding upon our results, we offered methodological insights applicable to interventions targeted at food environments in LMICs, and considerations for future research or development initiatives in this domain. Our findings revealed the capacity of vulnerable stakeholders to actively engage in public health initiatives and contribute to developing innovative solutions that are context-specific and conducive to the adoption of healthier dietary practices. These results confirm the potential of bottom-up, co-creation, real-world interventions within informal settings to contribute toward fostering inclusive transformation of food systems., (© 2024 The Author(s).)

The ventrolateral periaqueductal gray (vlPAG) functionally projects to diverse brain regions, including the locus coeruleus (LC). Excitatory projections from the vlPAG to the LC are well described, while few studies have indicated the possibility of inhibitory projections. Here, we quantified the relative proportion of excitatory and inhibitory vlPAG-LC projections in male and female mice, and found an unexpected overlapping population of neurons expressing both GAD2 and VGLUT2. Combined in vitro optogenetic stimulation and electrophysiology of LC neurons revealed that vlPAG neurons expressing channelrhodopsin-2 under the GAD2 promoter release both GABA and glutamate. Subsequent experiments identified a population of GAD2+/VGLUT2+ vlPAG neurons exclusively releasing glutamate onto LC neurons. Altogether, we demonstrate that ∼25% of vlPAG-LC projections are inhibitory, and that there is a significant GAD2 expressing population of glutamatergic projections. Our findings have broad implications for the utility of GAD2-Cre lines within midbrain and brainstem regions, and especially within the PAG., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Light and temperature sensing are important features of many organisms. Light may provide energy but may also be used by non-photosynthetic organisms for orientation in the environment. Recent evidence suggests that plant and fungal phytochrome and plant phototropin serve dual functions as light and temperature sensors. Here we characterized the fungal LOV-domain blue-light receptor LreA of Alternaria alternata and show that it predominantly contains FAD as chromophore. Blue-light illumination induced ROS production followed by protein agglomeration in vitro. In vivo ROS may control LreA activity. LreA acts as a blue-light photoreceptor but also triggers temperature-shift-induced gene expression. Both responses required the conserved amino acid cysteine 421. We therefore propose that temperature mimics the photoresponse, which could be the ancient function of the chromoprotein. Temperature-dependent gene expression control with LreA was distinct from the response with phytochrome suggesting fine-tuned, photoreceptor-specific gene regulation., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Livelihoods have changed dramatically over the past decade in low- and middle-income countries (LMIC). These shifts are happening in tandem with shifts in individual and household food choice behaviors. This scoping review aimed to identify and characterize mechanisms through which livelihood changes could affect food choice behaviors in LMIC, including behaviors relating to food production, acquisition, preparation, distribution, and consumption. A literature search was conducted using 4 databases: PubMed, PsycInfo, AGRICOLA, and Embase. The search was further enhanced by expert solicitations. Studies were included if they measured or focused on a livelihood change, described or assessed a change in ≥1 food choice behavior, and focused on LMIC. Studies were excluded if they focused on migration from LMIC to a high-income country. Of the 433 articles that were identified, 53 met the inclusion criteria. Five mechanisms of how livelihood change can affect food choice were identified: occupation, locality, time, income, and social relations. Changes in occupation altered the balance of the availability and affordability of foods in local food environments compared with individual food production. Changes in location, time use, and income influenced where food was purchased, what types of foods were acquired, and how or where foods were prepared. Additionally, changes in social relationships and norms led to expanded food preferences, particularly among urban populations. Time limitations and higher discretionary income were associated with consumption of ultraprocessed foods. Understanding the relationships between the changes in livelihood occuring in LMIC and food choices of households in these countries can inform the development of policies, programs, and other actions to promote sustainable healthy diets and planetary health., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chronic pain complicates many diseases and is notoriously difficult to treat. In search of new therapeutic targets, pannexin-1 (Panx1) channels have sparked intense interest as a key mechanism involved in a variety of chronic pain conditions. Panx1 channels are transmembrane proteins that release ions and small molecules, such as adenosine triphosphate (ATP). They are expressed along important nodes of the pain pathway, modulating activity of diverse cell types implicated in the development and progression of chronic pain caused by injury or pathology. This review highlights advances that have unlocked the core structure and machinery controlling Panx1 function with a focus on understanding and treating chronic pain., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Low fruit and vegetable (FV) intake in low- and middle-income countries, which is associated with noncommunicable diseases and micronutrient deficiencies, requires food system interventions addressing FV accessibility, affordability, and acceptability. Periodic FV intake monitoring during interventions informs progress toward achieving increased intakes and contributes to understanding the effectiveness of these interventions., Objectives: This study evaluates the trend in FV intake before, during, and after implementation of a set of nutrition-sensitive food system interventions addressing accessibility, affordability, and acceptability to increase FV consumption over a 1-y period in Vietnamese and Nigerian low-income urban and periurban females., Methods: We used the Diet Quality Questionnaire to assess FV food group consumption among 600 Vietnamese (Hanoi) and 610 Nigerian (Ibadan) females before, during, and after the interventions (Vietnam: July 2020-September 2021; Nigeria: November 2020-December 2021). A FV score was compared between exposure groups with (mixed) count modeling. The trend in consumption of individual FV groups was analyzed with mixed logistic regression., Results: The FV score was stable over time, and a small increase was observed after the intervention period especially in Nigeria and in urban Vietnam. A decrease in the total score was observed in periurban Vietnam. Fluctuations were detected in the probability of consumption of individual FV groups over time especially within the fruit groups, probably due to seasonal availability. The degree of exposure could not explain differences in FV intake., Conclusions: We found a marginal increase in the proportion of females consuming FV during the interventions in both countries. The FV score appeared to be a simple, quick, and easy-to-use indicator for monitoring diversity, variety, and consumption., (© 2023 The Author(s).)

Supply chain quality management practices are necessary to improve processes, meet consumer quality needs, and enhance supply chain quality management performance in sustainable food networks. Food supply chain quality management and associated practices are considerably studied in global food systems, less so for alternative food networks. There are salient differences between global food systems and alternative food networks, which may reflect on the applicable supply chain quality management practices in the food systems and networks. This paper reviews the literature on supply chain quality management practices, with a focus on alternative food networks. A systematic literature review methodology is adopted, resulting in the analysis of seventy-eight papers, identifying a total of one hundred and three supply chain quality management practices. The identified supply chain quality management practices were analysed in relation to their link to a) place, production, and producer and b) link to (bio)processes. Emerging themes from the analysis are discussed, and some areas of future research were put forward., Competing Interests: 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., (© 2023 The Authors.)

The search for healthy foods has attracted the industry's attention to developing products that use natural ingredients, including natural antioxidants. Antioxidants act as free radicals or oxygen scavengers, inhibiting lipid oxidation and adversely affecting meat products' sensory and nutritional quality. Several synthetic antioxidants have been used in the meat industry; however, studies point to health risks related to their consumption. Such fact drives research into natural antioxidants extracted from grains, oilseeds, spices, fruits, and vegetables, which may have a health-promoting effect. This manuscript evaluates the effectiveness of several natural antioxidants in improving the quality and shelf life of chicken meat products during processing, storage, and distribution. The potential effects of natural antioxidants widely used in chicken products are also discussed. It can be concluded that these natural antioxidants are possible substitutes for synthetic ones. However, their use can affect the product's characteristics.

Purpose: It has been estimated that, in 2019, 54,000 patients in Germany had uncontrolled GINA step 4/5 asthma. In the current study we analyzed which health care providers were involved in the management of these patients and their role in disease phenotyping., Patients and Methods: The year 2019 was retrospectively analyzed using the IQVIA TM LRx, a longitudinal anonymized prescription database, and the electronic, anonymized medical records database, the IQVIA Disease Analyzer., Results: Of 54,000 uncontrolled GINA step 4/5 asthma patients in Germany, 52% had consulted both general practitioners (GPs) and pulmonologists, and 48% were seen exclusively by a GP. Of these 54,000 patients, 45% were being prescribed and were thus overusing short-acting β2-agonists (SABAs) and oral corticosteroids (OCS) for ≥2 years, 26% for ≥3 years, and 16% for ≥4 years. In most regions, pulmonologists saw one of their uncontrolled GINA step 4/5 asthma patients per week. Laboratory tests from consultations with a GP were available for only 10% of patients referred to a pulmonologist. In 50% of uncontrolled asthma patients treated according to GINA step 4/5, these were initiated by the pulmonologist, and 34% received laboratory testing within the first year (in GINA step 4/5 asthma, the numbers are 20% and 18%, respectively)., Conclusion: Fifty percent of uncontrolled asthma patients treated according to GINA step 4/5 were regularly seen by pulmonologists, who performed most of the phenotyping confirming their importance in the management of severe, uncontrolled asthma in Germany. To understand treatment pathways for these patients, further studies are needed., Competing Interests: C.N. received honoraria and advisory board fees from GSK, Sanofi, AstraZeneca and Novartis. D.K. reports speaker and/or advisory fees from AstraZeneca, Boehringer, Chiesi, Berlin-Chemie, GSK, Novartis, and Sanofi. K.C.B. and O.S. have no relevant competing interests to disclose. S.H. is a GSK employee and shareholder. K.M. reports speaker and/or advisory fees from Astrazeneca, GSK, Novartis, Sanofi. D.S. received honoraria for lectures and/or consultancy from AstraZeneca, Bayer, Berlin-Chemie, BMBF, Boehringer, Chiesi, DFG, GSK, Janssen, MSD, Novartis, Sanofi, Pfizer. F.S. is affiliated with IQVIA Commercial GmbH & Co and reports grants from GSK. J.C.V. has lectured for and received honoraria from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Revotar, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, and Zydus/Cadila, and has participated in advisory boards for Avontec, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron, Revotar, Roche, Sanofi-Aventis, Sandoz-Hexal, TEVA, and UCB/Schwarz-Pharma, and has received research grants from Deutsche Forschungsgesellschaft, Land Mecklenburg-Vorpommern, GSK, and MSD, and is a full-time employee of the Universitätsmedizin Rostock. The authors report no other conflicts of interest in this work., (© 2023 Timmermann et al.)

Introduction: In malignant cerebral infarction decompressive hemicraniectomy has demonstrated beneficial effects, but the optimum size of hemicraniectomy is still a matter of debate. Some surgeons prefer a large-sized hemicraniectomy with a diameter of more than 14 cm (HC > 14). We investigated whether this approach is associated with reduced mortality and an improved long-term functional outcome compared to a standard hemicraniectomy with a diameter of less than 14 cm (HC ≤ 14)., Methods: Patients from the DESTINY (DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY) registry who received hemicraniectomy were dichotomized according to the hemicraniectomy diameter (HC ≤ 14 cm vs. HC > 14 cm). The primary outcome was modified Rankin scale (mRS) score ≤ 4 after 12 months. Secondary outcomes were in-hospital mortality, mRS ≤ 3 and mortality after 12 months, and the rate of hemicraniectomy-related complications. The diameter of the hemicraniectomy was examined as an independent predictor of functional outcome in multivariable analyses., Results: Among 130 patients (32.3% female, mean (SD) age 55 (11) years), the mean hemicraniectomy diameter was 13.6 cm. 42 patients (32.3%) had HC > 14. There were no significant differences in the primary outcome and mortality by size of hemicraniectomy. Rate of complications did not differ (HC ≤ 14 27.6% vs. HC > 14 36.6%, p = 0.302). Age and infarct volume but not hemicraniectomy diameter were associated with outcome in multivariable analyses., Conclusion: In this post-hoc analysis, large hemicraniectomy was not associated with an improved outcome or lower mortality in unselected patients with malignant middle cerebral artery infarction. Randomized trials should further examine whether individual patients could benefit from a large-sized hemicraniectomy., Clinical Trial Registration Information: German Clinical Trials Register (URL: https://www.drks.de ; Unique Identifier: DRKS00000624)., (© 2023. The Author(s).)

The interplay between electronic and nuclear motions in molecules is a central concept in molecular science. To what extent it influences attosecond photoionization delays is an important, still unresolved question. Here, we apply attosecond electron-ion coincidence spectroscopy and advanced calculations that include both electronic and nuclear motions to study the photoionization dynamics of CH 4 and CD 4 molecules. These molecules are known to feature some of the fastest nuclear dynamics following photoionization. Remarkably, we find no measurable delay between the photoionization of CH 4 and CD 4 , neither experimentally nor theoretically. However, we measure and calculate delays of up to 20 as between the dissociative and non-dissociative photoionization of the highest-occupied molecular orbitals of both molecules. Experiment and theory are in quantitative agreement. These results show that, in the absence of resonances, even the fastest nuclear motion does not substantially influence photoionization delays, but identify a previously unknown signature of nuclear motion in dissociative-ionization channels. These findings have important consequences for the design and interpretation of attosecond chronoscopy in molecules, clusters, and liquids., (© 2023. The Author(s).)

Background: Researchers and policy-makers have highlighted that the potential for organized sports to promote health has been underexploited. Sports clubs have limited capacity to promote health due to their voluntary nature and have called for support from their national sports federations. The present article provides guidelines, based on the theoretical principles of health promoting sports clubs and an analysis of practical tools and proven strategies, to support national sports federations to invest in health promotion (HP)., Methods: A qualitative iterative study was undertaken, based on five 2-h meetings of a group of 15 international researchers in HP in sports clubs. Notes and minutes from meetings, as well as shared outputs were analyzed based on the health promoting sports club framework., Results: Guidelines developed for national sports federations to promote health includes a definition of a health promoting sports federation (HPSF), a description of how the settings-based approach to HP adapts to national sports federations, as well as practical applications of health promoting sports club's intervention strategies. The analysis of existing tools also demonstrated that most tools are centered on a single dimension of health (social, mental, physical, spiritual or community), and often on a specific health topic. Furthermore, they do not cover HP as a continuous long-lasting process, but are generally short-term programs. The HPSF clarifies theoretical concepts, their practical implementation via case studies and outlines intervention components and tools useful for sports federations in their implementation of HP., Conclusion: The guidelines developed in this study are intended to facilitate national sports federations to acknowledge/understand, reinforce/underpin and foster current and further investment in HP., 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher., (Copyright © 2023 Van Hoye, Geidne, Vuillemin, Dowd, Glibo, Heck, Ibsen, Johnson, Kingsland, Kokko, Lane, Ooms, Overbye, Woods, Zeimers, Whiting and Winand.)

Vancomycin is a commonly used antibacterial agent in patients with primary central nervous system (CNS) infection. This study aims to examine predictors of vancomycin penetration into cerebrospinal fluid (CSF) in patients with external ventricular drainage and the feasibility of CSF sampling from the distal drainage port for therapeutic drug monitoring. Fourteen adult patients (9 with primary CNS infection) were treated with vancomycin intravenously. The vancomycin concentrations in blood and CSF (from proximal [CSF&#95;P] and distal [CSF&#95;D] drainage ports) were evaluated by population pharmacokinetics. Model-based simulations were conducted to compare various infusion modes. A three-compartment model with first-order elimination best described the vancomycin data. Estimated parameters included clearance (CL, 4.53 L/h), central compartment volume ( V c , 24.0 L), apparent CSF compartment volume ( V CSF , 0.445 L), and clearance between central and CSF compartments ( Q CSF , 0.00322 L/h and 0.00135 L/h for patients with and without primary CNS infection, respectively). Creatinine clearance was a significant covariate on vancomycin CL. CSF protein was the primary covariate to explain the variability of Q CSF . There was no detectable difference between the data for sampling from the proximal and the distal port. Intermittent infusion and continuous infusion with a loading dose reached the CSF target concentration faster than continuous infusion only. All infusion schedules reached similar CSF trough concentrations. Beyond adjusting doses according to renal function, starting treatment with a loading dose in patients with primary CSF infection is recommended. Occasionally, very high and possibly toxic doses would be required to achieve adequate CSF concentrations, which calls for more investigation of direct intraventricular administration of vancomycin. (This study has been registered at ClinicalTrials.gov under registration no. NCT04426383)., Competing Interests: The authors declare no conflict of interest.

Cell swelling as a result of hypotonic stress is counteracted in mammalian cells by a process called regulatory volume decrease (RVD). We have recently discovered that RVD of human keratinocytes requires the LRRC8 volume-regulated anion channel (VRAC) and that Ca 2+ exerts a modulatory function on RVD. However, the ion channel that is responsible for Ca 2+ influx remains unknown. We investigated in this study whether the Ca 2+ -permeable TRPV4 ion channel, which functions as cell volume sensor in many cell types, may be involved in cell volume regulation during hypotonic stress response of human keratinocytes. We interfered with TRPV4 function in two human keratinocyte cell lines (HaCaT and NHEK-E6/E7) by using two TRPV4-specific inhibitors (RN1734 and GSK2193874), and by creating a CRISPR/Cas9-mediated genetic TRPV4 -/- knockout in HaCaT cells. We employed electrophysiological patch clamp analysis, fluorescence-based Ca 2+ imaging and cell volume measurements to determine the functional importance of TRPV4. We could show that both hypotonic stress and direct activation of TRPV4 by the specific agonist GSK1016790A triggered intracellular Ca 2+ response. Strikingly, the Ca 2+ increase upon hypotonic stress was neither affected by genetic knockout of TRPV4 in HaCaT cells nor by pharmacological inhibition of TRPV4 in both keratinocyte cell lines. Accordingly, hypotonicity-induced cell swelling, downstream activation of VRAC currents as well as subsequent RVD were unaffected both in TRPV4 inhibitor-treated keratinocytes and in HaCaT-TRPV4 -/- cells. In summary, our study shows that keratinocytes do not require TRPV4 for coping with hypotonic stress, which implies the involvement of other, yet unidentified Ca 2+ channels., Competing Interests: Declaration of Competing Interest TF, DR and SH are employees of BRAIN Biotech AG. DR and SH own shares of BRAIN Biotech AG. TF owns share options of BRAIN Biotech AG. All other authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Endoscopy has evolved as the standard visualization tool for endonasal transsphenoidal resection of sellar lesions. The most widely used 2-dimensional (2D) endoscopes harbor the problem of limited depth perception. Therefore, 3-dimensional (3D) endoscopes have been developed to enable depth perception through a stereoscopic view., Objective: To evaluate the impact of high-definition (HD) 2D vs 3D HD endoscopes on spatial orientation within the sphenoid sinus., Methods: In this prospective single-center study, 21 patients have been investigated (2021-2022). Eleven standardized anatomic landmarks, which were preoperatively defined on neuronavigation imaging, were intraoperatively targeted with a navigation probe using either 2D HD or 3D HD endoscopes for visualization., Results: Overall, 3D HD endoscopes provided a statistically significant higher accuracy of identification of sphenoid sinus landmarks (median deviation: 5.2 mm vs 4.2 mm, P < .001). In detail: tuberculum sellae (3.0 mm vs 4.3 mm, P = .047), most anterior point of sella (3.3 mm vs 4.8 mm, P = .049), and clivus indentation (3.8 mm vs 5.3 mm, P = .035). Anatomic variations such as a complex sphenoid sinus configuration had no influence on identifying sphenoid sinus landmarks., Conclusion: According to our data, stereoscopic 3D HD endoscopy enhances intraoperative orientation by improved depth perception within the sphenoid sinus. This may add to the safety of endoscopic skull base procedures, especially in extended approaches and cases with distorted anatomy., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Cities increasingly envision sustainable future food systems. The realization of such futures is often understood from a planning perspective, leaving the role of entrepreneurship out of scope. The city of Almere in the Netherlands provides a telling example. In the neighborhood Almere Oosterwold, residents must use 50% of their plot for urban agriculture. The municipality formulated an ambition that over time, 10% off all food consumed in Almere must be produced in Oosterwold. In this study, we assume the development of urban agriculture in Oosterwold is an entrepreneurial process, i.e. a creative (re)organization that is ongoing and intervenes in daily life. To understand how this entrepreneurial process helps to realize sustainable food futures, this paper explores what futures for urban agriculture residents of Oosterwold prefer and deem possible and how these futures are organized in the present. We use futuring to explore possible and preferable images of the future, and to backcast those images to the present day. Our findings show residents have different perspectives of the future. Furthermore, they are capable in formulating specific actions to obtain the futures they prefer, but have trouble committing to the actions themselves. We argue this is the result of a temporal dissonance, a myopia where residents have trouble looking beyond their own situation. It shows imagined futures must fit with the lived experiences of citizens in order to be realized. We conclude that urban food futures need planning and entrepreneurship to be realized since they are complementary social processes., Competing Interests: Competing interestsThe authors have no relevant financial or non-financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. The authors have no financial or proprietary interests in any material discussed in this article., (© The Author(s) 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objective: Vitamin A deficiency (VAD) has serious public health consequences including morbidity and mortality for populations in low and middle-income countries (LMICs), especially for children under 5 years and pregnant women. LMICs are at greater risk of VAD, in part due to low levels of consumption of vitamin A-rich foods most of which are plant-based, such as orange-fleshed sweet potatoes (OFSP), with lower bioavailability than animal sources of the vitamin A. Food-based approaches such as biofortification of OFSP, including promoting the consumption of vitamin A-rich biofortified staple crops, has been shown to be potentially effective in improving the status of vitamin A and other micronutrients. This study examined vitamin A-rich food consumption and its predictors among women of reproductive age from OFSP-growing households in two regions of Uganda., Methods: A cross-sectional survey was conducted among 617 OFSP growing households, focusing on women in the reproductive age group from the northern and eastern regions of Uganda. Households were not receiving any VAD-related intervention at the time of the survey. Quantitative data included vitamin A-rich food consumption, knowledge on vitamin A, and rich food sources dietary intake, using a 7-day food frequency questionnaire. Vitamin A consumption and risk of deficiency were estimated using the Hellen Keller International guide., Results: The majority of women in this study were either pregnant (80%) or lactating (17%). More than 70% of the study population had a weighted vitamin A rich food consumption mean score of <6 days per week, indicating a high risk of VAD. Knowledge about vitamin A [b (SE) = -0.18 (0.50), p < 0.001] was significantly and inversely associated with vitamin A rich food consumption., Conclusion: Components of food insecurity such as availability, affordability, utilization, and changing food preferences may contribute to the unexpected inverse relationship between knowledge and consumption of vitamin A rich foods. Scaling up biofortified food initiatives, including OFSP, can improve consumption of vitamin A rich foods with effective strategies to comprehensively address consumption barriers such as lack of nutrition education, cooking skills, and storage facilities, as well as low production levels and perceived contamination of biofortified foods., 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 Nankumbi, Grant, Sibeko, Mercado, Kwikiriza, Heck and Cordeiro.)

Malnutrition continues to affect many vulnerable populations worldwide, with the majority of these residing in developing and underdeveloped countries. This problem has been exacerbated by the changing climate and more recently by the COVID-19 pandemic. Urgent efforts geared towards enhancing sustainable production and value chains of nutritious foods to ensure access to healthier diets are therefore critical. A recent partnership between the World Food Programme and the International Potato Center to enhance utilization of biofortified crops in fragile environments in Kenya is a step in this direction, aimed at improving the diets of households at risk of hunger and malnutrition. This study sets out to provide early evidence on the potential impacts of the interventions spearheaded in this partnership, together with lessons for further scaling efforts. Using household level data, the study adopts an impact evaluation framework to understand the effect of nutrition awareness through the dissemination of information on Vitamin A deficiency, on the utilization of orange fleshed sweetpotato, a biofortified crop rich in Vitamin A. Results show positive and significant effects of nutrition awareness on utilization of the orange-fleshed sweetpotato. Several factors were also identified as key to determining the exposure to nutrition awareness, including proximity to markets and extension agents, gender, and education levels. For widespread and inclusive adoption and utilization of orange-fleshed sweetpotato, out-scaling efforts need to consider these determinants in designing interventions aimed at raising nutrition awareness, as a key entry point to enhancing utilization of orange-fleshed sweetpotato., Competing Interests: Conflict of interestThe authors declared that they have no conflict of interest., (© The Author(s) 2022.)

Introduction: Posterior reversible encephalopathy syndrome is a rare neurologic complication that can occur under immunosuppressive therapy with CNI after organ transplantation., Methods: We retrospectively reviewed medical records of 545 patients who underwent lung transplantation between 2012 and 2019. Within this group, we identified 30 patients with neurological symptoms typical of PRES and compared the characteristics of patients who were diagnosed with PRES (n = 11) to those who were not (n = 19)., Results: The incidence of PRES after lung transplantation was 2%. Notably, 73% of the patients with PRES were female and the mean age was 39.2. Seizure (82% vs. 21%, p = .002) was the most common neurological presentation. The risk of developing PRES was significantly associated with age (OR = .92, p < .0001) and having cystic fibrosis (CF) (OP = 10.1, p < .0001). Creatinine level (1.9 vs. 1.1 mg/dl, p = .047) and tacrolimus trough level (19.4 vs. 16.5 ng/ml, p = .048) within 1 week prior to neurological symptoms were significantly higher in patients with PRES., Conclusion: Renal insufficiency and high tacrolimus levels are associated with PRES. A change of immunosuppressive drug should be done after confirmed PRES diagnosis or immediately in case of severe neurological dysfunction to improve neurological outcomes and minimize the risk of early allograft rejection., (© 2022 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Background: Consumption of unsafe foods increases morbidity and mortality and is currently an issue, particularly in low- and middle-income countries. Policy actions to ensure food safety are dominated by mitigation of biological and chemical hazards through supply-side risk management, lessening the degree to which consumer perspectives of food safety are considered., Objectives: This study aimed to provide an in-depth understanding, from vendor and consumer perspectives, of how food-safety concerns of consumers translate into their subsequent food-choice behaviors in 6 diverse low- and middle-income countries., Methods: Six Drivers of Food Choice projects (2016-2022) provided transcripts from 17 focus group discussions and 343 interviews conducted in Ghana, Guinea, India, Kenya, Tanzania, and Vietnam. Qualitative thematic analysis was used to identify emerging themes important to food safety., Results: The analysis suggests that consumers constructed meaning about food safety through personal lived experience and social influences. Community and family members contributed knowledge about food safety. Concerns about food safety were influenced by reputations of and relationships with food vendors. Consumers' mistrust of food vendors was amplified by purposeful adulteration or unsafe selling practices and new methods used to produce food. Moreover, consumers were reassured of food safety by positive relationships with vendors; meals cooked at home; implementation of policies and following regulations; vendor adherence to environmental sanitation and food-hygiene practices; cleanliness of vendors' appearance; and vendors' or producers' agency to use risk mitigation strategies in production, processing, and distribution of food., Conclusions: Consumers integrated their meanings, knowledge, and concerns about food safety to achieve assurance about the safety of their foods when making food-choice decisions. The success of food-safety policies hinges on consideration of consumers' food-safety concerns in their design and implementation, alongside actions to reduce risk in food supply., (© 2023 The Authors.)

Objectives: Complications after CT-guided lung biopsy is a burden both for the individual patient and for the overall healthcare. Pneumothorax is the most common complication. This study determined the association between lung function tests and pneumothorax and chest drainage following CT-guided lung biopsy in consecutive patients in a large university hospital., Results: We prospectively registered 875 biopsy procedures from 786 patients in one institution from January 27th 2012 to March 1st 2017 and recorded complications including pneumothorax with or without chest drainage. Lung function data from 637 patients undergoing 710 of the procedures were available. The association of lung function measures with pneumothorax with or without chest drainage was assessed using multivariable logistic regression analyses. Diffusion capacity for carbon monoxide (DLCO) below 4.70 mmol/min/kPa was associated with increased occurrence of pneumothorax and chest drainage after CT guided lung biopsy. We found no association between FEV 1 , RV and occurrence of pneumothorax and chest drainage. We found low DLCO to be a risk factor of pneumothorax and chest drainage after CT-guided lung biopsy. This should be taken into account in planning and performing the procedure., (© 2022. The Author(s).)

We present the experimental observation of two-center interference in the ionization time delays of Kr&#95;{2}. Using attosecond electron-ion-coincidence spectroscopy, we simultaneously measure the photoionization delays of krypton monomer and dimer. The relative time delay is found to oscillate as a function of the electron kinetic energy, an effect that is traced back to constructive and destructive interference of the photoelectron wave packets that are emitted or scattered from the two atomic centers. Our interpretation of the experimental results is supported by solving the time-independent Schrödinger equation of a 1D double-well potential, as well as coupled-channel multiconfigurational quantum-scattering calculations of Kr&#95;{2}. This work opens the door to the study of a broad class of quantum-interference effects in photoionization delays and demonstrates the potential of attosecond coincidence spectroscopy for studying weakly bound systems.

Electron dynamics in water are of fundamental importance for a broad range of phenomena 1-3 , but their real-time study faces numerous conceptual and methodological challenges 4-6 . Here we introduce attosecond size-resolved cluster spectroscopy and build up a molecular-level understanding of the attosecond electron dynamics in water. We measure the effect that the addition of single water molecules has on the photoionization time delays 7-9 of water clusters. We find a continuous increase of the delay for clusters containing up to four to five molecules and little change towards larger clusters. We show that these delays are proportional to the spatial extension of the created electron hole, which first increases with cluster size and then partially localizes through the onset of structural disorder that is characteristic of large clusters and bulk liquid water. These results indicate a previously unknown sensitivity of photoionization delays to electron-hole delocalization and indicate a direct link between electronic structure and attosecond photoionization dynamics. Our results offer new perspectives for studying electron-hole delocalization and its attosecond dynamics., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Immortalized or continuous cell lines are invaluable tools in basic and preclinical research. However, the widespread use of misidentified cell lines is a serious threat to scientific reproducibility. Based on the experiences of mandatory cell line authentication at the International Journal of Cancer (IJC), we provide an overview of the issues pertinent to misidentified cell lines and discuss available solutions. We also summarize the lessons learned, revealing that at least 5% of the human cell lines used in manuscripts considered for peer review are misidentified. About 4% of the considered manuscripts are rejected for severe cell line problems, and most are subsequently published in other journals. In order to diminish such malpractice and its consequences for the scientific record, we postulate that strict multi-layered quality control is essential. Besides journals and publishers, we encourage scientists, research institutions, and funders to take action on the matter and revise their respective policies. Hence, we provide concrete recommendations on introducing regular authentication schemes and staff training, and discuss future steps for enhancing good cell culture practices., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Purpose: Asthma is one of the most prevalent chronic diseases in Germany affecting 4-5% of all adults and 10% of children. Despite the availability of biologicals in recent years, studies show patients with inadequately controlled severe asthma in real life. The aim of the current study was to characterize and estimate the number of patients with NVL/GINA level 4 or 5 asthma and signs of poor control in Germany., Patients and Methods: In 2021, we retrospectively analyzed data collected during 2019 using the IQVIA™ LRx and IQVIA™ Disease Analyzer databases which contain anonymized longitudinal data covering approximately 80% of statutory health insurance (GKV) prescriptions in Germany with most relevant information about prescriptions, basic patient demographics or location of the prescriber; the IQVIA™ Disease Analyzer anonymized electronic medical records from a representative sample of office-based GPs and specialists. An expert committee of pulmonologists from different hospitals and expert practices supported the study. Asthma patients treated according to NVL/GINA 4/5 who used SABAs frequently (≥3 on days with no ICS-containing prescriptions/year) and/or received prescriptions for oral corticosteroids (OCS) (score of ≥2/year, a pulmonologist prescription scored 1.0, GP 0.75) were classified as severe, uncontrolled asthma., Results: In 2019, 3.4 million patients received at least two prescriptions of respiratory medications and 2.4 million patients on maintenance respiratory treatment have asthma. A total of 625,000 asthma patients were treated according to NVL/GINA step 4 or 5. Among these, 54,000 were uncontrolled according to the pre-defined OCS and/or SABA use, which corresponds to approximately 15% of patients in certain regions., Conclusion: In 2019, approximately 54,000 patients in Germany treated according to NVL/GINA step 4/5 had evidence suggestive for poor asthma control, up to 15% of patients in certain regions. Yet, only 12,000 patients overall were being treated with biologicals suggesting a possible treatment gap that requires further investigation., Competing Interests: KCB and OS have no relevant competing interests to disclose. SH is a GSK employee and shareholder. KM reports speaker and/ or advisory fees from AstraZeneca, GSK, Novartis, Sanofi. CN received honoraria and advisory board fees from GSK, Sanofi, AstraZeneca and Novartis. DS received honoraria for lectures and/or consultancy from AstraZeneca, Bayer, Berlin-Chemie, Boehringer, Chiesi, GSK, Janssen, Novartis, Pfizer. RL is an employee of IQVIA. IQVIA is a technology service provider that carried out the database studies within the scope of a commercial engagement with GSK. DK reports personal fees from GSK. JCV has lectured for and received honoraria from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Revotar, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, Zydus/Cadila and has participated in advisory boards for Avontec, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron, Revotar, Roche, Sanofi-Aventis, Sandoz-Hexal, TEVA, UCB/Schwarz-Pharma and has received research grants from Deutsche Forschungsgesellschaft, Land Mecklenburg-Vorpommern, GSK, MSD and is a full time employee of the Universitätsmedizin Rostock. The authors report no other conflicts of interest in this work., (© 2022 Bergmann et al.)

Interleukin 23 and the interleukin 23 receptor (IL-23-IL23R) are described as the major enhancing factors for Interleukin 17 (IL-17) in allergic airway inflammation. IL-17 is considered to induce neutrophilic inflammation in the lung, which is often observed in severe, steroid-resistant asthma-phenotypes. For that reason, understanding of IL-23 and IL-17 axis is very important for future therapy strategies, targeting neutrophil pathway of bronchial asthma.This study aimed to investigate the distribution and expression of IL-23R under physiological and inflammatory conditions. Therefore, a house dust mite (HDM) model of allergic airway inflammation was performed by treating mice with HDM intranasally. Immunofluorescence staining with panel of antibodies was performed in lung tissues to examine the macrophage, dendritic cell, and T cell subpopulations. The allergic airway inflammation was quantified by histopathological analysis, ELISA measurements, and airway function.HDM-treated mice exhibited a significant allergic airway inflammation including higher amounts of NE + cells in lung parenchyma. We found only a small amount of IL-23R positives, out of total CD3 + T cells, and no upregulation in HDM-treated animals. In contrast, the populations of F4/80 + macrophages and CD11c + F4/80 - dendritic cells (DCs) with IL-23R expression were found to be higher. But HDM treatment leads to a significant increase of IL-23R + macrophages, only. IL-23R was expressed by every examined macrophage subpopulation, whereas only Mϕ1 and hybrids between Mϕ1 and Mϕ2 phenotype and not Mϕ2 were found to upregulate IL-23R. Co-localization of IL-23R and IL-17 was only observed in F4/80 + macrophages, suggesting F4/80 + macrophages express IL-23R along with IL-17 in lung tissue.The study revealed that macrophages involving the IL-23 and IL-17 pathway may provide a potential interesting therapeutic target in neutrophilic bronchial asthma., (© 2022. The Author(s).)

Photoionization is a process taking place on attosecond time scales. How its properties evolve from isolated particles to the condensed phase is an open question of both fundamental and practical relevance. Here, we review recent work that has advanced the study of photoionization dynamics from atoms to molecules, clusters and the liquid phase. The first measurements of molecular photoionization delays have revealed the attosecond dynamics of electron emission from a molecular shape resonance and their sensitivity to the molecular potential. Using electron-ion coincidence spectroscopy these measurements have been extended from isolated molecules to clusters. A continuous increase of the delays with the water-cluster size has been observed up to a size of 4-5 molecules, followed by a saturation towards larger clusters. Comparison with calculations has revealed a correlation of the time delay with the spatial extension of the created electron hole. Using cylindrical liquid-microjet techniques, these measurements have also been extended to liquid water, revealing a delay relative to isolated water molecules that was very similar to the largest water clusters studied. Detailed modeling based on Monte-Carlo simulations confirmed that these delays are dominated by the contributions of the first two solvation shells, which agrees with the results of the cluster measurements. These combined results open the perspective of experimentally characterizing the delocalization of electronic wave functions in complex systems and studying their evolution on attosecond time scales., (Copyright 2022 Xiaochun Gong, Inga Jordan, Martin Huppert, Saijoscha Heck, Denitsa Baykusheva, Denis Jelovina, Axel Schild, Hans Jakob Wörner. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

Background: Invadopodia, actin-rich structures that release metallo-proteases at the interface with extra-cellular matrix, in a punctate manner are thought to be important drivers of tumour invasion. Invadopodia formation has been observed in-vitro and in-vivo in numerous metastatic cell lines derived from multiple tumour types. However, prostate cancer cell lines have not been routinely reported to generate invadopodia and the few instances have always required external stimulation., Methods: In this study, the invasive potential of primary prostate adenocarcinoma cell lines, which have never been fully characterised before, was investigated both in-vitro invadopodia assays and in-vivo zebrafish dissemination assay. Subsequently, circulating tumour cells from prostate cancer patients were isolated and tested in the invadopodia assay., Results: Retention of E-cadherin and N-cadherin expression indicated a transitional state of EMT progression, consistent with the idea of partial EMT that has been frequently observed in aggressive prostate cancer. All cell lines tested were capable of spontaneous invadopodia formation and possess a significant degradative ability in-vitro under basal conditions. These cell lines were invasive in-vivo and produced visible metastasis in the zebrafish dissemination assay. Importantly we have proceeded to demonstrate that circulating tumour cells isolated from prostate cancer patients exhibit invadopodia-like structures and degrade matrix with visible puncta. This work supports a role for invadopodia activity as one of the mechanisms of dissemination employed by prostate cancer cells., Conclusion: The combination of studies presented here provide clear evidence that invadopodia activity can play a role in prostate cancer progression., (© 2022. The Author(s).)

Crop breeding programs must accelerate crop improvement, spur widespread adoption of new varieties and increase variety turnover they are to meet the diverse needs of their clients. More comprehensive quantitative approaches are needed to better inform breeding programs about the preferred traits among farmers and other actors. However, the ability of current breeding programs to meet the demands of their clients is limited by the lack of insights about value chain actor preference for individual or packages of traits. Ranking traits based on monetary incentives, rather than subjective values, represents a more comprehensive, consistent, and quantitative approach to inform breeding programs. We conducted a large pilot in Uganda to assess the implementation of a novel approach to trait ranking, using a uniquely large sample of diverse sweetpotato value chain actors. We found meaningful differences in trait ranking and heterogeneity among different actors using this approach. We also show our approach's effectiveness at uncovering unmet demand for root quality traits and at characterizing the substantial trait demand heterogeneity among value chain players. Implementing this approach more broadly for sweetpotato and other crops would increase the effectiveness of breeding programs to improve food security in developing countries., Competing Interests: TB was employed by AbacusBio Ltd., United Kingdom. BS and AS were employed by the company AbacusBio Ltd., New Zealand. JS was employed by Aardevo Ltd. 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 © 2022 Okello, Swanckaert, Martin-Collado, Santos, Yada, Mwanga, Schurink, Quinn, Thiele, Heck, Byrne, Hareau and Campos.)

Shape resonances play a central role in many areas of science, but the real-time measurement of the associated many-body dynamics remains challenging. Here, we present measurements of recoil frame angle-resolved photoionization delays in the vicinity of shape resonances of CF 4 . This technique provides insights into the spatiotemporal photoionization dynamics of molecular shape resonances. We find delays of up to ∼600 as in the ionization out of the highest occupied molecular orbital (HOMO) with a strong dependence on the emission direction and a pronounced asymmetry along the dissociation axis. Comparison with quantum-scattering calculations traces the asymmetries to the interference of a small subset of partial waves at low kinetic energies and, additionally, to the interference of two overlapping shape resonances in the HOMO-1 channel. Our experimental and theoretical results establish a broadly applicable approach to space- and time-resolved photoionization dynamics in the molecular frame.

Background: Recent advances in the treatment algorithms of early breast cancer have markedly improved overall survival. However, anthracycline- and trastuzumab-associated cardiotoxicity may lead to dose-reduction or halt in potentially life-saving adjuvant cancer therapy. Early initiated neurohormonal blockade may prevent or attenuate the cardiotoxicity-induced reduction in cardiac function, but prior studies have been inconclusive. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to be superior to traditional treatment in heart failure with reduced ejection fraction, but its cardioprotective effects in the cardio-oncology setting remains to be tested., Objective: To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction., Methods: PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations., Results: The study is ongoing. Results will be published when the study is completed., Conclusion: PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy., Trial Registration: The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588 ). Registered 30 November 2018., (© 2021. The Author(s).)

Reconstruction of attosecond beating by interference of two-photon transitions (RABBITT) is one of the most widely used approaches to measure the time delays in photoionization. The time delay, which corresponds to a phase difference of two oscillating signals, is usually retrieved by cosine fitting or fast Fourier transform (FFT). We propose two estimators for the phase uncertainty of cosine fitting from the signal per se of an individual experiment: (i) σ ( φ fit )≈ B A 2 N , where B/A is the mean-value-to-amplitude ratio, and N is the total count number, and (ii) σ ( φ fit )≈1- R 2 R 2 n bins , where n bins is the total number of bins in the time domain, and R 2 is the coefficient of determination. The former estimator is applicable for the statistical fluctuation, while the latter includes the effects from various uncertainty sources, which is mathematically proven and numerically validated. This leads to an efficient and reliable approach to determining quantitative uncertainties in RABBITT experiments and evaluating the observed discrepancy among individual measurements, as demonstrated on the basis of experimental data.

Objectives: In oncology and palliative care, patient question prompt lists (QPLs) with sample questions for patient and family increased patients' involvement in decision-making and improved outcomes if physicians actively endorsed asking questions. Therefore, we aim to evaluate practitioners' perceptions of acceptability and possible use of a QPL about palliative and end-of-life care in dementia., Design: Mixed-methods evaluation study of a QPL developed with family caregivers and experts comprising a survey and interviews with practitioners., Setting: Two academic medical training centres for primary and long-term care in the Netherlands., Participants: Practitioners (n=66; 73% woman; mean of 21 (SD 11) years of experience) who were mostly general practitioners and elderly care physicians., Outcomes: The main survey outcome was acceptability measured with a 15-75 acceptability scale with ≥45 meaning 'acceptable'., Results: The survey response rate was 21% (66 of 320 participated). The QPL was regarded as acceptable (mean 51, SD 10) but 64% felt it was too long. Thirty-five per cent would want training to be able to answer the questions. Those who felt unable to answer (31%) found the QPL less acceptable (mean 46 vs 54 for others; p=0.015). We identified three themes from nine interviews: (1) enhancing conversations through discussing difficult topics, (2) proactively engaging in end-of-life conversations and (3) possible implementation., Conclusion: Acceptability of the QPL was adequate, but physicians feeling confident to be able to address questions about end-of-life care is crucial when implementing it in practice, and may require training. To facilitate discussions of advance care planning and palliative care, families and persons with dementia should also be empowered to access the QPL themselves., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2, and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of α4β7 integrin and lower expression of IL-4 receptor (IL4R) compared with the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZBs). Lineage progression from T1 cells to MZBs via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut-homing T2 cells is observed in severe SLE and is associated with reduction of MZBs and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence in health., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Tull et al.)

Most epigenome-wide association studies (EWAS) quantify DNA methylation (DNAm) in peripheral tissues such as whole blood to identify positions in the genome where variation is statistically associated with a trait or exposure. As whole blood comprises a mix of cell types, it is unclear whether trait-associated DNAm variation is specific to an individual cellular population. We collected three peripheral tissues (whole blood, buccal epithelial and nasal epithelial cells) from thirty individuals. Whole blood samples were subsequently processed using fluorescence-activated cell sorting (FACS) to purify five constituent cell-types (monocytes, granulocytes, CD4+ T cells, CD8+ T cells, and B cells). DNAm was profiled in all eight sample-types from each individual using the Illumina EPIC array. We identified significant differences in both the level and variability of DNAm between different sample types, and DNAm data-derived estimates of age and smoking were found to differ dramatically across sample types from the same individual. We found that for the majority of loci variation in DNAm in individual blood cell types was only weakly predictive of variance in DNAm measured in whole blood, although the proportion of variance explained was greater than that explained by either buccal or nasal epithelial samples. Covariation across sample types was much higher for DNAm sites influenced by genetic factors. Overall, we observe that DNAm variation in whole blood is additively influenced by a combination of the major blood cell types. For a subset of sites, however, variable DNAm detected in whole blood can be attributed to variation in a single blood cell type providing potential mechanistic insight about EWAS findings. Our results suggest that associations between whole blood DNAm and traits or exposures reflect differences in multiple cell types and our data will facilitate the interpretation of findings in epigenetic epidemiology., Competing Interests: The authors have declared that no competing interests exist.

This 2018 study, conducted in six Tusky's supermarkets in Nairobi, Kenya, combined the Just-About-Right, Penalty and Mean-End-Chain analyses to examine the quality and psychosocial factors influencing the purchase of a novel bread made from orange-fleshed sweet potato (OFSP), a biofortified crop, focusing on sixty-one male and eighty female urban OFSP bread buyers recruited at point of purchase. It finds that sensory and psychosocial factors drive purchasing decisions and that some of the bread's sensory characteristics are misaligned with consumers' expectations. It also finds that women and men's evaluations of the bread's characteristics are different, as are their motivations for purchase. However, good sensory attributes and the knowledge of the bread's nutritional value were key drivers. Some misaligned characteristics reveal levers for the reformulation of the bread and present opportunities for segmenting the market. Several other implications of the findings for policy and future improvement of the bread are discussed., Competing Interests: The authors declare no conflict of interest in this work., (© 2020 The Authors. International Journal of Food Science & Technology published by John Wiley & Sons Ltd on behalf of Institute of Food, Science and Technology (IFSTTF).)

Background: Antibody responses to virus reflect exposure and potential protection., Methods: We developed a highly specific and sensitive approach to measuring antibodies against SARS-CoV-2 for population-scale immune surveillance. Antibody positivity was defined as a dual-positive response against both the receptor-binding domain and nucleocapsid proteins of SARS-CoV-2. Antibodies were measured by immunoprecipitation assays in capillary blood from 15,771 children aged 1 to 18 years living in Bavaria, Germany, and participating in a public health type 1 diabetes screening program (ClinicalTrials.gov: NCT04039945), in 1,916 dried blood spots from neonates in a Bavarian screening study (ClinicalTrials.gov: NCT03316261), and in 75 SARS-CoV-2-positive individuals. Virus positive incidence was obtained from the Bavarian health authority data., Findings: Dual-antibody positivity was detected in none of the 3,887 children in 2019 (100% specificity) and 73 of 75 SARS-CoV-2-positive individuals (97.3% sensitivity). Antibody surveillance in children during 2020 resulted in frequencies of 0.08% in January to March, 0.61% in April, 0.74% in May, 1.13% in June, and 0.91% in July. Antibody prevalence from April 2020 was 6-fold higher than the incidence of authority-reported cases (156 per 100,000 children), showed marked variation between the seven Bavarian regions (p < 0.0001), and was not associated with age or sex. Transmission in children with virus-positive family members was 35%. 47% of positive children were asymptomatic. No association with type 1 diabetes autoimmunity was observed. Antibody frequency in newborns was 0.47%., Conclusions: We demonstrate the value of population-based screening programs for pandemic monitoring., Funding: The work was supported by funding from the BMBF (FKZ01KX1818)., Competing Interests: The authors declare no competing interests., (© 2020 Elsevier Inc.)

A group of European FOCIS Centers of Excellence adapted panels of the Human Immunophenotyping Consortium (HIPC) for whole blood analysis. Using four core panels [T/regulatory T cell/B/natural killer (T/T reg /B/NK) and myeloid cells] the main leukocyte populations were analyzed in a clinical-diagnostic setting in a harmonized manner across different platforms. As a first step, the consortium presents here the absolute and relative frequencies of the leukocyte subpopulations in the peripheral blood of more than 300 healthy volunteers across six different European centers., (© 2020 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)

The study assesses the psychosocial predictors of intention to integrate biofortified pro-vitamin A orange-fleshed sweet potato (OFSP) in proper complementary feeding (PCF) among women who received either verbal or verbal and visual demonstrations on OFSP-based foods. A total of 764 randomly selected women grouped into four categories, namely pregnant women, women with infants, women with young children, and potential mothers, participated in this study. Using a structural equation model of predicted intentions based on an extended Theory of Planned Behavior (TPB) the study found goal-setting, perceived behavior control, subjective norms, and attitudes had a significant influence on intention to integrate OFSP in PCF. Unexpectedly, knowledge of the various health benefits of OFSP did not positively influence intention. Probabilistic recursive regression was then used to estimate the relationship between the intention to provide PCF practices and its potential antecedents. The results then showed that the model structure and explanatory power was information-specific and also revealing outcome differences by category of women. These results have implications on how interventions targeting the improvement of PCF should be organized and delivered. They underscore the need to segment the audience during nutrition education.

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Idiopathic aplastic anemia (AA) has 2 key characteristics: an autoimmune response against hematopoietic stem/progenitor cells and regulatory T-cells (Tregs) deficiency. We have previously demonstrated reduction in a specific subpopulation of Treg in AA, which predicts response to immunosuppression. The aims of the present study were to define mechanisms of Treg subpopulation imbalance and identify potential for therapeutic intervention. We have identified 2 mechanisms that lead to skewed Treg composition in AA: first, FasL-mediated apoptosis on ligand interaction; and, second, relative interleukin-2 (IL-2) deprivation. We have shown that IL-2 augmentation can overcome these mechanisms. Interestingly, when high concentrations of IL-2 were used for in vitro Treg expansion cultures, AA Tregs were able to expand. The expanded populations expressed a high level of p-BCL-2, which makes them resistant to apoptosis. Using a xenograft mouse model, the function and stability of expanded AA Tregs were tested. We have shown that these Tregs were able to suppress the macroscopic clinical features and tissue manifestations of T-cell-mediated graft-versus-host disease. These Tregs maintained their suppressive properties as well as their phenotype in a highly inflammatory environment. Our findings provide an insight into the mechanisms of Treg reduction in AA. We have identified novel targets with potential for therapeutic interventions. Supplementation of ex vivo expansion cultures of Tregs with high concentrations of IL-2 or delivery of IL-2 directly to patients could improve clinical outcomes in addition to standard immunosuppressive therapy., (© 2020 by The American Society of Hematology.)