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Abstract This study aimed at leveraging data from phase I/II clinical trials to build a nonlinear joint model of serum M‐protein kinetics and progression‐free survival (PFS) accounting for the effects of isatuximab (Isa), pomalidomide (Pom), and dexamethasone (Dex) in patients with relapsed and/or refractory multiple myeloma. Serum M‐protein levels and PFS data from 203 evaluable patients, included either in a phase I/II study (n = 173) or in a phase I study (n = 30), were used to build the model. First, we independently developed a longitudinal model and a PFS model. Then, we linked them in a nonlinear joint model by selecting the link function that best captured the association between serum M‐protein kinetics and PFS. A Claret tumor growth‐inhibition model accounting for the additive effects of Isa, with an Emax function, Pom, and Dex on serum M‐protein elimination was selected to describe serum M‐protein kinetics. PFS was best described with a log‐logistic model and associations with baseline beta‐2 microglobulin level, age, and coadministration of Dex were identified. The instantaneous change in serum M‐protein level was found to be associated with PFS in the final joint model. Using model simulations, we retrospectively supported the Isa 10 mg/kg weekly for 4 weeks, then biweekly (QW/Q2W) dosing regimen of the ICARIA‐MM phase III pivotal study, and validated it using the same phase III pivotal study data.

Abstract Sickle cell disease is a rare genetic disease resulting from an abnormality in hemoglobin. Hemostasis in the steady state, defined as ≥2 months without vaso‐occlusive crises, is poorly described in the literature. We report the routine hemostasis profile in steady state patients with sickle cell disease (SCD), including during pregnancy and according to phenotype. This retrospective study collected data over the period 2010 to 2021. Data on routine hemostasis parameters (prothrombin time [PT] activated partial thromboplastin time [aPTT], and platelets) were collected from medical records and were compared with laboratory norms including during pregnancy; the HbSS phenotype was compared with the HbSC, HbSB°thalassemia, and HbSB+thalassemia phenotypes. we included 119 adults (representing 190 day‐hospitals) with SCD who had attended at least one checkup in the steady state. Seven patients (15 day‐hospitals) on anticoagulants were excluded. Eleven (17 day‐hospitals) were pregnant. Mean routine hemostasis parameters were within normal values regardless of pregnancy. Mean PT was lower during pregnancy (12.3 ± 0.6 s vs. 13.2 ± 1.0 s; P = .01). PT and platelet counts were higher (P = .01) and aPTT was lower (P = .03) in men and nonpregnant women in the HbSS group compared with those in the HbSC group. routinely collected hemostasis parameters in steady state patients were within normal laboratory values, including in pregnant women. PT values differed significantly between pregnant women and nonpregnant women, and PT, aPTT, and platelet counts differed between HbSS, HbSC, and HbSB+thalassemia phenotypes.

Abstract Treatment of type 3 von Willebrand disease by infusion of von Willebrand factor (VWF) and factor VIII (FVIII) concentrates may lead to the development of anti‐VWF antibodies, challenging haemostasis management. The systematic review of the literature presented here retrieved 15 such cases (surgery n = 11, bleeding n = 4). The heterogeneous patient management mostly involved continuous infusion of FVIII, or recombinant FVIIa together with various other strategies. Off‐label infusion of the bispecific monoclonal antibody emicizumab was prescribed in three cases and in a complex local case, ultimately well‐controlled with emicizumab. This illustrates the fact that emicizumab appears as a therapeutic option in this context of allo‐immunisation.

Abstract Aims Many European healthcare providers struggle to adopt multidisciplinary, integrated care pathways for people with heart failure (HF) as recommended by the European Society of Cardiology. PRO‐HF (Program to Optimize Heart Failure Patient Pathways) was developed to help clinicians identify strengths, gaps, and shortcomings in their HF pathways and support tailored interventions to optimize pathways and enhance patient care. We report initial findings from baseline assessments of HF pathway characteristics and challenges from 10 hospitals in six European countries (France, Ireland, Portugal, Spain, The Netherlands, and United Kingdom). Methods and results Baseline assessments were holistic appraisals of full HF services to calibrate current status and development needs and assist management teams in prioritizing improvement projects. Assessments were performed using a comprehensive checklist of measures covering the HF patient journey from diagnosis to ongoing follow‐up. These included a digital survey sent to full HF care teams and one‐to‐one interviews. The digital survey focused on four key areas (HF outpatient clinic; remote patient management; efficient device implantation and inpatient pathways; and network maximization) and 16 dimensions of excellence. Priority areas and themes for action identified in baseline assessments were (i) provision of HF specialist care; (ii) data capture and analysis; (iii) institutional care protocols; (iv) hospital‐wide strategies; and (v) multidisciplinary teams (MDTs). Suboptimal specialist care of emergency inpatients was an issue at all hospitals and prioritized at 8/10. Availability and accessibility of data on patients, activities, and outcomes was an issue at all hospitals and prioritized by 4/10. A lack of clear protocols, templates, and tools for some HF activities created variability in patient care (e.g., HF specialist consultations, diagnostic testing, follow‐up appointments, medications, and device eligibility) and inefficient use of clinician time. This made it difficult to initiate new technologies (e.g., remote patient monitoring) due to the risk of overburdening staff. MDTs were frequently understaffed. Multiple interventions were identified to address gaps and shortcomings that could be tailored to specific needs of individual hospitals (e.g., inpatient pathway optimization, creation/optimization of HF outpatient clinics, development of an HF performance dashboard, enhancement of protocol adherence, streamlining cardiac resynchronisation therapy pathways, and MDT coordination). Conclusions PRO‐HF provides a valuable opportunity to identify gaps and significant shortcomings in HF pathways in European hospitals. Preliminary findings from hospitals that have initiated suggested changes to address these challenges are encouraging, though longer‐term follow‐up from more hospitals is needed to confirm the impact of PRO‐HF on HF pathway optimization and patient care.

Abstract Urothelial carcinoma (UC) occurs uncommonly in cats and no association has previously been observed with long‐term indwelling urinary implants. An 18‐year‐old male castrated domestic shorthair cat initially was presented for hematuria, leading to the diagnosis of a right‐sided ureterolithiasis and severe pyelectasia on ultrasound examination, prompting right‐sided subcutaneous ureteral bypass (SUB) device placement. The cat subsequently had intermittent hematuria and dysuria, without ultrasonographic abnormality of the bladder or positive urine culture. Thirteen months later the patient developed refractory lower urinary tract signs, azotemia, a proliferative mass in the region of the cystostomy tube component of the SUB device and evidence of left ureteral obstruction. Cystostomy tube revision and left‐sided SUB device placement were performed, as well as a partial cystectomy for removal of the mass. Upon histopathology, the mass was diagnosed as a UC. To our knowledge, UC associated with a long‐term indwelling cystostomy catheter component of a SUB device has not been reported in veterinary medicine.

Abstract Marine Protected Areas (MPAs) are a cornerstone of marine conservation efforts, with the potential to protect biodiversity and provide socioeconomic benefits. We quantified the effect of MPAs on fishing outcomes, economic activities, and material living standards in 24 coastal villages of Tanzania over two decades. We accessed original data from a study conducted in 2003 that found no effect of MPAs 3–8 years after their creation. Eighteen years later, we replicated the survey and used a Before‐After Control‐Intervention design to quantify the effect of MPAs. We found that villages near MPAs experienced a 50% higher improvement in living standards compared to those further from MPAs. This benefit is not related to higher fishing outcomes but to a diversification of economic sectors. Our findings highlight a decoupling between fish catches and economic benefits, revealing that socio‐economic outcomes can be observed for MPAs whose ecosystems’ productivity has declined.

Abstract Genetically modified maize DP51291 was developed to confer control against susceptible corn rootworm pests and tolerance to glufosinate‐containing herbicide; these properties were achieved by introducing the ipd072Aa, pmi and mo‐pat expression cassettes. The molecular characterisation data and bioinformatic analyses do not identify issues requiring food/feed safety assessment. None of the identified differences in the agronomic/phenotypic and compositional characteristics tested between maize DP51291 and its conventional counterpart needs further assessment, except for phosphorus in forage and manganese, proline, oleic acid (C18:1) and linoleic acid (C18:2) in grain, which do not raise safety and nutritional concerns. The GMO Panel does not identify safety concerns regarding the toxicity and allergenicity of the IPD072Aa, PAT and PMI proteins as expressed in maize DP51291 and finds no evidence that the genetic modification would change the overall allergenicity of maize DP51291. In the context of this application, the consumption of food and feed from maize DP51291 does not represent a nutritional concern in humans and animals. The GMO Panel concludes that maize DP51291 is as safe as its conventional counterpart and non‐GM maize varieties tested, and no post‐market monitoring of food/feed is considered necessary. In the case of accidental release of viable maize DP51291 grains into the environment, this would not raise environmental safety concerns. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of maize DP51291. The GMO Panel concludes that maize DP51291 is as safe as its conventional counterpart and the tested non‐GM maize varieties with respect to potential effects on human and animal health and the environment.

Abstract Genetically modified Komagataella phaffii strain MXY0541 was developed to produce soy leghemoglobin by introducing the LGB2 coding sequence encoding leghemoglobin from soybean (Glycine max). The molecular characterisation data and bioinformatic analyses do not raise any safety concerns. The safety of soy leghemoglobin as a food additive has already been assessed by the EFSA FAF Panel (EFSA‐Q‐2022‐00031). The GMO Panel does not identify safety concerns regarding the toxicity and allergenicity of soy leghemoglobin protein as expressed in K. phaffii, and finds no evidence that the genetic modification would change its overall allergenicity. The GMO Panel concludes that the LegH Prep derived from genetically modified K. phaffii strain MXY0541 is safe for human consumption with regard to the effects of the genetic modification. No environmental impact from the use of this product is expected regarding the recombinant DNA sequences possibly remaining in the product. The GMO Panel concludes that LegH Prep from genetically modified K. phaffii strain MXY0541 is safe with respect to potential effects on human health and the environment at the proposed use and use level as far as the impact of the genetic modification is concerned. The overall conclusion is that the genetic modification does not lead to safety issues.

ABSTRACT In Pseudomonas putida KT2440, a prime chassis for biotechnology, the clustered distribution of glucose catabolism genes and four related transcription factors (TFs) may facilitate the tight regulation of glucose catabolism. However, the genes under the direct control of these TFs remain unidentified, leaving their regulatory roles elusive. Furthermore, the carbon source gluconate was metabolised similarly to glucose in KT2440, but the responses of these catabolic and TF genes to gluconate were unclear. Here, these mysteries were unravelled through multi‐omics analysis integrated with physiological studies. First, we found that the expression of these catabolic and TF genes were significantly induced by both glucose and gluconate in KT2440. The independent responses of these genes to glucose and gluconate were differentiated in the gcd deletion mutant. We then defined the regulon of GnuR, one of the four related TFs, and discovered that GnuR directly repressed the expression of catabolic genes involved in the Entner–Doudoroff and the peripheral glucose and gluconate metabolism pathways. These results were further confirmed by physiological studies. Finally, a regulatory mode of an incoherent feedforward loop involving GnuR is proposed.

Abstract Immunoglobulin E (IgE)‐mediated food allergies are the most common type of food allergy, often causing rapid symptoms after exposure to allergens posing a serious health risk and a high impact on patient's and caregiver's quality of life. Omalizumab, a humanized anti‐IgE monoclonal antibody, reduces allergic reactions by binding to circulating IgE. Omalizumab has been successfully used in allergic asthma, chronic rhinosinusitis with nasal polyps, and chronic urticaria, and was recently approved for treating IgE‐mediated food allergies by the US Food and Drug Administration (FDA). This GA2LEN ANACARE Consensus Statement presents our position on the use of omalizumab for treating IgE‐mediated food allergies, based on a systematic review and meta‐analysis, experience with use for other conditions, and expert consensus achieved via an eDelphi process. Following publication of the recent OUtMATCH study (stage 1) results and subsequent FDA approval, we propose that there is now sufficient evidence to recommend omalizumab as the only drug currently available that can mechanistically reduce IgE‐mediated food allergic reactions. We acknowledge that the evidence does not reach the highest level of evidence which would be needed for a guideline recommendation.

ABSTRACT Background Age is one of the strongest risk factors for breast cancer. Measures of biological age based on DNA methylation have gained popularity for their strong association with risk of many diseases, including cancer, which may help to identify high‐risk subgroups for targeted prevention. Methods We carried out a systematic review of prospective studies that examined the association of methylation‐based markers of ageing with risk of invasive breast cancer in healthy (breast cancer‐free) women, published up to May 2023. The search of three databases (MEDLINE, EMBASE and Web of Science) identified 2913 individual abstracts eligible for screening. Risk of bias assessment was conducted using ROBINS‐E. Results Ten prospective studies met the eligibility criteria, and these were heterogeneous in design and findings. The most frequently assessed epigenetic ageing measures were Horvath's first‐generation clock, PhenoAge and GrimAge. Four studies reported mainly positive associations, five null associations and one reported a negative association. These associations were generally weak and the results were not consistent across epigenetic ageing measures. Conclusion The summarised evidence is insufficient to support a role for current epigenetic ageing measures to stratify breast cancer risk. PROSPERO Registration: This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023417559)

Abstract Global environmental change will cause shifts in species communities, with non‐native species likely replacing native ones at an unprecedented rate. This will have consequences for biodiversity and ecosystem services, in addition to the ecological and economic damage caused by those non‐native species that are invasive. Understanding general patterns driving distributions of native and non‐native species is therefore vital, but no study has compared yet whether environmental variables that correlate with a species' presence differ between the two groups other than at local scale and often with very limited sample size. In this study, we focus on 141 native and non‐native congeneric plant species pairs at the scale of Switzerland. In the framework of correlative species distribution models, we used newly developed methods for efficient automated selection of a parsimonious number of predictor environmental variables to determine which ones, out of a large candidate set in eight classes, have the strongest explanatory power for both species groups. Our results indicated that variables influence the two groups in significantly different ways. Climate was by far the strongest determinant of both native and non‐native species distributions, although it had significantly more explanatory power in native species models. Models for non‐native species were significantly more influenced by anthropogenic factors, land use variables and forest cover. The presence of non‐native species was also associated with habitats with a significantly lower mean naturality value than native species. These findings provide novel empirical evidence for the different environmental factors driving native and non‐native plants' distributions and guidance for non‐native species management. Practical implications: species distribution models are an increasingly frequently advised tool for conservation management and our results provide guidelines on which covariates should be specifically considered to assess the habitat suitability of non‐native versus native species. The distributions of the former group of species are particularly important to research, as, in time, they may turn invasive. In addition, areas close to infrastructure should be scanned regularly for incipient colonizations by non‐native species, especially in as yet uninvaded areas, such as high mountains.

Abstract Background Basal cell carcinoma (BCC) is the most common form of skin cancer, typically developing in sun‐exposed areas such as the face. Surgery is the treatment of choice, with a overall good prognosis. However, some scars can be unsightly or bothersome, and some tumours are too large or badly located to be eligible for surgery. Plasmonic photothermal therapy is presented here as an alternative treatment. Our team has developed green gold nanoparticles that have demonstrated their efficacy in inducing hyperthermia in the tumour‐microenvironment when combined with near‐infrared laser (NIR laser). Objectives The aim of this study is to demonstrate the effectiveness of gold nanoparticles combined with laser treatment against BCC. Methods In vitro, BCC cells were exposed to gold nanoparticles, both with and without laser treatment, to study the effects of this therapy on skin cells. Subsequently, mice bearing BCC were treated with photothermal therapy to assess tumour growth. Results Gold nanoparticles were found to be nontoxic to the cell line, and photothermal therapy induced apoptosis. In vivo studies showed complete regression of tumours without unsightly scarring and no recurrence after 40 days. Conclusions Plasmonic photothermal therapy using gold nanoparticles proved its efficacy in the destruction of BCC.

Abstract Microvascular impairments are typical of several cardiovascular diseases. Near‐infrared spectroscopy (NIRS) combined with a vascular occlusion test provides non‐invasive insights into microvascular responses by monitoring skeletal muscle oxygenation changes during reactive hyperaemia. Despite increasing interest in the effects of sex and ageing on microvascular responses, evidence remains inconsistent. Therefore, the present study aimed to investigate the effects of sex and age on microvascular responsiveness. Twenty‐seven participants (seven young men and seven young women; seven older men and six older women; aged 26 ± 1, 26 ± 4, 67 ± 3 and 69 ± 4 years, respectively) completed a vascular occlusion test consisting of 5 min of arterial occlusion followed by 5 min reperfusion. Oxygenation changes in the vastus lateralis were monitored by near‐infrared spectroscopy. The findings revealed that both women (referring to young and older women) and older participants (referring to both men and women) exhibited lower microvascular responsiveness. Notably, both women and older participants demonstrated reduced desaturation (−38% and −59%, respectively) and reperfusion rates (−24% and −40%, respectively) along with a narrower range of tissue oxygenation (−39% and −39%, respectively) and higher minimal tissue oxygenation levels (+34% and +21%, respectively). Women additionally displayed higher values in resting (+12%) and time‐to‐peak (+15%) tissue oxygenation levels. In conclusion, this study confirmed decreased microvascular responses in women and older individuals. These results emphasize the importance of considering sex and age when studying microvascular responses. Further research is needed to uncover the underlying mechanisms and clinical relevance of these findings, enabling the development of tailored strategies for preserving vascular health in diverse populations.

Abstract Following a request from the European Commission, the GMO Panel assessed additional information related to the application for authorisation of food and feed containing, consisting of and produced from genetically modified soybean MON × MON 87708 × MON 89788 (EFSA‐GMO‐NL‐2015‐126). The applicant conducted a 90‐day feeding study on GM soybean MON 87705 and provided a proposal for post‐market monitoring considering the altered fatty acid profile of GM soybean MON 87705 × MON 87708 × MON 89788, to fulfil the deficiencies identified by EFSA GMO Panel, addressing elements that remained inconclusive from a previous EFSA scientific opinion issued in 2020. The GMO Panel concludes that the 90‐day feeding study on GM soybean MON 87705 is in line with the requirements of Regulation (EU) No 503/2013 and that no treatment‐related adverse effects were observed in rats after feeding diets containing soybean MON 87705 meals at 30% or 15% for 90 days. The GMO Panel reiterates the recommendation for a PMM for food in accordance with Regulation (EC) No 1829/2003 and Regulation (EU) No 503/2013 and concludes that the proposal provided by the applicant is in line with the recommendations described for the PMM plan of soybean MON 87705 × MON 87708 × MON 89788 in the adopted scientific opinion. Taking into account the previous assessment and the new information, the GMO Panel concludes that soybean MON 87705 × MON 87708 × MON 89788, as assessed in the scientific opinion on application EFSA‐GMO‐NL‐2015‐126 and in the supplementary toxicity study, is as safe as its non‐GM comparator and the non‐GM reference varieties tested and does not represent a nutritional concern in humans and animals, within the scope of this application.

ABSTRACT Biological invasions have caused the loss of freshwater biodiversity worldwide. The interplay between adaptive responses and demographic characteristics of populations impacted by invasions is expected to be important for their resilience, but the interaction between these factors is poorly understood. The freshwater gastropod Amnicola limosus is native to the Upper St. Lawrence River and distributed along a water calcium concentration gradient within which high‐calcium habitats are impacted by an invasive predator fish (Neogobius melanostomus, round goby), whereas low‐calcium habitats provide refuges for the gastropods from the invasive predator. Our objectives were to (1) test for adaptation of A. limosus to the invasive predator and the low‐calcium habitats, and (2) investigate if migrant gastropods could move from refuge populations to declining invaded populations (i.e., demographic rescue), which could also help maintain genetic diversity through gene flow (i.e., genetic rescue). We conducted a laboratory reciprocal transplant of wild F0 A. limosus sourced from the two habitat types (high calcium/invaded and low calcium/refuge) to measure adult survival and fecundity in home and transplant treatments of water calcium concentration (low/high) and round goby cue (present/absent). We then applied pooled whole‐genome sequencing of 12 gastropod populations from across the calcium/invasion gradient. We identified patterns of life‐history traits and genetic differentiation across the habitats that are consistent with local adaptation to low‐calcium concentrations in refuge populations and to round goby predation in invaded populations. We also detected restricted gene flow from the low‐calcium refugia towards high‐calcium invaded populations, implying that the potential for demographic and genetic rescue is limited by natural dispersal. Our study highlights the importance of considering the potentially conflicting effects of local adaptation and gene flow for the resilience of populations coping with invasive predators.

ABSTRACT While it is recognised that most, if not all, multicellular organisms harbour neoplastic processes within their bodies, the timing of when these undesirable cell proliferations are most likely to occur and progress throughout the organism's lifetime remains only partially documented. Due to the different mechanisms implicated in tumourigenesis, it is highly unlikely that this probability remains constant at all times and stages of life. In this article, we summarise what is known about this variation, considering the roles of age, season and circadian rhythm. While most studies requiring that level of detail be done on humans, we also review available evidence in other animal species. For each of these timescales, we identify mechanisms or biological functions shaping the variation. When possible, we show that evolutionary processes likely played a role, either directly to regulate the cancer risk or indirectly through trade‐offs. We find that neoplastic risk varies with age in a more complex way than predicted by early epidemiological models: rather than resulting from mutations alone, tumour development is dictated by tissue‐ and age‐specific processes. Similarly, the seasonal cycle can be associated with risk variation in some species with life‐history events such as sexual competition or mating being timed according to the season. Lastly, we show that the circadian cycle influences tumourigenesis in physiological, pathological and therapeutic contexts. We also highlight two biological functions at the core of these variations across our three timescales: immunity and metabolism. Finally, we show that our understanding of the entanglement between tumourigenic processes and biological cycles is constrained by the limited number of species for which we have extensive data. Improving our knowledge of the periods of vulnerability to the onset and/or progression of (malignant) tumours is a key issue that deserves further investigation, as it is key to successful cancer prevention strategies.

Abstract Merkel cell polyomavirus (MCPyV) is the foremost causative factor of Merkel cell carcinoma (MCC), a rare yet highly aggressive skin cancer. Although the evaluation of circulating IgG antibodies against Merkel cell polyomavirus (MCPyV) LT/sT oncoproteins is clinically useful for MCC diagnosis/prognosis, a limited number of assays for identifying such antibodies have been developed. Herein, a novel indirect immunoassay with synthetic epitopes/mimotopes of MCPyV oncoproteins was computationally designed and experimentally validated on control sera and sera from healthy individuals and MCC patients. Upon computational design of five synthetic peptides, the performance of the immunoassay in detecting anti‐oncoprotein IgGs in MCPyV‐positive and ‐negative control sera was evaluated. The immunoassay was afterwards extended on sera from healthy individuals, and, for longitudinal analysis, MCC patients. Performance properties such as sensitivity and specificity and positive/negative predictive values were adequate. Receiver‐operating characteristic (ROC) curves indicated that the areas under the curves (AUCs) were within the low/moderately accurate ranges. Immunoassay was repeatable, reproducible and accurate. As expected, the serum anti‐oncoprotein IgG prevalence in healthy individuals was low (2%–5%). Anti‐oncoprotein IgGs slightly increased when MCC patients experienced partial tumour remission and/or stable disease, compared to baseline. Our data indicate that the newly developed immunoassay is reliable for detecting circulating anti‐oncoprotein IgGs both in healthy individuals and MCC patients.

Abstract The emergence of new techniques in both microbial biotechnology and artificial intelligence (AI) is opening up a completely new field for monitoring and sometimes even controlling the evolution of pathogens. However, the now famous generative AI extracts and reorganizes prior knowledge from large datasets, making it poorly suited to making predictions in an unreliable future. In contrast, an unfamiliar perspective can help us identify key issues related to the emergence of new technologies, such as those arising from synthetic biology, whilst revisiting old views of AI or including generative AI as a generator of abduction as a resource. This could enable us to identify dangerous situations that are bound to emerge in the not‐too‐distant future, and prepare ourselves to anticipate when and where they will occur. Here, we emphasize the fact that amongst the many causes of pathogen outbreaks, often driven by the explosion of the human population, laboratory accidents are a major cause of epidemics. This review, limited to animal pathogens, concludes with a discussion of potential epidemic origins based on unusual organisms or associations of organisms that have rarely been highlighted or studied.

Abstract Transparent electrodes (TEs) are vital in optoelectronic devices, enabling the interaction of light and charges. While indium tin oxide (ITO) has traditionally served as a benchmark TE, its high cost prompts the exploration of alternatives to optimize electrode characteristics and improve device efficiencies. Conducting polymers, which combine polymer advantages with metal‐like conductivity, emerge as a promising solution for TEs. This work introduces a two‐in‐one electron transport layer (ETL) and TE based on films of polyethylenimine ethoxylated (PEIE)‐modified poly(benzodifurandione) (PBFDO). These PEIE‐modified PBFDO layers exhibit a unique combination of properties, including low sheet resistance (130 Ω sq−1), low work function (4.2 eV), and high optical transparency (>85% in the UV–vis‐NIR range). In contrast to commonly used poly(3,4‐ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), the doping level of PBFDO remains unaffected by the PEIE treatment, as verified through UV–vis‐NIR absorption and X‐ray photoelectron spectroscopy measurements. When employed as a two‐in‐one ETL/TE in organic solar cells, the PEIE‐modified PBFDO electrode exhibits performance comparable to conventional ITO electrodes. Moreover, this work demonstrates all‐organic solar cells with record‐high power conversion efficiencies of >15.1% under indoor lighting conditions. These findings hold promise for the development of fully printed, all‐organic optoelectronic devices.

Abstract The ROS1 proto‐oncogene encodes a receptor tyrosine kinase with structural homology to other oncogenic drivers, including ALK and TRKA‐B‐C. The FDA‐approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion‐positive NSCLC. However, limitations such as poor blood‐brain barrier penetration and acquired resistance, particularly the ROS1 G2032R solvent‐front mutation, hinder treatment durability. Repotrectinib, a next‐generation macrocyclic TKI, was rationally designed to overcome on‐target resistance mutations and improve brain distribution through its low molecular weight. In the TRIDENT‐1 clinical trial, repotrectinib demonstrated significant efficacy in both TKI‐naïve and TKI‐pretreated patients with ROS1‐rearranged NSCLC, including those with CNS metastases and G2032R resistance mutations. In the TKI‐naïve cohort (n = 71), 79% of patients achieved an objective response, with a median progression‐free survival (PFS) of 35.7 months, surpassing all previously approved ROS1 TKIs. In patients who had received one prior ROS1 TKI but were chemotherapy‐naïve (n = 56), objective responses were observed in 38%, and median PFS was 9.0 months. The safety profile of repotrectinib was consistent with earlier‐generation ROS1 TKIs and common adverse events included anemia, neurotoxicity, increased creatine kinase levels, and weight gain. These findings underscore the potential of repotrectinib to address unmet needs in ROS1‐rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next‐generation, selective ROS1 inhibitors to reduce Trk‐mediated toxicities and improve treatment tolerance.

Background Brain injury is one of the most serious complications after cardiac arrest (CA). To prevent this phenomenon, rapid cooling with total liquid ventilation (TLV) has been proposed in small animal models of CA (rabbits and piglets). Here, we aimed to determine whether hypothermic TLV can also offer neuroprotection and mitigate cerebral inflammatory response in large animals. Methods and Results Anesthetized pigs were subjected to 14 minutes of ventricular fibrillation followed by cardiopulmonary resuscitation. After return of spontaneous circulation, animals were randomly subjected to normothermia (control group, n=8) or ultrafast cooling with TLV (TLV group, n=8). In the latter group, TLV was initiated within a window of 15 minutes after return of spontaneous circulation and allowed to reduce tympanic, esophageal, and bladder temperature to the 32 to 34 °C range within 30 minutes. After 45 minutes of TLV, gas ventilation was resumed, and hypothermia was maintained externally until 3 hours after CA, before rewarming using heat pads (0.5 °C–1 °C/h). After an additional period of progressive rewarming for 3 hours, animals were euthanized for brain withdrawal and histological analysis. At the end of the follow‐up (ie, 6 hours after CA), histology showed reduced brain injury as witnessed by the reduced number of Fluroro‐Jade C‐positive cerebral degenerating neurons in TLV versus control. IL (interleukin)‐1ra and IL‐8 levels were also significantly reduced in the cerebrospinal fluid in TLV versus control along with cerebral infiltration by CD3+ cells. Conversely, circulating levels of cytokines were not different among groups, suggesting a discrepancy between local and systemic inflammatory levels. Conclusions Ultrafast cooling with TLV mitigates neuroinflammation and attenuates acute brain lesions in the early phase following resuscitation in large animals subjected to CA.

Abstract Following a request from the European Commission, the European Food Safety Authority (EFSA) assessed the 2022 post‐market environmental monitoring (PMEM) report on the cultivation of Cry1Ab‐expressing maize event MON 810. Overall, the 2022 PMEM report provides no evidence of adverse effects of maize MON 810 cultivation. It shows a high level of compliance with refuge requirements by Spanish and Portuguese farmers growing maize MON 810, but uncertainty remains on compliance in areas where the clustered surface of maize MON 810 farms exceeds 5 ha. There are no signs of practical resistance to Cry1Ab in the field in corn borer populations collected in north‐eastern Spain in 2022, although a decrease in Cry1Ab susceptibility in Mediterranean corn borer populations from this area cannot be excluded. Information retrieved through farmer questionnaires in Spain and from the scientific literature reveals no unanticipated adverse effects on human and animal health or the environment arising from the cultivation of maize MON 810. Uncertainties remain on whether ‘very highly’ and ‘extremely’ sensitive non‐target lepidoptera are potentially exposed to harmful amounts of MON 810 pollen. EFSA notes that several recommendations made in the frame of the assessment of previous PMEM reports remain unaddressed and identified additional shortcomings in the 2022 PMEM report that require further consideration by the consent holder in future annual PMEM reports. Particularly, EFSA emphasises the urgent need to increase the sensitivity of the insect resistance monitoring strategy and implement mitigation measures to ensure that the exposure of non‐target lepidoptera to maize MON 810 pollen is reduced to levels of no concern.

Abstract Growing evidence indicates that human activities are causing cancer rates to rise in both human and wildlife populations. This is due to the inability of ancestral anti‐cancer defences to cope with modern environmental risks. The evolutionary mismatch between modern oncogenic risks and evolved cancer defences has far‐reaching effects on various biological aspects at different timeframes, demanding a comprehensive study of the biology and evolutionary ecology of the affected species. Firstly, the increased activation of anti‐cancer defences leads to excessive energy expenditure, affecting other biological functions and potentially causing health issues like autoimmune diseases. Secondly, tumorigenesis itself can impact important fitness‐related parameters such as competitiveness, predator evasion, resistance to parasites, and dispersal capacity. Thirdly, rising cancer risks can influence the species' life‐history traits, often favoring early reproduction to offset fitness costs associated with cancer. However, this strategy has its limits, and it may not ensure the sustainability of the species if cancer risks continue to rise. Lastly, some species may evolve additional anti‐cancer defences, with uncertain consequences for their biology and future evolutionary path. In summary, we argue that the effects of increased exposure to cancer‐causing substances on wildlife are complex, ranging from immediate responses to long‐term evolutionary changes. Understanding these processes, especially in the context of conservation biology, is urgently needed.

Abstract Background Early access program (formerly cohort Temporary Authorization for Use) was granted for trastuzumab deruxtecan (T‐DXd) in France based on DESTINY‐Breast01 trial which demonstrated its efficacy and safety in HER2‐positive metastatic/unresectable breast cancer after ≥2 anti‐HER2‐based regimens received at metastatic stage. Methods This multicenter real‐world early access program included HER2‐positive metastatic/unresectable breast patients pretreated with at least two lines of anti‐HER2 regimens who received T‐DXd 5.4 mg/kg intravenously in monotherapy every 3 weeks. Results Four hundred and fifty‐nine patients (median age, 58 years; hormone receptor‐positive, 67%; brain metastases, 28.1%) received T‐DXd. Before inclusion, 81.7% of patients had radiation therapy and 76.5% had undergone surgery. Median number of prior metastatic treatment lines was four (range, 2–22); 99.8% patients had received trastuzumab, 94.8% trastuzumab emtansine and 79.3% pertuzumab. Follow‐up was performed from September 30, 2020 to March 30, 2021; when the early access program stopped, the median duration of T‐DXd treatment was 3.4 (range, 0–7.8) months. In 160 patients with available tumor assessment, objective response rate was 56.7% and 12.1% had progression. In 57 patients with available brain tumor assessment, complete or partial intracranial response was reported for 35.7% patients and 5.4% had progression. A total of 17 (3.7%) patients with interstitial lung disease (ILD) was reported with no cases of ILD‐related death. Conclusions In this early access program in patients with heavily pretreated HER2‐positive metastatic/unresectable breast cancer, T‐DXd had antitumor activity with a similar response to that reported in previous clinical studies. T‐DXd was well tolerated and no new safety signals were observed.

Abstract Ultra‐wideband (UWB) microwave sources driven by specialised pulsed power generators have experienced a considerable development in the last decade due to their wide domain of new applications such as defence or counter‐terrorism activity. The authors present the main findings of a research dedicated to the development of a pulsed power‐driven electromagnetic field source for disabling improvised explosive devices (IED). The pulsed power generator driving the source is a 13‐stage compact Marx producing voltage pulses reaching an amplitude of 0.5 MV, with a pulse repetition frequency (PRF) of up to 100 Hz. The generator is coupled to a bipolar pulse forming line, providing bipolar pulses with a dV/dt of around 1.6 MV/ns. This pulsed power system feeds an array composed of 16 Koshelev‐type UWB antennas through an impedance matching transformer. The resulting electromagnetic source is capable to produce pulsed electric fields (PEFs) having a figure‐of‐merit (FOM) of 1 MV. First, practical experiments were carried out to study the effects of the PEFs on targets. The targets used in the present study are M2B type flashbulbs, known to have the same susceptibility as the US army M6 detonator. Different configurations of wires (shielded, twisted, etc) with different lengths were used in connecting items inside these targets. The tests were performed by placing the flashbulbs at different distances to determine the essential parameters (i.e., amplitude, duration, and frequency range) of the PEFs required to trigger them. An overview of the experimental campaign and the main findings are also presented followed by conclusions.

Abstract Objective The stroke risk for persons living with human immunodeficiency virus (PLHIVs) doubled compared to uninfected individuals. Stroke‐unit (SU)—access, acute reperfusion therapy—use and outcome data on PLHIVs admitted for acute ischemic stroke (AIS) are scarce. Methods AIS patients admitted (01 January 2017 to 31 January 2021) to 10 representative Paris‐area SUs were screened retrospectively from the National Hospitalization Database. PLHIVs were compared to age‐, initial NIHSS‐ and sex‐matched HIV‐uninfected controls (HUCs). Outcome was the 90‐day modified Rankin Scale score. Results Among 126 PLHIVs with confirmed first‐ever AIS, ~80% were admitted outside the thrombolysis‐administration window. Despite antiretrovirals, uncontrolled plasma HIV loads exceeded 50 copies/mL (26% of all PLHIVs; 38% of those ≤55 years). PLHIVs' stroke causes by decreasing frequency were large artery atherosclerosis (LAA), undetermined, other cause, cerebral small‐vessel disease (CSVD) or cardioembolism. No stroke etiology was associated with HIV duration or detectable HIVemia. MRI revealed previously unknown AIS in one in three PLHIVs, twice the HUC rate (p = 0.006). Neither group had optimally controlled modifiable cardiovascular risk factors (CVRFs): 20%–30% without specific hypertension, diabetes, and/or dyslipidemia treatments. Their stroke outcomes were comparable. Multivariable analyses retained good prognosis associated solely with initial NIHSS or reperfusion therapy. Older age and hypertension were associated with CSVD/LAA for all PLHIVs. Standard neurovascular care and reperfusion therapy were well‐tolerated. Interpretation The high uncontrolled HIV‐infection rate and suboptimal CVRF treatment support heightened vigilance to counter suboptimal HIV suppression and antiretroviral adherence, and improve CVRF prevention, mainly for younger PLHIVs. Those preventive, routine measures could lower PLHIVs' AIS risk.

Abstract Quantitative ecosystem‐based management typically relies on hypothetical ecosystem models that are difficult to validate for all but the best‐studied systems. Here, we develop a management scheme that is based on predictive models driven by the observed dynamics. We show that near‐optimal management policies can be constructed from time‐series data by merging empirical dynamic modelling and stochastic dynamic programming. The Empirical Dynamic Programming approach performs well in cases we examined and outperformed a commonly used single‐species alternative. We expect model‐free ecosystem‐based management to be of use wherever ecosystem dynamics are uncertain or observations of the system do not cover all relevant species.

Abstract According to the review of the literature, rubella virus‐related granuloma is an entity first described in 2014 mainly affecting children with primary immune deficiencies infected with the rubella vaccine strain. The development of rubella virus‐associated granulomas seems to be related to a defect in cellular immunity and their severity varies from a simple cutaneous lesion to deep visceral involvement in some patients. Since then, this type of granuloma has been described in immunocompetent adults, including two cases involving a wild‐type strain of the virus (genotype 2). We report the case of a 70‐year‐old man had suffered from a granuloma of the leg for almost 40 years, in the absence of immunodeficiency. The assessment of the skin granuloma revealed a positive polymerase chain reaction for a wild‐type rubella virus genotype 1a. Genetic studies performed using whole exome sequencing suggest that the disease is due to a homozygous splice site mutation in the ITK gene.

Abstract Background Breast cancer patients are commonly treated with sequential administrations of epirubicin–cyclophosphamide (EC) and paclitaxel (TAX). The chronic effect of this treatment induces skeletal muscle alterations, but the specific effect of each chemotherapy agent is unknown. This study aimed to investigate the effect of EC or TAX administration on skeletal muscle homeostasis in breast cancer patients. Methods Twenty early breast cancer patients undergoing EC followed by TAX chemotherapies were included. Two groups of 10 women were established and performed vastus lateralis skeletal muscle biopsies either before the first administration (pre) of EC (50 ± 14 years) or TAX (50 ± 16 years) and 4 days later (post). Mitochondrial respiratory capacity recording, reactive oxygen species production, western blotting and histological analyses were performed. Results Decrease in muscle fibres cross‐sectional area was only observed post‐EC (−25%; P

Abstract Purpose To investigate the healing of the quadriceps tendon donor site after partial thickness graft harvesting through ultrasound imaging at a short‐term follow‐up of 6‐month following anterior cruciate ligament reconstruction (ACLR) and to investigate the clinical outcomes. Methods Between March 2019 and August 2020, 61 knees were retrospectively included in this study. Intraoperatively, the length, width and thickness of the harvested QT graft were measured. At a 6‐month follow‐up, patients were assessed by one of five radiologists, following the same protocol to calculate the defect volume, and patients performed a self‐evaluation of pain on the Visual Analogue Scale, International Knee Documentation Committee (IKDC) and the Knee injury and Osteoarthritis Outcome Scores (KOOS). Results Intraoperatively, the QT grafts had a volume of 4635.4 ± 912.5 mm3. Postoperatively, ultrasound was performed at 6.5 ± 0.7 months, and the defect volume was 323.3 ± 389.2 mm3, representing a healing rate of 93% ± 9% of the donor site. At a minimum 6‐month follow‐up, IKDC was 61.6 ± 16 and KOOS was 70.2 ± 16.6. Age was significantly associated with the healing rate (β: −0.005; p = 0.032). Conclusion At 6 months follow‐up, the defect size of the QT donor site had healed by 93 ± 9% leaving a mean defect volume of 323.3 mm3 according to ultrasound measurements. This suggests that the QT has a high capacity for healing after graft harvesting, with 10 patients reaching full defect closure 6 months after surgery. The clinical relevance of these findings is that the quadriceps tendon donor site has high rates of healing, but surgeons should be aware of lower healing rates in older patients. Level of Evidence Level IV, retrospective case series.

Abstract The hyperdiverse wood‐inhabiting fungi play a crucial role in the global carbon cycle, but often are threatened by deadwood removal, particularly in temperate forests dominated by European beech (Fagus sylvatica) and Oriental beech (Fagus orientalis). To study the impact of abiotic drivers, deadwood factors, forest management and biogeographical patterns in forests of both beech species on fungal composition and diversity, we collected 215 deadwood‐drilling samples in 18 forests from France to Armenia and identified fungi by meta‐barcoding. In our analyses, we distinguished the patterns driven by rare, common, and dominant species using Hill numbers. Despite a broad overlap in species, the fungal composition with focus on rare species was determined by Fagus species, deadwood type, deadwood diameter, precipitation, temperature, and management status in decreasing order. Shifting the focus on common and dominant species, only Fagus species, both climate variables and deadwood type remained. The richness of species within the deadwood objects increased significantly only with decay stage. Gamma diversity in European beech forests was higher than in Oriental beech forests. We revealed the highest gamma diversity for old‐growth forests of European beech when focusing on dominant species. Our results implicate that deadwood retention efforts, focusing on dominant fungi species, critical for the decay process, should be distributed across precipitation and temperature gradients and both Fagus species. Strategies focusing on rare species should additionally focus on different diameters and on the conservation of old‐growth forests.

Abstract Macroclimatic data are widely used to estimate the realized environmental niche of species and predict the current or the future spatial distribution of species. Because the realized niche is a subset of the fundamental niche—constrained by biotic interactions and dispersal limitations—proxies of the fundamental niche (e.g., thermal limits obtained from physiological experiments) are sometimes combined with macroclimatic data under the assumption that areas predicted as unsuitable from a realized niche perspective may belong to the species' fundamental niche. However, it is unclear whether this assumption is valid and whether thermal limits can be combined with macroclimatic data. Here, we explored these questions using available physiological thermal limits measured for 151 ectotherms. Specifically, we explored whether physiological thermal limits are larger than observed (realized) thermal limits measured using macroclimatic data, and what would be the effect of considering the physiological niche in addition to the realized niche for current and future predictions. Our results confirm previously raised concerns, as physiological limits can delimit a narrower range of thermal tolerance than the realized niche, particularly at the cold end of the thermal gradient where adaptive and/or facilitative mechanisms could allow species to survive in temperatures below physiological limits. These findings show that combining data on physiological thermal limits with macroclimatic data is dubious and that spatial predictions should be interpreted with caution because data on physiological thermal limits do not fit well with macroclimatic data that do not capture the conditions that organisms experience in the wild. While estimated physiological thermal limits are likely of value to complement species distribution studies, they are likely more useful in biophysical models that account for additional processes including the animal's behavior.

Abstract INTRODUCTION To eliminate cervical cancer (CC), access to and quality of prevention and care services must be monitored, particularly for women living with HIV (WLHIV). We assessed implementation practices in HIV clinics across sub‐Saharan Africa (SSA) to identify gaps in the care cascade and used aggregated patient data to populate cascades for WLHIV attending HIV clinics. METHODS Our facility‐based survey was administered between November 2020 and July 2021 in 30 HIV clinics across SSA that participate in the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. We performed a qualitative site‐level assessment of CC prevention and care services and analysed data from routine care of WLHIV in SSA. RESULTS Human papillomavirus (HPV) vaccination was offered in 33% of sites. Referral for CC diagnosis (42%) and treatment (70%) was common, but not free at about 50% of sites. Most sites had electronic health information systems (90%), but data to inform indicators to monitor global targets for CC elimination in WLHIV were not routinely collected in these sites. Data were collected routinely in only 36% of sites that offered HPV vaccination, 33% of sites that offered cervical screening and 20% of sites that offered pre‐cancer and CC treatment. CONCLUSIONS Though CC prevention and care services have long been available in some HIV clinics across SSA, patient and programme monitoring need to be improved. Countries should consider leveraging their existing health information systems and use monitoring tools provided by the World Health Organization to improve CC prevention programmes and access, and to track their progress towards the goal of eliminating CC.

Abstract Extracellular vesicles have gained wide momentum as potential therapeutics for osteoarthritis, a highly prevalent chronic disease that still lacks an approved treatment. The membrane‐bound vesicles are secreted by all cells carrying different cargos that can serve as both disease biomarkers and disease modifiers. Nonetheless, despite a significant peak in research regarding EVs as OA therapeutics, clinical implementation seems distant. In addition to scalability and standardization challenges, researchers often omit to focus on and consider the proper tropism of the vesicles, the practicality and relevance of their source, their low native therapeutic efficacy, and whether they address the disease as a whole. These considerations are necessary to better understand EVs in a clinical light and have been comprehensively discussed and ultimately summarized in this review into a conceptualized framework termed the nanodiamond concept. Future perspectives are also discussed, and alternatives are presented to address some of the challenges and concerns.

Abstract The liver plays a key role in the metabolism of lipoproteins, controlling both production and catabolism. To accelerate the development of new lipid‐lowering therapies in humans, it is essential to have a relevant in vitro study model available. The current hepatocyte‐like cells (HLCs) models derived from hiPSC can be used to model many genetically driven diseases but require further improvement to better recapitulate the complexity of liver functions. Here, we aimed to improve the maturation of HLCs using a three‐dimensional (3D) approach using Biomimesys®, a hyaluronic acid‐based hydroscaffold in which hiPSCs may directly form aggregates and differentiate toward a functional liver organoid model. After a 28‐day differentiation 3D protocol, we showed that many hepatic genes were upregulated in the 3D model (liver organoids) in comparison with the 2D model (HLCs). Liver organoids, grown on Biomimesys®, exhibited an autonomous cell organization, were composed of different cell types and displayed enhanced cytochromes P450 activities compared to HLCs. Regarding the functional capacities of these organoids, we showed that they were able to accumulate lipids (hepatic steatosis), internalize low‐density lipoprotein and secrete apolipoprotein B. Interestingly, we showed for the first time that this model was also able to produce apolipoprotein (a), the apolipoprotein (a) specific of Lp(a). This innovative hiPSC‐derived liver organoid model may serve as a relevant model for studying human lipopoprotein metabolism, including Lp(a).

Abstract Andean glaciers are losing mass rapidly but a centennial‐scale context to those rates is lacking. Here we show the extent of >5,500 glaciers during the Little Ice Age chronozone (LIA; c. 1,400 to c. 1,850) and compute an overall area change of −25% from then to year 2000 at an average rate of −36.5 km2 yr−1 or −0.11% yr−1. Glaciers in the Tropical Andes (Peru, Bolivia) have depleted the most; median −56% of LIA area, and the fastest; median −0.16% yr−1. Up to 10 × acceleration in glacier area loss has occurred in Tropical mountain sub‐regions comparing LIA to 2,000 rates to post‐2000 rates. Regional climate controls inter‐regional variability, whereas local factors affect intra‐region glacier response time. Analyzing glacier area change by river basins and by protected areas leads us to suggest that conservation and environmental management strategies should be re‐visited as proglacial areas expand.

Abstract A minequake of magnitude ML 4.1 occurred on 18 May 2020 early in the morning at the LKAB underground iron ore mine in Kiruna, Sweden. This is the largest mining‐induced earthquake in Scandinavia. It generated acoustic signals observed at three infrasound arrays at 9.3 (KRIS, Sweden), 155 (IS37, Norway), and 286 km (ARCI, Norway) distance. We perform full‐waveform focal mechanism inversion based on regional seismic data and local infrasound data. These independently highlight that this event was dominated by a shallow‐depth collapse in agreement with in‐mine seismic station data. However, regional infrasound data cannot inform the inversion process without an accurate model of atmospheric winds and temperatures. Yet, our numerical simulations demonstrate a potential of using local and regional infrasound data to constrain an event's focal mechanism and depth.

Abstract ERK3/MAPK6 activates MAP kinase‐activated protein kinase (MK)‐5 in selected cell types. Male MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in Col1a1 mRNA in response to increased cardiac afterload. In addition, MK5 deficiency impairs cardiac fibroblast function. This study determined the effect of reduced ERK3 on cardiac hypertrophy following transverse aortic constriction (TAC) and fibroblast biology in male mice. Three weeks post‐surgery, ERK3, but not ERK4 or p38α, co‐immunoprecipitated with MK5 from both sham and TAC heart lysates. The increase in left ventricular mass and myocyte diameter was lower in TAC‐ERK3+/− than TAC‐ERK3+/+ hearts, whereas ERK3 haploinsufficiency did not alter systolic or diastolic function. Furthermore, the TAC‐induced increase in Col1a1 mRNA abundance was diminished in ERK3+/− hearts. ERK3 immunoreactivity was detected in atrial and ventricular fibroblasts but not myocytes. In both quiescent fibroblasts and “activated” myofibroblasts isolated from adult mouse heart, siRNA‐mediated knockdown of ERK3 reduced the TGF‐β‐induced increase in Col1a1 mRNA. In addition, intracellular type 1 collagen immunoreactivity was reduced following ERK3 depletion in quiescent fibroblasts but not myofibroblasts. Finally, knocking down ERK3 impaired motility in both atrial and ventricular myofibroblasts. These results suggest that ERK3 plays an important role in multiple aspects of cardiac fibroblast biology.

Abstract Background First‐line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab‐containing regimens in many countries. We report longer‐term follow‐up data. Methods This open‐label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression‐free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD‐L1) expression of ≥1% and then in the overall population. Results A total of 970 patients were randomly assigned. After 29 months of minimum follow‐up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46–0.76]) in patients with tumor cell PD‐L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65–0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48–0.80]) in patients with tumor cell PD‐L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65–0.92]). In patients with tumor cell PD‐L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51–0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79–1.36]). Among all treated patients (n = 936), Grade 3–4 treatment‐related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients. Conclusions Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow‐up, further supporting use as first‐line standard treatment options for patients with advanced ESCC.

Societal Impact Statement The rapidity of evolutionary changes in trees and whether this pace is sufficient to cope with ongoing climatic change are hotly debated issues in ecology today. Climate warming began in the mid‐19th century, after the Little Ice Age (LIA). Monitoring temporal genetic changes during this climatic transition in multicentennial oak populations revealed evidence of fluctuating selection and rapid evolution. These findings suggest that rapid evolution is probably also currently underway. They may lead to management options for operational forestry aiming to stimulate evolutionary mechanisms during the renewal of oak stands and to decrease potential temporal gene flow. Summary Retrospective studies of the evolutionary responses of tree populations to past documented climate change can provide insight into the adaptive responses of these organisms to ongoing environmental changes. We used a retrospective approach to monitor genetic changes over time in multicentennial sessile oak (Quercus petraea L.) forests. We compared the offspring of three age‐structured cohorts (340, 170, and 60 years old, dating from about 1680, 1850, and 1960) spanning the late Little Ice Age and early Anthropocene. The experiment was repeated in three different forests in western France. The offspring were raised in a common garden experiment, with 30 to 53 open‐pollinated families per cohort. We assessed 16 phenotypic traits in the common garden and observed significant shifts between cohorts for growth and phenology‐related traits. These shifts were correlated with differences in the prevailing temperatures in the past and could be interpreted as temporal genetic changes. However, there was no temporal trend for genetic variation. The genetic changes between the cold (late Little Ice Age) and warm (early Anthropocene) periods were mostly opposite for growth and phenology‐related traits. These findings highlight fluctuations of selection and a rapid evolutionary response of tree populations to climatic transitions in the past, suggesting that similar trends may be at work now. We discuss these results in terms of the mode and direction of evolution, and their potential implications for the adaptive management of oak forests.

Abstract We report a case of cutaneous leishmaniasis caused by Leishmania guyanensis with sporotrichoid lymphocutaneous dissemination of the parasite and thrombophlebitic complication in a 32‐year‐old man who had recently travelled to French Guiana. After initial failure of empirical treatment with amphotericin B, the patient evolved favourably on high doses of intramuscular injections of meglumine antimoniate for 2 months. This case illustrates the existence of lymphocutaneous forms and possible thrombophlebitic complications of leishmaniasis. It also highlights the challenges in the management of leishmaniasis, despite the existence of guidelines and a wide therapeutic arsenal.

Abstract Background Cryoballoon ablation is safe and effective for pulmonary vein isolation in patients with symptomatic drug‐refractory paroxysmal atrial fibrillation. To monitor adhesion between the balloon and the pulmonary vein, an alternative technique to pulmonary venography is to analyze changes in the pressure curve. Methods We have described the adhesion level characterized by four types of pressure waveforms. Results These correlated with the extent of contrast agent leakage (Cohen's kappa of 0.81 [IC 95%: 0.63–0.99]). Conclusion Monitoring the venous pressure curve is easy to perform and has the advantage of being able to detect balloon movement during the first few seconds of treatment.

Abstract Background Digital health technologies have expanded tremendously in the last two decades, creating an emerging research and clinical field. They are regarded as cost‐effective, and their use in healthcare is prioritized by many countries. However, the constant evolution of these technologies has led to an abundance of related literature. Thus, we conducted an umbrella review to identify and characterize digital supportive care interventions for patients with cancer and their relatives. Methods A preregistered umbrella review was conducted (PROSPERO registration number CRD42022333110). Five databases were searched (Embase, PsycINFO, PubMed, CINAHL, and the Cochrane Library). To be considered, studies had to be systematic reviews or meta‐analyses, be performed on pediatric or adult patients with cancer or survivors or their relatives, report results on web‐based or app‐based supportive care interventions, and measure psychological, functional, or behavioral variables or quality of life related to cancer. The methodological quality of the studies was assessed using the AMSTAR‐2 tool. Findings Twenty eligible studies were identified. Most of the included studies reported results from adult patients with cancer. Globally, digital interventions were shown to be effective for physical activity in patients with cancer but had mixed results regarding emotional outcomes and quality of life. Additionally, a lack of methodological quality was noted for most of the included reviews. Discussion Digital supportive care interventions could be an effective tool in cancer care for some outcomes. Recommendations have been formulated for further research in this field using adapted methodologies for the development of digital health interventions.

Exportin 1 (XPO1) is the main nuclear export receptor that controls the subcellular trafficking and the functions of major regulatory proteins. XPO1 is overexpressed in various cancers and small inhibitors of nuclear export (SINEs) have been developed to inhibit XPO1. In primary mediastinal B‐cell lymphoma (PMBL) and classical Hodgkin's lymphoma (cHL), the XPO1 gene may be mutated on one nucleotide and encodes the mutant XPO1E571K. To understand the impact of mutation on protein function, we studied the response of PMBL and cHL cells to selinexor, a SINE, and ibrutinib, an inhibitor of Bruton tyrosine kinase. XPO1 mutation renders lymphoma cells more sensitive to selinexor due to a faster degradation of mutant XPO1 compared to the wild‐type. We further showed that a mistrafficking of p65 (RELA) and p52 (NFκB2) transcription factors between the nuclear and cytoplasmic compartments accounts for the response toward ibrutinib. XPO1 mutation may be envisaged as a biomarker of the response of PMBL and cHL cells and other B‐cell hemopathies to SINEs and drugs that target even indirectly the NFκB signaling pathway.

Abstract Aims From a patient and health system perspective, managing worsening heart failure (WHF) as an outpatient has become a priority. Remote management allows early detection of WHF, enabling timely intervention with the aim of preventing hospitalization. The objective of the study was to evaluate the feasibility and safety of remotely managing WHF events using a multiparametric platform. Methods and results All patients enrolled in the heart failure remote management programme of the Bordeaux University Hospital Telemedicine Center between 1 January and 31 December 2021 were included in the study. Follow‐up data were collected until 1 March 2022. Inclusion criteria were chronic heart failure (HF) with New York Heart Association ≥II symptoms and an elevated B‐type natriuretic peptide (BNP > 100 pg/mL or N‐terminal‐pro‐BNP > 1000 pg/mL). Patient assessments were performed remotely and included measurements of body weight, blood pressure, heart rate, symptoms, biochemical parameters, and data from cardiac implantable electronic devices when available. In total, 161 patients (71 ± 11 years old, 79% male) were followed for a mean of 291 ± 66 days with a mean adherence to the remote monitoring system of 80 ± 20%. Over this period, 52 (32.3%) patients had 105 WHF events, of which 66 (63%) were successfully managed remotely, the remaining requiring hospitalization. Freedom from WHF events and hospitalization at 300 days were 66% and 85%, respectively (P

Abstract Background The SARS CoV‐2 pandemic disrupted healthcare systems. We compared the cancer stage for new breast cancers (BCs) before and during the pandemic. Methods We performed a retrospective multicenter cohort study on the data warehouse of Greater Paris University Hospitals (AP‐HP). We identified all female patients newly referred with a BC in 2019 and 2020. We assessed the timeline of their care trajectories, initial tumor stage, and treatment received: BC resection, exclusive systemic therapy, exclusive radiation therapy, or exclusive best supportive care (BSC). We calculated patients' 1‐year overall survival (OS) and compared indicators in 2019 and 2020. Results In 2019 and 2020, 2055 and 1988, new BC patients underwent cancer treatment, and during the two lockdowns, the BC diagnoses varied by −18% and by +23% compared to 2019. De novo metastatic tumors (15% and 15%, p = 0.95), pTNM and ypTNM distributions of 1332 cases with upfront resection and of 296 cases with neoadjuvant therapy did not differ (p = 0.37, p = 0.3). The median times from first multidisciplinary meeting and from diagnosis to treatment of 19 days (interquartile 11–39 days) and 35 days (interquartile 22–65 days) did not differ. Access to plastic surgery (15% and 17%, p = 0.08) and to treatment categories did not vary: tumor resection (73% and 72%), exclusive systemic therapy (13% and 14%), exclusive radiation therapy (9% and 9%), exclusive BSC (5% and 5%) (p = 0.8). Among resected patients, the neoadjuvant therapy rate was lower in 2019 (16%) versus 2020 (20%) (p = 0.02). One‐year OS rates were 99.3% versus 98.9% (HR = 0.96; 95% CI, 0.77–1.2), 72.6% versus 76.6% (HR = 1.28; 95% CI, 0.95–1.72), 96.6% versus 97.8% (HR = 1.09; 95% CI, 0.61–1.94), and 15.5% versus 15.1% (HR = 0.99; 95% CI, 0.72–1.37), in the treatment groups. Conclusions Despite a decrease in the number of new BCs, there was no tumor stage shift, and OS did not vary.