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Abstract Background Diffuse invasion of glioblastoma cells through normal brain tissue is a key contributor to tumor aggressiveness, resistance to conventional therapies, and dismal prognosis in patients. A deeper understanding of how components of the tumor microenvironment (TME) contribute to overall tumor organization and to programs of invasion may reveal opportunities for improved therapeutic strategies. Results Towards this goal, we apply a novel computational workflow to a spatiotemporally profiled GBM xenograft cohort, leveraging the ability to distinguish human tumor from mouse TME to overcome previous limitations in the analysis of diffuse invasion. Our analytic approach, based on unsupervised deconvolution, performs reference-free discovery of cell types and cell activities within the complete GBM ecosystem. We present a comprehensive catalogue of 15 tumor cell programs set within the spatiotemporal context of 90 mouse brain and TME cell types, cell activities, and anatomic structures. Distinct tumor programs related to invasion align with routes of perivascular, white matter, and parenchymal invasion. Furthermore, sub-modules of genes serving as program network hubs are highly prognostic in GBM patients. Conclusion The compendium of programs presented here provides a basis for rational targeting of tumor and/or TME components. We anticipate that our approach will facilitate an ecosystem-level understanding of the immediate and long-term consequences of such perturbations, including the identification of compensatory programs that will inform improved combinatorial therapies.

Abstract Parasitic diseases, particularly malaria (caused by Plasmodium falciparum) and theileriosis (caused by Theileria spp.), profoundly impact global health and the socioeconomic well-being of lower-income countries. Despite recent advances, identifying host metabolic proteins essential for these auxotrophic pathogens remains challenging. Here, we generate a novel metabolic model of human hepatocytes infected with P. falciparum and integrate it with a genome-wide CRISPR knockout screen targeting Theileria-infected cells to pinpoint shared vulnerabilities. We identify key host metabolic enzymes critical for the intracellular survival of both of these lethal hemoparasites. Remarkably, among the metabolic proteins identified by our synergistic approach, we find that host purine and heme biosynthetic enzymes are essential for the intracellular survival of P. falciparum and Theileria, while other host enzymes are only essential under certain metabolic conditions, highlighting P. falciparum’s adaptability and ability to scavenge nutrients selectively. Unexpectedly, host porphyrins emerge as being essential for both parasites. The shared vulnerabilities open new avenues for developing more effective therapies against these debilitating diseases, with the potential for broader applicability in combating apicomplexan infections.

Observations of glacier mass changes are key to understanding the response of glaciers to climate change and related impacts, such as regional runoff, ecosystem changes, and global sea level rise. Spaceborne optical and radar sensors make it possible to quantify glacier elevation changes, and thus multi-annual mass changes, on a regional and global scale. However, estimates from a growing number of studies show a wide range of results with differences often beyond uncertainty bounds. Here, we present the outcome of a community-based inter-comparison experiment using spaceborne optical stereo (ASTER) and synthetic aperture radar interferometry (TanDEM-X) data to estimate elevation changes for defined glaciers and target periods that pose different assessment challenges. Using provided or self-processed digital elevation models (DEMs) for five test sites, 12 research groups provided a total of 97 spaceborne elevation-change datasets using various processing approaches. Validation with airborne data showed that using an ensemble estimate is promising to reduce random errors from different instruments and processing methods but still requires a more comprehensive investigation and correction of systematic errors. We found that scene selection, DEM processing, and co-registration have the biggest impact on the results. Other processing steps, such as treating spatial data voids, differences in survey periods, or radar penetration, can still be important for individual cases. Future research should focus on testing different implementations of individual processing steps (e.g. co-registration) and addressing issues related to temporal corrections, radar penetration, glacier area changes, and density conversion. Finally, there is a clear need for our community to develop best practices, use open, reproducible software, and assess overall uncertainty to enhance inter-comparison and empower physical process insights across glacier elevation-change studies.

Abstract The millions of specimens stored in entomological collections provide a unique opportunity to study historical insect diversity. Current technologies allow to sequence entire genomes of historical specimens and estimate past genetic diversity of present-day endangered species, advancing our understanding of anthropogenic impact on genetic diversity and enabling the implementation of conservation strategies. A limiting challenge is the extraction of historical DNA (hDNA) of adequate quality for sequencing platforms. We tested four hDNA extraction protocols on five body parts of pinned false heath fritillary butterflies, Melitaea diamina, aiming to minimise specimen damage, preserve their scientific value to the collections, and maximise DNA quality and yield for whole-genome re-sequencing. We developed a very effective approach that successfully recovers hDNA appropriate for short-read sequencing from a single leg of pinned specimens using silica-based DNA extraction columns and an extraction buffer that includes SDS, Tris, Proteinase K, EDTA, NaCl, PTB, and DTT. We observed substantial variation in the ratio of nuclear to mitochondrial DNA in extractions from different tissues, indicating that optimal tissue choice depends on project aims and anticipated downstream analyses. We found that sufficient DNA for whole genome re-sequencing can reliably be extracted from a single leg, opening the possibility to monitor changes in genetic diversity maintaining the scientific value of specimens while supporting current and future conservation strategies.

Vegetation structural complexity is an important component of forest ecosystems, influencing biodiversity and functioning. Due to the heterogeneous distribution of vegetation elements, structural complexity underpins ecological dynamics, species composition, microclimate, and habitat diversity. Field measurements and Light Detection and Ranging (LiDAR) data, such as airborne (ALS) and terrestrial (TLS), can assess structural characteristics of forest and agroforestry systems at various spatial scales. This assessment is urgently needed for monitoring ecosystem restoration in degraded lands (e.g., in oil palm landscapes), where it is not well-known how structural measures derived from these different approaches relate to each other. Here, we compared the degree of correlation between individual and multivariate datasets of vegetation structural complexity metrics derived from ALS, TLS, and ground-based inventory approaches. The study was conducted in a 140 ha oil palm monoculture, enriched with 52 plots in the form of tree islands representing agroforestry systems of varying sizes and planted diversity levels in Sumatra, Indonesia. Our datasets comprised 25 ALS, five TLS, and nine ground-based inventory metrics. We studied correlations among metrics related to traditional stand summary, heterogeneity, and vertical and horizontal stand structure. We used principal component analysis for data dimensionality reduction, correlation analysis to quantify the strength of relationships between metrics, and Procrustes analysis to investigate the agreement between datasets. Significant correlations were found between ALS and TLS metrics for canopy density (r = 0.79) and maximum tree height (r = 0.58) and between ALS and ground-based inventory measures of stand heterogeneity and height diversity (r between 0.60 and −0.63). Further, we observed significant agreements between the ordinations of multivariate datasets (r = 0.56 for ALS − TLS; and r = 0.46 for ALS – ground-based inventory). Our findings underline the ability of ALS to capture structural complexity patterns, especially for canopy gap dynamics and vegetation height metrics, as captured by TLS, and for measures of heterogeneity and vertical structure as captured by ground-based inventories. Our study highlights the strength of each approach and underscores the potential of integrating ALS and TLS with ground-based inventories for a comprehensive characterization of vegetation structure in complex agroforestry systems, which can provide guidance for their management and support ecosystem restoration monitoring efforts.

Various scholars have criticized that formal Western thinking was dichotomous and substantialist, leading to an alienation from nature and to its exploitation in industrialized societies. Critics argue that a relational turn towards a more holistic, process-based and relational approach to address the world would be an important step to overcome these problems. Such a relational turn involves a shift towards more flexible and inclusive concepts. We analyse ‘nature’ concepts of local stakeholders in Swiss nature parks to examine whether they contain any relational elements. Indeed, we found that all stakeholders interviewed see themselves as part of nature. Many reported how they experience nature in active processes and see nature as a collaborator and partner. Moreover, they do not strictly separate between natural and cultural elements in their environment. We conclude that a relational turn in environmental policy in Western countries could build on these relational elements in nature concepts of the local population.

Ecologically considerate use of nature (including agriculture) has often been associated with ‘stewardship’ as a human-nature relationship which involves human care, responsibility and accountability and is thus more sustainable than the alternative human-nature relationship of manager of nature. We show that the consideration of nature in agriculture can go further than stewardship by presenting data from qualitative interviews with Swiss Alpine farmers indicating that many of them view their relationship with nature as a form of partnership. Drawing on literature of human-nature partnership, we characterize this relationship by 1) bidirectionality – a give and take between nature and humans–, 2) the understanding of nature as a subject rather than an object and 3) interaction with nature that consists of collaboration rather than giving commands. The mountain farmers expressed all of these features in their farming practices and descriptions of their role in nature. A few farmers even saw their role as subordinates to nature, for which we introduced the new human-nature relationship category of “apprenticeship”. We further suggest that the partnership relation between humans and nature in many respects shares key features with relational values, for instance in its non-centric nature and in its emphasis of the combination of benefits for people with care for nature. In that sense, we aim at combining different accounts of inclusive, non-dichotomous and context-sensitive dealings with nature and we suggest that this combination is applicable also to contexts beyond agriculture.

Summary: Background: Tumour-infiltrating lymphocytes (TILs) are crucial for effective immune checkpoint blockade (ICB) therapy in solid tumours. However, ∼70% of these tumours exhibit poor lymphocyte infiltration, rendering ICB therapies less effective. Methods: We developed a bioinformatics pipeline integrating multiple previously unconsidered factors or datasets, including tumour cell immune-related pathways, copy number variation (CNV), and single tumour cell sequencing data, as well as tumour mRNA-seq data and patient survival data, to identify targets that can potentially improve T cell infiltration and enhance ICB efficacy. Furthermore, we conducted wet-lab experiments and successfully validated one of the top-identified genes. Findings: We applied this pipeline in solid tumours of the Cancer Genome Atlas (TCGA) and identified a set of genes in 18 cancer types that might potentially improve lymphocyte infiltration and ICB efficacy, providing a valuable drug target resource to be further explored. Importantly, we experimentally validated SUN1, which had not been linked to T cell infiltration and ICB therapy previously, but was one of the top-identified gene targets among 3 cancer types based on the pipeline, in a mouse colon cancer syngeneic model. We showed that Sun1 KO could significantly enhance antigen presentation, increase T-cell infiltration, and improve anti-PD1 treatment efficacy. Moreover, with a single-cell multiome analysis, we identified subgene regulatory networks (sub-GRNs) showing Stat proteins play important roles in enhancing the immune-related pathways in Sun1-KO cancer cells. Interpretation: This study not only established a computational pipeline for discovering new gene targets and signalling pathways in cancer cells that block T-cell infiltration, but also provided a gene target pool for further exploration in improving lymphocyte infiltration and ICB efficacy in solid tumours. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Abstract The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP’s potential as a novel therapeutic target.

Recently, capacitive micromachined ultrasound transducers (CMUTs) with long rectangular membranes have demonstrated performance advantages over conventional piezoelectric transducers; however, modeling these CMUT geometries has been limited to computationally burdensome numerical methods. Improved fast modeling methods, such as equivalent circuit models, could help achieve designs with even better performance. The primary obstacle in developing such methods is the lack of tractable methods for computing the radiation impedance of clamped rectangular radiators. This paper presents a method that approximates the velocity profile using a polynomial shape model to rapidly and accurately estimate radiation impedance. The validity of the approximate velocity profile and corresponding radiation impedance calculation was assessed using finite element simulations for a variety of membrane aspect ratios and bias voltages. Our method was evaluated for rectangular radiators with width:length ratios from 1:1 up to 1:25. At all aspect ratios, the radiation resistance was closely modeled. However, when calculating the radiation reactance, our initial approach was only accurate for low aspect ratios. This motivated us to consider an alternative shape model for high aspect ratios, which was more accurate when compared with FEM. To facilitate the development of future rectangular CMUTs, we provide a MATLAB script that quickly calculates radiation impedance using both methods.

Abstract Background Manual wheelchair propulsion is widely accepted to be biomechanically inefficient, with a high prevalence of shoulder pain and injuries among users. Directional control during wheelchair movement is a major, yet largely overlooked source of energy loss: changing direction or maintaining straightforward motion on tilted surfaces requires unilateral braking. This study evaluates the efficiency of a novel steering-by-leaning mechanism that guides wheelchair turning through upper body leaning. Methods 16 full-time wheelchair users and 15 able-bodied novices each completed 12 circuits of an adapted Illinois Agility Test-course that included tilted, straight, slalom, and 180° turning sections in a prototype wheelchair at a self-selected functional speed. Trials were alternated between conventional and steering-by-leaning modes while propulsion forces were recorded via instrumented wheelchair wheels. Time to completion, travelled distance, positive/negative power, and work done, were all calculated to allow comparison of the control modes using repeated measures analysis of variance. Results Substantial average energy reductions of 51% (able-bodied group) and 35% (wheelchair user group) to complete the task were observed when using the steering-by-leaning system. Simultaneously, able-bodied subjects were approximately 23% faster whereby completion times did not differ for wheelchair users. Participants in both groups wheeled some 10% further with the novel system. Differences were most pronounced during turning and on tilted surfaces where the steering-by-leaning system removed the need for braking for directional control. Conclusions Backrest-actuated steering systems on manual wheelchairs can make a meaningful contribution towards reducing shoulder usage while contributing to independent living. Optimisation of propulsion techniques could further improve functional outcomes.

Abstract The goal of oncologic surgeries is complete tumor resection, yet positive margins are frequently found postoperatively using gold standard H&E-stained histology methods. Frozen section analysis is sometimes performed for rapid intraoperative margin evaluation, albeit with known inaccuracies. Here, we introduce a label-free histological imaging method based on an ultraviolet photoacoustic remote sensing and scattering microscope, combined with unsupervised deep learning using a cycle-consistent generative adversarial network for realistic virtual staining. Unstained tissues are scanned at rates of up to 7 mins/cm2, at resolution equivalent to 400x digital histopathology. Quantitative validation suggests strong concordance with conventional histology in benign and malignant prostate and breast tissues. In diagnostic utility studies we demonstrate a mean sensitivity and specificity of 0.96 and 0.91 in breast specimens, and respectively 0.87 and 0.94 in prostate specimens. We also find virtual stain quality is preferred (P = 0.03) compared to frozen section analysis in a blinded survey of pathologists.

Abstract The European cockchafer Melolontha melolontha is an agricultural pest in many European countries. Populations have a synchronized 3 or 4 years life cycle, leading to temporally isolated populations. Despite the economic importance and availability of comprehensive historical as well as current records on cockchafer occurrence, population genomic analyses of M. melolontha are missing. For example, the effects of geographic separation caused by the mountainous terrain of the Alps and of temporal isolation on the genomic structure of M. melolontha still remain unknown. To address this gap, we genotyped 475 M. melolontha adults collected during 3 years from 35 sites in a central Alpine region. Subsequent population structure analyses discriminated two main genetic clusters, i.e., the South Tyrol cluster including collections located southeast of the Alpine mountain range, and a northwestern alpine cluster with all the other collections, reflecting distinct evolutionary history and geographic barriers. The “passo di Resia” linking South and North Tyrol represented a regional contact zone of the two genetic clusters, highlighting genomic differentiation between the collections from the northern and southern regions. Although the collections from northwestern Italy were assigned to the northwestern alpine genetic cluster, they displayed evidence of admixture with the South Tyrolean genetic cluster, suggesting shared ancestry. A linear mixed model confirmed that both geographic distance and, to a lower extent, also temporal isolation had a significant effect on the genetic distance among M. melolontha populations. These effects may be attributed to limited dispersal capacity and reproductive isolation resulting from synchronized and non‐synchronized swarming flights, respectively. This study contributes to the understanding of the phylogeography of an organism that is recognized as an agricultural problem and provides significant information on the population genomics of insect species with prolonged temporally shifted and locally synchronized life cycles.

Abstract Enhancing biodiversity in monoculture-dominated landscapes is a key sustainability challenge that requires considering the spatial organization of ecological communities (beta diversity). Here, we tested whether increasing landscape heterogeneity, through establishing 52 tree islands in an oil-palm landscape, is a suitable restoration strategy to enhance the diversity of six taxa (multi-taxa diversity). Further, we elucidated whether patterns in the spatial distribution of above- and below-ground taxa are related, and their role in shaping multi-taxa beta diversity. After five years, islands enhanced diversity at the landscape scale by fostering unique species (turnover). Partial correlation networks revealed that dissimilarity, in vegetation structural complexity and soil conditions, impacts multi-taxa beta diversity and turnover. In addition, soil fauna, bacteria, and fungi were more strongly associated with the overall community than aboveground taxa. Thus, strategies aiming to enhance multi-taxa diversity should consider the central role of landscape heterogeneity and soil biota.

Disability and mental ill-health may be especially prevalent in Somalia, largely due to a protracted armed conflict and its consequent humanitarian crises. Little, if any, research to date, however, has simultaneously explored disability- and mental health-related factors in the Somali context. Using both descriptive and regression analytical techniques, we aimed to determine how increasing levels of functional impairment reported across different disability domains (i.e., visual, hearing and cognition), number of concomitant disabilities, and other empirically supported variables (such as employment and sex) are associated with the likelihood of self-identifying the need for mental health support among a sample (N = 1,355) of Somalis with disabilities, as well as identify the common barriers to such support. Despite most participants self-identifying a need for mental health support, only 15% were able to access it, with the most common barriers being the cost of services and the unavailability of local services. Being female, married, and having increasing levels of functional difficulty in the cognitive, mobility and self-care domains of disability were each significantly associated with an increased likelihood of the self-identified need for mental health support. This study’s findings highlight potential points of prioritisation for mental health policy and programming in Somalia. A Somali version of this abstract can be found in the Supplementary Material.

Depuis l’adoption des recommandations de la CDIP concernant l’enseignement des langues au primaire en 1975, les conditions pour une mise en oeuvre et une harmonisation réussie de l’enseignement précoce des langues étrangères n‘ont toujours pas été réunies. Le problème a par ailleurs été encore aggravé par l‘introduction de l’anglais comme troisième langue puis plus récemment par les mesures d’économies mises en place. Pourtant, nous montrerons que le soutien massif du gouvernement fédéral ainsi que des organisations faîtières des enseignants a permis d’éviter un affaiblissement des langues nationales et de trop grandes divergences entre les cantons. Enfin, nous jetterons un regard en arrière et montrerons que le scepticisme des enseignants de l’époque appparait aujourd‘hui légitime: De l’enseignement ludique promis, nous sommes en effet passés à des branches de certification.

Background Falls can strongly impact older people’s quality of life, health, and lifestyle. Multifactorial assessment can determine an individual’s risk of falling as the first step for fall prevention intervention. Physiotherapists have an essential role to play in assessing fall risk by older adults living in the community. In the absence of published data on this topic in Switzerland, this study investigated the current practices of physiotherapists to determine whether those are in line with recommendations. Methods An anonymous cross-sectional survey was undertaken among physiotherapists practising in Switzerland between the 21st of November and the 31st of December 2020. A priori and exploratory hypotheses were tested. Responses to open-ended questions were grouped into themes for analysis. Results A total of 938 questionnaires from all three language regions of Switzerland was analysed. Participants worked in different settings, with a higher representation of private practice self-employees (56%). Standardised fall risk assessments or instruments were used by 580 (62%) participants, while 235 (25%) preferred subjective assessment of fall risk only. Differences in fall risk assessment were observed according to the workplace setting (adjusted OR 1.93, 95% CI 1.37 to 2.7) and education level (trend test, p

Abstract Self-renewal is a crucial property of glioblastoma cells that is enabled by the choreographed functions of chromatin regulators and transcription factors. Identifying targetable epigenetic mechanisms of self-renewal could therefore represent an important step toward developing effective treatments for this universally lethal cancer. Here we uncover an epigenetic axis of self-renewal mediated by the histone variant macroH2A2. With omics and functional assays deploying patient-derived in vitro and in vivo models, we show that macroH2A2 shapes chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal. macroH2A2 also sensitizes cells to small molecule-mediated cell death via activation of a viral mimicry response. Consistent with these results, our analyses of clinical cohorts indicate that high transcriptional levels of this histone variant are associated with better prognosis of high-grade glioma patients. Our results reveal a targetable epigenetic mechanism of self-renewal controlled by macroH2A2 and suggest additional treatment approaches for glioblastoma patients.

Abstract Background Postpartum home-based midwifery care is covered by basic health insurance in Switzerland for all families with newborns but must be self-organized. To ensure access for all, Familystart, a network of self-employed midwives, launched a new care model in 2012 by ensuring the transition from hospital to home through cooperation with maternity hospitals in the Basel area. It has particularly improved the access to follow-up care for families in vulnerable situations needing support beyond basic services. In 2018, the SORGSAM (Support at the Start of Life) project was initiated by Familystart to enhance parental resources for better postpartum health outcomes for mothers and children through offering improved assistance to psychosocially and economically disadvantaged families. First, midwives have access to first-line telephone support to discuss challenging situations and required actions. Second, the SORGSAM hardship fund provides financial compensation to midwives for services not covered by basic health insurance. Third, women receive financial emergency support from the hardship fund. Aim The aim was to explore how women living in vulnerable family situations experienced the new early postpartum home-based midwifery care model provided in the context of the SORGSAM project, and how they experienced its impact. Methods Findings are reported from the qualitative part of the mixed-methods evaluation of the SORGSAM project. They are based on the results of seven semi-structured interviews with women who, due to a vulnerable family postpartum situation at home, received the SORGSAM support. Data were analyzed following thematic analysis. Results Interviewed women experienced the early postpartum care at home, as “relieving and strengthening” in that midwives coordinated patient care that opened up access to appropriate community-based support services. The mothers expressed that they felt a reduction in stress, an increase in resilience, enhanced mothering skills, and greater parental resources. These were attributed to familiar and trusting relationships with their midwives where participants acknowledged deep gratitude. Conclusion The findings show the high acceptance of the new early postpartum midwifery care model. These indicate how such a care model can improve the well-being of women in vulnerable family situations and may prevent early chronic stress in children.

The Earth climate system is out of energy balance, and heat has accumulated continuously over the past decades, warming the ocean, the land, the cryosphere, and the atmosphere. According to the Sixth Assessment Report by Working Group I of the Intergovernmental Panel on Climate Change, this planetary warming over multiple decades is human-driven and results in unprecedented and committed changes to the Earth system, with adverse impacts for ecosystems and human systems. The Earth heat inventory provides a measure of the Earth energy imbalance (EEI) and allows for quantifying how much heat has accumulated in the Earth system, as well as where the heat is stored. Here we show that the Earth system has continued to accumulate heat, with 381±61 ZJ accumulated from 1971 to 2020. This is equivalent to a heating rate (i.e., the EEI) of 0.48±0.1 W m−2. The majority, about 89 %, of this heat is stored in the ocean, followed by about 6 % on land, 1 % in the atmosphere, and about 4 % available for melting the cryosphere. Over the most recent period (2006–2020), the EEI amounts to 0.76±0.2 W m−2. The Earth energy imbalance is the most fundamental global climate indicator that the scientific community and the public can use as the measure of how well the world is doing in the task of bringing anthropogenic climate change under control. Moreover, this indicator is highly complementary to other established ones like global mean surface temperature as it represents a robust measure of the rate of climate change and its future commitment. We call for an implementation of the Earth energy imbalance into the Paris Agreement's Global Stocktake based on best available science. The Earth heat inventory in this study, updated from von Schuckmann et al. (2020), is underpinned by worldwide multidisciplinary collaboration and demonstrates the critical importance of concerted international efforts for climate change monitoring and community-based recommendations and we also call for urgently needed actions for enabling continuity, archiving, rescuing, and calibrating efforts to assure improved and long-term monitoring capacity of the global climate observing system. The data for the Earth heat inventory are publicly available, and more details are provided in Table 4.

Glacier monitoring has been internationally coordinated for more than 125 years. Despite this long history, there is no authoritative answer to the popular question: ‘Which glaciers are the largest in the world?’ Here, we present the first systematic assessment of this question and identify the largest glaciers in the world – distinct from the two ice sheets in Greenland and Antarctica but including the glaciers on the Antarctic Peninsula. We identify the largest glaciers in two domains: on each of the seven geographical continents and in the 19 first-order glacier regions defined by the Global Terrestrial Network for Glaciers. Ranking glaciers by area is non-trivial. It depends on how a glacier is defined and mapped and also requires differentiating between a glacier and a glacier complex, i.e. glaciers that meet at ice divides such as ice caps and icefields. It also depends on the availability of a homogenized global glacier inventory. Using separate rankings for glaciers and glacier complexes, we find that the largest glacier complexes have areas on the order of tens of thousands of square kilometers whereas the largest glaciers are several thousands of square kilometers. The world's largest glaciers and glacier complexes are located in the Antarctic, Arctic and Patagonia.

Patients with metastatic renal cell cancer (mRCC) who respond to upfront immune checkpoint inhibitor (ICI) combination therapies may be treated with cytoreductive nephrectomy (CN) to remove radiographically viable primary tumors. Early data for post-ICI CN suggested that ICI therapies induce desmoplastic reactions in some patients, increasing the risk of surgical complications and perioperative mortality. We evaluated perioperative outcomes for 75 consecutive patients treated with post-ICI CN at four institutions from 2017 to 2022. Our cohort of 75 patients had minimal or no residual metastatic disease but radiographically enhancing primary tumors after ICI and were treated with CN. Intraoperative complications were identified in 3/75 patients (4%) and 90-d postoperative complications in 19/75 (25%), including two patients (3%) with high-grade (Clavien ≥III) complications. One patient was readmitted within 30 d. No patients died within 90 d after surgery. Viable tumor was present in all but one specimen. Approximately half of the patients (36/75, 48%) remained off systemic therapy at last follow-up. These data suggest that CN following ICI therapy is safe and associated with low rates of major postoperative complications in appropriately selected patients at experienced centers. Post-ICI CN may facilitate observation without additional systemic therapy in patients without significant residual metastatic disease. Patient summary: Current first-line treatment for patients with kidney cancer that has spread to other sites (metastatic cancer) is immunotherapy. For cases in which metastatic sites respond to this therapy but primary tumor is still detected in the kidney, surgical treatment of the tumor is feasible and has a low rate of complications, and may delay the need for further chemotherapy.

Introduction and Objective: Muscle invasive bladder cancer with extravesical extension is an aggressive disease entity that requires multimodal therapy. The benefits of adjuvant chemotherapy (AC) in patients with a positive soft-tissue surgical margin (STSM), however, are relatively unknown due to exclusion of this population in randomized controlled trials of AC. We sought to define survival benefits in this patient population through our institutional bladder cancer database. Methods: Retrospective review of all patients undergoing radical cystectomy for urothelial carcinoma of the bladder from 2004–2020 with ≥pT3b disease irrespective of neoadjuvant chemotherapy (NAC) use was conducted. Progression-free survival (PFS) and overall survival (OS) estimates were obtained using the Kaplan-Meier method with log-rank test, and the Cox-proportional hazards model was used to identify predictors of improved PFS and OS. AC was defined by any chemotherapy use within 90 days of cystectomy, regardless of STSM status. Results: 476 patients with pT3b disease or worse were identified. Median follow-up was 12.3 months. An amount of 21% of patients were treated with AC. An amount of 24% of patients had positive STSM. Median OS for patients with positive STSM was 8.4 months [95% CI 7–11.5] and 18.3 months [95% CI 15.6–20.8] (p < 0.001) for patients with negative STSM. In the overall cohort, positive STSM (HR 1.93, 95% CI 1.45–2.57, p < 0.001), AC use (HR 0.68, 95% CI 0.51–0.90, p = 0.007), and pN1–3 disease (HR 1.47, 95% CI 1.16–1.87, p = 0.002) were independent predictors of OS when adjusted for performance status, pT-stage, and neoadjuvant chemotherapy use. In patients with positive STSM, median survival was seven months [95% CI 5.2–8.4] without AC, compared to 16.2 months [95% CI 11.5–52.5] with AC (p = 0.0038). For patients with negative STSM, median survival was 17.4 months [95% CI 14–20.1] without AC compared to 22.3 months [95% CI 17.2–36.9] with AC (p = 0.23). In patients with positive STSM, AC use was the only factor associated with an OS benefit with a HR of 0.41 (95% CI 0.21–0.78, p = 0.007). In patients with negative STSM, pT4 and pN1–3 disease were the only factors associated with worse overall survival with a HR of 1.32 (95% CI 1.00–1.74, p = 0.050) and 1.97 (95% CI 1.49–2.60, p < 0.001), respectively. Conclusions: Administration of adjuvant chemotherapy is of particular benefit in patients with positive STSM following radical cystectomy for gross extravesical disease. Positive STSM may be a representative of “early metastatic” or micrometastatic disease.