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Abstract This study presents in situ, high-resolution optical measurements of particle size distributions (PSD) within sediment plumes generated by a pre-prototype deep seabed nodule collector vehicle operating in the abyssal Pacific Ocean. These measurements were obtained using a cutting-edge instrument, the LISST-RTSSV sensor. The data collected in situ reveal marked differences compared to previously reported laboratory-based, ex situ measurements. The grain size and other key particle shape characteristics are found to be dependent on multiple factors, including the collector vehicle maneuvers, the time elapsed following sediment discharge, and the complex hydrodynamic processes that generate the sediment in suspension. Significantly, the PSD from a highly complex succession of straight-line maneuvers converges to that of the canonical case of a simple straight-line driving maneuver within a timescale of ten minutes. Our results underscore the importance of parameterizing sediment plume transport models based on well-informed, comprehensive PSDs of detrained suspended sediment measured in situ at adequate timescales and in regions no longer strongly influenced by active and complex hydrodynamic processes.

Penile erection is unwanted during transurethral interventions as it may be associated with adverse events such as impaired access, prolonged operation time, abortion of the procedure, or a need for ancillary measures to reach penis flaccidity, such as intracorporeal injection of vasoactive drugs. In recent years, anesthesia with propofol has been favored over sevoflurane for environmental reasons. To the best of our knowledge, there have been no prospective randomized clinical trials evaluating the impact of general narcosis medications on the risk of such unwanted penile erections during transurethral surgery. To fill this gap, we have planned a prospective, double-blind (surgeon and patient), single-center, randomized controlled trial. The primary outcome is the occurrence of an intraoperative penile erection. The secondary outcomes are related to the impact of the primary outcome on the surgery, such as changes in operative strategy or operation duration, abortion of the procedure, and adverse events. The plan is to randomize 200 patients undergoing transurethral surgery to receive general anesthesia with either propofol or sevoflurane. The inclusion criteria are men aged

Abstract Background Popularity of electrical impedance tomography (EIT) and esophageal pressure (Pes) monitoring in the ICU is increasing, but there is uncertainty regarding their bedside use within a personalized ventilation strategy. We aimed to gather insights about the current experiences and perceived role of these physiological monitoring techniques, and to identify barriers and facilitators/solutions for EIT and Pes implementation. Methods Qualitative study involving (1) a survey targeted at ICU clinicians with interest in advanced respiratory monitoring and (2) an expert focus group discussion. The survey was shared via international networks and personal communication. An in-person discussion session on barriers, facilitators/solutions for EIT implementation was organized with an international panel of EIT experts as part of a multi-day EIT meeting. Pes was not discussed in-person, but we found the focus group results relevant to Pes as well. This was confirmed by the survey results and four additional Pes experts that were consulted. Results We received 138 survey responses, and 26 experts participated in the in-person discussion. Survey participants had diverse background [physicians (54%), respiratory therapists (19%), clinical researchers (15%), and nurses (6%)] with mostly > 10 year ICU experience. 84% of Pes users and 74% of EIT users rated themselves as competent to expert users. Techniques are currently primarily used during controlled ventilation for individualization of PEEP (EIT and Pes), and for monitoring lung mechanics and lung stress (Pes). EIT and Pes are considered relevant techniques to guide ventilation management and is helpful for educating clinicians; however, 57% of EIT users and 37% of Pes users agreed that further validation is needed. Lack of equipment/materials, evidence-based guidelines, clinical protocols, and/or the time-consuming nature of the measurements are main reasons hampering Pes and EIT application. Identified facilitators/solutions to improve implementation include international guidelines and collaborations between clinicians/researcher and manufacturers, structured courses for training and use, easy and user-friendly devices and standardized analysis pipelines. Conclusions This study revealed insights on the role and implementation of advanced respiratory monitoring with EIT and Pes. The identified barriers, facilitators and strategies can serve as input for further discussions to promote the development of EIT-guided or Pes-guided personalized ventilation strategies.

Abstract Contrary to expert readers, children learning to read have limited ability to preprocess letters in parafoveal vision. Parafoveal letters induce crowding cost: the features of neighboring letters interfere with target letter identification. We longitudinally studied the weight of parafoveal cost and benefit in two group of children (N = 42), during their first school year (Group 1) and at the end of second school year (Groupe 2). Using a novel digit-tracking method, a blurred text was presented and rendered unblurred by touching the screen, allowing the user to discover a window of visible text as the finger moved along it. We compared two conditions: (1) a large window, where crowding was enhanced by the presence of parafoveal information; (2) a small window, where crowding was suppressed by blurred parafoveal information. Finger kinematics were simultaneously recorded. We found that at the beginning of first-grade, digital fixations - brief slowing or stopping of the finger on a specific point - are significantly longer in the large compared to the small window condition, as parafoveal crowding increases text processing difficulty. This effect diminishes and disappears at the end of second-grade as reading performance improves. In the large window condition, longer digital saccades - rapid movements of the finger changing position - appear by the end of first grade suggesting that parafoveal exposure become more beneficial than harmful when children acquire basic reading skills. Our results show that in beginning readers, crowding has a cognitive cost that interfere with the speed of the learning reading process. Our findings are relevant to the field of education by showing that visual crowding in first grade should not be underestimated.

Abstract Pollination is a key ecosystem service crucial for supporting agricultural production, economic growth, social inclusion, and environmental protection. Understanding the economic value of pollination and its impact on human health and nutrition is essential for effective pollinator conservation and management. This study evaluates the economic and nutritional value of pollination services in Nepal and quantifies historic changes in pollinator reliance. Using public data on agricultural production and commodity prices, in combination with published nutritional composition values, we employ the dependency-ratio method to quantify economic and nutritional value across different regions of the country and through time. We conservatively estimate the annual economic value of pollination services in Nepal at US $477 million, representing 9% of total agricultural revenue. Pollinator-dependent crops, particularly fruits and vegetables are the source of essential nutrients; 40% of plant-based vitamin A and 14% of vitamin C are directly attributable to insect pollination. The cultivated area of these pollinator-dependent crops has increased by 91% in Nepal over 20 years – 3.7 times faster than equivalent increases in non-pollinator-dependent crops. The decline in wild pollinators during the same time period poses a threat, leading to potential pollination deficits and crop losses. Our study underscores the importance of conserving and managing pollinators to ensure sustainable agriculture, food security, and nutrition. Targeted efforts, including policy interventions and conservation strategies, are needed to safeguard pollinator populations and enhance pollination services.

Abstract Background Some settings continue to experience a high malaria burden despite scale-up of malaria vector control to high levels of coverage. Characterisation of persistent malaria transmission in the presence of standard control measures, also termed residual malaria transmission, to understand where and when individuals are exposed to vector biting is critical to inform refinement of prevention and control strategies. Methods Secondary analysis was performed using data collected during a phase III cluster randomized trial of attractive targeted sugar bait stations in Western Province, Zambia. Two seasonal cohorts of children aged 1–14 years were recruited and monitored monthly during the malaria transmission season, concurrent with entomological surveillance using a combination of human landing catch (HLC) and Centres for Disease Control (CDC) light traps at randomly selected households in study clusters. Behavioural data from cohort participants were combined with measured Anopheles funestus landing rates and sporozoite positivity to estimate the human behaviour-adjusted entomological inoculation rate (EIR). Results Behavioural data from 1237 children over 5456 child-visits in 20 entomology surveillance clusters were linked with hourly landing rates from 8131 female An. funestus trapped by HLC. Among all An. funestus tested by enzyme-linked immunosorbent assay (ELISA), 3.3% were sporozoite-positive. Mean EIR directly measured from HLC was 0.07 infectious bites per person per night (ib/p/n). When accounting for child locations over the evening and night, the mean behaviour-adjusted EIR was 0.02 ib/p/n. Children not sleeping under insecticide-treated nets (ITNs) experienced 13.6 infectious bites per person per 6 month season, 8% of which occurred outdoors, while ITN users received 1.3 infectious bites per person per 6 month season, 86% of which were received outdoors. Sleeping under an ITN can prevent approximately 90% of potential An. funestus bites among children. Conclusions In this setting ITNs have a high personal protective efficacy owing to peak An. funestus biting occurring indoors while most individuals are asleep. However, despite high household possession of ITNs (>90%) and high individual use (>70%), children in this setting experience more than one infectious bite per person per 6 month transmission season, sufficient to maintain high malaria transmission and burden. New tools and strategies are required to reduce the malaria burden in such settings. Graphical Abstract

Abstract The lion (Panthera leo) was extirpated from the Cape region of South Africa during the mid-nineteenth century. Whilst historically classified as a distinct subspecies known as the Cape lion (P. l. melanochaita), recent molecular studies challenge the distinctiveness of this population, suggesting that it represents the southernmost population of the species' Southern Clade. The Cape lion is often cited as having a distinctive skull morphology, which has justified its subspecific classification, but only a limited number of specimens have been available for examination, so that the Cape lion’s skull morphology has not been satisfactorily understood. In this study we collected morphometric data from a greatly enlarged sample of 22 Cape lion skulls, including 12 adults, constituting the largest sample size analysed for this possible subspecies. The results suggest that (1) morphological characteristics of the skull previously thought to distinguish the Cape lion are not diagnostic, and (2) nor is the skull morphology of male and female Cape lions distinct from that of males and females of other southern African lions. Our results independently support those based on molecular investigations, which suggest that the Cape lion was not distinct from other lions within the Southern Clade.

Abstract Monocytes directly contribute to atherosclerosis development by their recruitment to plaques in which they differentiate into macrophages. In the present study, we ask how modulating monocyte glucose metabolism could affect their homeostasis and their impact on atherosclerosis. Here we investigate how circulating metabolites control monocyte behavior in blood, bone marrow and peripheral tissues of mice. We find that serum glucose concentrations correlate with monocyte numbers. In diet-restricted mice, monocytes fail to metabolically reprogram from glycolysis to fatty acid oxidation, leading to reduced monocyte numbers in the blood. Mechanistically, Glut1-dependent glucose metabolism helps maintain CD115 membrane expression on monocytes and their progenitors, and regulates monocyte migratory capacity by modulating CCR2 expression. Results from genetic models and pharmacological inhibitors further depict the relative contribution of different metabolic pathways to the regulation of CD115 and CCR2 expression. Meanwhile, Glut1 inhibition does not impact atherosclerotic plaque development in mouse models despite dramatically reducing blood monocyte numbers, potentially due to the remaining monocytes having increased migratory capacity. Together, these data emphasize the role of glucose uptake and intracellular glucose metabolism in controlling monocyte homeostasis and functions.

Abstract Short bowel syndrome (SBS) leads to severe morbidity and mortality. Intestinal adaptation is crucial in improving outcomes. To understand the human gene pathways associated with adaptation, we perform single-cell transcriptomic analysis of human small intestinal organoids explanted from mice with experimental SBS. We show that transmembrane ion pathways, specifically the transepithelial zinc transport pathway genes SLC39A4 and SLC39A5, are upregulated in SBS. This discovery is corroborated by an external dataset, bulk RT-qPCR, and Western blots. Oral zinc supplementation is shown to improve survival and weight gain of SBS mice and increase the proliferation of intestinal crypt cells in vitro. Finally, we identify the upregulation of SLC39A5 and associated transcription factor KLF5 in biopsied intestinal tissue specimens from patients with SBS. Thus, we identify zinc supplementation as a potential therapy for SBS and describe a xenotransplantation model that provides a platform for discovery in other intestinal diseases.

Abstract Monitoring tumor evolution and predicting survival using non-invasive liquid biopsy is an unmet need for glioblastoma patients. The era of proteomics and metabolomics blood analyzes, may help in this context. A case–control study was conducted. Patients were included in the GLIOPLAK trial (ClinicalTrials.gov Identifier: NCT02617745), a prospective bicentric study conducted between November 2015 and December 2022. Patients underwent biopsy alone and received radiotherapy and temozolomide. Blood samples were collected at three different time points: before and after concomitant radiochemotherapy, and at the time of tumor progression. Plasma samples from patients and controls were analyzed using metabolomics and proteomics, generating 371 omics features. Descriptive, differential, and predictive analyses were performed to assess the relationship between plasma omics feature levels and patient outcome. Diagnostic performance and longitudinal variations were also analyzed. The study included 67 subjects (34 patients and 33 controls). A significant differential expression of metabolites and proteins between patients and controls was observed. Predictive models using omics features showed high accuracy in distinguishing patients from controls. Longitudinal analysis revealed temporal variations in a few omics features including CD22, CXCL13, EGF, IL6, GZMH, KLK4, and TNFRSP6B. Survival analysis identified 77 omics features significantly associated with OS, with ERBB2 and ITGAV consistently linked to OS at all timepoints. Pathway analysis revealed dynamic oncogenic pathways involved in glioblastoma progression. This study provides insights into the potential of plasma omics features as biomarkers for glioblastoma diagnosis, progression and overall survival. Clinical implication should now be explored in dedicated prospective trials.

Abstract Altermagnets are a novel class of magnetic materials, where magnetic order is staggered both in coordinate and momentum space. The metallic rutile oxide RuO2, long believed to be a textbook Pauli paramagnet, recently emerged as a putative workhorse altermagnet when resonant X-ray and neutron scattering studies reported nonzero magnetic moments and long-range collinear order. While some experiments seem consistent with altermagnetism, magnetic order in RuO2 remains controversial. We show that RuO2 is nonmagnetic, both in bulk and thin film. Muon spectroscopy complemented by density-functional theory finds at most 1.14 × 10−4 μ B/Ru in bulk and at most 7.5 × 10−4 μ B/Ru in 11 nm epitaxial films, at our spectrometers’ detection limit, and dramatically smaller than previously reported neutron results that were used to rationalize altermagnetic behavior. Our own neutron diffraction measurements on RuO2 single crystals identify multiple scattering as the source for the false signal in earlier studies.

The formation of ε-martensite is generally considered as detrimental to cracking resistance. The essential work of fracture (EWF) of high-Mn steels with ε-martensite has been determined in the near plane-stress regime. The analysis of the thickness dependence of EWF shows that an alloy with more ε-martensite involves a higher work of material separation and a lower contribution from crack-tip necking. Therefore, the presence of ε-martensite leads to a lower cracking resistance at large thickness, but to an enhanced fracture toughness at small thickness. The beneficial effect of ε-martensite to the work of fracture is explained by an increased strength without any reduction of void spacing, and related to the ε-martensite/austenite plastic co-deformation and to microcrack blunting and crack branching. The key finding of the study is thus that the best compromise depends on the structural application which imposes the strength and stiffness requirements, hence the thickness.

Abstract The Claustrum/dorsal endopiriform cortex complex (CLA) is an enigmatic brain region with extensive glutamatergic projections to multiple cortical areas. The transcription factor Nurr1 is highly expressed in the CLA, but its role in this region is not understood. By using conditional gene-targeted mice, we show that Nurr1 is a crucial regulator of CLA neuron identity. Although CLA neurons remain intact in the absence of Nurr1, the distinctive gene expression pattern in the CLA is abolished. CLA has been hypothesized to control hallucinations, but little is known of how the CLA responds to hallucinogens. After the deletion of Nurr1 in the CLA, both hallucinogen receptor expression and signaling are lost. Furthermore, functional ultrasound and Neuropixel electrophysiological recordings revealed that the hallucinogenic-receptor agonists’ effects on functional connectivity between prefrontal and sensorimotor cortices are altered in Nurr1-ablated mice. Our findings suggest that Nurr1-targeted strategies provide additional avenues for functional studies of the CLA.

Abstract Many parts of the world face severe and prolonged drought conditions, stressing the sustainability of water resources and agriculture. Transitioning to water-efficient crops is one strategy that can help adapt to water scarcity. An emerging drought-tolerant crop of interest is chia (Salvia hispanica). Yet, no study has compared its large-scale water use dynamics to those of widely established crops across the globe. Here, we use satellite data over multiple years to assess the water use efficiency of chia, alfalfa, corn, and soybean globally. Results show that chia consumed 13-38% less water than alfalfa, corn, and soy and assimilated 14-20% more carbon per amount of water used. Substituting 10% of Southwest United States alfalfa cultivation with chia would save 184 million liters of water per growing season, equivalent to the annual water consumption of 1,300 households. Future research shall explore the economic, societal, and environmental ramifications of substituting alfalfa with chia in dry areas worldwide. These insights can guide decision-makers in promoting sustainable agriculture and water resource management.

Abstract Background Bacterial antimicrobial resistance (AMR) is a global threat to both humans and livestock. Despite this, there is limited global consensus on data-informed, priority areas for intervention in both sectors. We compare current livestock AMR data collection efforts with other variables pertinent to human and livestock AMR to identify critical data gaps and mutual priorities. Methods We globally synthesized livestock AMR data from open-source surveillance reports and point prevalence surveys stratified for six pathogens (Escherichia coli, Staphylococcus aureus, non-typhoidal Salmonella, Campylobacter spp., Enterococcus faecalis, Enterococcus faecium) and eleven antimicrobial classes important in human and veterinary use, published between 2000 and 2020. We also included all livestock species represented in the data: cattle, chickens, pigs, sheep, turkeys, ducks, horses, buffaloes, and goats. We compared this data with intended priorities calculated from: disability-adjusted life years (DALYs), livestock antimicrobial usage (AMU), livestock biomass, and a global correlation exercise between livestock and human proportion of resistant isolates. Results Resistance to fluoroquinolones and macrolides in Staphylococcus aureus were identified as priorities in many countries but, less than 10% of these reported livestock AMR data. Resistance data for Escherichia coli specific to cattle, chickens, and pigs, which we prioritized, were also well collected. AMR data collection on non-typhoidal Salmonella and other livestock species were often not prioritized. Of 232 categories prioritized by at least one country, data were only collected for 48% (n = 112). Conclusions The lack of livestock AMR data globally for broad resistance in Staphylococcus aureus could underplay their zoonotic threat. Countries can bolster livestock AMR data collection, reporting, and intervention setting for Staphylococcus aureus as done for Escherichia coli. This framework can provide guidance on areas to strengthen AMR surveillance and decision-making for humans and livestock, and if done routinely, can adapt to resistance trends and priorities.

Abstract Background The COVID-19 pandemic has had an unprecedented impact in the global research production and has also increased research waste. Living evidence syntheses (LESs) seek to regularly update a body of evidence addressing a specific question. During the COVID-19 pandemic, the production and dissemination of LESs emerged as a cornerstone of the evidence infrastructure. This critical interpretive synthesis answers the questions: What constitutes an LES to support decision-making?; when should one be produced, updated, and discontinued?; and how should one be disseminated? Methods Searches included the Cochrane Library, EMBASE (Ovid), Health Systems Evidence, MEDLINE (Ovid), PubMed, and Web of Science up to 23 April 2024 and included articles that provide any insights on addressing the compass questions on LESs. Articles were selected and appraised, and their insights extracted. An interpretive and iterative coding process was used to identify relevant thematic categories and create a conceptual framework. Results Among the 16,630 non-duplicate records identified, 208 publications proved eligible. Most were non-empirical articles, followed by actual LESs. Approximately one in three articles were published in response to the COVID-19 pandemic. The conceptual framework addresses six thematic categories: (1) what is an LES; (2) what methodological approaches facilitate LESs production; (3) when to produce an LES; (4) when to update an LES; (5) how to make available the findings of an LES; and (6) when to discontinue LES updates. Conclusion LESs can play a critical role in reducing research waste and ensuring alignment with advisory and decision-making processes. This critical interpretive synthesis provides relevant insights on how to better organize the global evidence architecture to support their production. Trial registration PROSPERO registration: CRD42021241875.

Introduction: The introduction of CAR-T cell treatment for relapsed/refractory (r/r) mantle cell lymphoma improved survival rates of these patients. Along with its introduction in clinical routine, long-term events after CAR-T cell treatment are increasingly emerging. Case Presentation: We report the case of a patient developing acute erythroid leukemia with biallelic TP53 inactivation occurring 26 months after CAR-T therapy with brexucabtagene autoleucel (brexu-cel) for r/r mantle cell lymphoma. The patient presented with a healthy bone marrow prior to lymphoma treatments. Discussion: Secondary malignancies seem more frequent after CAR-T therapies. More studies are needed to assess potential long-term toxicities of CAR-T cell therapies including the frequency of secondary myeloid malignancies.

Abstract Recent trials have shown the efficacy of trastuzumab deruxtecan (T-DXd) in HER2-negative patients, but there is not yet a way to identify which patients will best respond, especially with the inability of current HER2 IHC and FISH assays to accurately determine HER2 expression in the unamplified setting. Here, we present a heavily pre-treated patient with triple-negative breast cancer (HER2 IHC 0 who had a complete response to T-DXd. In this case, we used a CLIA-certified reverse-phase protein array-based proteomic assay (RPPA) to determine that the patient had moderate HER2 protein expression (HER2Total 2+, 42%) and activation (HER2Y1248 1+, 23%). Using these results, we determined that the patient may benefit from T-Dxd despite being traditionally qualified as HER2 IHC 0. These findings highlight the potential for proteomics-based assays that may more accurately quantitate HER2 and (its activation) in the HER2 unamplified/IHC 0 setting to better select patients whose tumors are classically molecularly defined as HER2 IHC 0, but still could respond to HER2-directed therapy, and give patients access to therapies which for which they otherwise would not be eligible.

Abstract Background Improving the uptake of relevant and reliable research is an important priority in long-term care to achieve sustainable and high-quality services for the increasingly older population. Aim The purpose was to assess the effectiveness of a tailored, adaptive and a multifaceted KT capacity program, relative to usual practice, on the implementation of National Early Warning Score 2 (NEWS2). Methods This study was carried out as a pragmatic cluster-randomized controlled trial. The capacity program consisted of an educational part to address implementation capacity gaps and a facilitation-upon-implementation part to address a relevant knowledge gap in nursing homes. A collective decision was made to address the challenge of early detection of clinical deterioration among nursing home residents, by implementing the (NEWS2) as clinical innovation. Public nursing homes in a Norwegian municipality (n = 21) with a total of 1 466 beds were eligible for inclusion. The study-period spanned over a 22-month period, including a 12-month follow-up. Data was extracted from the Electronic Patient Journal system and analyzed using multilevel growth model analysis. Results The intervention had a large effect on the use of NEWS2 among care staff in intervention nursing homes, compared to the control group (standardized mean difference, d = 2.42). During the final month of the implementation period, residents in the intervention group was assessed with NEWS2 1.44 times (95% CI: 1.23, 1.64) per month, which is almost four times more often than in the control group (mean = 0.38, 95% CI: 0.19, 0.57). During the follow-up period, the effect of the intervention was not only sustained in the intervention group but there was a substantial increase in the use of NEWS2 in both the intervention (mean = 1.75, 95% CI: 1.55, 1.96) and control groups (mean = 1.45, 95% CI: 1.27, 1.65). Conclusions This tailored implementation strategy had a large effect on the use of NEWS2 among care staff, demonstrating that integrated knowledge translation strategies can be a promising strategy to achieve evidence-based care in the nursing home sector. Trial registration ISRCTN12437773 . Registered 19/3 2020, retrospectively.

Abstract Our brains create new memories by capturing the ‘who/what’, ‘where’ and ‘when’ of everyday experiences. On a neuronal level, mechanisms facilitating a successful transfer into episodic memory are still unclear. We investigated this by measuring single neuron activity in the human medial temporal lobe during encoding of item-location associations. While previous research has found predictive effects in population activity in human MTL structures, we could attribute such effects to two specialized sub-groups of neurons: concept cells in the hippocampus, amygdala and entorhinal cortex (EC), and a second group of parahippocampal location-selective neurons. In both item- and location-selective populations, firing rates were significantly higher during successfully encoded trials. These findings are in line with theories of hippocampal indexing, since selective index neurons may act as pointers to neocortical representations. Overall, activation of distinct populations of neurons could directly support the connection of the ‘what’ and ‘where’ of episodic memory.

Abstract Diamondoids are a class of organic molecules with the carbon skeletons isostructural to nano-diamond, and have been shown to be promising precursors for diamond formation. In this work, the formation of diamond crystals from various diamondoid molecule building blocks was studied using our developed molecular geometry specific Monte Carlo method. We maintained the internal carbon skeletons of the diamondoid molecules, and investigated how the carbon-carbon bonds form between diamondoid molecules and how efficient the process is to form diamond crystals. The simulations show that higher diamondoid molecules can produce structures closer to a diamond crystal compared with lower diamondoid molecules. Specifically, using higher diamondoid molecules, larger bulk diamond crystals are formed with fewer vacancies. The higher propensity of certain diamondoids to form diamond crystals reveals insights into the microscopic processes of diamond formation under high-pressure high-temperature conditions.

Background: This study investigated the incidence and clinical consequences of abnormal radiological and clinical findings during routinely performed 6-week outpatient visits in patients treated conservatively for multiple (3 or more) rib fractures. Methods: A retrospective analysis was conducted among patients with multiple rib fractures treated conservatively between 2018 and 2021 (Opvent database). The primary outcome was the incidence of abnormalities on chest X-ray (CXR) and their clinical consequences, which were categorized as requiring intervention or additional clinical/radiological examination. The secondary focus was the incidence of deviation from standard treatment in response to the findings (clinical or radiological) at the routine 6-week outpatient visit. Results: In total, 364 patients were included, of whom 246 had a 6-week visit with CXR. The median age was 57 years (interquartile range, 46–70 years) and the median Injury Severity Score was 17 (interquartile range, 13–22). Forty-six abnormalities (18.7%) were found on CXR. These abnormalities resulted in additional outpatient visits in 4 patients (1.5%) and in chest drain insertion in 2 (0.8%). Only 2 patients (0.8%) with an abnormality on CXR presented without symptoms. None of the 118 patients who had visits without CXR experienced problems. Conclusion: Routine 6-week outpatient visits for patients with conservatively treated multiple rib fractures infrequently revealed abnormalities requiring treatment modifications. It may be questioned whether the 6-week outpatient visit is even necessary. Instead, a more targeted approach could be adopted, providing follow-up to high-risk or high-demand patients only, or offering guidance on recognizing warning signs and providing aftercare through a smartphone application.

Abstract Entangled photon-pair sources are at the core of quantum applications like quantum key distribution, sensing, and imaging. Operation in space-limited and adverse environments such as in satellite-based and mobile communication requires robust entanglement sources with minimal size and weight requirements. Here, we meet this challenge by realizing a cubic micrometer scale entangled photon-pair source in a 3R-stacked transition metal dichalcogenide crystal. Its crystal symmetry enables the generation of polarization-entangled Bell states without additional components and provides tunability by simple control of the pump polarization. Remarkably, generation rate and state tuning are decoupled, leading to equal generation efficiency and no loss of entanglement. Combining transition metal dichalcogenides with monolithic cavities and integrated photonic circuitry or using quasi-phasematching opens the gate towards ultrasmall and scalable quantum devices.

Abstract Background Community acceptance is an important criterion to assess in community trials, particularly for new tools that require high coverage and use by a target population. Installed on exterior walls of household structures, the attractive targeted sugar bait (ATSB) is a new vector control tool designed to attract and kill mosquitoes. ATSBs were evaluated in Western Zambia during a two-year cluster randomized controlled trial to assess the efficacy of ATSBs in reducing malaria transmission. Community acceptance of ATSBs was critical for successful trial implementation. Methods A community engagement strategy outlined activities and key messages to promote acceptance. Annual cross-sectional surveys, conducted during the peak transmission period, assessed households for presence of ATSBs as well as perceived benefits, concerns, and willingness to use ATSBs. Sixteen focus group discussions and 16 in-depth interviews, conducted at the end of each ATSB station deployment period, obtained a range of perceptions and household experiences with ATSB stations, as well as ITN use in the context of ATSB deployment. Results Methods used during the study to promote acceptance and continued use of ATSBs were effective in achieving greater than 90% coverage, a high (greater than 70%) level of perceived benefits, and fewer than 10% of households reporting safety concerns. Common facilitators of acceptance included the desire for protection against malaria and reduction of mosquitoes, trust in health initiatives, and understanding of the product. Common barriers to acceptance included misconceptions of product impact on mosquitoes, continued cases of malaria, association with satanism, and damage to household structures. Discussion Future use of the ATSB intervention will likely require activities that foster community acceptance before, during, and after the intervention is introduced. Additional research may be needed to understand the impact of different levels of community engagement on ATSB station coverage, ATSB station perception, and ITN use. Conclusion There was high acceptance of ATSB stations during the trial in Western Zambia. Continuous and intense community engagement efforts contributed to sustained ATSB coverage and trust in the product. Acceptance of ATSBs during programmatic delivery requires further research.

Abstract Background Attractive targeted sugar bait (ATSB) stations are a novel tool with potential to complement current approaches to malaria vector control. To assess the public health value of ATSB station deployment in areas of high coverage with standard vector control, a two-arm cluster-randomized controlled trial (cRCT) of Sarabi ATSB® stations (Westham Ltd., Hod-Hasharon, Israel) was conducted in Western Province, Zambia, a high-burden location were Anopheles funestus is the dominant vector. The trial included 70 clusters and was designed to measure the effect of ATSBs on case incidence and infection prevalence over two 7-month deployments. Reported here are results of the vector surveillance component of the study, conducted in a subset of 20 clusters and designed to provide entomological context to guide overall interpretation of trial findings. Methods Each month, 200 paired indoor-outdoor human landing catch (HLC) and 200 paired light trap (LT) collections were conducted to monitor An. funestus parity, abundance, biting rates, sporozoite prevalence, and entomological inoculation rates (EIR). Results During the study 20,337 female An. funestus were collected, 11,229 from control and 9,108 from intervention clusters. A subset of 3,131 HLC specimens were assessed for parity: The mean non-parous proportion was 23.0% (95% CI 18.2–28.7%, total n = 1477) in the control and 21.2% (95% CI 18.8–23.9%, total n = 1654) in the intervention arm, an OR = 1.05 (95% CI 0.82–1.34; p = 0.688). A non-significant reduction in LT abundance (RR = 0.65 [95% CI 0.30–1.40, p = 0.267]) was associated with ATSB deployment. HLC rates were highly variable, but model results indicate a similar non-significant trend with a RR = 0.68 (95%CI 0.22–2.00; p = 0.479). There were no effects on sporozoite prevalence or EIR. Conclusions Anopheles funestus parity did not differ across study arms, but ATSB deployment was associated with a non-significant 35% reduction in vector LT density, results that are consistent with the epidemiological impact reported elsewhere. Additional research is needed to better understand how to maximize the potential impact of ATSB approaches in Zambia and other contexts. Trial registration number: This trial was registered with Clinicaltrials.gov (NCT04800055, 16 March 2021).

Abstract White adipose tissue (WAT) has been recognized as a fundamental and crucial organ of interest in research focusing on inflammation during obesity or aging. WAT is also proposed as a significant component of cholecalciferol and 25-hydroxyvitamin D (25(OH)D) storage, which participates in the decrease of 25(OH)D plasma levels reported during aging and obesity. In the present study, we evaluated WAT and plasma cholecalciferol and 25(OH)D content together with inflammatory status to highlight the putative relationship between vitamin D status and inflammatory process during aging alone or combined with obesity. Circulating cholecalciferol and 25(OH)D and the stored quantity of cholecalciferol and 25(OH)D in WAT were quantified in young and old mice fed a control or obesogenic diet. The inflammation was assessed by measuring plasma inflammatory cytokines, mRNA, and microRNAs inflammatory-associated in WAT. The combination of aging and obesity decreased 25(OH)D plasma levels but did not modify circulating inflammatory markers. A cumulative effect of aging and obesity was observed in WAT, with rising mRNA inflammatory cytokines, notably Ccl5 and Tnf. Interestingly, aging and obesity-associated were also characterized by increased inflammatory microRNA expression. The inflammatory parameters in WAT were negatively correlated with the plasma 25(OH)D but positively correlated with the quantity of cholecalciferol and 25(OH)D in WAT. These results support the cumulative effect of obesity and aging in aggravation of WAT inflammation and suggest that accumulation of cholecalciferol and 25(OH)D in WAT could constitute a mechanism to counteract WAT inflammation during aging and obesity.

Abstract Background Attractive Targeted Sugar Baits (ATSBs) offer a complementary vector control strategy to interventions targeting blood feeding or larval control by attacking the sugar feeding behaviour of adult mosquitoes using an attract-and-kill approach. Western Zambia was the first location to receive and deploy ATSB Sarabi version 1.2 stations in a Phase III cluster randomized controlled trial. This paper describes ATSB station installation, monitoring, removal, and disposal, quantifies ATSB station coverage, and reports major reasons for ATSB station replacement. Methods ATSB stations were deployed during two annual transmission seasons, through scheduled installation and removal campaigns. During deployment, monitoring was conducted per protocol to maintain high coverage of the ATSB stations in good condition. Routine monitoring visits during the trial captured details on ATSB station damage necessitating replacement following pre-defined replacement criteria. Annual cross-sectional household surveys measured ATSB station coverage during peak malaria transmission. Results A total of 67,945 ATSB stations were installed in Year 1 (41,695 initially installed+ 26,250 installed during monitoring) and 69,494 ATSB stations were installed in Year 2 (41,982 initially installed+ 27,512 installed during monitoring) across 35 intervention clusters to maintain high coverage of two ATSB stations in good condition per eligible household structure. The primary reasons for ATSB station replacement due to damage were holes/tears and presence of mold. Cross-sectional household surveys documented high coverage of ATSB stations across Year 1 and Year 2 with 93.1% of eligible structures having ≥ 2 ATSB stations in any condition. Discussion ATSB station deployment and monitoring efforts were conducted in the context of a controlled cRCT to assess potential product efficacy. Damage to ATSB stations during deployment required replacement of a subset of stations. High coverage of eligible structures was maintained over the two-year study despite replacement requirements. Additional research is needed to better understand the impact of damage on ATSB station effectiveness under programmatic conditions, including thresholds of threats to physical integrity and biological deterioration on product efficacy. Conclusions Optimizing ATSB stations to address causes of damage and conducting implementation research to inform optimal delivery and cost-effective deployment will be important to facilitate scale-up of ATSB interventions.

Abstract Oxygen homeostasis is maintained in plants and animals by O2-sensing enzymes initiating adaptive responses to low O2 (hypoxia). Recently, the O2-sensitive enzyme ADO was shown to initiate degradation of target proteins RGS4/5 and IL32 via the Cysteine/Arginine N-degron pathway. ADO functions by catalysing oxidation of N-terminal cysteine residues, but despite multiple proteins in the human proteome having an N-terminal cysteine, other endogenous ADO substrates have not yet been identified. This could be because alternative modifications of N-terminal cysteine residues, including acetylation, prevent ADO-catalysed oxidation. Here we investigate the relationship between ADO-catalysed oxidation and NatA-catalysed acetylation of a broad range of protein sequences with N-terminal cysteines. We present evidence that human NatA catalyses N-terminal cysteine acetylation in vitro and in vivo. We then show that sequences downstream of the N-terminal cysteine dictate whether this residue is oxidised or acetylated, with ADO preferring basic and aromatic amino acids and NatA preferring acidic or polar residues. In vitro, the two modifications appear to be mutually exclusive, suggesting that distinct pools of N-terminal cysteine proteins may be acetylated or oxidised. These results reveal the sequence determinants that contribute to N-terminal cysteine protein modifications, with implications for O2-dependent protein stability and the hypoxic response.

Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to

ObjectivesLarge granular lymphocyte (LGL) leukemia is a rare hematologic malignancy characterized by clonal expansion of cytotoxic T-cells frequent somatic activating STAT3 mutations. Based on the disease overlap between LGL leukemia rheumatoid arthritis (RA)a putative role for CD8+ T-cells in RA we hypothesized that STAT3 mutations may be detected in RA patient CD8+ T-cells correlate with clinical characteristics.MethodsBlood samples, clinical parameters, and demographics were collected from 98 RA patients and 9 healthy controls (HCs). CD8+ cell DNA was isolated and analyzed via droplet digital (dd)PCR to detect STAT3 mutations common in LGL leukemia: Y640F, D661Y, and the S614 to G618 region. STAT3 data from 99 HCs from a public dataset supplemented our 9 HCs.ResultsRA patients had significantly increased presence of STAT3 mutations compared to controls (Y640F p=0.0005, D661Y p=0.0005). The majority of these were low variant allele frequency (VAF) (0.008-0.05%) mutations detected in a higher proportion of the RA population (31/98 Y640F, 17/98 D661Y) vs. HCs (0/108 Y640F, 0/108 D661Y). In addition, 3/98 RA patients had a STAT3 mutation at a VAF >5% compared to 0/108 controls. Serological markers, RF and anti-CCP positivity, were more frequently positive in RA patients with STAT3 mutation relative to those without (88% vs 59% RF, p=0.047; 92% vs 58% anti-CCP, p=0.031, respectively).ConclusionsSTAT3 activating mutations were detected in RA patient CD8+ cells and associated with seropositivity. Thus, STAT3 activating mutations may play a role in disease pathogenesis in a subset of RA patients.

Introduction: Uterine carcinosarcoma is an aggressive gynecologic malignancy that accounts for 5% of all gynecological malignancies. There is a disproportion in its incidence and mortality among different races. This study describes demographic and clinicopathological factors and racial disparities affecting the survival of patients with uterine carcinosarcoma. Methods: Data on uterine carcinosarcoma patients were obtained from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2020. Results: Of the 11,338 patients identified, the median age at diagnosis was 68 years, and the five-year cause-specific survival (CSS) rate was 38.7%. for all races. Compared with Asian patients (39.5%, 95% CI, 36.0–43.4%), Hispanic patients (39.4%, 95% CI, 36.5–42.5%), and White patients (37.9%, 95% CI, 36.7–39.2%), Black patients accounted for 21% of the patients and had a significantly lower 5-year CSS (95% CI, 27.2–31.2%). The CSS rates were 84.4% (95% CI, 83.3–85.6%) for localized tumors, 68.5% (95% CI, 66.9–70.1%) for regional tumors, and 39.0% (95% CI, 36.9–41.2%) for distant tumors. Multimodal treatment involving chemotherapy, surgery, and radiation improved the overall one- and five-year survival rates by 88.2% (95% CI, 87.0–89.5%) and 52.8% (95% CI, 50.7–55.1%), respectively, across all disease stages. Multivariate analysis identified age >60 years, Black race, tumor size >4 cm, and distant metastases as independent risk factors for mortality (p < 0.0001). Conclusions: This large database study presents the most up-to-date epidemiological information regarding cases of uterine carcinosarcoma. The findings suggest that a combination of surgery, chemotherapy, and radiation may be most efficacious in treating this malignancy, especially in patients with distant disease.

Previously, we estimated the net change in energy use from ridehail services in Austin Texas. This estimate was based, in part, on assumptions regarding the number of rides involving two pooled parties and the distance drivers commuted into their service area to begin their driving day. The recent release of a year’s worth of Uber ridehail rides provided to California agencies, as well as recent surveys of driver commute behavior and the previous mode replaced by ridehail services, have enabled more accurate estimates of the net change in energy use from ridehail services statewide and in five regional markets. We find that the net reduction in energy use from more-efficient vehicles and pooled rides does not offset the additional increase in commute and between-ride deadhead kilometers and replacing more efficient modes with ridehail services. The net result is a 96% increase in statewide energy use (ranging from a 75% to a 123% increase in each region).

RESUMO Um dos princípios da democracia digital é informar ativamente os cidadãos e mobilizá-los para participarem no debate político. Este artigo apresenta uma ferramenta de processamento de documentos políticos públicos para tornar as informações mais acessíveis aos cidadãos e grupos profissionais específicos. Em particular, investigamos e desenvolvemos técnicas de Inteligência Artificial para mineração de textos do Diário da Assembleia da República de Portugal para particionar, analisar, extrair e sintetizar a informação das atas das sessões parlamentares. Desenvolvemos ainda dashboards que mostram as informações extraídas de forma simples e visual, como resumos de falas e tópicos discutidos. O nosso objetivo principal é, mais do que caracterizar o comportamento político, aumentar a transparência e a responsabilidade dos eleitores e das autoridades eleitas.

RESUMO O uso massivo de Inteligência Artificial na moderação de conteúdo na internet é uma realidade dos tempos atuais. No entanto, isso levanta uma série de questionamentos, seja sobre a pertinência do uso de sistemas automáticos opacos, seja se as plataformas podem sozinhas tomar decisões que antes cabiam ao Estado. Nesse contexto, o uso de IA “caixa-preta” passa a ser considerado uma ameaça à liberdade de expressão. Por outro lado, manter conteúdos que promovam abuso virtual é igualmente danoso a este direito fundamental. Nesse cenário, este estudo sumariza os principais problemas apontados pela literatura quanto ao paradigma atual, avalia as respostas que as novas tecnologias trazem, e propõe um caminho para um novo paradigma de moderação que seja justo e ético, no qual Estado e plataformas de mídias sociais têm papel relevante. Esse passa pela adoção de IA explicável associada a critérios transparentes e legítimos definidos pela sociedade.

Abstract Background Attractive Targeted Sugar Baits (ATSBs) are a proposed new vector control tool for malaria that contain sugar and an ingestion toxicant, and are designed to attract and kill sugar-feeding mosquitoes. During a two-arm cluster randomized Phase III trial conducted in Zambia to test the efficacy of ATSB stations on malaria incidence, ATSB stations deployed on eligible household structures within intervention clusters were routinely monitored to ensure their good physical condition and high coverage. This study investigates trends in prevalence and rate of damage to ATSB stations during year 2 of the two-year trial. Methods The analysis was conducted using monitoring data collected in year 2, which included types of damage observed, location, and date of removal and/or replacement of ATSB stations. The study evaluated temporal trends in the prevalence of overall damage and different damage types among 68,299 ATSB stations deployed. A profile of all ATSB stations installed on each structure was constructed, and spatial analyses conducted on overall damage and different damage types observed on 18,890 structures. Mixed effects regression analyses were conducted to investigate drivers of damage to ATSB stations on these structures. Results Prevalence of overall damage and different damage types was temporally and spatially heterogeneous. Among damaged ATSB stations observed during monitoring, tears and mold had the highest prevalences on average, with tears maintaining above 50.0% prevalence through most of the monitoring period, while mold prevalence increased steadily during the first few months, peaking in February. Overall, 45.6% of structures had at least one damaged ATSB station, however this varied spatially across the trial site. Both structure characteristics and environmental factors significantly impacted the odds and rate of damage to ATSB stations on structures, including: ATSB stations’ level of protection from rainfall and sunshine; roof and wall material of the structure; night-time temperature; rainfall; enhanced vegetation index, and land cover. Conclusion Damage to ATSB stations in this setting was common and was temporally and spatially heterogeneous. This has implications on operational feasibility, sustainability, and cost of future deployment. Further research is required to understand the mechanisms of damage, and to minimize prevalence and rate of damage to ATSB stations.

Abstract Loss of peat through increased burning will have major impacts on the global carbon cycle. In a normal hydrological state, the risk of fire propagation is largely controlled by peat bulk density and moisture content. However, where humans have interfered with the moisture status of peat either via drainage, or indirectly via climate change, we hypothesise that its botanical composition will become important to flammability, such that peats from different latitudes might have different compositionally-driven susceptibility to ignition. We use pyrolysis combustion flow calorimetry to determine the temperature of maximum thermal decomposition (T max) of peats from different latitudes, and couple this to a botanical composition analysis. We find that tropical peat has higher T max than other regions, likely on account of its higher wood content which appears to convey a greater resistance to ignition. This resistance also increases with depth, which means that loss of surface peat in tropical regions may lead to a reduction in the subsequent ignitability of deeper peat layers as they are exposed, potentially resulting in a negative feedback on increased fire occurrence and severity.

Abstract This study utilized a pilot-scale distribution network to examine the impact of temperature increases (16 °C, 20 °C, 24 °C) and source variations (treated ground- and surface water) on bulk and biofilm communities over 137 days. Microbial characterization employed flow cytometry and 16 S rRNA gene-based amplicon sequencing to elucidate bulk-biofilm interactions. Bacterial bulk cell densities increased with higher temperatures, while water source variations significantly influenced bulk cell densities as well as the community composition. Additionally, growth curves were fitted on the flow cytometry results, and growth rates and carrying capacities were higher with treated groundwater at elevated temperatures. Conversely, biofilm cell densities remained unaffected by temperature. A mature biofilm was observed from day 70 onwards and a core biofilm microbiome, resilient to temperature and water source changes, was identified. These findings emphasize the importance of water source quality for maintaining biological stability in drinking water systems, particularly in the face of changing environmental conditions.

Abstract For photo-dissociation of a single hydrogen molecule ( $$H_2$$ H 2 ) with combined XUV and IR laser pulses, we demonstrate optical control of the emission direction of the photoelectron with respect to the outgoing neutral fragment (the H-atom). Depending on the relative delay between the two laser fields, adjustable with sub-femtosecond time resolution, the photoelectron is emitted into the same hemisphere as the H-atom or opposite. This emission asymmetry is a result of entanglement of the two-electron final-state involving the spatially separated bound and emitted electron.

Abstract Silicon-vacancy (SiV) centers in diamond are emerging as promising quantum emitters in applications such as quantum communication and quantum information processing. Here, we demonstrate a sub-μs pulsed annealing treatment that dramatically increases the photoluminescence of SiV centers in diamond. Using a silane-functionalized adamantane precursor and a laser-heated diamond anvil cell, the temperature and energy conditions required to form SiV centers in diamond were mapped out via an optical thermometry system with an accuracy of ±50 K and a 1 μs temporal resolution. Annealing scheme studies reveal that pulsed annealing can obviously minimize the migration of SiV centers out of the diamond lattice, and a 2.5-fold increase in the number of emitting centers was achieved using a series of 200-ns pulses at a 50 kHz repetition rate via acousto-optic modulation. Our study provides a novel pulsed annealing treatment approach to improve the efficiency of the creation of SiV centers in diamond.

Abstract Despite major advances in molecular profiling and classification of primary brain tumors, personalized treatment remains limited for most patients. Here, we explored the feasibility of individual molecular profiling and the efficacy of biomarker-guided therapy for adult patients with primary brain cancers in the real-world setting within the molecular tumor board Freiburg, Germany. We analyzed genetic profiles, personalized treatment recommendations, and clinical outcomes of 102 patients with 21 brain tumor types. Alterations in the cell cycle, BRAF, and mTOR pathways most frequently led to personalized treatment recommendations. Molecularly informed therapies were recommended in 71% and implemented in 32% of patients with completed molecular diagnostics. The disease control rate following targeted treatment was 50% and the overall response rate was 30%, with a progression-free survival 2/1 ratio of at least 1.3 in 31% of patients. This study highlights the efficacy of molecularly guided treatment and the need for biomarker-stratified trials in brain cancers.

Abstract Sex chromosomes underlie the development of male or female sex organs across species. While systemic signals derived from sex organs prominently contribute to sex-linked differences, it is unclear whether the intrinsic presence of sex chromosomes in somatic tissues has a specific function. Here, we use genetic tools to show that cellular sex is crucial for sexual differentiation throughout the body in Drosophila melanogaster. We reveal that every somatic cell converts the intrinsic presence of sex chromosomes into the active production of a sex determinant, a female specific serine- and arginine-rich (SR) splicing factor. This discovery dismisses the mosaic model which posits that only a subset of cells has the potential to sexually differentiate. Using cell-specific sex reversals, we show that this prevalence of cellular sex drives sex differences in organ size and body weight and is essential for fecundity. These findings demonstrate that cellular sex drives differentiation programs at an organismal scale and highlight the importance of cellular sex pathways in sex trait evolution.

Abstract Many epithermal gold and gold-rich porphyry-type ore deposits are associated with potassic magmas. Hence, potassic magmas are commonly assumed to have been unusually Au-rich or to have contained high Au/Cu ratios. However, these hypotheses remain poorly tested. Here, we report Au concentrations and Au/Cu ratios in silicate melt inclusions analyzed in potassic rocks worldwide. The results suggest that mafic potassic magmas generally contain only 2‒7 ng/g Au, despite common sulfide exhaustion during partial mantle melting. Both the absolute Au concentrations and Au/Cu ratios are comparable to those of mafic calc-alkaline magmas, and they vary little during subsequent magma differentiation because magmatic sulfide precipitation is strongly dominated by monosulfide solid solution that is relatively poor in Au and Cu. We thus suggest that the close association of Au-rich deposits with potassic magmas is not due to Au enrichment in the magma, but rather due to selective Au precipitation at the hydrothermal stage.

Abstract Animal vigilance is often investigated under a narrow set of scenarios, but this approach may overestimate its contribution to animal lives. A solution may be to sample all looking behaviours and investigate numerous competing hypotheses in a single analysis. In this study, using a wild group of habituated chacma baboons (Papio ursinus griseipes) as a model system, we implemented a framework for predicting the key drivers of looking by comparing the strength of a full array of biological hypotheses. This included methods for defining individual-specific social threat environments, quantifying individual tolerance to human observers, and incorporating predator resource selection functions. Although we found evidence supporting reactionary and within-group (social) vigilance hypotheses, risk factors did not predict looking with the greatest precision, suggesting vigilance was not a major component of the animals’ behavioural patterns generally. Instead, whilst some behaviours constrain opportunities for looking, many shared compatibility with looking, alleviating the pressure to be pre-emptively vigilant for threats. Exploring looking patterns in a thorough multi-hypothesis framework should be feasible across a range of taxa, offering new insights into animal behaviour that could alter our concepts of fear ecology.

Abstract Multidrug efflux pumps have been found to play a crucial role in drug resistance in bacteria and eukaryotes. In this study, we investigated the presence of functional multidrug and toxic compound extrusion (MATE) efflux pumps, inferred from whole genome sequencing, in the halophilic archaeon Halorubrum amylolyticum CSM52 using Hoechst 33342 dye accumulation and antimicrobial sensitivity tests in the presence and absence of efflux pump inhibitors (EPIs). The whole genome sequence of H. amylolyticum CSM52 contained two putative MATE-type efflux pump genes, which may contribute to the inherent resistance to conventional antimicrobial agents reported in archaea. Antimicrobial susceptibility of the wild-type H. amylolyticum CSM52 testing revealed a lack of sensitivity to a wide range of antimicrobials, including glycopeptides, aminoglycosides, macrolides, fluoroquinolones, tetracycline, and chloramphenicol. However, the presence of EPIs, such as thioridazine, fluoxetine, and chlorpromazine, significantly increased the susceptibility of H. amylolyticum CSM52 to a number of these antimicrobials, indicating the potential involvement of efflux pumps in the observed resistance. A molecular modelling study with EPIs and substrate antimicrobials provided important insights into the molecular interactions with the putative transporter. It suggests that the occupancy of the transporter channel by EPIs has the potential to impact the efflux of antimicrobials. Phylogenetic analysis of the amino acid sequences of both MATE pumps showed low similarity with bacterial representatives, suggesting the presence of novel and distinct MATE efflux pumps in archaea. Our findings provide the first experimental evidence of active antibiotic efflux mechanisms in archaea and their potential roles in antimicrobial resistance, broadening our understanding of mechanisms of archaeal antimicrobial resistance, an overlooked aspect of AMR research.

IntroductionRespiratory viral infections (RVIs) are a major global contributor to morbidity and mortality. The susceptibility and outcome of RVIs are strongly age-dependent and show considerable inter-population differences, pointing to genetically and/or environmentally driven developmental variability. The factors determining the age-dependency and shaping the age-related changes of human anti-RVI immunity after birth are still elusive. MethodsWe are conducting a prospective birth cohort study aiming at identifying endogenous and environmental factors associated with the susceptibility to RVIs and their impact on cellular and humoral immune responses against the influenza A virus (IAV), respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The MIAI birth cohort enrolls healthy, full-term neonates born at the University Hospital Würzburg, Germany, with follow-up at four defined time-points during the first year of life. At each study visit, clinical metadata including diet, lifestyle, sociodemographic information, and physical examinations, are collected along with extensive biomaterial sampling. Biomaterials are used to generate comprehensive, integrated multi-omics datasets including transcriptomic, epigenomic, proteomic, metabolomic and microbiomic methods. DiscussionThe results are expected to capture a holistic picture of the variability of immune trajectories with a focus on cellular and humoral key players involved in the defense of RVIs and the impact of host and environmental factors thereon. Thereby, MIAI aims at providing insights that allow unraveling molecular mechanisms that can be targeted to promote the development of competent anti-RVI immunity in early life and prevent severe RVIs.Clinical trial registrationhttps://drks.de/search/de/trial/, identifier DRKS00034278.

This review explores the production of the fungal polysaccharide pullulan by mutants and natural isolates of Aureobasidium species using strain improvement. Pullulan is a neutral polysaccharide gum whose structure is a maltotriose-containing glucan. This polysaccharide gum has applications in the fields of food, pharmaceuticals, biomedical and wastewater treatment. The strain improvement of Aureobasidium species has focused on the pullulan production process, including the isolation of strains exhibiting reduced pigmentation, polysaccharide overproduction, the production of pullulan with variable molecular weight, and increased osmotolerant strains promoting pullulan production at high carbon source concentrations and pullulan production on hemicellulosic substrates. The majority of studies have emphasized the isolation of reduced pigmentation and pullulan hyperproducer strains since the goal of large-scale commercial pullulan production is to synthesize non-pigmented polysaccharides. A promising area of strain improvement is the isolation of strains that synthesize authentic pullulan from hemicellulosic substrates. If strain improvement in this area is successful, the goal of commercially producing pullulan at a competitive cost will eventually be achieved.

Multiple myeloma (MM) first-line treatment algorithms include immuno-chemotherapy (ICT) induction, high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) consolidation, followed by lenalidomide maintenance. After these initial therapies, most patients suffer a disease relapse and require subsequent treatment lines including ICT, additional HDCT and ASCT, or novel immunotherapies. The presence of somatic mutations in peripheral blood cells has been associated with adverse outcomes in a variety of hematological malignancies. Nonsense and frameshift mutations in the PPM1D gene, a frequent driver alteration in clonal hematopoiesis (CH), lead to the gain-of-function of Wip1 phosphatase, which may impair the p53-dependent G1 checkpoint and promote cell proliferation. Here, we determined the presence of PPM1D gene mutations in peripheral blood cells of 75 subsequent myeloma patients in remission after first or second HDCT/ASCT. The prevalence of truncating PPM1D gene mutations emerged at 1.3% after first HDCT/ASCT, and 7.3% after second HDCT/ASCT, with variant allele frequencies (VAF) of 0.01 to 0.05. Clinical outcomes were inferior in the PPM1D-mutated (PPM1Dmut) subset with median progression-free survival (PFS) of 15 vs. 37 months (p = 0.0002) and median overall survival (OS) of 36 vs. 156 months (p = 0.001) for the PPM1Dmut and PPM1Dwt population, respectively. Our data suggest that the occurrence of PPM1D gene mutations in peripheral blood cells correlates with inferior outcomes after ASCT in patients with multiple myeloma.