Search

Abstract Effective approaches are needed to conserve the planet's remaining wildlife and wilderness landscapes, especially concerning global biodiversity conservation targets. Here, we present a new software system called EarthRanger: an open‐source platform built to help monitor, research and manage ecosystems. EarthRanger consists of seven main components (Core Server, API, Storage, Gundi, Web App, Mobile App, Ecoscope) that provide functionality for data (i) aggregation & collection, (ii) storage & management, (iii) real‐time and post hoc analysis, (iv) visualisation and (v) dissemination. The mobile application provides field‐based data recording and visualisation tools. EarthRanger may be deployed for single project use or can aggregate across multiple geographies as a centralised hub. EarthRanger can be used to collect standardised tracking data (e.g. from wildlife collars, vehicles and ranger patrols) and configurable event information (e.g. a singular recording with associated user‐defined attribute information such as a wildlife sighting or encounter with a poacher). Since development began in 2015, the platform has (at the time of writing) been deployed at over 500 sites across 70 countries and with myriad configurations and objectives. EarthRanger has improved the ability to monitor data feeds and manage conservation‐related operations in real time. For instance, the deployment of EarthRanger by African Parks has led to the removal of over 50,000 snares, steady population growth of key species of concern and near cessation of poaching. In Liwonde's protected area, enhanced mitigation efforts supported by EarthRanger reduced the number of deaths from wildlife conflict by more than 91%. EarthRanger is also providing a platform to enhance standardisation, aggregation, transfer and long‐term storage of ecological information and promote collaboration between groups conducting protected area management and ecology and biodiversity research.

Abstract Aerobic granular sludge is a compact and efficient biofilm process used for wastewater treatment which has received much attention and is currently being implemented worldwide. The microbial associations and their ecological implications occurring during granule development, especially those involving inter-kingdom interactions, are poorly understood. In this work, we monitored the prokaryote and eukaryote community composition and structure during the granulation of activated sludge for 343 days in a sequencing batch reactor (SBR) and investigated the influence of abiotic and biotic factors on the granule development. Sludge granulation was accomplished with low-wash-out dynamics at long settling times, allowing for the microbial communities to adapt to the SBR environmental conditions. The sludge granulation and associated changes in microbial community structure could be divided into three stages: floccular, intermediate, and granular. The eukaryotic and prokaryotic communities showed parallel successional dynamics, with three main sub-communities identified for each kingdom, dominating in each stage of sludge granulation. Although inter-kingdom interactions were shown to affect community succession during the whole experiment, during granule development random factors like the availability of settlement sites or drift acquired increasing importance. The prokaryotic community was more affected by deterministic factors, including reactor conditions, while the eukaryotic community was to a larger extent shaped by biotic interactions (including inter-kingdom interactions) and stochasticity.

Abstract Background A series of modifiable lifestyle factors, such as diet quality, physical activity, alcohol intake, and smoking, may drive the rising burden of type 2 diabetes (T2DM) among sub-Saharan Africans globally. It is unclear whether epigenetic changes play a mediatory role in the associations between these lifestyle factors and T2DM. We assessed the associations between a comprehensive lifestyle index, DNA methylation and T2DM among Ghanaian adults. Methods We used whole-blood Illumina 450 k DNA methylation data from 713 Ghanaians from the Research on Obesity and Diabetes among African Migrants (RODAM) study. We constructed a comprehensive lifestyle index based on established cut-offs for diet quality, physical activity, alcohol intake, and smoking status. In the T2DM-free discovery cohort (n = 457), linear models were fitted to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) associated with the lifestyle index after adjustment for age, sex, body mass index (BMI), and technical covariates. Associations between the identified DMPs and the primary outcome (T2DM), as well as secondary outcomes (fasting blood glucose (FBG) and HbA1c), were determined via logistic and linear regression models, respectively. Results In the present study population (mean age: 52 ± 10 years; male: 42.6%), the comprehensive lifestyle index showed a significant association with one DMP annotated to an intergenic region on chromosome 7 (false discovery rate (FDR) = 0.024). Others were annotated to ADCY7, SMARCE1, AHRR, LOXL2, and PTBP1 genes. One DMR was identified and annotated to the GFPT2 gene (familywise error rate (FWER) from bumphunter bootstrap = 0.036). None of the DMPs showed significant associations with T2DM; directions of effect were positive for the DMP in the AHRR and inverse for all the other DMPs. Higher methylation of the ADCY7 DMP was associated with higher FBG (p = 0.024); LOXL2 DMP was associated with lower FBG (p = 0.023) and HbA1c (p = 0.049); and PTBP1 DMP was associated with lower HbA1c (p = 0.002). Conclusions In this explorative epigenome-wide association study among Ghanaians, we identified one DMP and DMR associated with a comprehensive lifestyle index not previously associated with individual lifestyle factors. Based on our findings, we infer that lifestyle factors in combination, affect DNA methylation, thereby influencing the risk of T2DM among Ghanaian adults living in different contexts.

Abstract Quantum Computing has emerged as a promising alternative, utilising quantum mechanics for faster computations. This paper explores the nearest neighbour compliance (NNC) Problem in Gate-based Quantum Computers, where quantum gates are constrained to operate on physically adjacent qubits. The NNC problem aims to optimise the insertion of SWAP-gates to ensure compliance with these constraints while minimising their count. This work introduces Quantum Annealing to tackle the NNC problem, proposing two Quadratic Unconstrained Optimisation Problem formulations. The formulations are tested on a contemporary Quantum Annealer, and their performance is compared with previous methods. It shows that the prospect of using Quantum Annealing is promising, however, the current state of the hardware makes that finding the embedding is the limiting factor.

Abstract Background The first 24 h of infection represent a critical time window in interactions between pathogens and host tissue. However, it is not possible to study such early events in human lung during natural infection due to lack of clinical access to tissue this early in infection. We, therefore, applied RNA sequencing to ex vivo cultured human lung tissue explants (HLTE) from patients with emphysema to study global changes in small noncoding RNA, mRNA, and long noncoding RNA (lncRNA, lincRNA) populations during the first 24 h of infection with influenza A virus (IAV), Mycobacterium bovis Bacille Calmette-Guerin (BCG), and Pseudomonas aeruginosa. Results Pseudomonas aeruginosa caused the strongest expression changes and was the only pathogen that notably affected expression of microRNA and PIWI-associated RNA. The major classes of long RNAs (> 100 nt) were represented similarly among the RNAs that were differentially expressed upon infection with the three pathogens (mRNA 77–82%; lncRNA 15–17%; pseudogenes 4–5%), but lnc-DDX60-1, RP11-202G18.1, and lnc-THOC3-2 were part of an RNA signature (additionally containing SNX10 and SLC8A1) specifically associated with IAV infection. IAV infection induced brisk interferon responses, CCL8 being the most strongly upregulated mRNA. Single-cell RNA sequencing identified airway epithelial cells and macrophages as the predominant IAV host cells, but inflammatory responses were also detected in cell types expressing few or no IAV transcripts. Combined analysis of bulk and single-cell RNAseq data identified a set of 6 mRNAs (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) as the core transcriptomic response to IAV infection. The two bacterial pathogens induced qualitatively very similar changes in mRNA expression and predicted signaling pathways, but the magnitude of change was greater in P. aeruginosa infection. Upregulation of GJB2, VNN1, DUSP4, SerpinB7, and IL10, and downregulation of PKMYT1, S100A4, GGTA1P, and SLC22A31 were most strongly associated with bacterial infection. Conclusions Human lung tissue mounted substantially different transcriptomic responses to infection by IAV than by BCG and P. aeruginosa, whereas responses to these two divergent bacterial pathogens were surprisingly similar. This HLTE model should prove useful for RNA-directed pathogenesis research and tissue biomarker discovery during the early phase of infections, both at the tissue and single-cell level.

Abstract Sleep disruption and negative affect are attendant features of many psychiatric and neurological conditions that are often co-morbid including major depressive disorder, generalized anxiety disorder and chronic pain. Whether there is a causal relationship between negative affect and sleep disruption remains unclear. We therefore asked if mechanisms promoting negative affect can disrupt sleep and whether inhibition of pathological negative affect can normalize disrupted sleep. Signaling at the kappa opioid receptor (KOR) elicits dysphoria in humans and aversive conditioning in animals. We tested the possibility that (a) increased KOR signaling in the anterior cingulate cortex (ACC), a brain region associated with negative emotions, would be sufficient to promote both aversiveness and sleep disruption and (b) inhibition of KOR signaling would normalize pathological negative affect and sleep disruption induced by chronic pain. Chemogenetic Gi-mediated inhibition of KOR-expressing ACC neurons produced conditioned place aversion (CPA) as well as sleep fragmentation in naïve mice. CRISPR/Cas9 editing of ACC KOR normalized both the negative affect and sleep disruption elicited by pathological chronic pain while maintaining the physiologically critical sensory features of pain. These findings suggest therapeutic utility of KOR antagonists for treatment of disease conditions that are associated with both negative affect and sleep disturbances.

Abstract Background COVID-19 is primarily considered a respiratory tract infection, but it can also affect the central nervous system (CNS), which can result in long-term sequelae. In contrast to CNS infections by classic neurotropic viruses, SARS-CoV-2 is usually not detected in cerebrospinal fluid (CSF) from patients with COVID-19 with neurological involvement (neuro-COVID), suggesting fundamental differences in pathogenesis. Methods To assess differences in CNS metabolism in neuro-COVID compared to CNS infections with classic neurotropic viruses, we applied a targeted metabolomic analysis of 630 metabolites to CSF from patients with (i) COVID-19 with neurological involvement [n = 16, comprising acute (n = 13) and post-COVID-19 (n = 3)], (ii) viral meningitis, encephalitis, or myelitis (n = 10) due to herpes simplex virus (n = 2), varicella zoster virus (n = 6), enterovirus (n = 1) and tick-borne encephalitis virus (n = 1), and (iii) aseptic neuroinflammation (meningitis, encephalitis, or myelitis) of unknown etiology (n = 21) as additional disease controls. Results Standard CSF parameters indicated absent or low neuroinflammation in neuro-COVID. Indeed, CSF cell count was low in neuro-COVID (median 1 cell/µL, range 0–12) and discriminated it accurately from viral CNS infections (AUC = 0.99) and aseptic neuroinflammation (AUC = 0.98). 32 CSF metabolites passed quality assessment and were included in the analysis. Concentrations of differentially abundant (fold change ≥|1.5|, FDR ≤ 0.05) metabolites were both higher (9 and 5 metabolites) and lower (2 metabolites) in neuro-COVID than in the other two groups. Concentrations of citrulline, ceramide (d18:1/18:0), and methionine were most significantly elevated in neuro-COVID. Remarkably, triglyceride TG(20:1_32:3) was much lower (mean fold change = 0.09 and 0.11) in neuro-COVID than in all viral CNS infections and most aseptic neuroinflammation samples, identifying it as highly accurate biomarker with AUC = 1 and 0.93, respectively. Across all samples, TG(20:1_32:3) concentration correlated only moderately with CSF cell count (ρ = 0.65), protein concentration (ρ = 0.64), and Q-albumin (ρ = 0.48), suggesting that its low levels in neuro-COVID CSF are only partially explained by less pronounced neuroinflammation. Conclusions The results suggest that CNS metabolite responses in neuro-COVID differ fundamentally from viral CNS infections and aseptic neuroinflammation and may be used to discover accurate diagnostic biomarkers in CSF and to gain insights into differences in pathophysiology between neuro-COVID, viral CNS infections and aseptic neuroinflammation.

Background: Perianal rhabdomyosarcoma ((P)RMS) are rare and have a poor prognosis. Data in young children are limited and local therapy is not well defined. Combined brachytherapy and surgery is routinely being used for RMS at other sites in children as it provides good oncologic outcomes and allows for organ-sparing surgery. The objective of this study was to evaluate this combination treatment for local tumor control and organ-sparing surgery in young children with (P)RMS. Methods: A retrospective review of the medical records of all children who underwent surgery and brachytherapy for (P)RMS at our institution since 2009 was conducted. Results: Surgery for (P)RMS was performed in 6 patients at a median age of 19 months (range 8–50). Embryonal RMS was diagnosed in 4 patients and alveolar RMS in 2 patients, of which 1 patient had FOXO1 fusion-positive RMS. All patients underwent postoperative high-dose rate (HDR) brachytherapy. Organ-preserving surgery was achieved in 5 of 6 patients (83 %). In 1 patient, the entire sphincter was infiltrated, making organ-preserving resection impossible. 5 of 6 patients (83 %) exhibited an event-free and overall survival at a median follow-up of 26 months (range 8–107). One patient died due to locoregional recurrence. Complications were urethral leakage in 1 patient followed by urethral stenosis and delayed wound healing and vaginal stenosis in another patient. No patient reported fecal incontinence. Conclusions: Combined treatment with surgery and HDR brachytherapy is feasible in very young children with (P)RMS and leads to a favorable oncologic outcome. Preliminary data show a good functional preservation.

Abstract The deterioration of fibre-reinforced sprayed concrete was studied in the Oslofjord subsea tunnel (Norway). At sites with intrusion of saline groundwater resulting in biofilm growth, the concrete exhibited significant concrete deterioration and steel fibre corrosion. Using amplicon sequencing and shotgun metagenomics, the microbial taxa and surveyed potential microbial mechanisms of concrete degradation at two sites over five years were identified. The concrete beneath the biofilm was investigated with polarised light microscopy, scanning electron microscopy and X-ray diffraction. The oxic environment in the tunnel favoured aerobic oxidation processes in nitrogen, sulfur and metal biogeochemical cycling as evidenced by large abundances of metagenome-assembled genomes (MAGs) with potential for oxidation of nitrogen, sulfur, manganese and iron, observed mild acidification of the concrete, and the presence of manganese- and iron oxides. These results suggest that autotrophic microbial populations involved in the cycling of several elements contributed to the corrosion of steel fibres and acidification causing concrete deterioration.

Abstract Pathogenic changes in gut microbial composition precede the onset of HIV-1 infection in men who have sex with men (MSM). This process is associated with increased levels of systemic inflammatory biomarkers and risk for AIDS development. Using mediation analysis framework, in this report we link the effects of unprotected receptive intercourse among MSM prior to primary HIV-1 infection to higher levels of proinflammatory cytokines sCD14 and sCD163 in plasma and a significant decrease in the abundance of A. muciniphila, B. caccae, B. fragilis, B. uniformis, Bacteroides spp., Butyricimonas spp., and Odoribacter spp., and a potential increase in the abundance of Dehalobacterium spp. and Methanobrevibacter spp. in stools of MSM with the highest number of sexual partners. These differences in microbiota, together with a reduction in the pairwise correlations among commensal and short-chain fatty acid-producing bacteria with a number of sexual partners, support an increase in gut dysbiosis with the number of sexual partners. These results demonstrate the interconnectedness of sexual behavior, immune response, and microbiota composition, notably among MSM participating in high-risk sexual behaviors.

Abstract Quantum fluctuations can inhibit long-range ordering in frustrated magnets and potentially lead to quantum spin liquid (QSL) phases. A prime example are gapless QSLs with emergent U(1) gauge fields, which have been understood to be described in terms of quantum electrodynamics in 2+1 dimension (QED3). Despite several promising candidate materials, however, a complicating factor for their realisation is the presence of other degrees of freedom. In particular lattice distortions can act to relieve magnetic frustration, precipitating conventionally ordered states. In this work, we use field-theoretic arguments as well as extensive numerical simulations to show that the U(1) Dirac QSL on the triangular and kagome lattices exhibits a weak-coupling instability due to the coupling of monopoles of the emergent gauge field to lattice distortions, leading to valence-bond solid ordering. This generalises the spin-Peierls instability of one-dimensional quantum critical spin chains to two-dimensional algebraic QSLs. We study static distortions as well as quantum-mechanical phonons. Even in regimes where the QSL is stable, the singular spin-lattice coupling leads to marked temperature-dependent corrections to the phonon spectrum, which provide salient experimental signatures of spin fractionalisation. We discuss the coupling of QSLs to the lattice as a general tool for their discovery and characterisation.

Abstract Saponins are plant secondary metabolites comprising glycosylated triterpenoids, steroids or steroidal alkaloids with a broad spectrum of toxicity to microbial pathogens and pest organisms that contribute to basal plant defense to biotic attack. Secretion of glycosyl hydrolases that enzymatically convert saponins into less toxic products was thus far the only mechanism reported to enable fungal pathogens to colonize their saponin-containing host plant(s). We studied the mechanisms that the fungus Botrytis cinerea utilizes to be tolerant to well-characterized, structurally related saponins from tomato and Digitalis purpurea. By gene expression studies, comparative genomics, enzyme assays and testing a large panel of fungal (knockout and complemented) mutants, we unraveled four distinct cellular mechanisms that participate in the mitigation of the toxic activity of these saponins and in virulence on saponin-producing host plants. The enzymatic deglycosylation that we identified is novel and unique to this fungus-saponin combination. The other three tolerance mechanisms operate in the fungal membrane and are mediated by protein families that are widely distributed in the fungal kingdom. We present a spatial and temporal model on how these mechanisms jointly confer tolerance to saponins and discuss the repercussions of these findings for other plant pathogenic fungi, as well as human pathogens.

Abstract This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC.

Abstract Background General Movement Assessment (GMA) is recommended for early detection of risk for cerebral palsy but requires trained clinical experts. We aimed to implement home- and hospital-based filming for remote GMA in a Norwegian high-risk infant cohort, as well as evaluating parents’ experiences in filming their infant at home. Methods This knowledge translational study used a prospective cohort design including participants referred to neurodevelopmental follow-up across three sites in the Central Norway Regional Health Authority. Two home films of the fidgety type of general movements were collected between 12+1–14+6 and 15+1–17+6 weeks after term by parents. An additional film was collected at the hospital between 12+1 and 17+6 weeks after term. The instructional guide for all filming was the In-Motion App standards. Videos were transferred to a remote GMA team and classified as either “GMA scorable” or “GMA not scorable” based on Prechtl’s GMA standards. Parents responded to an online survey using a 5-point Likert scale to collect information about their perspectives, experiences, and possible worries by filming their infant at home. Results One-hundred-and-two infants from 95 families participated. Ninety-two (96.8%) families transferred 177 home-based videos. Eighty-four (92%) of these had 95 videos taken in their local hospital. All 177 home-videos were “GMA scorable” and three (3,1%) out of 95 hospital-based videos were classified as “GMA not scorable”. Eight families did not respond to the survey and two families did not receive the survey due to a technical error. Seventy-eight (91.7%) respondents agreed or strongly agreed that it was easy to perform home filming and five (5.9%) agreed that they were more worried about their child`s development after filming at home. Almost 80% of respondents agreed that a video for GMA can be taken at home instead of in hospital. Conclusions This study strengthens the clinical implementation of home filming by parents and remote GMA for early detection of CP in high-risk follow-up programs. The implementation of remote GMA has the potential to facilitate early intervention to improve function in children with CP in line with international recommendations. Trial registration ClinicalTrials.gov ID: NCT04287166 Date of registration: 27/02/2020.

The classification of tree species in urban contexts is pivotal in assessing ecosystem services and fostering sustainable urban development. This paper explores using graph neural networks (GNNs) on graph structure data derived from quantitative structure models (QSMs) and tree structural measurement for appropriate species classification. The study addresses gaps in existing methods by integrating relationships between tree components, such as branches and cylinders, and considering the entire tree structure in a novel graph data format. The results demonstrate the efficacy of GNNs, particularly the Gated Graph Convolutional Network (GatedGCN), in appropriately classifying urban tree species. It gained an overall classification accuracy and weighted F1 score of 0.84. An analysis of confusion matrices revealed similarities in visual characteristics among several species, including A. platanoides and T. cordata, which pose significant challenges in accurately distinguishing between them. However, certain species, such as A. hippocastanum and P. nigra var. italica, have proved easier to classify than others. Furthermore, the results highlight the importance of relationships between different tree components in species recognition, such as the ratio between branch radius and parent branch radius, the factors often overlooked by previous methods. This underscores the novelty and effectiveness of the proposed approach in this study. Future research could explore integrating additional data sources, such as Leaf Area Density (LAD) calculated from LiDAR and hyperspectral data, to enhance classification accuracy. In conclusion, the evaluation results of the GatedGCN model demonstrated its effectiveness in classifying tree species using a novel data structure format derived from QSM tree characteristics. Advancing urban tree species classification through such methods can enhance future urban tree management using automated AI and robotics solutions.

Research-for-development (R4D) refers to research activities specifically designed to address critical social, environmental, and economic challenges and improve human well-being. It is essential to have well-designed indicators to monitor and evaluate progress, guide decision-making, and support learning and improvement. This paper reviews and compares two sets of indicators in use by a large international research consortium: i) ad hoc indicators developed by and for individual (non-pooled) projects, and ii) a standard set of indicators designed as part of a common results framework for a new portfolio of research initiatives. We assess both sets of indicators against the SMART (specific, measurable, achievable, relevant and time-bound) criteria, identify common errors in indicator formulation, compare the thematic coverage of the two sets of indicators, and derive lessons for improved indicator formulation. A large proportion of the non-pooled indicators fail to meet the SMART criteria. The indicators in the standard set are stronger, but with scope for improvement, especially in terms of relationship to the result of interest, specification of the indicator, measurability, standardization of outcome indicators, and impact indicators. We recommend having a balanced set of indicators of key outputs, outcomes, and impacts, based on clear and well-defined result statements.

Aspergillosis causes significant health risks to both birds and mammals. The outcome of these infections is often poor due to delayed diagnosis and treatment failure. We investigated 152 cases of aspergillosis from birds and mammals in Belgium. Most samples originated from the taxonomic orders Artiodactyla (40.1 %) and Columbiformes (19.7 %). Five isolates (3.3 %) showed phenotypical resistance against at least one medical azole. Three of these isolates were pan-azole resistant bearing the TR34/L98H mutation. The predominance of this resistance mutation supports an environmental route for exposure and resistance selection, highlighting the importance of the One Health concept.

The sebaceous gland (SG) is a vital appendage of the epidermis, and its normal homeostasis and function is crucial for effective maintenance of the skin barrier. Notch signaling is a well-known regulator of epidermal differentiation, and has also been shown to be involved in postnatal maintenance of SGs. However, the precise role of Notch signaling in regulating SG differentiation in the adult homeostatic skin remains unclear. While there is evidence to suggest that Notch1 is the primary Notch receptor involved in regulating the differentiation process, the ligand remains unknown. Using monoclonal therapeutic antibodies designed to specifically inhibit of each of the Notch ligands or receptors, we have identified the Jag2/Notch1 signaling axis as the primary regulator of sebocyte differentiation in mouse homeostatic skin. Mature sebocytes are lost upon specific inhibition of the Jag2 ligand or Notch1 receptor, resulting in the accumulation of proliferative stem/progenitor cells in the SG. Strikingly, this phenotype is reversible, as these stem/progenitor cells re-enter differentiation when the inhibition of Notch activity is lifted. Thus, Notch activity promotes correct sebocyte differentiation, and is required to restrict progenitor proliferation.

ABSTRACT Objective This study aims to describe patterns, sources, and reasons for cannabis use among cancer patients during active treatment (+CDTX) compared to no‐use during active treatment (−CDTX). Methods Data are from 385 surveys collected via REDCap during phase I of an ongoing study among adult cancer patients seen at an NCI‐designated comprehensive cancer center within the last 5 years of treatment. A harmonized survey was created with 11 other NCI centers to assess cannabis use patterns, sources, and reasons for use. Sociodemographics and cancer details were also collected via self‐report. Descriptive statistics were calculated and stratified by +/−CDTX. Chi‐squared tests were conducted to compare proportions between groups. Results Among the sample [49.5 years (SD 15.9); 53.0% male; and 41.6% Hispanic/Latino], 41.0% + CDTX and 59.0% −CDTX. A majority (71.8%) of +CDTX initiated use before diagnosis versus 44.1% in −CDTX (p

Abstract Human–elephant conflict is growing in Africa as human populations and development increases, creating disturbance to elephant habitats. Beehive fences have been trialed as a coexistence tool with some success but all studies have looked at small sample sizes over a short time period. Our study analyses the behavior of African elephants (Loxodonta africana) that approached a network of beehive fence protected farms in two conflict villages over 9 years next to Tsavo East National Park. We compare differences in elephant raids and beehive occupation rates annually, during a drought, and during peak crop production seasons. Out of 3999 elephants approaching our study farms 1007 elephants broke the beehive fence and entered the protected farm areas (25.18%). This was significantly less than the 2649 encounters where elephants remained either outside the farm boundary or broke into the control farms (66.24%). A further 343 elephants entered the farm by walking through a gap at the end of a fence (8.56%). The annual beehive fence break‐through rates averaged 23.96% (±SE 3.15) resulting in a mean of 76.04% elephants deterred from beehive fences protected farm plots. Over six peak crop growing seasons the beehive fences kept between 78.3% and 86.3% of elephants out of the farms and crops. The beehive fences produced one ton of honey sold for $2250; however, a drought caused a 75% reduction in hive occupation rates and honey production for 3 years after negatively impacting honey profits and the effectiveness of the fences. Beehive fences are very effective at reducing up to 86.3% of elephant crop‐raids during peak crop seasons after good rainfall, but any increase in elephant habitat disturbance or the frequency and duration of droughts could reduce their effectiveness as a successful coexistence tool.

Ewing sarcoma is the second most common primary malignant bone cancer in children and adolescents. This rare type of cancer is characterized by its high malignancy and therefore high risk of metastases. Typically, Ewing sarcomas originate from bones. However, extraosseous Ewing sarcoma such as pulmonary Ewing sarcoma can also be found. In this case report, we present a 55-year old male patient who was initially diagnosed with non-small cell lung cancer at his local district hospital. However, the diagnosis was changed to one of pulmonary Ewing sarcoma after subsequent histopathological and molecular pathological analysis performed in a reference pathology laboratory. After patient referral to a certified (according to the German Cancer Society) high-volume sarcoma center, multimodal chemotherapy was initiated based on recently published clinical data as opposed to the more commonly used treatment regimen in Europe. The patient responded well to treatment and underwent a complete surgical tumor resection followed by radiotherapy. In summary, this case report highlights the importance of a rigorous and timely histopathological examination of biopsy samples by a specialized cancer center to enable a correct diagnosis of the cancer type. Additionally, molecular pathology plays a crucial part in this analysis and allows the necessary differentiation between cancer types. Up to now, there is no international treatment guideline available for the treatment of Ewing sarcoma. Patients should be referred to specialist centers to allow the best possible treatment of the cancer type in view of current published clinical data. In the case of Ewing sarcoma, and in accordance with the most recent research, patients should be treated with vincristine, doxorubicin and cyclophosphamide plus ifosfamide and etoposide in combination with local treatment such as surgery and/or radiotherapy because this has been demonstrated to be the more effective therapy.

Ion bombardment during inductively coupled plasma reactive-ion etching and ion-implantation introduces irreparable crystalline damage to gallium nitride (GaN) power devices, leading to early breakdown and high leakage current. To circumvent this, a bi-layer selective area growth mask was engineered to grow up to 3.0 µm thick epitaxy of GaN using plasma-assisted molecular beam epitaxy as an ion-damage-free alternative to standard epitaxial processing routes. The masks and regrown architectures are characterized via SEM, conductive-atomic force microscopy (AFM), x-ray photo electron spectroscopy, Raman, and cathodoluminescence. Mask deposition conditions were varied to modulate and minimize the stress induced during thermal cycling. The resulting mesas exhibit low leakage, attributed to naturally terminated sidewalls as measured by an innovative perpendicular AFM measurement of the regrown sidewall. The regrown sidewall exhibited RMS (root mean square) roughness of 1.50 (±0.34) nm and defect density of 1.36 × 106 (±1.11 × 106) cm−2. This work provides a method to eliminate defect-inducing steps from GaN vertical epitaxial processing and stands to enhance GaN as a material platform for high-efficiency power devices.

Recognizing the influence of pathogen diversity on infection dynamics is crucial for mitigating emerging infectious diseases. Characterising such diversity is often complex, for instance when multiple pathogen variants exist that interact differently with the environment and host. Here, we explore genotypic and phenotypic variation of Batrachochytrium salamandrivorans (Bsal), an emerging fungal pathogen that is driving declines among an increasing number of European amphibian species. For thirteen isolates, spanning most of the known temporal and geographical Bsal range in Europe, we mapped phenotypic diversity through numerous measurements that describe varying reproductive rates in vitro across a range of temperatures. Bsal isolates are revealed to have different thermal optima and tolerances, with phenotypic variation correlating with genomic diversity. Using a mechanistic niche model of the fire salamander (Salamandra salamandra) as an example, we illustrate how host steady-state body temperature and Bsal thermal range variation may influence pathogen growth through space and time across Europe. Our combined findings show how the identity of emergent pathogen variants may strongly influence when and which host populations are most at risk.

ABSTRACT Oncorhynchus mykiss is a partially migratory salmonid species, and many migratory populations (known as steelhead) have declined in recent decades in the western United States and Canada. Closely related resident populations (known as rainbow trout) may be an effective resource in the recovery of these declining migratory populations. However, the extent to which different populations of resident rainbow trout produce migratory individuals and how likely these individuals are to return as adults to spawn remains unknown. One limitation to answering these questions is the identification of loci that accurately segregate between migratory and resident populations. To address this limitation, we used existing genomic data from a well‐studied population of O. mykiss from Southeastern Alaska (Sashin Creek) to identify loci that segregate between phenotypes. We then utilized Double Mismatch Allele‐Specific qPCR (DMAS‐qPCR) to genotype 233 smolts out‐migrating from Sashin Creek and 99 returning adult steelhead trout across a five‐year period to determine (a) the origin of out‐migrating smolts and returning adults and (b) to quantify the extent to which the resident population contributes to the migratory population. Our results show that 37.3% of out‐migrating smolts were produced from resident parents, whereas 19.3% of returning adults had resident parents. Ultimately, these results demonstrate that resident populations of rainbow trout produce migrant offspring that successfully complete their migration and return to spawn, increasing population sizes and likely improving genetic diversity. Therefore, conservation efforts should consider landlocked resident populations for producing smolts when developing recovery plans for migratory steelhead populations.

Background Metronomic chemotherapy (‘less is more, regularly’) could be an alternative to the maximum tolerated dose (‘the more, the better’) in the chemotherapeutic cancer treatment of high-risk malignant solid extracranial tumours in children or young adults.Objective To evaluate the efficacy of metronomic chemotherapy compared with placebo or stop treatment in paediatric patients with extracranial malignant solid tumours.Methods We searched the databases MEDLINE and CENTRAL on 8 September 2023 and included randomised clinical trials (RCTs). Primary outcome was overall survival, and the main outcome measure was the HR.Results We identified three RCTs with parallel assignment and intention-to-treat analyses of data from 775 people. The studies primarily reported on participants with rhabdomyosarcoma, neuroblastoma and osteosarcoma. The HR favoured the metronomic chemotherapy group (0.75 (95% CI 0.56 to 0.98)).Conclusions The evidence base is compatible with a favourable effect of metronomic chemotherapy on children and young adults with high-risk extracranial malignant solid tumours, especially other than bone tumours, when compared with placebo or stop treatment. Statistical heterogeneity is low while clinical heterogeneity is substantial. Thus, the results must be interpreted with caution and applicability of the results is limited. Future RCTs could provide more data on individual tumour entities and subsequently add information on tumour-specific responses.PROSPERO registration number CRD42023457195.

Abstract Background Non-invasive brain stimulation (NIBS) is a promising intervention for treatment-resistant schizophrenia. However, there are multiple available techniques and a comprehensive synthesis of evidence is lacking. Thus, we will conduct a systematic review and network meta-analysis to investigate the comparative efficacy and safety of NIBS techniques as an add-on to antipsychotics for treatment-resistant schizophrenia. Methods We will include single- and double-blind randomized-controlled trials (RCT) comparing any NIBS technique with each other or with a control intervention as an add-on to antipsychotics in adult patients with treatment-resistant schizophrenia. We will exclude studies focusing on predominant negative symptoms, maintenance treatment, and single sessions. The primary outcome will be a change in overall symptoms, and secondary outcomes will be a change in symptom domains, cognitive performance, quality of life, functioning, response, dropouts, and side effects. We will search for eligible studies in previous reviews, multiple electronic databases and clinical trial registries from inception onwards. At least two independent reviewers will perform the study selection, data extraction, and risk of bias assessment. We will measure the treatment differences using standardized mean difference (SMD) and odds ratio (OR) for continuous and dichotomous outcomes, respectively. We will conduct pairwise and network meta-analysis within a frequentist framework using a random-effects model, except for rare event outcomes where we will use a fixed-effects Mantel–Haenszel method. We will investigate potential sources of heterogeneity in subgroup analyses. Reporting bias will be assessed with funnel plots and the Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) tool. The certainty in the evidence will be evaluated using the Confidence in Network Meta-analysis (CINeMA) approach. Discussion Our network meta-analysis would provide an up-to-date synthesis of the evidence from all available RCTs on the comparative efficacy and safety of NIBS for treatment-resistant schizophrenia. This information could guide evidence-based clinical practice and improve the outcomes of patients. Systematic review registration PROSPERO-ID CRD42023410645.

Abstract Within the past decade, incremental integration of molecular characteristics into the classification of central nervous system neoplasms increasingly facilitated precise diagnosis and advanced stratification, beyond potentially providing the foundation for advanced targeted therapies. We report a series of three cases of infant-type hemispheric glioma (IHG) involving three infants diagnosed with neuroepithelial tumors of the cerebral hemispheres harboring a novel, recurrent TRIM24::MET fusion. Histopathology showed glial tumors with either low-grade or high-grade characteristics, while molecular characterization found an additional homozygous CDKN2A/B deletion in two cases. Two patients showed leptomeningeal dissemination, while multiple supra- and infratentorial tumor manifestations were found in one case. Following subtotal resection (two cases) and biopsy (one case), treatment intensity of adjuvant chemotherapy regimens did not reflect in the progression patterns within the reported cases. Two patients showed progression after first-line treatment, of which one patient died not responding to tyrosine kinase inhibitor cabozantinib. As the detection of a recurrent TRIM24::MET fusion expands the spectrum of renowned driving fusion genes in IHG, this comparative illustration may indicate a distinct clinico-pathological heterogeneity of tumors bearing this driver alteration. Upfront clinical trials of IHG promoting further characterization and the implementation of individualized therapies involving receptor tyrosine kinase inhibition are required.

Abstract Model‐based acoustic localisation estimates the locations of underwater objects by comparing sensor measurements with model predictions. To obtain high quality predictions, propagation models need to be run for a large set of environmental parameters. However, real‐time Model‐based acoustic localisation estimations using onboard computational resources are often limited. To address this, the authors propose a Quantum annealing (QA) algorithm for enhancing underwater acoustic localisation. A restricted Boltzmann machine (RBM) is trained to predict the probability distribution of underwater targets. Advantage of this approach is that part of the computation is moved to offline‐training. Moreover, the probability distribution can potentially be sampled efficiently using a quantum annealer possibly enabling real‐time accurate target estimations being made onboard.The RBM is applied to a simplified multi‐sensor horizontal localisation problem where a constant and linear acoustic propagation is assumed. Using simulated annealing the authors show that the RBM is able to learn probability distributions that resemble target locations. Preliminary results show that training and sampling the RBM can be done using QA hardware by D‐Wave Systems.However, there remains room for improvement especially in ranging predictions. Further research into possible benefits of QA RBMs is needed to provide theoretical and practical results of a speed‐up.

Background and purpose: MR-guided radiotherapy (MRgRT) online plan adaptation accounts for tumor volume changes, interfraction motion and thus allows daily sparing of relevant organs at risk. Due to the high interfraction variability of bladder and rectum, patients with tumors in the pelvic region may strongly benefit from adaptive MRgRT. Currently, fast automatic annotation of anatomical structures is not available within the online MRgRT workflow. Therefore, the aim of this study was to train and validate a fast, accurate deep learning model for automatic MRI segmentation at the MR-Linac for future implementation in a clinical MRgRT workflow. Materials and methods: For a total of 47 patients, T2w MRI data were acquired on a 1.5 T MR-Linac (Unity, Elekta) on five different days. Prostate, seminal vesicles, rectum, anal canal, bladder, penile bulb, body and bony structures were manually annotated. These training data consisting of 232 data sets in total was used for the generation of a deep learning based autocontouring model and validated on 20 unseen T2w-MRIs. For quantitative evaluation the validation set was contoured by a radiation oncologist as gold standard contours (GSC) and compared in MATLAB to the automatic contours (AIC). For the evaluation, dice similarity coefficients (DSC), and 95% Hausdorff distances (95% HD), added path length (APL) and surface DSC (sDSC) were calculated in a caudal-cranial window of ± 4 cm with respect to the prostate ends. For qualitative evaluation, five radiation oncologists scored the AIC on the possible usage within an online adaptive workflow as follows: (1) no modifications needed, (2) minor adjustments needed, (3) major adjustments/ multiple minor adjustments needed, (4) not usable. Results: The quantitative evaluation revealed a maximum median 95% HD of 6.9 mm for the rectum and minimum median 95% HD of 2.7 mm for the bladder. Maximal and minimal median DSC were detected for bladder with 0.97 and for penile bulb with 0.73, respectively. Using a tolerance level of 3 mm, the highest and lowest sDSC were determined for rectum (0.94) and anal canal (0.68), respectively.Qualitative evaluation resulted in a mean score of 1.2 for AICs over all organs and patients across all expert ratings. For the different autocontoured structures, the highest mean score of 1.0 was observed for anal canal, sacrum, femur left and right, and pelvis left, whereas for prostate the lowest mean score of 2.0 was detected. In total, 80% of the contours were rated be clinically acceptable, 16% to require minor and 4% major adjustments for online adaptive MRgRT. Conclusion: In this study, an AI-based autocontouring was successfully trained for online adaptive MR-guided radiotherapy on the 1.5 T MR-Linac system. The developed model can automatically generate contours accepted by physicians (80%) or only with the need of minor corrections (16%) for the irradiation of primary prostate on the clinically employed sequences.

Abstract The proto-oncogene MYC encodes a nuclear transcription factor that has an important role in a variety of cellular processes, such as cell cycle progression, proliferation, metabolism, adhesion, apoptosis, and therapeutic resistance. MYC amplification is consistently observed in aggressive forms of several solid malignancies and correlates with poor prognosis and distant metastases. While the tumorigenic effects of MYC in patients with head and neck squamous cell carcinoma (HNSCC) are well known, the molecular mechanisms by which the amplification of this gene may confer treatment resistance, especially to immune checkpoint inhibitors, remains under-investigated. Here we present a unique case of a patient with recurrent/metastatic (R/M) HNSCC who, despite initial response to nivolumab-based treatment, developed rapidly progressive metastatic disease after the acquisition of MYC amplification. We conducted comparative transcriptomic analysis of this patient’s tumor at baseline and upon progression to interrogate potential molecular processes through which MYC may confer resistance to immunotherapy and/or chemoradiation and used TCGA-HNSC dataset and an institutional cohort to further explore clinicopathologic features and key molecular networks associated with MYC amplification in HNSCC. This study highlights MYC amplification as a potential mechanism of immune checkpoint inhibitor resistance and suggest its use as a predictive biomarker and potential therapeutic target in R/M HNSCC.

The use of hypofractionated radiotherapy in prostate cancer has been increasingly evaluated, whereas accumulated evidence demonstrates comparable oncologic outcomes and toxicity rates compared to normofractionated radiotherapy. In this prospective study, we evaluate all patients with intermediate-risk prostate cancer treated with ultrahypofractionated (UHF) MRI-guided radiotherapy on a 1.5 T MR-Linac within our department and report on workflow and feasibility, as well as physician-recorded and patient-reported longitudinal toxicity. A total of 23 patients with intermediate-risk prostate cancer treated on the 1.5 T MR-Linac with a dose of 42.7 Gy in seven fractions (seven MV step-and-shoot IMRT) were evaluated within the MRL-01 study (NCT04172753). The duration of each treatment step, choice of workflow (adapt to shape-ATS or adapt to position-ATP) and technical and/or patient-sided treatment failure were recorded for each fraction and patient. Acute and late toxicity were scored according to RTOG and CTC V4.0, as well as the use of patient-reported questionnaires. The median follow-up was 12.4 months. All patients completed the planned treatment. The mean duration of a treatment session was 38.2 min. In total, 165 radiotherapy fractions were delivered. ATS was performed in 150 fractions, 5 fractions were delivered using ATP, and 10 fractions were delivered using both ATS and ATP workflows. Severe acute bother (G3+) regarding IPS-score was reported in five patients (23%) at the end of radiotherapy. However, this tended to normalize and no G3+ IPS-score was observed later at any point during follow-up. Furthermore, no other severe genitourinary (GU) or gastrointestinal (GI) acute or late toxicity was observed. One-year biochemical-free recurrence survival was 100%. We report the excellent feasibility of UHF MR-guided radiotherapy for intermediate-risk prostate cancer patients and acceptable toxicity rates in our preliminary study. Randomized controlled studies with long-term follow-up are warranted to detect possible advantages over current state-of-the-art RT techniques.

Abstract Background Vitamin C deficiency, or scurvy, is rare but poses risks for children with poor diets, limited resources, or malabsorption issues. It may also be common in children with restrictive or selective dietary habits in children with global developmental delay, autism spectrum disorder, and physical disabilities. Symptoms include fatigue, irritability, joint and muscle pain, joint swellings, edema, swollen gums, easy bruising, and delayed wound healing. Early recognition and prompt intervention are essential to prevent the progression of symptomatic vitamin C deficiency in children. Case presentation We present a case of a 13-year-old boy with developmental delay secondary to Lennox Gastaut syndrome referred for suspected recurrent, severe, and atypical IgA vasculitis. He presented with irritability, loss of appetite, petechial and ecchymotic lower limb lesions, unilateral gum swelling, severe arthritis, peripheral oedema, severe weight loss, anaemia, and raised inflammatory markers. Multiple investigations were performed before the diagnosis of scurvy was made. A surgical finding of friable gingival tissue with multiple loose teeth, a skin biopsy with follicular hyperkeratosis and extravasated perifollicular red blood cells, and a typical X-ray finding led to the diagnosis of scurvy. Conclusion Scurvy should be given careful consideration as a differential diagnosis in patients presenting with musculoskeletal issues, mucocutaneous complaints, and constitutional symptoms such as malaise, asthenia, irritability, and loss of appetite. A focused and detailed dietary history looking for a lack of good sources of vitamin C can be an easy indicator of this differential. Imaging studies revealing the typical features can also help make the diagnosis. Pathology of the skin revealing pathognomonic features can add to the certainty of the diagnosis. In the absence of all else, the rapid response to treatment with an appropriate dose of vitamin C has a diagnostic and therapeutic role.

Abstract Sexual dimorphism has been revealed for many neurological disorders including chronic pain. Prelicinal studies and post-mortem analyses from male and female human donors reveal sexual dimorphism of nociceptors at transcript, protein and functional levels suggesting different mechanisms that may promote pain in men and women. Migraine is a common female-prevalent neurological disorder that is characterized by painful and debilitating headache. Prolactin is a neurohormone that circulates at higher levels in females and that has been implicated clinically in migraine. Prolactin sensitizes sensory neurons from female mice, non-human primates and humans revealing a female-selective pain mechanism that is conserved evolutionarily and likely translationally relevant. Prolactin produces female-selective migraine-like pain behaviors in rodents and enhances the release of calcitonin gene-related peptide (CGRP), a neurotransmitter that is causal in promoting migraine in many patients. CGRP, like prolactin, produces female-selective migraine-like pain behaviors. Consistent with these observations, publicly available clinical data indicate that small molecule CGRP-receptor antagonists are preferentially effective in treatment of acute migraine therapy in women. Collectively, these observations support the conclusion of qualitative sex differences promoting migraine pain providing the opportunity to tailor therapies based on patient sex for improved outcomes. Additionally, patient sex should be considered in design of clinical trials for migraine as well as for pain and reassessment of past trials may be warranted.

Abstract The Ice Sheet Model Intercomparison Project for CMIP6 (ISMIP6) is the primary effort of CMIP6 (Coupled Model Intercomparison Project–Phase 6) focusing on ice sheets, designed to provide an ensemble of process‐based projections of the ice‐sheet contribution to sea‐level rise over the twenty‐first century. However, the behavior of the Antarctic Ice Sheet beyond 2100 remains largely unknown: several instability mechanisms can develop on longer time scales, potentially destabilizing large parts of Antarctica. Projections of Antarctic Ice Sheet evolution until 2300 are presented here, using an ensemble of 16 ice‐flow models and forcing from global climate models. Under high‐emission scenarios, the Antarctic sea‐level contribution is limited to less than 30 cm sea‐level equivalent (SLE) by 2100, but increases rapidly thereafter to reach up to 4.4 m SLE by 2300. Simulations including ice‐shelf collapse lead to an additional 1.1 m SLE on average by 2300, and can reach 6.9 m SLE. Widespread retreat is observed on that timescale in most West Antarctic basins, leading to a collapse of large sectors of West Antarctica by 2300 in 30%–40% of the ensemble. While the onset date of retreat varies among ice models, the rate of upstream propagation is highly consistent once retreat begins. Calculations of sea‐level contribution including water density corrections lead to an additional ∼10% sea level and up to 50% for contributions accounting for bedrock uplift in response to ice loading. Overall, these results highlight large sea‐level contributions from Antarctica and suggest that the choice of ice sheet model remains the leading source of uncertainty in multi‐century projections.

IntroductionColorectal cancer (CRC) is one of the main causes of deaths worldwide. Early detection and diagnosis of its precursor lesion, the polyp, is key to reduce its mortality and to improve procedure efficiency. During the last two decades, several computational methods have been proposed to assist clinicians in detection, segmentation and classification tasks but the lack of a common public validation framework makes it difficult to determine which of them is ready to be deployed in the exploration room.MethodsThis study presents a complete validation framework and we compare several methodologies for each of the polyp characterization tasks.ResultsResults show that the majority of the approaches are able to provide good performance for the detection and segmentation task, but that there is room for improvement regarding polyp classification.DiscussionWhile studied show promising results in the assistance of polyp detection and segmentation tasks, further research should be done in classification task to obtain reliable results to assist the clinicians during the procedure. The presented framework provides a standarized method for evaluating and comparing different approaches, which could facilitate the identification of clinically prepared assisting methods.

IntroductionWound closure with triclosan-coated sutures (TCS) appears to reduce the risk of surgical site infection (SSI). Because there is a strong association between postoperative SSI and the development of acute abdominal wall dehiscence (AWD) after laparotomy, we hypothesized that the use of TCS for wound closure after laparotomy may also reduce the risk of AWD.MethodsThe MEDLINE, Embase, and CENTRAL databases were searched from their inception to 01 November 2022. Randomized trials that compared the use of TCS with identical but uncoated sutures for fascial closure were eligible if they could provide individual participant data (IPD) on AWD. From these trials, we only included in the analysis those subjects who underwent open abdominal surgery. The primary outcome was the incidence of AWD within 30 days postoperatively, requiring emergency reoperation. The certainty of evidence was assessed using the GRADE methodology (PROSPERO: CRD42019121173.ResultsWe identified twelve eligible trials. Eight studies shared IPD. The incidence of AWD within 30 days after surgery was 27/1,565 (1.7%) in the TCS group vs. 40/1,430 (2.8%) in the control group (Relative Risk: 0.70 [95% confidence interval (CI) 0.44–1.11, I2 = 0%, τ2 = 0.00]). The certainty of evidence was moderate after downgrading for imprecision. The incidence of incisional SSI was 163/1,576 (10.3%) vs. 198/1,439 (13.8%), RR 0.80 (95% CI 0.67–0.97).ConclusionWe found no conclusive evidence to support the use of triclosan-coated sutures for the prevention of acute abdominal wall dehiscence after laparotomy. In these selected studies, a significant reduction in incisional SSI was observed.

Multiple Sclerosis (MS) is a multifactorial autoimmune disease of the central nervous system (CNS). It is characterized by a heightened activation of the immune system with ensuing inflammation, demyelination and neurodegeneration with consequences such as motor, sensory, cognitive, as well as autonomic dysfunctions. While a range of immune-modulatory drugs have shown certain efficacy in alleviating pathology and symptoms, none of the currently available therapeutics regenerates the damaged CNS to restore function. There is emerging evidence for leukotrienes and leukotriene receptors being involved in the various aspects of the MS pathology including neuroinflammation and de/remyelination. Moreover, leukotriene receptor antagonists such as the asthma drug montelukast diminish inflammation and promote regeneration/remyelination. Indeed, montelukast has successfully been tested in animal models of MS and a recent retrospective case-control study suggests that montelukast treatment reduces relapses in patients with MS. Therefore, we propose montelukast as a therapeutic adjuvant to the standard immune-modulatory drugs with the potential to reduce pathology and promote structural and functional restoration. Here, we review the current knowledge on MS, its pathology, and on the potential of leukotriene receptor antagonists as therapeutics for MS.

In statistical inferences, the estimation of population parameters using information obtained from a sample is an important method. This involves choosing an appropriate sampling method to collect data. An efficient sampling method used for data collection is Ranked Set Sampling (RSS). In this study, we investigate the reproducibility of four well-known mean estimators under RSS using parametric predictive bootstrapping. These estimators are called conventional, ratio, exponential ratio, and regression estimators. Reproducibility is the ability of a statistical technique to obtain results similar to those based on the original experiment if the experiment is repeated under the same conditions. We conduct a simulation study to compare the reproducibility of mean estimators for varying sample sizes when sampling is based on perfect and imperfect rankings. We consider data on abalone in our simulations to demonstrate real-world applications. This study concludes that the regression estimator is the best reproducible estimator, while the conventional estimator is the worst in this regard.

Objectives: In Western society, high-caloric diets rich in fats and sugars have fueled the obesity epidemic and its related disorders. Disruption of the body-brain communication, crucial for maintaining glucose and energy homeostasis, arises from both obesogenic and genetic factors, leading to metabolic disorders. Here, we investigate the role of hypothalamic tanycyte shuttles between the pituitary portal blood and the third ventricle cerebrospinal fluid in regulating energy balance. Methods: We inhibited vesicle-associated membrane proteins (VAMP1-3)-mediated release in tanycytes by expressing the botulinum neurotoxin type B light chain (BoNT/B) in a Cre-dependent manner in tanycytes. This was achieved by injecting either TAT-Cre in the third ventricle or an AAV1/2 expressing Cre under the control of the tanycyte-specific promoter iodothyronine deiodinase 2 into the lateral ventricle of adult male mice. Results: In male mice fed a standard diet, targeted expression of BoNT/B in adult tanycytes blocks leptin transport into the mediobasal hypothalamus and results in normal-weight central obesity, including increased food intake, abdominal fat deposition, and elevated leptin levels but no marked change in body weight. Furthermore, BoNT/B expression in adult tanycytes promotes fatty acid storage, leading to glucose intolerance and insulin resistance. Notably, these metabolic disturbances occur despite a compensatory increase in insulin secretion, observed both in response to exogenous glucose boluses in vivo and in isolated pancreatic islets. Intriguingly, these metabolic alterations are associated with impaired spatial memory in BoNT/B-expressing mice. Conclusions: These findings underscore the central role of tanycytes in brain-periphery communication and highlight their potential implication in the age-related development of type 2 diabetes and cognitive decline. Our tanycytic BoNT/B mouse model provides a robust platform for studying how these conditions progress over time, from prediabetic states to full-blown metabolic and cognitive disorders, and the mechanistic contribution of tanycytes to their development. The recognition of the impact of tanycytic transcytosis on hormone transport opens new avenues for developing targeted therapies that could address both metabolic disorders and their associated cognitive comorbidities, which often emerge or worsen with advancing age.

Background: Pulmonary embolism (PE) is a potentially life-threatening condition. Admission and treatment in the intensive care unit (ICU) is an important element in critically ill PE patients. Objectives: We aimed to identify risk factors for ICU admission and differences in patient profiles regarding risk factors and comorbidities between PE patients who had to be admitted to an ICU and those who were treated in a normal ward without ICU. Methods: We used the German nationwide inpatient sample to analyze all hospitalizations of PE patients in Germany from 2016 to 2020 stratified for ICU admission. Results: Overall, 484,859 hospitalized PE patients were treated in German hospitals from 2016 to 2020. Among these, 92,313 (19.0%) were admitted to ICU. Patients treated in ICU were younger (69.0 [IQR, 58.0-78.0] vs 72.0 [IQR, 60.0-80.0] years; P < .001) and had higher prevalence of cardiovascular risk factors and comorbidities. In-hospital case fatality rate was elevated in PE patients treated in ICU (22.7% vs 10.7%; P < .001), and ICU admission was independently associated with increased in-hospital case fatality (odds ratio [OR], 2.54; 95% CI, 2.49-2.59; P < .001). Independent risk factors for ICU admission comprised PE with imminent or present decompensation (OR, 3.30; 95% CI, 3.25-3.35; P < .001), hemodynamic instability (OR, 4.49; 95% CI, 4.39-4.59; P < .001), arterial hypertension (OR, 1.20; 95% CI, 1.18-1.22; P < .001), diabetes mellitus (OR, 1.16; 95% CI, 1.14-1.18; P < .001), obesity (OR, 1.300; 95% CI, 1.27-1.33; P < .001), surgery (OR, 2.55; 95% CI, 2.50-2.59; P < .001), stroke (OR, 2.86; 95% CI, 2.76-2.96; P < .001), pregnancy (OR, 1.45; 95% CI, 1.21-1.74; P < .001), heart failure (OR, 1.74; 95% CI, 1.71-1.77; P < .001), atrial fibrillation/flutter (OR, 1.69; 95% CI, 1.66-1.73; P < .001), chronic obstructive pulmonary disease (OR, 1.21; 95% CI, 1.18-1.24; P < .001), and renal failure (OR, 1.92; 95% CI, 1.88-1.95; P < .001). Conclusion: ICU treatment is an important element in the treatment of PE patients. Besides hemodynamic compromise, cardiovascular risk factors, stroke, pregnancy, and cardiopulmonary as well as renal comorbidities were independent predictors of ICU admission. Necessity of ICU admission was afflicted by increased case fatality.

Icy bodies with subsurface oceans are a prime target for astrobiology investigations, with an increasing number of scientists participating in the planning, development, and realization of space missions to these worlds. Within Germany, the Ocean Worlds and Icy Moons working group of the German Astrobiology Society provides an invaluable platform for scientists and engineers from universities and other organizations with a passion for icy ocean worlds to share knowledge and start collaborations. We here present an overview about astrobiology research activities related to icy ocean worlds conducted either in Germany or in strong collaboration with scientists in Germany. With recent developments, Germany offers itself as a partner to contribute to icy ocean world missions.

We describe a case of a young patient with a recurrent pleomorphic xanthoastrocytoma (PXA) showing unusual cell-in-cell (CiC) phenomena. We observed mostly viable but also necrotic neutrophils engulfed within tumor cells. The recurrent tumor was immunopositive for BRAFV600E mutant protein and showed CDKN2 homozygous deletions typical of PXA. Both genetic alterations were also reported in the original primary tumor. Unlike the original tumor that was GFAP and Olig-2 immunopositive, the recurrent neoplasm was largely negative for GFAP and Olig-2 suggesting dedifferentiation. The large malignant cells that contained the neutrophils were negative for histiocytic and lymphohematopoietic markers. Whereas CDKN2 homozygous deletion is common in PXA, its presence is rare in histiocytic neoplasms. Both reactive astrocytes and glial neoplasms very rarely may engulf neutrophils in a process resembling emperipolesis or cellular cannibalism. Future work may clarify which type of CiC pathway is involved.

Using a DNA barcoding approach, we document an extensive number of inter-species cryptic introductions of bladed Bangiales (Pyropia) at an historic oyster aquaculture site in the Southern North Sea. We sampled the intertidal of 20 locations along the Belgian and Dutch coastline, ranging from sheltered to exposed, between February 2022 and April 2023 for bladed Bangiales. 230 individuals of bladed Bangiales were collected, morphological and ecological characteristics described and identified based on chloroplast rbcL gene sequences, revealing the presence of 13 species belonging to the genera Porphyra and Pyropia. While seven species (P. dioica, P. linearis, P. purpurea, P. umbilicalis, Py. collinsii, Py. elongata, Py. leucosticta) are regarded as native to the Northeast Atlantic, four species (Py. katadae, Py. koreana, Py. kinositae and Py. yezoensis) are considered non-indigenous. The records of Py. katadae, Py. kinositae and Py. koreana are the first confirmed observations for the Northeast Atlantic region. In addition, we identified two distinct rbcL clades, for which a definite species identification could not be established due to a lack of matching reference sequences. Species diversity was generally higher during winter and at exposed sites facing the open North Sea. The surprisingly high species diversity of the bladed Bangiales could only be revealed by molecular identification – a crucial tool for reliable species identification in this group of organisms.

BackgroundStrongyloidiasis is caused by a neglected nematode, manifesting as chronic intestinal infection with potentially severe manifestations. The disease is an emerging problem in non-endemic countries affecting travelers and migrants. Diagnosis of strongyloidiasis is hampered by the lack of standardization and absence of a gold standard. Since adequate direct methods to detect the motile larvae in stool samples are not widely available, other techniques such as serology have been developed.MethodsWe evaluated three commercial ELISA kits (DRG Instruments, IVD Research, and Bordier Affinity Products) to detect IgG antibodies against Strongyloides stercoralis assays utilizing serum samples from travelers with microscopically confirmed strongyloidiasis (n = 50) and other imported helminthic infections (n = 159) as well as healthy controls (n = 50).ResultsThe DRG, IVD, and Bordier assays showed sensitivities of 58.0%, 64.0%, and 56.0%, respectively. Specificity values were 96.0%, 96.0%, and 92.0% in healthy controls, and 67.3%, 62.9%, and 76.7% in cases with other helminth infections, respectively. Cross-reactions were mostly observed in cases with other nematodes (37.5%, 42.5%, and 20.0%, respectively), but also in trematode (33.3%, 38.1%, and 19.0%, respectively) and in cestode infections (25.0%, 30.0%, and 32.5%, respectively).ConclusionThe study demonstrates the diagnostic limitations of serological assays to detect or exclude cases of strongyloidiasis in returning travelers, who frequently present with recent or acute infections.

Sea turtles are a taxon of conservation concern and are highly migratory, exposing them to a variety of threats (e.g., fisheries bycatch, direct harvest) across their lifetime. Understanding the abundance of nesting females, hatchling production, and migratory movements - three of the most basic biological data needs for this species group - is imperative for population assessment. This study summarizes novel data most relevant to population assessments of the endangered central south Pacific (CSP) green turtle (Chelonia mydas) population, determined from annual rapid assessment surveys (mean survey duration=7.6 days year-1, n=61 survey days over 8 nesting seasons) and satellite telemetry at Rose Atoll, American Samoa, from 2012 to 2019. A minimum of 138 unique females nested in the Rose Atoll National Wildlife Refuge (RANWR) over the study period with 218 total females observed. Satellite tracks of post-nesting females suggest Fiji (n=33/48, 70.2%) is the primary foraging ground for turtles nesting at RANWR, though other areas throughout the south Pacific Ocean are also important. Limited data suggest hatchling production was high (average hatching success=92.3%) and nest temperature data collected from 2017-2019 suggest primary sex ratios were likely balanced during this time. These are positive signs for the resilience of this nesting population, but climate change poses threats to RANWR and other low-lying tropical islands throughout the central south Pacific, as nesting areas are potentially exposed to beach erosion, tidal inundations, and increasing temperatures leading to sex bias and embryonic death.

Individuals might be exposed to intense acute stress while having to make decisions with far-reaching consequences. Acute stress impairs processes required for decision-making by activating different biological stress cascades that in turn affect the brain. By knowing which stress system, brain areas, and receptors are responsible for compromised decision-making processes, we can effectively find potential pharmaceutics that can prevent the deteriorating effects of acute stress. We used a systematic review procedure and found 44 articles providing information on this topic. Decision-making processes could be subdivided into 4 domains (cognitive, motivational, affective, and predictability) and could be referenced to specific brain areas, while mostly being impaired by molecules associated with the sympathetic-adrenal-medullar and hypothalamic-pituitary-adrenal axes. Potential drugs to alleviate these effects included α1 and β adrenoceptor antagonists, α2 adrenoceptor agonists, and corticotropin releasing factor receptor1/2 antagonists, while consistent stress-like effects were found with yohimbine, an α2 adrenoceptor antagonist. We suggest possible avenues for future research.

Background: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. Methods: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). Results: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1–391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5–142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00–0.69) and the right lacrimal gland (median 0.59, range 0.42–0.78). Conclusions: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. Trial registration: NCT05871021

Abstract Background Partial nitritation-anammox (PNA) is a biological nitrogen removal process commonly used in wastewater treatment plants for the treatment of warm and nitrogen-rich sludge liquor from anaerobic digestion, often referred to as sidestream wastewater. In these systems, biofilms are frequently used to retain biomass with aerobic ammonia-oxidizing bacteria (AOB) and anammox bacteria, which together convert ammonium to nitrogen gas. Little is known about how these biofilm communities develop, and whether knowledge about the assembly of biofilms in natural communities can be applied to PNA biofilms. Results We followed the start-up of a full-scale PNA moving bed biofilm reactor for 175 days using shotgun metagenomics. Environmental filtering likely restricted initial biofilm colonization, resulting in low phylogenetic diversity, with the initial microbial community comprised mainly of Proteobacteria. Facilitative priority effects allowed further biofilm colonization, with the growth of initial aerobic colonizers promoting the arrival and growth of anaerobic taxa like methanogens and anammox bacteria. Among the early colonizers were known ‘oligotrophic’ ammonia oxidizers including comammox Nitrospira and Nitrosomonas cluster 6a AOB. Increasing the nitrogen load in the bioreactor allowed colonization by ‘copiotrophic’ Nitrosomonas cluster 7 AOB and resulted in the exclusion of the initial ammonia- and nitrite oxidizers. Conclusions We show that complex dynamic processes occur in PNA microbial communities before a stable bioreactor process is achieved. The results of this study not only contribute to our knowledge about biofilm assembly and PNA bioreactor start-up but could also help guide strategies for the successful implementation of PNA bioreactors. Video Abstract

Background: Real-time review of frozen sections underpins the quality of Mohs surgery. There is an unmet need for low-cost techniques that can improve Mohs surgery by reliably corroborating cancerous regions of interest and surgical margin proximity. Objective: To test that deep learning models can identify nonmelanoma skin cancer regions in Mohs frozen section specimens. Methods: Deep learning models were developed on archival images of focused microscopic views (FMVs) containing regions of annotated, invasive nonmelanoma skin cancer between 2015 and 2018, then validated on prospectively collected images in a temporal cohort (2019-2021). Results: The tile-based classification models were derived using 1423 focused microscopic view images from 154 patients and tested on 374 images from 66 patients. The best models detected basal cell carcinomas with a median average precision of 0.966 and median area under the receiver operating curve of 0.889 at 100x magnification (0.943 and 0.922 at 40x magnification). For invasive squamous cell carcinomas, high median average precision of 0.904 was achieved at 100x magnification. Limitations: Single institution study with limited cases of squamous cell carcinoma and rare nonmelanoma skin cancer. Conclusion: Deep learning appears highly accurate for detecting skin cancers in Mohs frozen sections, supporting its potential for enhancing surgical margin control and increasing operational efficiency.