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In the era of immune checkpoint inhibitors, understanding the metastatic microenvironment of proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) is of paramount importance to both prognostication and the development of more effective novel therapies. In this study, primary and paired metastasis tissue samples were collected from patients with resectable metastatic CRC treated with adjuvant FOLFOX or peri‐operative chemotherapy in the MIROX phase III prospective study. In total, 74 cancer tissues were stained for CD3, CD8, Forkhead box protein 3 (FOXP3), programmed cell death protein‐1 (PD‐1, invasive front, stromal, intra‐epithelial compartments), and programmed death‐ligand 1 (PD‐L1, tumor, immune cells). The immune profiling of primary CRC had a limited value to predict the immune context of paired metastases for all markers but CD3+. The expression of CD8 and PD‐L1 was higher in metastases after neoadjuvant FOLFOX. In metastases, both CD3 T cells at the invasive front and PD‐L1 expressions on immune cells were predictive of better disease‐free survival. These results show that the effect of FOLFOX on modifying the immune microenvironment in resected CRC metastases and measurement of PD‐L1 expression and tumor‐infiltrating CD8 T cells in pMMR/MSS metastatic tissue samples could improve treatment strategies of metastatic CRC patients.

Vacuolization of hematopoietic precursors cells is a common future of several otherwise non-related clinical settings such as VEXAS, Chediak–Higashi syndrome and Danon disease. Although these disorders have a priori nothing to do with one other from a clinical point of view, all share abnormal vacuolization in different cell types including cells of the erythroid/myeloid lineage that is likely the consequence of moderate to drastic dysfunctions in the ubiquitin proteasome system and/or the endo-lysosomal pathway. Indeed, the genes affected in these three diseases UBA1, LYST or LAMP2 are known to be direct or indirect regulators of lysosome trafficking and function and/or of different modes of autophagy. Furthermore, all three genes are highly expressed in the more mature myeloid cells pointing out their likely important function in these cells. LAMP2 deficiency for instance is known to be associated with alterations of lysosome architecture and function. It is thus well established that different cell types from Danon disease patients that harbor invalidating mutations in LAMP2 exhibit giant lysosomes containing undigested materials characteristic of defects in the fusion of lysosomes with autophagosomes, a feature also found in VEXAS and CHS. Other similarities regarding these three diseases include granulocyte and monocyte dysfunctions and a recurrent inflammatory climate. In the present review we discuss the possibility that some common clinical manifestations of these diseases, notably the hematopoietic ones are consecutive to a dysfunction of the endo-lysosomal pathway in myeloid/erythroid progenitors and in mature myeloid cells including neutrophiles, monocytes and macrophages. Finally, we propose reacidification as a way of reinducing lysosome functionalities and autophagy as a potential approach for a better management of these diseases. [ABSTRACT FROM AUTHOR]

Voluntary genetic testing (GT) leverages low-cost DNA sequencing and other testing methods to provide genetic risk screening for healthy individuals. Given the potential to prevent disease and promote health, some employers now offer GT as an employee benefit (workplace GT, or wGT), but participation remains low. To investigate facilitators and barriers to wGT participation, we conducted one of the first representative surveys of working U.S. adults on this topic (n = 958). We assessed factors that could influence participation, including: sponsoring entity (health provider or employer), program design, and individual demographics. Two-thirds (68%) of respondents indicated willingness to participate in some type of GT, but only half (49%) expressed willingness to participate through their employer. Women were 60% more willing to participate than men, and individuals with previous genetic testing experience were 143% more willing to participate than those without such experience. Across all demographic groups, certain GT program design features tended to increase or decrease willingness to participate. The ability to have one's data deleted from the GT database increased willingness most often (true for 67% of respondents), while selling data to pharmaceutical companies decreased willingness most often (true for 63% of respondents). [ABSTRACT FROM AUTHOR]

Background: Several major sensitization profiles have been described in children with asthma, but it remains unclear how these profiles relate to asthma phenotypes. The aim of this study was to determine allergenic sensitization profiles in a megacity cohort (SAMP). Methods: This was a cross‐sectional analysis performed from 2011 to 2015 including preschool and school‐age children with severe and moderate asthma from the SAMP cohort. We performed ALEX multiplex array and carried out cluster analysis. Results: Data from 367 children were analyzed: 224 of preschool age and 143 of school age, respectively 84 (38%) and 114 (80%) presented at least one allergic sensitization. At preschool age, three clusters were identified: Cluster 1, Few sensitizations to inhaled allergen molecular families and non‐type 2 (T2) inflammation (n = 61); Cluster 2, Predominant sensitization to HDM molecular families (n = 16); Cluster 3, Severe asthma with multiple sensitizations to inhaled and food allergen molecular families (n = 7). At school age, five clusters were identified: Cluster 1, Few sensitizations to inhaled allergen molecular families and non‐T2 inflammation (n = 43); Cluster 2, Predominant sensitization to HDM molecular families (n = 31); Cluster 3, Predominant sensitization to PR‐10 protein family (n = 25); Cluster 4, Severe asthma with predominant sensitization to tropomyosin family (n = 11); Cluster 5, Severe asthma with multiple sensitizations to inhaled and food allergen molecular families (n = 4). Conclusion: These results underline the heterogeneity of sensitization profiles in severe allergic childhood asthma. The most severe asthma phenotypes were associated with multiple sensitizations to both inhaled and food allergen molecular families as expected, and to the tropomyosin molecular family, a novel finding. [ABSTRACT FROM AUTHOR]

Background: Hereditary angioedema (HAE) in children has specific features and requires multidisciplinary management. Methods: We performed a literature search and underwent in‐depth discussions to provide practical tools for physicians. Results: HAE is a rare, life‐threatening genetic disorder. Its epidemiology is poorly documented in children. Clinical manifestations usually appear during childhood or early adolescence. Classical signs, often preceded by prodromal symptoms, include transient, localized, non‐pitting, non‐pruritic swelling of deep dermal/subcutaneous or mucosal/submucosal tissues, leading to oedema of the extremities, face, lips, tongue, trunk and genitals, recurring gastrointestinal symptoms and laryngeal edema possibly causing asphyxiation and death. Diagnosis is often delayed due to low awareness in the medical community, and particularly challenging in case of isolated abdominal crises or atypical presentation and in neonates or infants. It relies on biological tests (measurement of serum/plasma levels of C1INH function, C1INH protein, and C4), genetic testing in selected cases, and imaging for differential diagnosis of acute abdominal crises. Main differential diagnosis for peripheral oedema is mast cell‐mediated oedema that accounts for 95% of angioedema in clinical practice. Quality of life can be significantly impaired. Disease management includes treatment of attacks, short‐term and long‐term prophylaxis, psychological support, avoidance of triggers, patients' and parents' education and coordination of all stakeholders, ideally within a specialized healthcare network. New plasma kallikrein inhibitors, namely lanadelumab (subcutaneous route) and berotralstat (oral route) have facilitated long‐term prophylaxis thanks to improved usability. Conclusion: Diagnostic and treatment of HAE are particularly challenging in children and require specific management by multiple stakeholders. [ABSTRACT FROM AUTHOR]

Successful bioinspired design depends on practitioners’ access to biological data in a relevant form. Although multiple open-access biodiversity databases exist, their presentation is often adapted to life scientists, rather than bioinspired designers. In this paper, we present a new tool, “Bioinspire-Explore”, for navigating biodiversity data in order to uncover biological systems of interest for a range of sectors. Bioinspire-Explore allows users to search for inspiring biological models via taxa (species, genera, etc.) as an entry point. It provides information on a taxon’s position in the “tree of life”, its distribution and climatic niche, as well as its appearance. Bioinspire-Explore also shows users connections in the bioinspiration literature between their taxon of interest and associated biological processes, habitats, and physical measurements by way of their semantic proximity. We believe Bioinspire-Explore has the potential to become an indispensable resource for both biologists and bioinspired designers in different fields.

Ticks are major vectors of various pathogens of health importance, such as bacteria, viruses and parasites. The problems associated with ticks and vector-borne pathogens are increasing in mountain areas, particularly in connection with global climate change. We collected ticks (n = 2,081) from chamois and mouflon in 4 mountainous areas of France. We identified 6 tick species: Ixodes ricinus, Rhipicephalus bursa, Rh. sanguineus s.l., Haemaphysalis sulcata, H. punctata and Dermacentor marginatus. We observed a strong variation in tick species composition among the study sites, linked in particular to the climate of the sites. We then analysed 791 ticks for DNA of vector-borne pathogens: Babesia/Theileria spp., Borrelia burgdorferi s.l., Anaplasma phagocytophilum, A. marginale, A. ovis, and Rickettsia of the spotted fever group (SFG). Theileria ovis was detected only in Corsica in Rh. bursa. Babesia venatorum (2 sites), Borrelia burgdorferi s.l. (B. afzelii and B. garinii; 2 sites) and Anaplasma phagocytophilum (3 sites) were detected in I. ricinus. Anaplasma ovis was detected at one site in I. ricinus and Rh. sanguineus s.l. SFG Rickettsia were detected at all the study sites: R. monacensis and R. helvetica in I. ricinus at the 3 sites where this tick is present; R. massiliae in Rh. sanguineus s.l. (1 site); and R. hoogstraalii and Candidatus R. barbariae in Rh. bursa in Corsica. These results show that there is a risk of tick-borne diseases for humans and domestic and wild animals frequenting these mountain areas.

This article provides an overview of the developments made over the last 10 years within RayXpert®, a CAD-based geometry 3D Monte Carlo software developed by TRAD – Tests & Radiations. The main features of RayXpert® are its 3D Monte Carlo engine and its CAD-based geometry. It is also possible to import STEP file, automatically detect overlaps, and perform parallel Monte Carlo computations. During the last 10 years, numerous new features were added to the software: TTB approximation, dose and flux mapping, computation resumption, radioactive decay computation, script support, MPI computation, advanced convergence indicators, etc. New features such as advanced biasing or neutron-induced activation simulation are under development. This article presents the past and future functionalities of RayXpert®.

BackgroundPaediatric acute respiratory distress syndrome (PARDS) is associated with high mortality in children, but until recently no paediatric-specific diagnostic criteria existed. The Pediatric Acute Lung Injury Consensus Conference (PALICC) definition was developed to overcome limitations of the Berlin definition, which was designed and validated for adults. We aimed to determine the incidence and outcomes of children who meet the PALICC definition of PARDS.MethodsIn this international, prospective, cross-sectional, observational study, 145 paediatric intensive care units (PICUs) from 27 countries were recruited, and over a continuous 5 day period across 10 weeks all patients were screened for enrolment. Patients were included if they had a new diagnosis of PARDS that met PALICC criteria during the study week. Exclusion criteria included meeting PARDS criteria more than 24 h before screening, cyanotic heart disease, active perinatal lung disease, and preparation or recovery from a cardiac intervention. Data were collected on the PICU characteristics, patient demographics, and elements of PARDS (ie, PARDS risk factors, hypoxaemia severity metrics, type of ventilation), comorbidities, chest imaging, arterial blood gas measurements, and pulse oximetry. The primary outcome was PICU mortality. Secondary outcomes included 90 day mortality, duration of invasive mechanical and non-invasive ventilation, and cause of death.FindingsBetween May 9, 2016, and June 16, 2017, during the 10 study weeks, 23 280 patients were admitted to participating PICUs, of whom 744 (3·2%) were identified as having PARDS. 95% (708 of 744) of patients had complete data for analysis, with 17% (121 of 708; 95% CI 14-20) mortality, whereas only 32% (230 of 708) of patients met Berlin criteria with 27% (61 of 230) mortality. Based on hypoxaemia severity at PARDS diagnosis, mortality was similar among those who were non-invasively ventilated and with mild or moderate PARDS (10-15%), but higher for those with severe PARDS (33% [54 of 165; 95% CI 26-41]). 50% (80 of 160) of non-invasively ventilated patients with PARDS were subsequently intubated, with 25% (20 of 80; 95% CI 16-36) mortality. By use of PALICC PARDS definition, severity of PARDS at 6 h after initial diagnosis (area under the curve [AUC] 0·69, 95% CI 0·62-0·76) discriminates PICU mortality better than severity at PARDS diagnosis (AUC 0·64, 0·58-0·71), and outperforms Berlin severity groups at 6 h (0·64, 0·58-0·70; p=0·01).InterpretationThe PALICC definition identified more children as having PARDS than the Berlin definition, and PALICC PARDS severity groupings improved the stratification of mortality risk, particularly when applied 6 h after PARDS diagnosis. The PALICC PARDS framework should be considered for use in future epidemiological and therapeutic research among children with PARDS.FundingUniversity of Southern California Clinical Translational Science Institute, Sainte Justine Children's Hospital, University of Montreal, Canada, Réseau en Santé Respiratoire du Fonds de Recherche Quebec-Santé, and Children's Hospital Los Angeles, Department of Anesthesiology and Critical Care Medicine.

Caroline Dufrois,1 Mélisande Bourgoin-Heck,1 Nathalie Lambert,1,2 Jocelyne Just,1 Aurore Bregeon,1,2 Camille Taillé,3 Stéphanie Wanin1 1Department of Paediatric Allergology, Armand Trousseau University Hospital, Groupe Hospitalier Universitaire, AP-HP Sorbonne-Université, Paris, France; 2Transversal Unit of Therapeutic Education of the Patient, Sorbonne University, Paris, France; 3Department of Respiratory Diseases, Hôpital Bichat, Groupe Hospitalier Universitaire, AP-HP Nord-Université de Paris, Paris, FranceCorrespondence: Stéphanie Wanin, Department of Paediatric Allergology, Armand Trousseau University Hospital, Groupe Hospitalier Universitaire, AP-HP Sorbonne-Université, 26, Avenue Arnold Netter, Paris, 75012, France, Tel +33 1 87 89 27 62, Email stephanie.wanin@aphp.frBackground: The prevalence of severe asthma in adolescents is estimated at 6.7%. Transition to adult health services is a vulnerable period for adolescents where there is a risk of poor treatment adherence and loss to follow-up.Purpose: This retrospective study evaluated the maintenance of asthma control in young severe asthmatics, 6 months and 1 year after transition to a specialist adult centre.Methods: Patients with severe asthma treated in a paediatric pulmonology centre in the Île-de-France and referred at least 6 months previously to an adult service were included. Asthma control was evaluated by measuring the ACT score and respiratory function. Patients were asked to answer an on-line questionnaire about their experiences during transition.Results: Fifty-four adolescents with severe asthma underwent transition to the adult service between 2014 and 2021. Thirteen patients (25%) were lost to follow-up after an average of 22.4 months of follow-up. Three-quarters (73%) of patients had well controlled asthma with an ACT score ≥ 20 during transition and the majority were able to maintain good control and respiratory function (> 60% FEV1 > 80%) during follow-up in adult pulmonology. Among the patients that answered the questionnaire, 64.8% were satisfied with the transition process.Conclusion: Asthma control and respiratory function were maintained 6 months and 1 year after transition to the adult centre in the majority of patients. Most patients were satisfied with the transition process, but several improvements can be proposed, including early discussion of the medical plan and the implementation of procedures to reduce loss to follow-up.Keywords: severe asthma, transition, adolescents, pulmonology, asthma control, adults

Macrophages are immune cells that originate from embryogenesis or from the differentiation of monocytes. They can adopt numerous phenotypes depending on their origin, tissue distribution and in response to different stimuli and tissue environment. Thus, in vivo, macrophages are endowed with a continuum of phenotypes that are rarely strictly pro-inflammatory or anti-inflammatory and exhibit a broad expression profile that sweeps over the whole polarization spectrum. Schematically, three main macrophage subpopulations coexist in human tissues: naïve macrophages also called M0, pro-inflammatory macrophages referred as M1 macrophages, and anti-inflammatory macrophages also known as M2 macrophages. Naïve macrophages display phagocytic functions, recognize pathogenic agents, and rapidly undergo polarization towards pro or anti-inflammatory macrophages to acquire their full panel of functions. Pro-inflammatory macrophages are widely involved in inflammatory response, during which they exert anti-microbial and anti-tumoral functions. By contrast, anti-inflammatory macrophages are implicated in the resolution of inflammation, the phagocytosis of cell debris and tissue reparation following injuries. Macrophages also play important deleterious or beneficial roles in the initiation and progression of different pathophysiological settings including solid and hematopoietic cancers. A better understanding of the molecular mechanisms involved in the generation, activation and polarization of macrophages is a prerequisite for the development of new therapeutic strategies to modulate macrophages functions in pathological situations.

Cixiidae are small strictly phytophagous hemipteran insects worldwide distributed. Ecology and systematics of Chinese fauna remains poorly investigated. For instance, does their distribution follows the patterns of biogeogaphical distribution established for their host plants or other related-taxa because they are all obligatory phytophagous taxa? Do they follow the usual distributional Chinese realms and boundaries already recognized? Which zoogeographical Chinese regions and connections between them do they depict. To investigate these issues, we provide here a referenced and comprehensive checklist of the 250 cixiid species currently reported from China (77 new records), with their precise distribution at the regional level. In the 8 Chinese main zoogeographical regions usually recognized and 2 adjacent areas, we analyzed further their diversity at the tribal, generic, and specific levels using a non-metric multidimensional scaling and an unweighted pairwise group analysis using an arithmetic mean cluster analyses. The observed distribution patterns shown that an intercalary Sino-Japanese realm is recognisable between the Palaearctic and Oriental realms. At the regional level, the South China region clusters more closely with the Southwest, Central and North China regions. Taiwan, clearly separated from the South China region and mainland China, is more closely related to the Qinghai-Tibet region and Indochina countries. Although Central and South China regions remain close to each other, the Qinghai-Tibet region appears singularly different.An updated checklist of the 250 Cixiidae species, known to occur in China and counting for 10% of the Chinese planthopper fauna, is presented based on literature, recent collections, and museum records. More than 400 records distributed among the 28 provinces and 8 regions in China are extensively provided, including 77 new records. Of these, more than 80% of the species (205 species, 82%) have been only reported from China, and most of them are endemic species, which could reflects the great diversity degree of the Chinese regions and local biotypes highlights the uniqueness of this fauna. These species are found in 8 Chinese zoogeographical regions: The Taiwan region is the most diversified with 161 species and the highest rate of endemic species (69.57%), followed by South China (78 species, 17.95%), Central China (60 species, 33.33%), Southwest China (43 species, 39.53%), North China (29 species, 34.48%), Qinghai-Tibet region (10 species, 20%), Northeast China (8 species, 12.5%), and 5 species found in the Inner Mongolia-Xinjiang region that are not endemic ones. Endemism was analyzed for each region and repeated for species distribution patterns across them, 9 being bi-regionally and tri-regionally distributed. The South China-Taiwan pattern is the most richest one, followed by the Central-South China-Taiwan pattern. Semonini and Pentastirini tribes are widespread among all the zoological regions, representing respectively 21.20% and 17.20% of all the species, while Cixiini being is the most common tribe with 45.20%, remains absent from the North-Eastern China region. Andini with only 5.20% of the species is distributed in the Sino-Japanese - Oriental Region; Eucarpini (6.40%) and Borysthenini (2.00%) are mainly concentrated in the south of the Qingling Mountain-Huai River. The remaining four tribes, Bennini (0.40%), Briixini (0.80%), Oecleini (1.20%) and Stenophlepsiini (0.40%) are relatively rare and restricted to Taiwan. At the generic level, Kuvera (7.2%) is the most widely distributed genus in China while Cixius, Betacixius, Kuvera, Oecleopsis and Andes are the more diversified. One genus (Oliparisca) is distributed only in the Tibet region, while 10 genera are distributed only in the Taiwan region. In addition, nearly half of the genera (16 genera, 48.48%) are distributed south of the Palearctic/Oriental boundary. A non-metric multidimensional scaling and an unweighted pairwise group method analysis using arithmetic mean clustering based on the Jaccard similarity coefficient matrix support a Palaearctic/Sino-Japanese boundary and a South China region closer to the Southwest, Central and North China regions. The Taiwan region appears clearly separated from the South China region and to mainland China, and more closely related to the Qinghai-Tibet region and Indochina countries. The Central and South China regions appear close to each other, but the Qinghai-Tibet region is singularly isolated.

Abstract Background Gastrointestinal nematodes are ubiquitous for both domestic and wild ungulates and have varying consequences for health and fitness. They exist as complex communities of multiple co-infecting species, and we have a limited understanding of how these communities vary in different hosts, regions and circumstances or of how this affects their impacts. Methods We have undertaken ITS2 rDNA nemabiome metabarcoding with next-generation sequencing on populations of nematode larvae isolated from 149 fecal samples of roe deer of different sex and age classes in the two isolated populations of Chizé and Trois Fontaines in France not co-grazing with any domestic ungulate species. Results We identified 100 amplified sequence variants (ASVs) that were assigned to 14 gastrointestinal nematode taxa overall at either genus (29%) or species (71%) level. These taxa were dominated by parasites classically found in cervids—e.g. Ostertagia leptospicularis, Spiculopteragia spp. Higher parasite species diversity was present in the Trois Fontaines population than in the Chizé population including the presence of species more typically seen in domestic livestock (Haemonchus contortus, Bunostomum sp., Cooperia punctata, Teladorsagia circumcincta). No differences in parasite species diversity or community composition were seen in the samples collected from three zones of differing habitat quality within the Chizé study area. Young roe deer hosted the highest diversity of gastrointestinal nematodes, with more pronounced effects of age apparent in Trois Fontaines. The effect of host age differed between gastrointestinal nematode species, e.g. there was little effect on O. leptospicularis but a large effect on Trichostrongylus spp. No effect of host sex was detected in either site. Conclusions The presence of some livestock parasite species in the Trois Fontaines roe deer population was unexpected given the isolation of this population away from grazing domestic livestock since decades. Overall, our results illustrate the influence of host traits and the local environment on roe deer nemabiome and demonstrate the power of the nemabiome metabarcoding approach to elucidate the composition of gastrointestinal nematode communities in wildlife. Graphical Abstract

Objectives To demonstrate acceptability and operational feasibility of introducing human papillomavirus (HPV) testing as a principal cervical cancer screening method in public health programmes in sub-Saharan Africa.Setting 45 primary and secondary health clinics in Malawi, Nigeria, Senegal, Uganda and Zimbabwe.Participants 15 766 women aged 25–54 years presenting at outpatient departments (Senegal only, general population) or at antiretroviral therapy clinics (all other countries, HIV-positive women only). Eligibility criteria followed national guidelines for cervical cancer screening.Interventions HPV testing was offered to eligible women as a primary screening for cervical cancer, and HPV-positive women were referred for visual inspection with acetic acid (VIA), and if lesions identified, received treatment or referral.Primary and secondary outcome measures The primary outcomes were the proportion of HPV-positive women who received results and linked to VIA and the proportion of HPV-positive and VIA-positive women who received treatment.Results A total of 15 766 women were screened and tested for HPV, among whom 14 564 (92%) had valid results and 4710/14 564 (32%) were HPV positive. 13 837 (95%) of valid results were returned to the clinic and 3376 (72%) of HPV-positive women received results. Of women receiving VIA (n=2735), 715 (26%) were VIA-positive and 622 (87%) received treatment, 75% on the same day as VIA.Conclusions HPV testing was found to be feasible across the five study countries in a public health setting, although attrition was seen at several key points in the cascade of care, namely results return to women and linkage to VIA. Once women received VIA, if eligible, the availability of on-site cryotherapy and thermal ablation allowed for same-day treatment. With sufficient resources and supportive infrastructure to ensure linkage to treatment, use of HPV testing for cervical cancer screening as recommended by WHO is a promising model in low-income and middle-income countries.

From 2007 to 2019, over 650 public schools closed in Puerto Rico. School closures not only affect students and teachers; these spaces serve as anchor institutions providing social infrastructure for the sustained health of communities. While closed schools remove a critical community asset, these vacant buildings provide adaptive reuse opportunities for alternative social infrastructure and community resources. This article explores how abandoned schools are repurposed in Puerto Rico, focusing on “rescued schools”—that is, grassroots, voluntary initiatives that repurpose schools to support community development. Through a multi-method approach, we categorized and mapped 161 repurposed schools throughout Puerto Rico—38 were rescued schools—and conducted twelve interviews and two focus groups on rescued school initiatives. Our results describe how abandoned schools offer a galvanizing opportunity for motivated community members to meet emerging, localized needs, and the challenges in gaining school ownership and attracting sustained financial and volunteer support, the lack of which impedes their potential impact. We demonstrate how rescued schools embody alternative regional political visions within Puerto Rico and argue that government authorities can minimize the harm from school closures by forging new partnerships between community-based organizations, municipal governments, and other supportive actors to repurpose schools and reproduce their role as community anchor institutions.