Editorial Comment on: „Short-acting β 2 -agonist use and asthma exacerbations in Swedish children: A SABINA Junior study.”Boccabella C. 1, Kalayci O. 2, Eigenmann P. 3Affiliations1Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario “A Gemelli” - IRCCS, University of the Sacred Heart, Rome, Italy2Pediatric Allergy and Asthma Unit, Hacettepe University School of Medicine, Ankara, Turkey3Pediatric Allergy Unit, Department of Women-Children-Teenagers, University Hospitals of Geneva, Geneva, SwitzerlandAsthma is one of the most common chronic lung diseases with major public health consequences for both children and adults, including high morbidity and even mortality (1). For years, standard asthma treatment for mild asthma has been as needed short acting beta agonist (SABA). Global Initiative for Asthma (GINA) guidelines have questioned this approach suggesting that the use of SABAs should always be accompanied by inhaled corticosteroids (ICSs) (2). Recently, Papi et al. have shown that in adolescents and adults with uncontrolled moderate-to-severe asthma receiving inhaled glucocorticoid-containing maintenance therapies, the risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of albuterol and budesonide than with as-needed use of albuterol alone (3). In children, on the other hand, even though many years ago Martinez et al. have shown that inhaled corticosteroids as rescue medication with albuterol might be an effective step-down strategy for children aged 5-18 years with well controlled mild asthma , SABA has remained to be the only reliever option recommended for those under 6 years of age (4).The SABA use IN Asthma (SABINA) program in adults and adolescents with asthma reported that SABA overuse (≥3 canisters/year) is prevalent in Sweden and is associated with poor asthma-related outcomes (5). Melen et al and the SABINA Junior investigators have attempted to investigate the same question in the paediatric population (6). This retrospective cohort study conducted in Sweden, has included patients with physician-diagnosed asthma (aged 0-17 years) in secondary care. Patients have been categorized by the number of SABA canisters collected (dichotomized as 0-2 vs ≥3, based on evidence from studies in adults and adolescents) from pharmacies at baseline and followed up over 12 months (5,7). During the baseline year, SABA overuse (≥3 canisters) has been registered for the majority of the study population, particularly for those aged 0-5 years. A strong correlation between SABA overuse and increased risk of exacerbation episodes has been observed. This result confirms what has been already seen among adult patients, that is strongly connected to the inflammatory nature of asthma disease. SABAs can resolve the immediate bronchospasm but have no anti-inflammatory actions and no effect on the late phase of inflammation. Furthermore, chronic and long-term use of SABAs seems also to contribute to a decreased response to SABA therapy as a reliever (8,9). SABINA investigators have also conducted a post-hoc analysis, stratifying study population based on the presence of atopic comorbidity. Interestingly, increased SABA use has been associated with a higher exacerbation risk also in nonatopic patients with asthma. This may be due to the lack of response to ICSs that is a distinctive aspect of non-atopic population who may in turn resort to the use SABA reliever treatment.There are still several questions that remain unanswered in children mainly due to the difficulties in obtaining data in this specific population. First, recruitment of paediatric patients especially those <6 years old into randomized controlled trials (RCTs) can be a challenge due to ethical issues. In addition, diagnosis of asthma in this age group is often problematic. Despite all the limits of a retrospective study, SABINA study provides extremely useful data in a population where there are hardly any solid data. These results emphasize the need for a better understanding of childhood asthma endotypes and the response to different drugs and disease behaviour over time. Avoiding asthma exacerbations and consequent disease progression should be the principal aim of clinical management in children. This may only be possible by linking the underlying pathophysiology with the clinical response to anti-asthma treatment.References1. Asher MI, Rutter CE, Bissell K, Chiang CY, El Sony A, Ellwood E, et al. Worldwide trends in the burden of asthma symptoms in school-aged children: Global Asthma Network Phase I cross-sectional study. Lancet. 2021;398(10311):1569–80.2. GINA committee. Global Strategy for Asthma Management and Prevention 2022 Update [Internet]. Global Initiative for Asthma. 2022. p. 225. Available from: http://www.ginasthma.org3. Alberto Papi, M.D., Bradley E. Chipps, M.D., Richard Beasley, D.Sc., Reynold A. Panettieri, Jr., M.D., Elliot Israel, M.D., Mark Cooper, M.Sc., Lynn Dunsire, M.Sc., Allison Jeynes-Ellis, M.D., Eva Johnsson, M.D., Robert Rees, Ph.D., Christy Cappelletti, P MD. Albuterol–Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma. N Engl J Med [Internet]. 2022 Aug 17;387(7):662–3. Available from: https://doi.org/10.1056/NEJMc22091894. Martinez L, Handel A, Shen Y, Chakraburty S, Quinn FD, Stein CM, et al. detect tuberculosis in child contacts are urgently needed in Sub-Saharan Africa to improve case detection. n. 2018;197(9):2016–9.5. Nwaru BI, Ekström M, Hasvold P, Wiklund F, Telg G, Janson C. Overuse of short-acting β2-agonists in asthma is associated with increased risk of exacerbation and mortality: A nationwide cohort study of the global SABINA programme. Eur Respir J [Internet]. 2020;55(4). Available from: http://dx.doi.org/10.1183/13993003.01872-20196. Melen E., Nwaaru B., Wiklund F., Licht S., Telg G., Maslova E., Valk R., Tran TN, Ekstrom M. JC. Short-acting β 2 -agonist use and asthma exacerbations in Swedish children: A SABINA Junior study. Pediatr Allergy Immunol Manuscr.7. Bloom CI, Cabrera C, Arnetorp S, Coulton K, Nan C, van der Valk RJP, et al. Asthma-Related Health Outcomes Associated with Short-Acting β2-Agonist Inhaler Use: An Observational UK Study as Part of the SABINA Global Program. Adv Ther [Internet]. 2020;37(10):4190–208. Available from: https://doi.org/10.1007/s12325-020-01444-58. Lohse MJ, Benovic JL, Caron MG, Lefkowitz RJ. Multiple pathways of rapid β2-adrenergic receptor desensitization. Delineation with specific inhibitors. J Biol Chem. 1990;265(6):3202–11.9. Gauvreau GM, Jordana M, Watson RM, Cockcroft DW, O’Byrne PM. Effect of regular inhaled albuterol on allergen-induced late responses and sputum eosinophils in asthmatic subjects. Am J Respir Crit Care Med. 1997;156(6):1738–45.

Thorough Assessment of Pain is the key to diagnosis and Management: Letter to Editor

In the Flora of China account (Pan et al. 2001) of Saxifraga mengtzeana Engl. & Irmsch., eight synonyms were attributed to it and one variant, recognised as S. epiphylla Gornall & Ohba, was split from it. This study re-evaluates the taxonomic status of some of the synonyms and of the segregated species in the light of new evidence presented here. Morphological and molecular evidence demonstrate that populations from north-western Yunnan and Sichuan are genetically differentiated from those in south-eastern Yunnan and neighbouring Guangxi. Observations in the field and in cultivation show that the peltate petiole attachment diagnostic of S. mengtzeana var. peltifolia Engl. & Irmsch. is developmentally labile. Similar observations combined with molecular data show that viviparous phenotypes, formerly treated as S. epiphylla, although largely under genetic control, occur sporadically throughout the ranges of both northern and southern taxa. Populations from north-western Yunnan and Sichuan are best recognised as S. geifolia Balf.f., whereas those from south-eastern Yunnan and neighbouring Guangxi are S. mengtzeana. Peltate-leaved variants of the latter are given no status and are relegated to complete synonymy. Viviparous phenotypes of S. mengtzeana are demoted to the rank of forma, as f. epiphylla; analogous phenotypes of S. geifolia are newly described as f. vivipara. Keywords China, Saxifragaceae, Phylogeny, Morphology, Taxonomy

Linear infrastructure stands as one of the main culprits of anthropogenically caused biodiversity decline. As it fragments landscapes, it ultimately results in a myriad of direct and indirect ecological consequences for wildlife. As transportation networks will continue to grow under increasing human population growth, biodiversity will continue to decline making the need to understand and mitigate their impact on species an urgent need for conservation worldwide. The implementation of mitigation measures to alleviate the barrier effect produced by linear transport infrastructure on local fauna is not new, and research has shown that their effectiveness has been shown to be influenced by their design, their placement and the biology of the impacted species. Our understanding of their effectiveness in preventing the longer-term impacts of linear transport infrastructure on habitat connectivity via gene flow, however, remains poorly understood. Here, we used a pre- and post-habitat fragmentation genetic dataset collected as part of an extensive Koala Management Program to ask questions about the immediate and predicted longer-term genetic consequences of linear transport infrastructure on the impacted species. Importantly, using forward migration simulations, we show that to preserve connectivity would need to result in around 20% of the population mixing to avoid long-term genetic drift. These results have important consequences for the management of species at the forefront of linear infrastructure. In particular, the study shows the importance of considering gene flow in our assessment of the effectiveness of fauna crossings.

Bladder prolapse is a rare condition in mares and may occur as a result of excessive straining during the parturition or in the postpartum period. We report a case of dystocia associated prolapse and incarceration of the small colon through the external urethral opening into a prolapsed urinary bladder. No previous reports of this condition were found. An 11-year-old Thoroughbred mare was presented to The Equine Hospital at the Jockey Club of Saudi Arabia for evaluation and treatment of dystocia. Prolapse of the urinary bladder was concomitantly diagnosed. Initial assessment deemed replacement of the urinary bladder in the normal position and vaginal delivery not possible. The mare was immediately prepared for caesarean section. The foal was successfully delivered and resuscitated. Detailed assessment of the bladder during the surgery revealed that the small colon had prolapsed through the external urethral opening and was inside the bladder. The urinary bladder was opened. The small colon was replaced into the abdominal cavity; a first surgeon gently replaced the small colon through the external urethral sphincter and a second surgeon retrieved the small colon by gentle traction. The mare recovered uneventfully from general anaesthesia. The mare and the foal were discharged from the hospital seventeen days post-operatively.

Background: Cystic fibrosis (CF) is an autosomal recessive disease affecting multiple organ systems, including the liver, leading to cystic fibrosis-related liver disease (CFLD). It was noted that CFLD in Egyptian children with CF is more common than in non-Egyptian people with CF (pwCF). The present study aimed to determine the incidence of CFLD and the potential risk factors for developing CFLD in Egyptian children. The correlation between CFLD and the various genotypes prevalent in Egyptian CF children and the comparison of CFLD in Egyptian and non-Egyptian CF patients will be done. Methods: The current cross-sectional study included 50 CF cases from Ain Sham University’s Pediatric Pulmonology Clinic in Children‘s Hospital, Cairo, Egypt. The sweat chloride test and genetic studies were done at the time of diagnosis. All patients’ caregivers provided informed consent. Additionally, all subjects underwent detailed history taking, laboratory investigations, clinical assessment, and pelviabdominal ultrasound for evaluation of hepatic involvement. Results: Male sex, severe genetic mutation (class I and II), long duration, and early onset of the disease were independent risk factors for CFLD development. In addition, pancreatic insufficiency, as well as meconium ileus history, were predictors of CFLD. Diabetes mellitus and severe lung disease were proven to significantly elevate the risk of CFLD development. Conclusion: CFLD is not uncommon in Egyptian CF patients as one-third of the patients were found to have liver affection. CF patients with multiple risk factors are at increased risk of developing liver disease.

Anaplastic meningioma rarely involves organs outside the brain. In our case a patient with cerebral meningioma developed lung metastases after 19 years from the initial appearance. This unusual tumor presentation could make complex the diagnosis.

The exponential rise in the incidence of peri-mitral flutter has paralleled the increasing use of more extensive atrial substrate ablation for atrial fibrillation (AF). Given the relative paucity of randomised evidence to support its role in AF management, mitral isthmus ablation should largely be reserved for patients with peri-mitral flutter. Catheter ablation for peri-mitral flutter is challenging due to complex anatomic relationships. The aim of this report is to review the anatomic considerations and approaches to catheter ablation for peri-mitral flutter.

Genotoxicity assessment is a critical component in the development and evaluation of chemicals. Traditional genotoxicity assays (i.e., mutagenicity, clastogenicity, aneugenicity) have been limited to dichotomous hazard classification, while other toxicity endpoints are assessed through quantitative determination of points-of-departure (PODs) for setting exposure limits. The more recent higher-throughput in vitro genotoxicity assays, many of which also provide mechanistic information, offer a powerful approach for determining high-precision PODs for potency ranking and risk assessment. In order to obtain relevant human dose context from the in vitro assays, in vitro to in vivo extrapolation (IVIVE) models are required to determine what dose would elicit a concentration in the body demonstrated to be genotoxic using in vitro assays. Previous work has demonstrated that application of IVIVE models to in vitro bioactivity data can provide PODs that are protective of human health, but there has been no evaluation of how these models perform with in vitro genotoxicity data. Thus, the Genetic Toxicology Technical Committee, under the Health and Environmental Sciences Institute, conducted a case study on 31 reference chemicals to evaluate the performance of IVIVE application to genotoxicity data. The results demonstrate that for most chemicals (20/31), the PODs derived from in vitro data and IVIVE are highly health protective relative to in vivo PODs from animal studies. PODs were also protective by individual assay type: mutations (8/13 chemicals), micronuclei (9/12) and aneugenicity markers (4/4). It is envisioned that this novel testing strategy could enhance prioritization, rapid screening, and risk assessment of genotoxic chemicals.

The integration of a transgene expression construct into the host genome is the initial step for the generation of recombinant cell lines used for biopharmaceutical production. The stability and level of recombinant gene expression in Chinese hamster ovary (CHO) can be correlated to the copy number, its integration site as well as the epigenetic context of the transgene vector. Also, undesired integration events, such as concatemers, truncated and inverted vector repeats, are impacting the stability of recombinant cell lines. Thus, to characterize cell clones and to isolate the most promising candidates it is crucial to obtain information on the site of integration, the structure of integrated sequence and the epigenetic status. Current sequencing techniques allow to gather this information separately but do not offer a comprehensive and simultaneous resolution. In this study, we present a fast and robust nanopore Cas9-targeted sequencing (nCats) pipeline to identify integration sites, the composition of the integrated sequence as well as its DNA methylation status in CHO cells that can be obtained simultaneously from the same sequencing run. A Cas9-enrichment step during library preparation enables targeted and directional nanopore sequencing with up to 724x median on-target coverage and up to 153 Kb long reads. The data generated by nCats provides sensitive, detailed and correct information on the transgene integration sites and the expression vector structure, which could only be partly produced by traditional Targeted Locus Amplification-Seq data. Moreover, with nCats the DNA methylation status can be analyzed from the same raw data without prior DNA amplification.

We report a case of leprosy presented with a nasal tip necrosis in a female in her 50s with no, apparently, risk factors of leprosy. We highlight the importance of taking a thorough clinical history and widen the differential diagnosis to avoid misdiagnosis and delay of treatment.

The COVID-19 pandemic has pushed health policy frontstage and exposed the stark differences in government capacities to respond to the crisis. This has created new demands for comparative heath policy to support knowledge creation on a large scale. However, comparative health policy has been ill prepared; studies have focused on health systems and used typologies together with descriptive, quantitative methods. This clouds the view for the multi-level nature of health policy, the diverse actors involved and the many societal facets of governance performance. We argue for health policy as a bottom-up process with diverse interests and suggest researching these processes comparatively to support policy learning. This calls for expanding the methodology of comparative health policy to include approaches that make greater use of explorative, qualitative research. We introduce possible developmental pathways to illustrate what this may look like. Firstly, the Pan-European Commission points to novel transnational and cross-sectoral collaborations, and a coordinated policy response to global challenges like the pandemic. Secondly, feminist networks show how to shift the focus towards social inequalities and the health needs of women and vulnerable populations. Thirdly, researchers demonstrate the value of new knowledge emerging from small-scale bottom-up comparisons based on structured assessment frameworks. Together, these developmental pathways demonstrate the potential to refocus comparative health policy towards greater responsiveness to the societal performance of governments, such as social inequalities created by the COVID-19 pandemic. This also opens opportunities for strengthening the global outlook of comparative health policy.

This work is concerned with the global existence of large solutions to the three-dimensional dissipative fluid-dynamical model, which is a strongly coupled nonlinear nonlocal system characterized by the incompressible Navier–Stokes–Poisson–Nernst–Planck equations. Making full use of the algebraic structure of the system, we obtain the global existence of solutions without smallness assumptions imposed on the third component of the initial velocity field and the summation of initial densities of charged species. More precisely, we prove that there exist two positive constants c 0 , C 0 such that if the initial data satisfies ( ∥ u 0 h ∥ B _ p , 1 − 1 + 3 p + ∥ N 0 − P 0 ∥ B _ q , 1 − 2 + 3 q ) exp { C 0 ( ∥ u 0 3 ∥ B _ p , 1 − 1 + 3 p 2 + ( ∥ N 0 + P 0 ∥ B _ r , 1 − 2 + 3 r + 1 ) exp { C 0 ∥ u 0 3 ∥ B _ p , 1 − 1 + 3 p } + 1 ) } ≤ c 0 , then the incompressible Navier–Stokes–Poisson–Nernst–Planck equations admits a unique global solution.

By evaluating genetic variation across the entire genome, one can address existing questions in a novel way while new can be asked. Such questions include how different local environments influence both adaptive and neutral genomic variation within and among populations, providing insights not only into local adaptation of natural populations, but also into their responses to global change and the exploitation-induced evolution. Here, under a seascape genomic approach, ddRAD genomic data were used along with environmental information to uncover the underlying processes (migration, selection) shaping European sardines (Sardina pilchardus) of the Western Mediterranean and adjacent Atlantic waters. This information can be relevant to the (re)definition of fishery stocks, and their short-term adaptive potential. We found that studied sardine samples form two clusters, detected using both neutral and adaptive (outlier) loci suggesting that natural selection and local adaptation play a key role in driving genetic change among the Atlantic and the Mediterranean sardines. Temperature and especially the trend in the number of days with sea surface temperature (SST) above 19oC was crucial at all levels of population structuring with implications on species’ key biological processes, especially reproduction. Our findings provide evidence for a dynamic equilibrium where population structure is maintained by physical and biological factors under the opposing influences of migration and selection. Given its dynamic nature, such a system postulates a continuous monitoring under a seascape genomic approach that can benefit by incorporating a temporal as well as a more detailed spatial dimension.

A middle-aged female veteran artistic gymnast sustained an avulsion-injury of the latissimus dorsi and teres major. The case reveals unclarity in the current classification system and illustrates how a non-operative approach, in opposition to interpretation of recommended guidelines, was adequate for an excellent clinical outcome.

A Coronavirus Disease 2019 (COVID-19) epidemiological model incorporating a boosted infection-acquired immunity and heterogeneity in infection-acquired immunity among recovered individuals is designed. The model is used to investigate whether incorporating these two processes can induce new epidemiological insights. Analytical findings reveal co-existence of multiple endemic equilibria on either regions divided by the fundamental threshold (control reproduction number). Numerical findings conducted to validate analytical results show that heterogeneity in infection-acquired immunity among recovered individuals can induce various bifurcation structures such as reversed backward bifurcation, forward bifurcation, backward bifurcation and reversed hysteresis effect. Moreover, numerical results show that reversed backward bifurcation is annihilated or switches to the usual forward bifurcation if infection-acquired immunity among recovered individuals with strong immunity is assumed to be everlasting. However, this is only possible if primary infection is more likely than reinfection. In case reinfection is more likely to occur than primary infection, reversed backward bifurcation structure switches to a backward bifurcation phenomenon. Further, longer duration of infection-acquired immunity does lead to COVID-19 decline over time but does not lead to flattening of the COVID-19 peak.

Increased access to genome-wide data provides new opportunities for plant conservation. However, information on neutral genetic diversity in a small number of marker loci can still be valuable because genomic data are not available to most rare plant species. In the hope of bridging the gap between conservation science and practice, we outline how conservation practitioners can more efficiently employ population genetic information in plant conservation. We first review the current knowledge about the within-population genetic variation and among-population differentiation in neutral genetic variation (NGV) and adaptive genetic variation (AGV) in seed plants. We then introduce the estimates of among-population genetic differentiation in quantitative traits (QST) and neutral markers (FST) to plant biology and summarize conservation applications derived from QST–FST comparisons, particularly on how to capture most AGV and NGV on both in-situ and ex-situ programs. Based on a review of published studies, we found that, on average, two and four populations would be needed for woody perennials (n = 18) to capture 99% of neutral and adaptive genetic variation, respectively, whereas four populations would be needed in case of herbaceous perennials (n = 14). On average, QST is about 3.6, 1.5, and 1.1 times greater than FST in woody plants, annuals, and herbaceous perennials, respectively. We suggest using maximum QST rather than average QST among trait comparisons. Hence, conservation and management policies or suggestions based solely on inference on FST could be misleading, particularly in woody species. We recommend conservation managers and practitioners consider this when formulating further conservation and restoration plans for plant species, and for woody species in particular.

Conversion of the North American prairies to cropland remains a prominent threat to grassland bird populations. Yet, a few species nest in these vastly modified systems. The thick-billed longspur (Rhynchophanes mccownii) is an obligate grassland bird whose populations have declined 4% annually during the past 50 years. Thick-billed longspurs historically nested in recently disturbed or sparsely vegetated patches within native mixed-grass prairie, but observations of longspurs in crop fields during the breeding season suggest such fields also provide cues for habitat selection. Maladaptive selection for poor quality habitat may contribute to ongoing declines in longspur populations, but information on thick-billed longspur breeding ecology in crop fields is lacking. We hypothesized that crop fields may function as ecological traps; specifically, we expected that crop fields may provide cues for territory selection but frequent human disturbance and increased exposure to weather and predators would have negative consequences for reproduction. To address this hypothesis, we compared measures of habitat selection (settlement patterns and trends in abundance) and productivity (nest density, nest survival, and number of young fledged) between crop fields and native sites in northeastern Montana, USA. Settlement patterns were similar across site types and occupancy ranged from 0.52 ± 0.17SE to 0.99 ± 0.01 on April 7 and 30, respectively. Early season abundance differed by year and changes in abundance during the breeding season were associated with precipitation-driven vegetation conditions, rather than habitat type. Standardized nest density (0.19 ± 0.27SD nests/plot/hour), the number of young fledged per successful nest (2.9 ± 0.18SE), and nest survival (0.24 ± 0.03 SE; n=222 nests) were similar for crop and native sites. Collectively, the data did not support our hypothesis that crop fields are ecological traps: longspurs did not exhibit a clear preference for cropland and reproductive output was not significantly reduced. Our results indicate that crop fields provide alternative breeding habitat within a human-dominated landscape.