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Abstract The only current strategy to test efficacy of novel interventions for sustained HIV control without antiretroviral therapy (ART) among people with HIV (PWH) is through an analytical treatment interruption (ATI). Inclusion of ‘placebo’ controls in ATIs poses ethical, logistical, and economic challenges. To understand viral dynamics and rates of post-treatment control (PTC) after ATI among PWH receiving either placebo or no intervention, we undertook an individual-participant data meta-analysis. In total, 24 eligible prospective studies with 382 individuals with ≥5 plasma HIV RNA viral loads (pVLs) within the first 84 days post-ATI were included. Early-ART was defined as ART initiation within 6 months of HIV acquisition; others were classified as late-ART or unknown. Median age was 42 years, 91% male, 75% white, 45% received early-ART. Median time to pVL >50, >400, and >10,000 copies/mL was 16 days (interquartile range [IQR]:13–25), 21 (IQR:15–28), and 32 (IQR:20–35), respectively. PTC defined as pVL

Abstract Background Exergames are interactive technology-based exercise programs. By combining physical and cognitive training components, they aim to preserve independence in older adults and reduce their risk of falling. This study explored whether primary end users (PEU, healthy older adults and patients with neurological and geriatric diagnoses) and secondary end users (SEU, health professionals) evaluated the ExerG functional model to be usable, providing a positive experience and therefore acceptable. Methods We conducted a multi-methods study using several assessments to quantify usability and enjoyment outcomes, along with semi-structured interviews to gain an in-depth understanding of the users’ experiences. Descriptive statistics were used for quantitative outcome measures. For qualitative data, a thematic analysis (TA) using an inductive, data-driven approach was carried out to develop themes for each user group. Results We interviewed 20 PEUs (13 healthy older adults, 7 patients) and 22 SEUs at two rehabilitation centres in Austria and Switzerland. Users' scores of over 70 on the System Usability Scale denoted good usability. On the Physical Activity Enjoyment Scale-16, both PEU groups rated the ExerG highly. Our TA approach identified four themes per user group. Themes from both PEU groups confirmed their enjoyment of training with the ExerG, however more variety and greater challenges were requested. Whilst the patient group appreciated the security given by the harness system, the healthy older adults reported feeling restricted. SEU themes reflected their approval of this novel training device, although a desire for increased difficulty and more individualisation was expressed. Clear instructions and an easy-to-use harness system were acknowledged and useful feedback for the developers emerged. Conclusions The ExerG is usable, offers a positive experience, and can therefore be regarded as an acceptable solution for the combined physical and mental training of older adults. Our findings contribute to the ongoing development of the ExerG, which will be a welcome addition to current training options for this target group. Further research is needed to confirm its effectiveness in preserving or improving functional independence in daily life and reducing the risk of falling.

Abstract Transitioning to renewables is critical to address the Caribbean's vulnerability to imported fossil fuel price volatility and concerns about climate change. This study presents a first‐of‐its‐kind comprehensive analysis of 17 illustrative pathways varying the impact of e‐fuel imports, grid interconnections and an accelerated energy transition towards the Caribbean's carbon neutrality by 2050. The research method is based on techno‐economic principles for designing a cost‐optimal energy system. An optimisation tool is used, the LUT Energy System Transition Model, to analyse the various pathways. The study finds that high uptake of renewables in Caribbean energy systems significantly lowers costs and enhances reliability, crucial for building competitive and resilient economies. Renewable energy dominated pathways show 7–24% lower cumulative costs compared to alternatives, with grid integration reducing costs by 1–10%. Accelerated transition pathways incur 3–12% higher costs than complete defossilisation by 2050. Solar photovoltaics, wind power, batteries, and electrolysers are pivotal for achieving carbon neutrality by 2050. Importing e‐fuels reduces system costs by 7–16% and supports local resource use. Offshore renewable energy overcome land limitations, driving sustainable development and a vibrant blue economy. High electrification levels with renewable energy, sector coupling, and Power‐to‐X solutions enhance system efficiency and flexibility. Given the dominance of solar photovoltaics, the Caribbean's energy transition could be more appropriately called a ‘Solar‐to‐X Economy’. This research contributes to the international perspective on sustainable energy transition for islands.

Abstract Viruses are dependent on cellular energy metabolism for their replication, and the drug nitazoxanide (Alinia) was shown to interfere with both processes. Nitazoxanide is an uncoupler of mitochondrial oxidative phosphorylation (OXPHOS). Our hypothesis was that mitochondrial uncoupling underlies the antiviral effects of nitazoxanide. Tizoxanide (the active metabolite of nitazoxanide), its derivative RM4848 and the uncoupler CCCP were applied to a virus-releasing cell line to obtain the same increasing levels of mitochondrial uncoupling, hence identical impact on OXPHOS. A decrease in infectious viral particle release was observed and reflected the intensity of impact on OXPHOS, irrespective of the nature of the drug. The antiviral effect was significant although the impact on OXPHOS was modest (≤ 25%), and disappeared when a high concentration (25 mM) of glucose was used to enhance glycolytic generation of ATP. Accordingly, the most likely explanation is that moderate interference with mitochondrial OXPHOS induced rearrangement of ATP use and acquisition of infective properties of the viral particles be highly sensitive to this rearrangement. The antiviral effect of nitazoxanide has been supported by clinical trials, and nitazoxanide is considered a safe drug. However, serious adverse effects of the uncoupler dinitrophenol occurred when used to increase significantly metabolic rate with the purpose of weight loss. Taken together, while impairment of mitochondrial bioenergetics is an unwanted drug effect, moderate interference should be considered as a basis for therapeutic efficacy.

Abstract CD163, a macrophage-specific receptor, plays a critical role in scavenging hemoglobin released during hemolysis, protecting against oxidative effects of heme iron. In the bloodstream, hemoglobin is bound by haptoglobin, leading to its immediate endocytosis by CD163. While haptoglobin’s structure and function are well understood, CD163’s structure and its interaction with the haptoglobin-hemoglobin complex have remained elusive. Here, we present the cryo-electron microscopy structure of the entire extracellular domain of human CD163 in complex with haptoglobin-hemoglobin. The structure reveals that CD163 assembles into trimers (and to some extent dimers), binding haptoglobin-hemoglobin in their center. Key acidic residues in CD163 interact with lysine residues from both haptoglobin and hemoglobin. Calcium-binding sites located near the haptoglobin-hemoglobin interface in CD163 provide explanation for the calcium dependence of the interaction. Furthermore, we show that the interaction facilitating CD163 oligomerization mimics ligand binding and is also calcium dependent. This structural insight into CD163 advances our understanding of its role in hemoglobin scavenging as well as its broader relevance to structurally related scavenger receptors.

Le match de football a toutes les apparences d’un rituel religieux, y compris à travers les valeurs qu’il communique, mais ne nous dit rien des causes premières et des fins dernières, à savoir d’où nous venons et où nous allons. Il s’agit d’un rituel « sans exégèse », une forme de rituel qui abonde dans les sociétés contemporaines.

Abstract Background Dark-field radiography imaging exploits the wave character of x-rays to measure small-angle scattering on material interfaces, providing structural information with low radiation exposure. We explored the potential of dark-field imaging of bone microstructure to improve the assessment of bone strength in osteoporosis. Methods We prospectively examined 14 osteoporotic/osteopenic and 21 non-osteoporotic/osteopenic human cadaveric vertebrae (L2–L4) with a clinical dark-field radiography system, micro-computed tomography (CT), and spectral CT. Dark-field images were obtained in both vertical and horizontal sample positions. Bone microstructural parameters (trabecular number, Tb.N; trabecular thickness, Tb.Th; bone volume fraction, BV/TV; degree of anisotropy, DA) were measured using standard ex vivo micro-CT, while hydroxyapatite density was measured using spectral CT. Correlations were assessed using Spearman rank correlation coefficients. Results The measured dark-field signal was lower in osteoporotic/osteopenic vertebrae (vertical position, 0.23 ± 0.05 versus 0.29 ± 0.04, p

Abstract North Atlantic hurricanes are a major driver of property losses in the United States and a critical peril for the reinsurance industry globally. We leverage insurance loss data and stochastic modeling to investigate the impacts of projected changes in hurricane climatology on the insurance industry, for +2 °C and +4 °C warming scenarios. We find that, relative to the historical baseline 1950-2022, expected changes in wind speed and rainfall may increase hurricane losses by 5% −15% (+2 °C) and 10% − 30% (+4 °C), with greater impacts at lower return periods than in the tail. The historical 100-year loss event may therefore be exceeded on average every 80 years (+2 °C) and 70 years (+4 °C). The expected changes in average annual loss are projected to be 10% (+2 °C) and 15% (+4 °C), with the largest relative increase attributable to precipitation-induced losses. Under the extreme SSP5-8.5 scenario, the expected loss inflation due to climate change is thus on the order of 0.5% per annum.

Despite the effectiveness of DNA metabarcoding for gaining insights into biodiversity and environmental species composition, a centralised management and storage option including easy accessibility of already-published data is lacking. Since most data are published as supplementary material or in private repositories, DNA metabarcoding has a huge untapped potential to be used for analyses across multiple taxa, sample locations or multiple research projects. We developed a platform to register, manage and identify amplicon sequence variants (ASVs) or zero-radius OTUs (ZOTUs), respectively, against several barcode reference datasets. Moreover, ASV tables can be uploaded, managed, versioned and published with DOIs thus contributing to the full research Data Life Cycle.

Abstract Personalized treatment for patients with advanced solid tumors critically depends on the deep characterization of tumor cells from patient biopsies. Here, we comprehensively characterize a pan-cancer cohort of 150 malignant serous effusion (MSE) samples at the cellular, molecular, and functional level. We find that MSE-derived cancer cells retain the genomic and transcriptomic profiles of their corresponding primary tumors, validating their use as a patient-relevant model system for solid tumor biology. Integrative analyses reveal that baseline gene expression patterns relate to global ex vivo drug sensitivity, while high-throughput drug-induced transcriptional changes in MSE samples are indicative of drug mode of action and acquired treatment resistance. A case study exemplifies the added value of multi-modal MSE profiling for patients who lack genetically stratified treatment options. In summary, our study provides a functional multi-omics view on a pan-cancer solid tumor cohort and underlines the feasibility and utility of MSE-based precision oncology.

Abstract Adopting aggregation techniques in power sector modelling led to disregarding the key characteristics of regions in terms of resource use, which may not completely capture the bottlenecks in the energy transition. This study provides a holistic approach to estimate its impact on the transition of the European power system from the perspective of energy return on investment (EROI) by using six energy transition scenarios based on three different spatial representations. The findings indicate that EROI trends are highly dependent on the spatial representation, technology selection and energy mix. Further additional capacities of complementary technologies along with an upsurge in renewable capacities drive EROI values down. Disregarding the physical distances in the energy modelling results in large EROI enhancement due to the artificial smoothing effect of the aggregation method. EROI values of the aggregated scenarios remain between 18 and 24 by 2050. In the case of 20 independent sub‐regions, the lowest EROI is obtained at about 14 by 2050, due to the limitation on optimal resource utilisation. Interconnection of the sub‐regions, which represents the best proximation to the real situation, increases the EROI to 17 by 2050.

Abstract Background Randomised controlled trials (RCTs) are considered the gold standard for generating clinical evidence. The focus on high internal validity in RCTs challenges the external validity and generalisability of findings, potentially hindering their application in routine care. In neurorehabilitation, limited literature addresses conducting RCTs feasibly and efficiently. We investigated barriers and facilitators to conducting RCTs within routine care of neurorehabilitation centres from the perspective of stakeholders in neurorehabilitation in Germany and Austria. Methods We conducted semi-structured interviews with stakeholders in neurorehabilitation from four centres in Germany and Austria, informed by the Theoretical Domains Framework (TDF) and the Capability, Opportunity, Motivation and Behaviour model (COM-B). Employing a hybrid approach, the interview analysis integrated both deductive, theory-driven analysis based on the TDF domains and COM-B model and inductive, reflexive thematic analysis. Results Twelve stakeholders (4 physicians, 4 therapy managers, 4 therapists; 5 females, 7 males; with research experience spanning 0–40 years) were interviewed. Key barriers to conducting RCTs in neurological rehabilitation centres include limited financial, human, and time resources, high clinical workloads, and a lack of interest of some therapists. Ineffective leadership, perceived lack of research expertise, and communication issues were also significant barriers. Social influence factors such as lack of employer support and inadequate training access further contributed to the challenges. Additionally, barriers included insufficient research infrastructure, limited space, internal power struggles, and rigid cost bearer specifications. Key facilitators included physicians’ and therapists’ motivation to advance the field, contribute to knowledge, and to prioritise patient health. Support from supervisors, joint decision-making, and efficient organisation were crucial facilitators. Flexible therapy planning, mutual support, and interdisciplinary collaboration also played important roles. Conclusion Our results suggest that increasing professional development and understanding, along with providing adequate financial, human, time, and spatial resources to support research endeavours, implementing effective communication strategies to enhance interdisciplinary collaboration and coordination among team members may contribute to increased motivation and facilitate RCTs within the setting of neurorehabilitation centres. Trial registration This study was prospectively registered with the German Clinical Trials Register (08.04.2021 DRKSID DRKS00024982).

Abstract Background The histone variant macroH2A (mH2A), the most deviant variant, is about threefold larger than the conventional histone H2A and consists of a histone H2A-like domain fused to a large Non-Histone Region responsible for recruiting PARP-1 to chromatin. The available data suggest that the histone variant mH2A participates in the regulation of transcription, maintenance of heterochromatin, NAD+ metabolism, and double-strand DNA repair. Results Here, we describe a novel function of mH2A, namely its implication in DNA oxidative damage repair through PARP-1. The depletion of mH2A affected both repair and cell survival after the induction of oxidative lesions in DNA. PARP-1 formed a specific complex with mH2A nucleosomes in vivo. The mH2A nucleosome-associated PARP-1 is inactive. Upon oxidative damage, mH2A is ubiquitinated, PARP-1 is released from the mH2A nucleosomal complex, and is activated. The in vivo-induced ubiquitination of mH2A, in the absence of any oxidative damage, was sufficient for the release of PARP-1. However, no release of PARP-1 was observed upon treatment of the cells with either the DNA alkylating agent MMS or doxorubicin. Conclusions Our data identify a novel pathway for the repair of DNA oxidative lesions, requiring the ubiquitination of mH2A for the release of PARP-1 from chromatin and its activation.

Flooding is a frequent environmental stress that reduces soybean growth and grain yield in many producing areas in the world, such as the United States, Southeast Asia, and Southern Brazil. In these regions, soybean is frequently cultivated in lowland areas in crop rotation with rice, which provides numerous technical, economic, and environmental benefits. In this context, the identification of the most important spectral variables for the selection of more flooding-tolerant soybean genotypes is a primary demand within plant phenomics, with faster and more reliable results enabled using multispectral sensors mounted on unmanned aerial vehicles (UAVs). Accordingly, this research aimed to identify the optimal UAV-based multispectral vegetation indices for characterizing the response of soybean genotypes subjected to flooding and to test the best linear model fit in predicting tolerance scores, relative maturity group, biomass, and grain yield based on phenomics analysis. Forty-eight soybean cultivars were sown in two environments (flooded and non-flooded). Ground evaluations and UAV-image acquisition were conducted at 13, 38, and 69 days after flooding and at grain harvest, corresponding to the phenological stages V8, R1, R3, and R8, respectively. Data were subjected to variance component analysis and genetic parameters were estimated, with stepwise regression applied for each agronomic variable of interest. Our results showed that vegetation indices behave differently in their suitability for more tolerant genotype selection. Using this approach, phenomics analysis efficiently identified indices with high heritability, accuracy, and genetic variation (>80%), as observed for MSAVI, NDVI, OSAVI, SAVI, VEG, MGRVI, EVI2, NDRE, GRVI, BNDVI, and RGB index. Additionally, variables predicted based on estimated genetic data via phenomics had determination coefficients above 0.90, enabling the reduction in the number of important variables within the linear model.

Abstract Background General practitioners (GPs) play a crucial role in identifying cognitive impairment and dementia and providing post-diagnostic care. This study investigates (1) how promising GP consider lifestyle changes to maintain cognitive performance in general, (2) GP beliefs about the power of modifiable health and lifestyle factors to maintain cognitive performance, and (3) whether those beliefs vary by GP age. Methods As part of the AgeWell.de trial, GPs (n = 72) completed a process evaluation questionnaire assessing their perspectives on lifestyle changes to preserve cognitive performance in elderly patients. In greater detail, their perceived efficacy of established risk and protective factors was investigated using a 5-point Likert scale. Descriptive statistical analyses were performed for research question (1) and (2). Spearman´s rank correlations and ordinal logistic regressions were used to answer research question (3). All results were interpreted exploratively. Results GPs rated the overall chance of lifestyle changes maintaining cognitive performance quite neutral with a median score of 3.0 (IQR = 2.0). They rated the efficacy of all the modifiable health and lifestyle factors high, with increase in physical and social activity ((Mdn = 5.0, IQR = 1.0) receiving the highest ratings with the narrowest range. Spearman's rank correlation indicated a significant positive relationship between age and the belief in “Optimization of nutrition” for preventing cognitive decline and dementia (ρ = .255, p = .041). However, ordinal logistic regressions showed no significant relationships between age and GP ratings of lifestyle change efficacy. Conclusion These findings highlight the positive perception of GPs on the efficacy of modifiable health and lifestyle factors for preventing cognitive decline and dementia. Trial registration The AgeWell.de trial is registered in the German Clinical Trials Register (DRKS; trial identifier: DRKS00013555, Registration Date 07 December 2017).

Abstract Sewage metagenomics has risen to prominence in urban population surveillance of pathogens and antimicrobial resistance (AMR). Unknown species with similarity to known genomes cause database bias in reference-based metagenomics. To improve surveillance, we seek to recover sewage genomes and develop a quantification and correlation workflow for these genomes and AMR over time. We use longitudinal sewage sampling in seven treatment plants from five major European cities to explore the utility of catch-all sequencing of these population-level samples. Using metagenomic assembly methods, we recover 2332 metagenome-assembled genomes (MAGs) from prokaryotic species, 1334 of which were previously undescribed. These genomes account for ~69% of sequenced DNA and provide insight into sewage microbial dynamics. Rotterdam (Netherlands) and Copenhagen (Denmark) show strong seasonal microbial community shifts, while Bologna, Rome, (Italy) and Budapest (Hungary) have occasional blooms of Pseudomonas-dominated communities, accounting for up to ~95% of sample DNA. Seasonal shifts and blooms present challenges for effective sewage surveillance. We find that bacteria of known shared origin, like human gut microbiota, form communities, suggesting the potential for source-attributing novel species and their ARGs through network community analysis. This could significantly improve AMR tracking in urban environments.

Given the rapid cross-country spread of SARS-CoV-2 and the resulting difficulty in tracking lineage spread, we investigated the potential of combining mobile service data and fine-granular metadata (such as postal codes and genomic data) to advance integrated genomic surveillance of the pandemic in the federal state of Thuringia, Germany. We sequenced over 6500 SARS-CoV-2 Alpha genomes (B.1.1.7) across 7 months within Thuringia while collecting patients’ isolation dates and postal codes. Our dataset is complemented by over 66,000 publicly available German Alpha genomes and mobile service data for Thuringia. We identified the existence and spread of nine persistent mutation variants within the Alpha lineage, seven of which formed separate phylogenetic clusters with different spreading patterns in Thuringia. The remaining two are subclusters. Mobile service data can indicate these clusters’ spread and highlight a potential sampling bias, especially of low-prevalence variants. Thereby, mobile service data can be used either retrospectively to assess surveillance coverage and efficiency from already collected data or to actively guide part of a surveillance sampling process to districts where these variants are expected to emerge. The latter concept was successfully implemented as a proof-of-concept for a mobility-guided sampling strategy in response to the surveillance of Omicron sublineage BQ.1.1. The combination of mobile service data and SARS-CoV-2 surveillance by genome sequencing is a valuable tool for more targeted and responsive surveillance.

Background and purpose: In contemporary medial unicompartmental knee arthroplasty (mUKA), non-lateral patellofemoral osteoarthritis (PFOA) is not considered a contraindication. However, we still lack knowledge on the association of PFOA severity on patient reported outcome measures (PROMs) after mUKA. We aimed to examine the association between PFOA severity and PROM-score changes after mUKA. Methods: We included 549 mobile-bearing mUKAs. PFOA was graded intraoperatively as 0 = normal cartilage, 1–2 = superficial changes or < 50% of depth, and 3–4 = changes of > 50% of depth or to the bone, using the International Cartilage Repair Society (ICRS) cartilage lesion classification system. All patients completed the Oxford Knee Score (OKS), Activity and Participation Questionnaire (APQ), and Forgotten Joint Score (FJS), preoperatively and 3, 12, and 24 months postoperatively. PROM changes were compared using linear regression models adjusted for sex, age, body mass index, and preoperative PROM score. Results: We found no significant differences in OKS, FJS, and APQ change when comparing group 3–4 with group 0 at any follow-up. When comparing group 1–2 with 0 we found a statistical but not clinical significantly higher change in OKS scores at 24-month follow-up (2.5, 95% confidence interval [CI] 0.36–4.6) and in APQ scores at 24-month follow-up (10.6, CI 1.2–20.0) in favor of group 1–2. Conclusion: Severe PFOA, excluding severe lateral facet PFOA, had no negative association on PROM score development following mobile-bearing mUKA.

The burden of diseases attributable to air pollution is comparable to those of global health risks such as unhealthy diets and tobacco smoking, with many air pollution sources also emitting climate heating gases. In this UK study we estimated the co-benefits of Net Zero (NZ) climate policy on the health benefits of air pollution reduction, increased active travel, outdoor exposure inequalities and indoor air pollution changes. The study focused on two of the largest UK sources, road transport and building heating, with comparisons made between NZ and UK existing policy, referred to as Business as Usual (BAU). Particulate matter (PM2.5), Nitrogen Dioxide (NO2) and Ozone (O3) projections were made between 2019 and 2050, with emphasis placed upon the NZ co-benefits in 2030 and 2040. We compared the UK BAU scenarios with the Climate Change Committee’s (CCC) Balanced Net Zero Pathway (BNZP) and Widespread Innovation (WI) pathway.Compared to BAU predictions, BNZP assumptions lead to more electric vehicles, reduced vehicle km, more low carbon building heating, and reduced emissions of NO2 and PM2.5. By 2040 under BNZP, relative to BAU, the buildings sector was predicted to be three times more effective at reducing PM2.5 than road transport. To help reduce the inequality gap the NZ building transition was tailored toward those most in need. Outdoor air pollution exposure inequalities prevailed across the socioeconomic spectrum, especially for NO2, but were less pronounced due in part to NZ policies. Core air quality health benefits for the BNZP buildings sector were £21.3 billion (16.4 to 26.2) by 2050 and £98.4 billion (75.7 to 121.1) by 2154. For the transport sector the health benefits were £9.1 billion (7.0 to 11.2) by 2050 and £36.5 billion (28.1 to 44.9) by 2154. NZ building sector operating costs did not achieve break-even via efficiency savings, but with Greenhouse Gas (GHG) (lower benefits) break-even was achieved in 2052. With additional air pollution health benefits, building-sector time to break-even improved by between 3.1 (2.5 to 4.7) and 6.3 (4.7 to 7.6) years to between 2046 and 2049. Analysis found that removing gas cooking at home, for NZ, may result in greater concentration reductions than outdoor air pollution for NO2. Net Zero health and economic co-benefits are large, as are the changes needed, requiring political leadership and public engagement. Our findings are relevant to other countries facing the NZ transition.

Summary: Climate modeling suggests that achieving international climate goals requires a reduction in current CO2 emissions by over 90%, with any remaining emissions to be addressed through carbon dioxide removal (CDR) solutions. Sixteen CDR strategies are evaluated by integrating technical potential, environmental, social, and governance (ESG) criteria, along with sequestration permanence. This evaluation, conducted by ENGIE’s scientific council using an interdisciplinary Delphi panel methodology, proposes a “quality” measure for each technology. This measure combines ESG scores and sequestration timescales to rank and select the most promising solutions. The findings highlight the necessity for further research to understand and mitigate ESG impacts, aiming to inform both future research and current decision-making to support the effective and legitimate use of CDR strategies.

The baboon endogenous retrovirus (BaEV) glycoprotein is superior to the commonly used vesicular stomatitis virus glycoprotein (VSVg) for retroviral gene transfer into resting hematopoietic stem cells and lymphocyte populations. The derivative BaEVRLess (lacking the R domain) produces higher viral titers compared with wild-type BaEV, but vector production is impaired by syncytia formation and cell death of the HEK293T cells due to the high fusogenic activity of the glycoprotein. This lowers viral titers, leads to increased batch-to-batch variability, and impedes the establishment of stable packaging cell lines essential for the economical production of viral supernatants. Here, we show that knockout of the entry receptor ASCT2 in HEK293T producer cells eliminates syncytia formation, resulting in a 2-fold increase in viral titers, reduced toxicity of viral supernatants, and enables the generation of stable packaging cell lines. In successive steps, we stably integrated BaEVRLess and α-retroviral a.Gag/Pol expression cassettes and isolated clones supporting titers up to 108 to 109 infectious particles/mL, a 10-fold increase in concentrated viral titers. The additional overexpression of CD47 and knockout of β2-microglobulin in the packaging cell line are tailored for future use in in vivo gene therapy applications by reducing non-specific uptake by macrophages and the immunogenicity of viral particles.

Objectives: On the basis of the positive results of CheckMate-743, first-line (1L) treatment of malignant pleural mesothelioma (MPM) with the combination of ipilimumab and nivolumab (ipi-nivo) has become a standard-of-care. Furthermore, patients who received 1L platinum/pemetrexed chemotherapy are often considered for second or further-line (2L+) ipi-nivo on the basis of MAPS2 results. Here we report on real-world survival and safety outcomes of ipi-nivo for patients with MPM in Switzerland. Methods: Twelve cancer centers contributed data to this retrospective cohort. Baseline characteristics including age, sex, histology, programmed death-ligand 1 expression, Eastern Cooperative Oncology Group performance status (ECOG PS), and previous/subsequent therapies were collected. The efficacy and safety outcomes were assessed by local investigators. Results: Of the 109 patients with MPM treated with ipi-nivo between November 2017 and March 2023 (median follow-up of 16.6 months) 75% had epithelioid, 9% biphasic, and 16% sarcomatoid histology. The median age was 72 years; 91% were males, and 83% had an ECOG PS of 0 to 1. Ipilimumab in combination with nivolumab was given as 1L in 43% and as 2L+ treatment in 57% of patients. The objective response rate was 21% in 1L and 15% in 2L+. Median progression-free survival was 6.5 and 2.8 months, respectively. Median overall survival (OS) from the start of ipi-nivo was 12.6 months for 1L and 6.9 months for 2L+. No differences in OS were observed depending on age and programmed death-ligand 1 expression. Nevertheless, the median OS was significantly worse in patients with an ECOG PS of 2 or higher than those with an ECOG PS of 0 to 1 (2.4 versus 11.9 months, p < 0.001). Treatment-related adverse events (TRAEs) of any grade related to ipi-nivo treatment occurred in 65 patients (62%). The highest-grade TRAE was 1 to 2 in 58% of these patients and 3 or higher in 42% Treatment discontinuation due to a TRAE occurred in 22% of patients. Conclusion: In this real-world cohort of patients with MPM treated with ipi-nivo survival outcomes were inferior to those reported in the CheckMate-743 and MAPS2 trials, whereas safety outcomes were similar.

HIV vaccine development has been hindered by significant challenges over four decades. Despite persistent efforts, all efficacy trials to date have yielded disappointing results. This has pushed the field back to the discovery phase and created uncertainty about the future involvement of large pharmaceutical companies. Currently, the HIV vaccine landscape is dominated by startup biotech firms, which face a complex array of obstacles. These include evolving HIV prevention methods, waning interest in vaccine research, and difficulties securing sustainable funding. This viewpoint explores the challenges faced by these biotech companies and the support mechanisms necessary for their continued involvement in HIV vaccine development. By leveraging insights from both pharmaceutical and biotech sectors, we propose a multi-faceted approach that includes enhanced communication, fostering innovation, and implementing strategic funding models.

We study the potential effects of introducing autonomous ferries in a transportation system of water buses. We develop two integer linear programming models and a heuristic to find weekly passenger transportation plans. One model is tailored for a fleet of autonomous ferries and the other one for manually operated ferries. The objective of the models is to minimize a penalty function for unmet demand, adding up penalties on time delays with respect to the wished time of arrivals of the passengers and penalties on the assignment of passengers to alternative transportation modes. The models differ because working laws affect the crews’ working capacities, and we study the changes when these requirements are absent with autonomous ferries. Our work is motivated by the case of Bergen, a coastal city in Norway. In this case, the use of autonomous ferries has the potential to improve passengers’ utility significantly. However, we suggest that it may be beneficial to consider autonomous ferries as a complementary alternative that can operate especially in low-demand hours—a recommendation that may be particularly relevant if there are few autonomous ferries available or the ferries can only be operative for a limited number of hours of the day.

Desalination offers options to augment water supplies for growing urban and industrial demand. Yet these facilities and related infrastructure projects have significant impacts on environmental, economic, and social sustainability. However, few studies examine how key actors in the sector understand or incorporate sustainability ideas and practices into the design, construction, and operation of desalination facilities. This study fills this gap by examining stakeholder perspectives on sustainability in the desalination sector using Q-method. We identified three dominant social perspectives on these topics. Factor 1 views desalination as important for the long-term sustainability of water supply. Factor 2 sees the social and environmental impacts of desalination as too big of a sustainability risk when there are other water resources to consider. Factor 3 indicates that the parties pursuing desalination have the responsibility of addressing sustainability concerns through their proposals and project specifications. These perspectives reveal how desalination stakeholders understand sustainability, key challenges, and responsibility for ensuring sustainable desalination projects. The findings provide insight into how desalination stakeholders can improve sustainability processes and outcomes.

Objectives To collaboratively develop a music-supported video-based exercise programme for people with multiple sclerosis (pwMS) with mild to severe disability.Design and setting We performed this participatory mixed methods study from 15 March 2022 to 22 July 2023 at two Austrian multiple sclerosis (MS) centres.Participants This research included 67 pwMS, of whom 18 pwMS (including two patient representatives and five MS support group leaders/members) and an additional three family members served as stakeholders. Six neurologists and six physiotherapists, each with >5 years of experience in treating pwMS were interviewed.Intervention Stakeholders actively participated as members of study advisory, project steering and research groups. Researcher-supported peer-to-peer focus groups and individual interviews, conducted in three stages, gathered information on musical preferences and exercise needs. We co-developed, co-evaluated and co-adapted the music-supported exercise programme with the stakeholders. Involvement levels were measured using the Participation Check and Patient Public Involvement (PPI) Assessment Survey, self-efficacy with the Unidimensional Self-Efficacy Scale for Multiple Sclerosis and emotional states with the Self-Assessment Manikin.Results We identified four themes through reflexive thematic analysis: (1) engagement; (2) ease; (3) autonomy; (4) musical meaning. Integration of qualitative and quantitative components highlighted the success of PPI activities: (a) 148 co-created, free videos are publicly available; (b) four videos provide expert interviews with general information, while 144 offer music-supported exercises tailored to pwMS with mild to severe disability; (c) patients found the videos relevant, feasible and usable in interviews and focus groups; (d) ‘easy’ category exercises (seated or lying) are suitable for severely affected pwMS; (e) stakeholders felt included, respected and heard, as shown by quantitative PPI assessments.Conclusions Stakeholders were essential in identifying key aspects, preferences and constraints early on. Their feedback on music and exercise shaped the project. This study transformed our approach to exercise for pwMS. Future studies are required to evaluate the programme’s efficacy.Trial registration number DRKS00027979.

Background: The UK is committed to achieve net zero greenhouse gas emissions by 2050. The suite of policies needed to reach net zero will lead to improvements in air quality and, consequently, could lessen air pollution inequalities. We assessed air pollution inequalities across different sociodemographic groups in England and Wales and explored how these might be differentially impacted by future air pollution projections in 2030 and 2040 under net zero policies. Methods: We employed a geodemographic classification approach to categorise neighbourhoods into five distinct clusters based on 2021 UK Census sociodemographic variables. We modelled fine particulate matter (PM2.5) and nitrogen dioxide (NO2) concentrations for the year 2019, and predicted concentrations in 2030 and 2040. We compared a business-as-usual (BAU) scenario and two policy pathways to achieve net zero currently considered by the UK government. We aggregated air pollution concentrations to the neighbourhood level and assessed differential neighbourhood-level concentrations across the geodemographic groups using descriptive statistics and box plots. Results: The Urban Central Professionals group experienced 14 µg/m3 higher average NO2 concentrations compared with the Rural Elderly group in 2019. Despite substantial improvements to air quality in 2030 and 2040 of up to 6.3 µg/m3 for NO2 based on BAU, and further reductions of up to 2.4 µg/m3 NO2 under net zero policies, the overall pattern of inequality persists, but is predicted to be less pronounced. Conclusions: Our findings demonstrate the effectiveness of targeted policies and innovations in reducing both air quality and greenhouse gas emissions and in bridging the environmental inequality gap. Our findings are essential to develop targeted communication campaigns to secure acceptance and willingness across the sociodemographic spectrum to support the significant behavioural changes needed to achieve net zero, by highlighting the wider co-benefits to the environment and health of such policies.

Title compound 1Ni, [Ni(C46H32N4O2)], a secochlorin nickel complex, was prepared by diol cleavage of a precursor trans-dihydroxydimethylchlorin. Two crystallographically independent molecules in the structure are related by pseudo-A lattice centering, with molecules differing mainly by a rotation of one of the acetyls and an adjacent phenyl groups. The two molecules have virtually identical conformations characterized by noticeable in-plane deformation in the A1g mode and a prominent out-of-plane deformation in the B1u (ruffling) mode. Directional interactions between molecules are scarce, limited to just a few C—H...O contacts, and intermolecular interactions are mostly dispersive in nature.

Abstract Background Aim of this study was to detect predictors of better adherence to the AgeWell.de-intervention, a two-year randomized multi-domain lifestyle intervention against cognitive decline. Methods Data of 317 intervention group-participants comprising a risk group for dementia (Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) score of ≥ 9; mean age 68.9 years, 49.5% women) from the AgeWell.de intervention study were analysed. Regression models with four blocks of predictors (sociodemographic, cognitive and psychosocial, lifestyle factors and chronic conditions) were run on adherence to the components of nutrition, enhancement of social and physical activity and cognitive training. Adherence to each component was operationalised by assessing the degree of goal achievement per component at up to seven time points during the intervention period, measured using a 5-point Likert scale (mean score of goal achievement). Results Increasing age was negatively associated with adherence, while higher education positively predicted adherence. Participants with better mental state (Montreal Cognitive Assessment (MoCA)-score > 25) at baseline and higher self-efficacy adhered better. Diabetes and cardiovascular conditions were not associated with adherence, whereas smoking negatively affected adherence. Highest education and quitting smoking in the past were the only predictors associated with all four intervention components. Conclusion Results identified predictors for better and worse adherence. Particularly self-efficacy seems to be of considerable influence on adherence. This should be considered when designing future intervention trials. Trial registration German Clinical Trials Register (ref. number: DRKS00013555).

We investigated links between antimicrobial resistance in community-onset bacteremia and 1-year bacteremia recurrence by using the clinical data warehouse of Europe’s largest university hospital group in France. We included adult patients hospitalized with an incident community-onset Staphylococcus aureus, Escherichia coli, or Klebsiella spp. bacteremia during 2017–2019. We assessed risk factors of 1-year recurrence using Fine–Gray regression models. Of the 3,617 patients included, 291 (8.0%) had >1 recurrence episode. Third-generation cephalosporin (3GC)-resistance was significantly associated with increased recurrence risk after incident Klebsiella spp. (hazard ratio 3.91 [95% CI 2.32–6.59]) or E. coli (hazard ratio 2.35 [95% CI 1.50–3.68]) bacteremia. Methicillin resistance in S. aureus bacteremia had no effect on recurrence risk. Although several underlying conditions and infection sources increased recurrence risk, 3GC-resistant Klebsiella spp. was associated with the greatest increase. These results demonstrate a new facet to illness induced by 3GC-resistant Klebsiella spp. and E. coli in the community setting.

Abstract Stress in early life can affect the progeny and increase the risk to develop psychiatric and cardiometabolic diseases across generations. The cross-generational effects of early life stress have been modeled in mice and demonstrated to be associated with epigenetic factors in the germline. While stress is known to affect gut microbial features, whether its effects can persist across life and be passed to the progeny is not well defined. Here we show that early postnatal stress in mice shifts the fecal microbial composition (binary Jaccard index) throughout life, including abundance of eight amplicon sequencing variants (ASVs). Further effects on fecal microbial composition, structure (weighted Jaccard index), and abundance of 16 ASVs are detected in the progeny across two generations. These effects are not accompanied by changes in bacterial metabolites in any generation. These results suggest that changes in the fecal microbial community induced by early life traumatic stress can be perpetuated from exposed parent to the offspring.

Polymeric materials have long been at the forefront of materials science due to their exceptional physical and chemical properties. Designing new polymeric materials traditionally relies on a combination of physical and chemical principles along with empirical trial and error methods. A big issue in this approach is that the traditional trial and error experiments/simulations are often time consuming and sometimes inefficient in order to achieve targeted properties. Machine learning (ML) offers a promising solution to this issue. By leveraging ML algorithms, researchers can accelerate the design process, predict material properties more rapidly, and optimize formulations. ML approaches can analyze vast amounts of data, uncover hidden patterns, and generate predictive models that significantly reduce the time needed to develop materials with desired properties. This paradigm shift allows for more efficient exploration of the material space and faster innovation in polymeric material design. The current review article focuses on the application of ML methods to help design polymeric materials, more especifically, thermosets, thermoplastics and elastomers. Additionally, the review explores future possibilities and opportunities arising from the state-of-the-art advancements in ML, offering perspectives on how these technologies might evolve and influence the polymer science domain.

Abstract Introduction This study evaluates the clinical value of a deep learning–based artificial intelligence (AI) system that performs rapid brain volumetry with automatic lobe segmentation and age‐ and sex‐adjusted percentile comparisons. Methods Fifty‐five patients—17 with Alzheimer's disease (AD), 18 with frontotemporal dementia (FTD), and 20 healthy controls—underwent cranial magnetic resonance imaging scans. Two board‐certified neuroradiologists (BCNR), two board‐certified radiologists (BCR), and three radiology residents (RR) assessed the scans twice: first without AI support and then with AI assistance. Results AI significantly improved diagnostic accuracy for AD (area under the curve −AI: 0.800, +AI: 0.926, p

Abstract Effective photoinduced charge transfer makes molecular bimetallic assemblies attractive for applications as active light‐induced proton reduction systems. Developing competitive base metal dyads is mandatory for a more sustainable future. However, the electron transfer mechanisms from the photosensitizer to the proton reduction catalyst in base metal dyads remain so far unexplored. A Fe─Co dyad that exhibits photocatalytic H2 production activity is studied using femtosecond X‐ray emission spectroscopy, complemented by ultrafast optical spectroscopy and theoretical time‐dependent DFT calculations, to understand the electronic and structural dynamics after photoexcitation and during the subsequent charge transfer process from the FeII photosensitizer to the cobaloxime catalyst. This novel approach enables the simultaneous measurement of the transient X‐ray emission at the iron and cobalt K‐edges in a two‐color experiment. With this methodology, the excited state dynamics are correlated to the electron transfer processes, and evidence of the Fe→Co electron transfer as an initial step of proton reduction activity is unraveled.

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Introduction Germany and the European Union have experienced successive waves of refugees since 2014, resulting in over 1.6 million arrivals, including families with young children. These vulnerable populations often face xenophobia, discrimination, substandard living conditions and limited healthcare access, contributing to a high prevalence of mental health problems (MHP). Our primary goal is to proactively address MHP in refugee parents and prevent its potential impact on their children through effective early interventions. Using a low-threshold, primary care-based approach, we aim to enhance parenting skills and address parental psychopathology, creating a supportive environment for parents and children.Methods and analysis In this randomised controlled trial, 188 refugee parents of 6-year-old children or younger who meet the clinical cut-off on the MHP scale will participate. They are randomly assigned to either the experimental psychotherapeutic intervention, delivered by general practitioners (10-week Improve intervention), or treatment as usual, in a ratio of 1:1. The randomisation will be masked only for outcome assessors. Improve includes face-to-face sessions with general practitioners, an interactive online parenting programme (Triple P Online) and regular protocol-based telephone calls by psychologists. Primary outcomes will assess the intervention’s effects on parental and child MHP and parenting skills, with secondary outcomes including psychosocial and physical health indicators. Outcomes will be assessed at pre, post and at 3-month and 6-month follow-ups. The study is scheduled to run from February 2019 to July 2025.Ethics and dissemination The project Improve-MH (application number 602) was approved by the local ethics committee of Ruhr-University of Bochum and is being conducted in accordance with the Declaration of Helsinki. The study is also conducted in full accordance with the German Data Protection Act, and the Good Clinical Practice guideline (GCP) and is sensitive to specific ethical considerations. Results will be disseminated at scientific conferences, published in peer-reviewed journals and provided to consumers of healthcare.Trial registration number The trial was prospectively registered at the German Clinical Trials Register (Deutsches Register Klinischer Studien, DRKS-ID: DRKS00019072) on 16 March 2020.

Transboundary water management in the Sixaola basin, shared by Costa Rica and Panama, has historically involved significant contributions from third parties. This study investigates their evolving roles and the implications for governance in this context. We conducted a comprehensive analysis of non-State actors interventions over time, focusing on changes in strategies, priorities, and their impact on transboundary basin governance. Our findings indicate that while non-state actor initiatives have attracted attention and financial resources, they have also introduced significant governance challenges, leading to inconsistencies in basin development. The analysis reveals that limited governmental involvement and the technocratic turn in development strategies have raised questions about basin development and its tangible impacts. Additionally, reterritorialization efforts highlight a local tendency to better align existing functional spaces with local concerns. This study contributes to the literature on transboundary basin management by providing insights into the multifaceted role of non-state actors in the Sixaola basin. It explores a case where governments remain distant in defining governance systems, highlighting the added value of focusing on non-state actors to grasp the complexity of hydropolitics and discussing the politics of river basin development.

IntroductionPosterior circulation stroke can lead to ataxia, manifesting in a loss of coordination and balance. Patients experience difficulty in activities of daily living and an increased risk of falling, both profoundly affecting quality of life. In individuals with neurodegenerative diseases, coordination exercises have been shown to lead to a reduction in ataxic symptoms. There is, however, limited evidence on the effect of physical therapy, specifically coordination exercises in patients with stroke-related ataxia. We therefore present a study protocol for a prospective trial.MethodsThe purpose of this trial is to investigate the effects of coordination exercises compared to standard physiotherapy on balance and walking in ataxic stroke patients. Therefore, a prospective, single-blinded randomized controlled trial is currently ongoing at the Clinical Department of Neurology, Medical University of Innsbruck, Austria, in collaboration with two local rehabilitation facilities in Austria, Hochzirl Hospital and the Clinic for Rehabilitation Münster. Balance is the primary outcome of the study as assessed using the Berg Balance Scale. Secondary outcomes are concerned with walking, risk and number of falls, independence in daily life, and quality of life, rated using appropriate scales and scores. Patients are allocated applying a 1:1 ratio and a stratified block randomization. In both groups recruited individuals undergo five 45-min treatment sessions per week, totaling 20 sessions of coordination exercises (IG) or standard physiotherapy (CG) over the course of 4 weeks. Data is collected at the baseline (T0), after the 4-week supervised practice (T1), and after another 8 weeks of independent home-based training (T2).DiscussionThis is the first randomized controlled trial investigating the effects of coordination exercises on balance and walking in people with stroke-related ataxia. As stroke guidelines emphasize the limited evidence of treatment for ataxic symptoms, this study aims to contribute further knowledge regarding tailored interventions for these patients.Clinical Trial RegistrationGerman Clinical Trials Registry (drks.de). Identifier: DRKS00020825.

Introduction The early detection of pancreatic cancer is an important step in reducing mortality by offering patients curative treatment. Screening strategies in risk populations and by means of different detection methods have been economically evaluated. However, a synthesis of screening studies to inform resource allocation towards early detection within the disease area has not been done. Therefore, studies evaluating the cost-effectiveness and costs of screening for pancreatic cancer should be systematically reviewed.Methods and analysis A systematic review of economic evaluations reporting the cost-effectiveness or costs of pancreatic cancer screening will be conducted. The electronic databases Medline, Web of Science and EconLit will be searched without geographical or time restrictions. Two independent reviewers will select eligible studies based on predefined criteria. The study quality will be assessed using the Consolidated Health Economic Evaluation Reporting Standards statement and the Bias in Economic Evaluation checklist. One reviewer will extract relevant data and a second reviewer will cross-check compliance with the extraction sheet. Key items will include characteristics of screened individuals, the screening strategies used, and costs, health effects and cost-effectiveness as study outputs. Differences of opinion between the reviewers will be solved by consulting a third reviewer.Ethics and dissemination Ethics approval is not required for this study since no original data will be collected. The results will be disseminated through presentations at conferences and publication in a peer-reviewed journal. The results of the systematic review will inform future economic evaluations of pancreatic screening, which provide guidance for decision-making in healthcare resource prioritisation.PROSPERO registration number CRD42023475348.

BackgroundIn research on instructional quality, the generic model of the three basic dimensions is an established framework, which postulates that the three dimensions of classroom management, student support and cognitive activation represent quality characteristics of instruction that can be generalized across subjects. However, there are hardly any studies that examine if the three basic dimensions model could represent a suitable approach to measure instructional quality in physical education. Based on an extended model of the basic dimensions, a measurement model of instructional quality for physical education is presented, which integrates different theoretical approaches from the fields of educational and psychological research as well as different subfields of sports science in order to test the factorial structure of the corresponding measurement model.Methods1,047 students from 72 seventh to ninth grade classes from different German-speaking Swiss cantons participated in the study. The conceptualization of the instrument is based on a hybrid approach that integrates generic and subject-specific characteristics. The simultaneous analysis at the individual and class level using MCFA was supplemented by more complex methodological techniques within the relatively new B-ESEM framework at the individual level.ResultsThe postulated five-factor structure was initially tested using ICM-CFA and showed a good model fit (e.g., χ2/df = 2.32, RMSEA = 0.03, CFI = 0.97, TLI = 0.97, SRMR = 0.04). MCFA revealed a differential factorial structure at both levels of analysis with five factors at the individual level and four factors at the class level (e.g., χ2/df = 2.23, RMSEA = 0.03, CFI = 0.96, TLI = 0.96, SRMR within = 0.04, SRMR between = 0.10). ESEM and B-ESEM outperformed the ICM-CFA and showed an excellent model fit (B-ESEM: χ2/df = 1.19, RMSEA = 0.01, CFI = 1.00, TLI = 1.00, SRMR = 0.01). Inter-factor correlations and factor loadings are largely in line with expectations, indicating arguments for construct validity.DiscussionThe study represents a substantial contribution in linking physical education and the generic research on instructional quality. Overall, strong arguments for the factorial structure of the measurement model were demonstrated. The study can be interpreted as a first step in a multi-step procedure in terms of further validity arguments.

Designs using planned missingness, such as the split questionnaire design, are becoming more and more important in social survey research. To ensure an acceptable questionnaire length, these approaches typically entail large amounts of planned missing data, which can be imputed after data collection. However, social surveys typically also include other types of missingness such as item nonresponse by survey participants, which need to be imputed as well. This entails a complex imputation task with amounts of missing data larger than initially planned and a potentially non-random, heterogeneous mechanism. Yet, it remains to be studied whether accurate multiple-imputation estimates can be obtained in practice with planned missingness and item nonresponse. To deal with this research gap, we apply a Monte Carlo simulation study using real social survey data. In this study, we simulate missing data based on item nonresponse with different mechanisms and proportions of item nonresponse as well as different proportions of planned missing data. We find that item nonresponse can jeopardize the quality of estimates after multiple imputation especially when the total amount of missing data from both sources is high or when there is a considerable proportion of item nonresponse that is missing not at random. Therefore, from an imputation perspective, survey designers should incorporate their expectations about item nonresponse on each variable when designing surveys with planned missing data.

Abstract Three quarters of all breast cancers express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancer, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and without direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry based proteomic approach to profile the protein and phosphoprotein differences in breast cancer cell lines expressing the frequent Y537N and Y537S ER mutations. Global proteome analysis revealed enrichment of mitotic and immune signaling pathways in ER mutant cells, while phosphoprotein analysis evidenced enriched activity of proliferation associated kinases, in particular CDKs and mTOR. Integration of protein expression and phosphorylation data revealed pathway-dependent discrepancies (motility vs proliferation) that were observed at varying degrees across mutant and wt ER cells. Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells. Our study is the first proteome-centric characterization of ESR1 mutant models, out of which we confirm estrogen independence of ER mutants and reveal the enrichment of immune signaling pathways at the proteomic level.

High-performance polymers are extensively used in various applications undergoing long-term cyclic loadings. The deformation behaviour of an amorphous thermoset epoxy resin undergoing cyclic compressive loading is investigated for a range of applied deformation levels. The measurements indicate significant hysteresis upon repeated loading and unloading cycles with progressive accumulation of plastic strain. Cyclic damage leads to a reduction of the stress needed to reach the peak strain per cycle, while cyclic stiffening corresponding to an increase of elastic modulus with increasing number of cycles is observed, attributed to chain orientation effects. The dissipated energy asymptotically decreases to zero under strain-controlled cycling conditions. Interestingly, when monotonically loaded after cycling, the epoxy exhibits an increase in yield strength. This ‘re-yield’ stress level is closely related to the selected value of the peak (unloading) strain level and increases with increasing number of loading cycles.

Abstract The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions.

Abstract HER2/ERBB2 evaluation is necessary for treatment decision-making in breast cancer (BC), however current methods have limitations and considerable variability exists. DNA copy number (CN) evaluation by droplet digital PCR (ddPCR) has complementary advantages for HER2/ERBB2 diagnostics. In this study, we developed a single-reaction multiplex ddPCR assay for determination of ERBB2 CN in reference to two control regions, CEP17 and a copy-number-stable region of chr. 2p13.1, validated CN estimations to clinical in situ hybridization (ISH) HER2 status, and investigated the association of ERBB2 CN with clinical outcomes. 909 primary BC tissues were evaluated and the area under the curve for concordance to HER2 status was 0.93 and 0.96 for ERBB2 CN using either CEP17 or 2p13.1 as reference, respectively. The accuracy of ddPCR ERBB2 CN was 93.7% and 94.1% in the training and validation groups, respectively. Positive and negative predictive value for the classic HER2 amplification and non-amplification groups was 97.2% and 94.8%, respectively. An identified biological “ultrahigh” ERBB2 ddPCR CN group had significantly worse survival within patients treated with adjuvant trastuzumab for both recurrence-free survival (hazard ratio, HR: 3.3; 95% CI 1.1–9.6; p = 0.031, multivariable Cox regression) and overall survival (HR: 3.6; 95% CI 1.1–12.6; p = 0.041). For validation using RNA-seq data as a surrogate, in a population-based SCAN-B cohort (NCT02306096) of 682 consecutive patients receiving adjuvant trastuzumab, the ultrahigh-ERBB2 mRNA group had significantly worse survival. Multiplex ddPCR is useful for ERBB2 CN estimation and ultrahigh ERBB2 may be a predictive factor for decreased long-term survival after trastuzumab treatment.

Optically responsive materials are applied in sensing, actuators, and optical devices. One such class of material is dye-doped liquid crystal polymers that self-assemble into cholesteric mesophases that reflect visible light. We report here the synthesis and characterization of a family of linear and mildly crosslinked terpolymers prepared by the ROMP of norbornene-based monomers. The three monomers were composed of (i) rhodamine dye through one or two norbornene end groups utilizing flexible C10-alkane spacers, (ii) a cholesteryl liquid crystal (LC) using C9-alkane spacers, and (iii) PEG side chains. We investigated how these architectural variations in these terpolymers impacted their hierarchically self-assembled mesophase properties. We probed their composition, morphology, thermal, mechanic, photochromic, and mechanochromic properties using, inter alia, 1H NMR spectroscopy, DSC, temperature-dependent SAXS, diffuse reflectance UV-vis spectroscopy, and optical polarization microscopy. The new terpolymers exhibited architecture-dependent thermochromic, mechanochromic, and piezochromic properties arising from LC–rhodamine dye interactions. We found that a compromise between the rigidity and flexibility of the terpolymer architectures needed to be stricken to fully express stimuli-responsive properties. These terpolymers also showed distinctly different properties compared to those of a previously reported structurally related liquid crystalline copolymer made from two monomers. These findings help to define the design principles for optimally stimuli-responsive liquid crystalline polymers.

Background: The rise in carbapenem-resistant Enterobacteriaceae (CRE) in Egypt, particularly in hospital settings, poses a significant public health challenge. This study aims to develop a combined epidemiological surveillance tool utilizing the Microreact online platform (version 269) and molecular microarray technology to track and analyze carbapenem-resistant Escherichia coli strains in Egypt. The objective is to integrate molecular diagnostics and real-time data visualization to better understand the spread and evolution of multidrug-resistant (MDR) bacteria. Methods: The study analyzed 43 E. coli isolates collected from Egyptian hospitals between 2020 and 2023. Nanopore sequencing and microarray analysis were used to identify carbapenemase genes and other resistance markers, whereas the VITEK2 system was employed for phenotypic antibiotic susceptibility testing. Microreact was used to visualize epidemiological data, mapping the geographic and temporal distribution of resistant strains. Results: We found that 72.09% of the isolates, predominantly from pediatric patients, carried the blaNDM-5 gene, while other carbapenemase genes, including blaOXA-48 and blaVIM, were also detected. The microarray method demonstrated 92.9% diagnostic sensitivity and 87.7% diagnostic specificity compared to whole-genome sequencing. Phenotypic resistance correlated strongly with next-generation sequencing (NGS) genotypic data, achieving 95.6% sensitivity and 95.2% specificity. Conclusions: This method establishes the utility of combining microarray technology, NGS and real-time data visualization for the surveillance of carbapenem-resistant Enterobacteriaceae, especially E. coli. The high concordance between genotypic and phenotypic data underscores the potential of DNA microarrays as a cost-effective alternative to whole-genome sequencing, especially in resource-limited settings. This integrated approach can enhance public health responses to MDR bacteria in Egypt.