Search

Abstract Background Appropriate use of medication is a key indicator of the quality of care provided in long-term care (LTC). The objective of this study was to determine whether resident-facility language concordance/discordance is associated with the odds of potentially inappropriate prescribing of antipsychotics (PIP-AP) in LTC. Methods We conducted a population-based, retrospective cohort study of LTC residents in Ontario, Canada from 2010 to 2019. We obtained resident language from standardized resident assessments, and derived facility language by determining the proportion of residents belonging to each linguistic group within individual LTC homes. Using linked administrative databases, we identified all instances of PIP-AP during a 1-year follow-up period. PIP-AP was defined using the STOPP-START criteria, which have previously been shown to predict adverse clinical events such as emergency department (ED) visits and hospitalizations. The association between linguistic factors and PIP-AP was assessed using adjusted multivariable logistic regression analysis. Results We identified 198,729 LTC residents consisting of 162,814 Anglophones (81.9%), 6,230 Francophones (3.1%), and 29,685 Allophones (14.9%). The odds of PIP-AP of were higher for both Francophones (aOR 1.15, 95% CI 1.08–1.23) and Allophones (aOR 1.11, 95% CI 1.08–1.15) when compared to Anglophones. When compared to English LTC homes, French LTC homes had greater odds of PIP-AP (aOR 1.12, 95% CI 1.05–1.20), while Allophone homes had lower odds of PIP-AP (aOR 0.82, 95% CI 0.77–0.86). Residents living in language-discordant LTC homes had higher odds of PIP-AP when compared to LTC residents living in language-concordant LTC homes (aOR 1.07, 95% CI 1.04–1.10). Conclusion This study identified linguistic factors related to the odds of PIP-AP in LTC, suggesting that the linguistic environment may have an impact on the quality of care provided to residents.

Abstract Background INCbase is an international, multicenter prospective observational study using a customizable web-based modular registry to study the clinical, biological and electrophysiological variation and boundaries of chronic inflammatory demyelinating polyneuropathy (CIDP). The primary objective of INCbase is to develop and validate a clinical prediction model for treatment response. Methods All patients meeting clinical criteria for CIDP can be included in INCbase. Collected data include demographics, clinical history, diagnostics and various domains of clinical outcomes. Data is collected at a minimum of every 6 months for two years, and more frequently at the discretion of the investigational site to allow for assessment of unexpected changes in treatment response or clinical status. Participants can be enrolled in various sub-studies designed to capture data relevant to specific groups of interest. Data is entered directly into the web-based data entry system by local investigators and/or participants. Collection and local storage of biomaterial is optional. To develop a clinical prediction model for treatment response, newly diagnosed patients with active disease warranting start of first-line treatment will be included. The study population will be split into a development and validation cohort. Univariate and multivariate logistic regression analysis will be used to identify and combine predictors at start of treatment for treatment response at six months. Model performance will be assessed through discrimination and calibration in an external validation cohort. The externally validated prediction model will be made available to researchers and clinicians on the INCbase website. Discussion With this study, we aim to create a clinically relevant and implementable prediction model for treatment response to first line treatments in CIDP. INCbase enrollment started in April 2021, with 29 centers across 8 countries and 303 patients participating to date. This collaborative effort between academia, patient advocacy organizations and pharmaceutical industry will deepen our understanding of how to diagnose and treat CIDP.

Abstract Background Although adequate physical activity has been shown to be beneficial in early breast cancer, evidence in metastatic breast cancer is sparse and contradictory, which could be related to distinct effects of physical activity on the different molecular cancer subtypes. Therefore, we here evaluated the effect of physical activity on progression-free and overall survival (PFS, OS) in metastatic breast cancer, specifically looking at molecular subtypes. Methods International Physical Activity Questionnaire (IPAQ) questionnaires, filled out by patients enrolled in the prospective PRAEGNANT registry (NCT02338167; n = 1,270) were used to calculate metabolic equivalent task (MET) minutes, which were subsequently categorized into low (n = 138), moderate (n = 995) or high IPAQ categories (n = 137). Cox regression analyses were used to evaluate the impact of IPAQ categories and its interaction with molecular subtypes on PFS and OS. Results Patient and tumor characteristics were equally distributed across IPAQ categories. HER2pos, HRpos and TNBC were present in 23.1%, 65.7% and 11.2% of patients, respectively. IPAQ scores did not have an impact on PFS and OS in addition to established prognostic factors, either overall or in particular molecular subtypes (PFS: p = 0.33 and OS: p = 0.08, likelihood ratio test). Exploratory analyses showed higher overall survival rates for high IPAQ categories compared to low/moderate IPAQ categories in luminal B-like breast cancer. Conclusions Self-reported physical activity using the IPAQ questionnaire did not significantly affect PFS or OS in patients suffering from metastatic breast cancer. Nevertheless, some hypothesis-generating differences between molecular subtypes could be observed, which may be interesting to evaluate further.

Abstract Aims Interatrial shunts are under evaluation as a treatment for heart failure (HF); however, their in vivo flow performance has not been quantitatively studied. We aimed to investigate the fluid dynamics properties of the 0.51 cm orifice diameter Ventura shunt and assess its lumen integrity with serial transesophageal echocardiography (TEE). Methods and results Computational fluid dynamics (CFD) and bench flow tests were used to establish the flow‐pressure relationship of the shunt. Open‐label patients from the RELIEVE‐HF trial underwent TEE at shunt implant and at 6 and 12 month follow‐up. Shunt effective diameter (Deff) was derived from the vena contracta, and flow was determined by the continuity equation. CFD and bench studies independently validated that the shunt's discharge coefficient was 0.88 to 0.89. The device was successfully implanted in all 97 enrolled patients; mean age was 70 ± 11 years, 97% were NYHA class III, and 51% had LVEF ≤40%. Patency was confirmed in all instances, except for one stenotic shunt at 6 months. Deff remained unchanged from baseline at 12 months (0.47 ± 0.01 cm, P = 0.376), as did the trans‐shunt mean pressure gradient (5.1 ± 3.9 mmHg, P = 0.316) and flow (1137 ± 463 mL/min, P = 0.384). TEE measured flow versus pressure closely correlated (R2 ≥ 0.98) with a fluid dynamics model. At 12 months, the pulmonary/systemic flow Qp/Qs ratio was 1.22 ± 0.12. Conclusions When implanted in patients with advanced HF, this small interatrial shunt demonstrated predictable and durable patency and performance.

Abstract This article has been co-authored by a patient living with hereditary transthyretin (ATTRv) amyloidosis and a neurologist. This rare, progressive disease is associated with impairment of multiple organ systems, including the nerves, heart, and the gastrointestinal tract, forcing patients to live with and adapt to a range of debilitating symptoms. Here, the patient and physician discuss how the symptoms of ATTRv amyloidosis profoundly impact day to day life, the difficulties with identifying the disease, and how this effects the diagnosis experience. In recent years, significant advancements have been made in the treatment and management of ATTRv amyloidosis. However, the authors highlight the urgency of increasing awareness of the disease among the wider medical community, as well as in patients who notice the symptoms, to ensure that earlier diagnosis and appropriate treatment are achieved.

Abstract VegDischarge v1, which covers over 64,000 river segments in Africa, is a natural river discharge dataset produced by coupled modeling; the agro-hydrologic VegET model and the mizuRoute routing model for the period 2001-2021. Using remote sensing data and hydrological modeling system, the 1-km runoff field simulated by VegET, was routed with mizuRoute. Performance metrics show strong model reliability, with R² of 0.5–0.9, NSE of 0.6–0.9, and KGE of 0.5–0.8 at the continental scale. The total average annual discharge for Africa is quantified at 3271.4 km³·year−1, with contributions to oceanic basins: 1000.0 km³·year−1 to the North Atlantic, primarily from the Senegal, Gambia, Volta, and Niger Rivers; 1327.2 km³·year−1 to the South Atlantic, largely from the Congo River; 214.7 km³·year−1 to the Mediterranean Sea, predominantly from the Nile River; and 729.4 km³·year−1 to the Indian Ocean, with inputs from rivers such as the Zambezi. The dataset is valuable for stakeholders and researchers to understand water availability, its temporal and spatial variations that affect water-related infrastructure planning, sustainable resource allocation, and the development of climate resilience strategies.

Abstract Background The purpose of the Accelerating Colorectal Cancer Screening and Follow-up through Implementation Science (ACCSIS) Program, a Cancer Moonshot℠ Initiative, is to support research to build the evidence base on multilevel interventions that increase rates of colorectal cancer screening, follow-up, and referral to care to address disparities in colorectal cancer screening. The National Cancer Institute funded eight Research Projects to implement multilevel interventions to improve colorectal cancer screening among communities who traditionally have been medically underserved. To analyze the impact of ACCSIS across Research Projects, the consortium developed a set of common data elements. The purpose of this paper is to describe the process of developing the common data elements to facilitate analysis of ACCSIS data as well as support and inform implementation science research studies. Methods The ACCSIS Data, Design, and Analysis Work Group was tasked with designing common data elements through a review of existing data collection instruments, examination of data elements proposed by the ACCSIS Research Projects, and deliberations on the data required to compare across the Research Projects. ACCSIS Consortium members drafted, revised, and finalized a common data elements document consisting of variables to collect and surveys to administer to evaluate ACCSIS implementation activities and outcomes in a standardized manner across the Research Projects. Results The ACCSIS Consortium decided to collect the following categories of common data elements: characteristics across multiple levels of the multicomponent interventions, implementation climate, and determinants; interventions and strategies; implementation outcome constructs and definitions; colorectal cancer screening episodes (screening, diagnostic testing follow-up, cancer detection, and cancer treatment); and cost measures. To assess implementation climate, the consortium prioritized constructs from five domains of the Consolidated Framework for Implementation Research. Conclusions The ACCSIS common data elements offer a set of harmonization data for future implementation efforts. The consortium is conducting a systematic assessment using both quantitative and qualitative approaches to assess data quality and approaches to improve and sustain data collection. Lessons learned from these ongoing activities will offer additional insights to tailor the ACCSIS common data elements and support efforts to increase colorectal cancer screening for populations experiencing disparities.

Abstract Accurate, unbiased, and reproducible assessment of skill is a vital resource for surgeons throughout their career. The objective in this research is to develop and validate algorithms for video-based assessment of intraoperative surgical skill. Algorithms to classify surgical video into expert or novice categories provide a summative assessment of skill, which is useful for evaluating surgeons at discrete time points in their training or certification of surgeons. Using a spatial-temporal neural network architecture, we tested the hypothesis that explicit supervision of spatial attention supervised by instrument tip locations improves the algorithm’s generalizability to unseen dataset. The best performing model had an area under the receiver operating characteristic curve (AUC) of 0.88. Augmenting the network with supervision of spatial attention improved specificity of its predictions (with small changes in sensitivity and AUC) and led to improved measures of discrimination when tested with unseen dataset. Our findings show that explicit supervision of attention learned from images using instrument tip locations can improve performance of algorithms for objective video-based assessment of surgical skill.

Abstract The island of Sri Lanka was part of the South Asian mainland for the majority of the past 115,000 years, and connected most recently during the Last Glacial Maximum via the now submerged Palk Strait. The degree to which rising sea levels shaped past human adaptations from the Pleistocene and into the mid to late Holocene in Sri Lanka has remained unclear, in part because the earliest reliable records of human occupation come from the island’s interior, where cave sites have revealed occupation of tropical forest ecosystems extending back to 48 thousand years (ka). The island’s earliest known open-air sites are all much younger in date, with ages beginning at 15 ka and extending across the Holocene. Here we report the earliest well-dated open-air coastal site in Sri Lanka, Pathirajawela, which records human occupation back to ca. 25,000 years ago. We show that humans at Pathirajawela consistently adapted to changing ecosystems linked to sea level transgression and coastal evolution from the Last Glacial Maximum into the Holocene. The presence of anthropogenic shell midden deposits at the site from ca. 4.8 ka, focused almost exclusively on a single taxon, indicates intensification of estuarine resource exploitation, as humans responded to opportunities presented by the formation of new coastal ecosystems.

Abstract Terpenoids are the largest class of natural products, found across all domains of life. One of the most abundant bacterial terpenoids is the volatile odorant 2-methylisoborneol (2-MIB), partially responsible for the earthy smell of soil and musty taste of contaminated water. Many bacterial 2-MIB biosynthetic gene clusters were thought to encode a conserved transcription factor, named EshA in the model soil bacterium Streptomyces griseus. Here, we revise the function of EshA, now referred to as Sg Enc, and show that it is a Family 2B encapsulin shell protein. Using cryo-electron microscopy, we find that Sg Enc forms an icosahedral protein shell and encapsulates 2-methylisoborneol synthase (2-MIBS) as a cargo protein. Sg Enc contains a cyclic adenosine monophosphate (cAMP) binding domain (CBD)-fold insertion and a unique metal-binding domain, both displayed on the shell exterior. We show that Sg Enc CBDs do not bind cAMP. We find that 2-MIBS cargo loading is mediated by an N-terminal disordered cargo-loading domain and that 2-MIBS activity and Sg Enc shell structure are not modulated by cAMP. Our work redefines the function of EshA and establishes Family 2B encapsulins as cargo-loaded protein nanocompartments involved in secondary metabolite biosynthesis.

Abstract The spatial and temporal dynamics of forces in cells coordinate essential behaviors like division, polarization, and migration. While intracellular signaling initiates contractile ring assembly during cell division, how mechanical forces coordinate division and their energetic costs remain unclear. Here, we develop an in vitro model where myosin-induced stress drives division-like shape changes in giant unilamellar vesicles (GUVs, liposomes). Myosin activity is controlled by light patterns globally or locally at the equator. Global activation causes slow, shallow cleavage furrows due to a tug-of-war between the equatorial and polar forces. By contrast, local activation leads to faster, deeper, and symmetric division as equatorial forces dominate. Dissociating the actin cortex at the poles is crucial for inducing significant furrowing. During furrowing, actomyosin flows align actin filaments parallel to the division plane, forming a contractile ring-like structure. Mechanical power is not greatest during contraction, but is maximized just before furrowing. This study reveals the quantitative relationship between force patterning and mechanical energy during division-like shape changes, providing insights into cell division mechanics.

Abstract Accelerating text input in augmentative and alternative communication (AAC) is a long-standing area of research with bearings on the quality of life in individuals with profound motor impairments. Recent advances in large language models (LLMs) pose opportunities for re-thinking strategies for enhanced text entry in AAC. In this paper, we present SpeakFaster, consisting of an LLM-powered user interface for text entry in a highly-abbreviated form, saving 57% more motor actions than traditional predictive keyboards in offline simulation. A pilot study on a mobile device with 19 non-AAC participants demonstrated motor savings in line with simulation and relatively small changes in typing speed. Lab and field testing on two eye-gaze AAC users with amyotrophic lateral sclerosis demonstrated text-entry rates 29–60% above baselines, due to significant saving of expensive keystrokes based on LLM predictions. These findings form a foundation for further exploration of LLM-assisted text entry in AAC and other user interfaces.

Background: Identification of high-impact chronic pain (HICP) among patients receiving total shoulder arthroplasty (TSA) may allow for the design and implementation of tailored pain interventions to address the negative impact on postoperative outcomes and quality of life. This analysis sought to determine if Patient-Reported Outcome Measurement Information System (PROMIS) measures could be used to estimate HICP status following TSA. Methods: This was a secondary analysis of a cohort of patients (n = 227) who received a TSA at a single, academic medical center, of whom 25 (11.5%) met HICP status postoperatively. Generalized linear models estimated HICP from each PROMIS measure of physical function, pain interference, sleep disturbance, anxiety, and dyspnea individually, then in a combined model. Area under the curve (AUC) was calculated using receiver operator characteristic curves to assess accuracy of each PROMIS measure to estimate HICP status for patients receiving TSA. Results: Bivariate generalized linear models and mean difference analyses revealed individuals with HICP had worse PROMIS scores in every included domain (all P values < .01). Only pain interference (AUC = 0.964) and physical function (AUC = 0.907) PROMIS measures met criteria (AUC > 0.850) to accurately predict HICP. A pain interference score ≥58.3 and/or a physical function score ≤41.2 could be used to estimate HICP from PROMIS measures in this cohort. Conclusion: Two PROMIS measures commonly administered in orthopedic surgery settings, physical function and pain interference, can be used to estimate HICP for patients receiving TSA. Further application and evaluation of these cutoff scores can be used to assist in refining assessment of outcomes for patients receiving TSA.

Abstract In a perfect world, scientists would develop analyses that are guaranteed to reveal the ground truth of a research question. In reality, there are countless viable workflows that produce distinct, often conflicting, results. Although reproducibility places a necessary bound on the validity of results, it is not sufficient for claiming underlying validity, eventual utility, or generalizability. In this work we focus on how embracing variability in data analysis can improve the generalizability of results. We contextualize how design decisions in brain imaging can be made to capture variation, highlight examples, and discuss how variability capture may improve the quality of results.

Abstract Deep single-cell multi-omic profiling offers a promising approach to understand and overcome drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML). Here, we combine single-cell ex vivo drug profiling (pharmacoscopy) with single-cell and bulk DNA, RNA, and protein analyses, alongside clinical data from 21 rrAML patients. Unsupervised data integration reveals reduced ex vivo response to the Bcl-2 inhibitor venetoclax (VEN) in patients treated with both a hypomethylating agent (HMA) and VEN, compared to those pre-exposed to chemotherapy or HMA alone. Integrative analysis identifies both known and unreported mechanisms of innate and treatment-related VEN resistance and suggests alternative treatments, like targeting increased proliferation with the PLK inhibitor volasertib. Additionally, high CD36 expression in VEN-resistant blasts associates with sensitivity to CD36-targeted antibody treatment ex vivo. This study demonstrates how single-cell multi-omic profiling can uncover drug resistance mechanisms and treatment vulnerabilities, providing a valuable resource for future AML research.

Abstract Animal foraging is an essential and evolutionarily conserved behavior that occurs in social and solitary contexts, but the underlying molecular pathways are not well defined. We discover that conserved autism-associated genes (NRXN1(nrx-1), NLGN3(nlg-1), GRIA1,2,3(glr-1), GRIA2(glr-2), and GLRA2,GABRA3(avr-15)) regulate aggregate feeding in C. elegans, a simple social behavior. NRX-1 functions in chemosensory neurons (ADL and ASH) independently of its postsynaptic partner NLG-1 to regulate social feeding. Glutamate from these neurons is also crucial for aggregate feeding, acting independently of NRX-1 and NLG-1. Compared to solitary counterparts, social animals show faster presynaptic release and more presynaptic release sites in ASH neurons, with only the latter requiring nrx-1. Disruption of these distinct signaling components additively converts behavior from social to solitary. Collectively, we find that aggregate feeding is tuned by conserved autism-associated genes through complementary synaptic mechanisms, revealing molecular principles driving social feeding.

Abstract The accurate characterization of local magnetic fields and temperature is vital for the design of electronic systems. To meet this imperative, we present a novel non-contact approach for simultaneous quantitative magnetic field imaging and temperature sensing using magnetooptics and a bismuth-doped yttrium iron garnet film with out-of-plane anisotropy. For the direct signal quantification, a Stokes polarization camera is employed in a conventional magnetooptical microscope. The magnetization in the garnet is modulated with an external magnetic field to continuously image the Faraday rotation at four distinct points along the saturating magnetization loop. The method enables sensing of the magnetooptical signal in saturation, the magnetooptical susceptibility, the temperature, and self-calibrated driftfree imaging of the out-of-plane magnetic field component. A spatial resolution of magnetic field in the micrometer range with millisecond exposure time is demonstrated. The method is verified by analyzing the stray magnetic field distribution of electrical current in a wire simultaneously to the Joule heating induced by the applied current.

Abstract Background Convalescent plasma (CP) reduced the mortality in COVID-19 induced ARDS (C-ARDS) patients treated in the CONFIDENT trial. As patients are immunologically heterogeneous, we hypothesized that clusters may differ in their treatment responses to CP. Methods We measured 20 cytokines, chemokines and cell adhesion markers using a multiplex technique at the time of inclusion in the CONFIDENT trial in patients of centers having accepted to participate in this secondary study. We performed descriptive statistics, unsupervised hierarchical cluster analysis, and examined the association between the clusters and CP effect on day-28 mortality. Results Of the 475 patients included in CONFIDENT, 391 (82%) were sampled, and 196/391 (50.1%) had been assigned to CP. We identified four sub-phenotypes representing 89 (22.8%), 178 (45.5%), 38 (9.7%), and 86 (22.0%) patients. The most contributing biomarkers in the principal component analysis were IL-1β, IL-12p70, IL-6, IFN-α, IL-17A, IFN-γ, IL-13, TFN-α, total IgG, and CXCL10. Sub-phenotype-1 displayed a lower immune response, sub-phenotype-2 a higher adaptive response, sub-phenotype-3 the highest innate antiviral, pro and anti-inflammatory response, and adhesion molecule activation, and sub-phenotype-4 a higher pro and anti-inflammatory response, migration protein and adhesion molecule activation. Sub-phenotype-2 and sub-phenotype-4 had higher severity at the time of inclusion. The effect of CP treatment on mortality appeared higher than standard care in each sub-phenotype, without heterogeneity between sub-phenotypes (p = 0.97). Conclusion In patients with C-ARDS, we identified 4 sub-phenotypes based on their immune response. These sub-phenotypes were associated with different clinical profiles. The response to CP was similar across the 4 sub-phenotypes. Trial registration: Ethics Committee of the University Hospital of Liège CE 2020/239. Clinicaltrials.gov NCT04558476. Registered 2020-09-11, https://www.clinicaltrials.gov/study/NCT04558476 .

Background: Oncocytic thyroid carcinoma (OTC) was previously considered a variant of follicular thyroid carcinoma (FTC) but has recently been reclassified as a separate form of thyroid cancer. This study aimed to demonstrate that FTC and OTC are fundamentally distinct entities that can potentially be differentiated preoperatively through cytology and/or molecular testing. Methods: A retrospective chart review of patients diagnosed with FTC and OTC operated upon at two university health centers from January 2016 to September 2023 (n = 3219) was conducted. Molecular testing results were correlated with histopathologic diagnosis. Results: Fifty patients met the inclusion criteria. FTC was identified in 27 (54.0%) patients, and OTC in 23 (46.0%) patients. Patients with OTC were older (61.8 years) than FTC patients (51.2 years) (p = 0.013). Moreover, aggressive tumors were found in 39.1% (9/23) of OTCs compared to 11.1% (3/27) of FTCs (p = 0.021). Amongst Bethesda category III and IV nodules, 17 out of 20 (85.0%) OTC cytology reports demonstrated an oncocytic subtype compared to only 5 out of 24 FTC cytology reports (20.8%) (p = 0.002). On molecular testing, the EIF1AX alteration was exclusively present in OTCs while the PAX8/PPARy and PTEN alterations were exclusively found in FTCs. Copy number alterations (CNAs) were found to be more prevalent in OTC (66.7%) compared to FTC (33.3%), and they were not indicative of tumor aggressiveness. Within the OTC group, all three patients who had a TP53 alteration were diagnosed with aggressive cancer. Lastly, the OTCs exhibited a higher frequency of multiple alterations on molecular testing (66.7%) compared to FTCs (33.3%). Conclusion: To our knowledge, this is the largest study to date comparing the clinical application of abnormalities found on molecular testing for FTC and OTC. It further demonstrates the distinct clinicopathological and molecular characteristics of OTC.

Abstract Background Understanding the frequency of violence experienced by female sex workers (FSWs) and how violence contributes to HIV transmission can help improve HIV programs. Methods Using recent recommendations for modelling structural factors and associated causal pathways, we developed a HIV transmission dynamic model for FSWs and their clients in Mombasa, Kenya, mechanistically representing three types of violence (sexual violence, SV; physical violence, PV; police assault and arrest, PAA). Each type of violence affects HIV transmission through key mediators (condom non-use, HIV testing). We parameterized the model using data from a cross-sectional study of FSWs aged 15–24 recruited from a systematic geographical mapping sampling frame in Mombasa, Kenya (Cheuk E et al., Frontiers in Reproductive Health 2(7), 2020). Using this model, calibrated (and cross-validated) to HIV epidemiological and violence outcomes, we estimated the incidence of violence episodes, the contribution of violence to the HIV epidemic measured by the transmission population-attributable fraction, and the potential impact of possible violence interventions. Results The median estimated incidence of PAA in 2023 among FSWs who had not previously experienced that type of violence was 0.20 (95% credible interval: 0.17–0.22) per person-year (ppy), about double the incidence of SV and PV (0.10 (0.09–0.11), 0.11 (0.09–0.12), respectively). The incidence of violence was higher among FSWs who had previously experienced violence: the incidence of recurrent PV was 2.65 (1.82–3.37) ppy, while the incidence of recurrent SV and PAA were 1.26 (0.80–1.67) and 1.37 (0.94–1.74 ppy, respectively. In this setting, we estimated that a median of 35.3% (3.4–55.8%) infections in FSWs and clients combined over the next 10 years may be due to all types of violence (and mediators), mainly through reduced condom use in FSWs who have ever experienced SV (34.6% (2.4–55.5%)). Interventions that prevent future violence without mitigating the effects of past violence may only prevent 8.8% (0.8–14.0%) infections over 10 years. Conclusions FSWs in Mombasa experience violence frequently. In this population, we find that addressing sexual violence, including mitigating the effects of past violence, is potentially important in reducing HIV transmission in this population. However, the wide uncertainty range shows longitudinal studies are needed to strengthen the evidence of the influence of violence on HIV risk behavior. We find that the recommendations for modelling structural factors provide a useful framework for describing the model.

Abstract Background Extracellular vesicles (EVs) are cell-secreted particles conceived as natural vehicles for intercellular communication. The capacity to entrap heterogeneous molecular cargoes and target specific cell populations through EV functionalization promises advancements in biomedical applications. However, the efficiency of the obtained EVs, the contribution of cell-exposed receptors to EV interactions, and the predictability of functional cargo release with potential sharing of high molecular weight recombinant mRNAs are crucial for advancing heterologous EVs in targeted therapy applications. Methods In this work, we selected the popular EV marker CD81 as a transmembrane guide for fusion proteins with a C-terminal GFP reporter encompassing or not Trastuzumab light chains targeting the HER2 receptor. We performed high-content imaging analyses to track EV-cell interactions, including isogenic breast cancer cells with manipulated HER2 expression. We validated the functional cargo delivery of recombinant EVs carrying doxorubicin upon EV-donor cell treatment. Then, we performed an in vivo study using JIMT-1 cells commonly used as HER2-refractory, trastuzumab-resistant model to detect a more than 2000 nt length recombinant mRNA in engrafted tumors. Results Fusion proteins participated in vesicular trafficking dynamics and accumulated on secreted EVs according to their expression levels in HEK293T cells. Despite the presence of GFP, secreted EV populations retained a HER2 receptor-binding capacity and were used to track EV-cell interactions. In time-frames where the global EV distribution did not change between HER2-positive (SK-BR-3) or -negative (MDA-MB-231) breast cancer cell lines, the HER2 exposure in isogenic cells remarkably affected the tropism of heterologous EVs, demonstrating the specificity of antiHER2 EVs representing about 20% of secreted bulk vesicles. The specific interaction strongly correlated with improved cell-killing activity of doxorubicin-EVs in MDA-MB-231 ectopically expressing HER2 and reduced toxicity in SK-BR-3 with a knocked-out HER2 receptor, overcoming the effects of the free drug. Interestingly, the fusion protein-corresponding transcripts present as full-length mRNAs in recombinant EVs could reach orthotopic breast tumors in JIMT-1-xenografted mice, improving our sensitivity in detecting penetrant cargoes in tissue biopsies. Conclusions This study highlights the quantitative aspects underlying the creation of a platform for secreted heterologous EVs and shows the limits of single receptor-ligand interactions behind EV-cell engagement mechanisms, which now become the pivotal step to predict functional tropism and design new generations of EV-based nanovehicles.

Abstract Background The purpose of this paper is to examine the evolution of physical activity research and the comprehensiveness of national physical activity policies and surveillance systems in Canada. Methods A systematic review was conducted by the Global Observatory for Physical Activity (GoPA! ) on physical activity and health publications between 1950 and 2019. Findings from Canada were extracted and included in the present analysis. The number of articles published, female researcher involvement in authorship, author institution affiliations, and publication themes were examined. Policies were evaluated by determining if there was a standalone physical activity plan and if national guidelines existed. Surveillance systems were assessed for periodicity, instruments used, and age inclusivity. Results Out of 23,000 + publications analyzed worldwide; 1,962 included data collected in Canada. Physical activity research in Canada increased considerably from the 2000s to 2010s (543 articles vs. 1,288 articles), but an apparent stabilization has been observed more recently. Most physical activity publications in Canada focused on surveillance (37%), with fewer articles on policy (8%) and interventions (7%). The proportion of female first authors increased from 38% in the 1980s to 60% in the last decade. However, females remain the minority for senior authors. With respect to policy, “A Common Vision” is Canada’s national plan, which has a singular policy focus on physical activity. National surveillance data is collected regularly with both the Canadian Health Measures Survey (CHMS) and the Canadian Community Health Survey. In addition to self-report, the CHMS also collects accelerometer data from participants. Conclusion Through collaborative and coordinated action, Canada remains well equipped to tackle physical inactivity. Continued efforts are needed to enhance sustained awareness of existing physical activity promotion resources to increase physical activity.

Abstract Polyolefins have a multitude of uses across packaging, automotive and construction sectors. Their resistance to degradation during reprocessing enables recyclability, but variability in recycled polymer feedstocks renders it difficult to assure their manufacturing suitability. The lack of quality control methods has disabled circular economy pathways; product failure is costly, wasteful and time-intensive. Using rheology-simulated and extrusion-based recycling experiments, we explore the degradation pathways of high-density polyethylene (HDPE). Chain scission dominates during the initial degradation of HDPE, and increasing exposure to O2 shifts the dominant mechanism to long-chain branching. Importantly, extending this method to post-consumer recyclate (PCR), the results show potential as a methodology to assess recyclate quality to enable a circular plastics economy. In this study, we establish the validity of this rheology simulation to define a characteristic degradation parameter, relating it to the structural evolution under different environments defined for virgin HDPE and post-consumer recyclate (PCR).

Abstract Cell survival under nutrient-deprived conditions relies on cells’ ability to adapt their organelles and rewire their metabolic pathways. In yeast, glucose depletion induces a stress response mediated by mitochondrial fragmentation and sequestration of cytosolic ribosomes on mitochondria. This cellular adaptation promotes survival under harsh environmental conditions; however, the underlying mechanism of this response remains unknown. Here, we demonstrate that upon glucose depletion protein synthesis is halted. Cryo-electron microscopy structure of the ribosomes show that they are devoid of both tRNA and mRNA, and a subset of the particles depicted a conformational change in rRNA H69 that could prevent tRNA binding. Our in situ structural analyses reveal that the hibernating ribosomes tether to fragmented mitochondria and establish eukaryotic-specific, higher-order storage structures by assembling into oligomeric arrays on the mitochondrial surface. Notably, we show that hibernating ribosomes exclusively bind to the outer mitochondrial membrane via the small ribosomal subunit during cellular stress. We identify the ribosomal protein Cpc2/RACK1 as the molecule mediating ribosomal tethering to mitochondria. This study unveils the molecular mechanism connecting mitochondrial stress with the shutdown of protein synthesis and broadens our understanding of cellular responses to nutrient scarcity and cell quiescence.

Abstract Here, we examined the potential role of mitochondrial DNA (mtDNA) levels in conveying aggressive phenotypes in cancer cells, using two widely-used breast cell lines as model systems (MCF7[ER+] and MDA-MB-231[ER-]). These human breast cancer cell lines were fractionated into mtDNA-high and mtDNA-low cell sub-populations by flow cytometry, using SYBR Gold as a vital probe to stain mitochondrial nucleoids in living cells. Enrichment of mtDNA-high and mtDNA-low cell sub-populations was independently validated, using a specific DNA-binding mAb probe (AC-30-10), and mitochondrial-based functional assays. As predicted, mtDNA-high MCF7 cells showed significant increases in mitochondrial mass, membrane potential, and superoxide production, as well as increased mitochondrial respiration and ATP production. Moreover, mtDNA-high MCF7 cells demonstrated increases in stemness features, such as anchorage-independent growth and CD44 levels, as well as drug-resistance to Gemcitabine and Tamoxifen. Proliferation rates were also significantly increased, with a dramatic shift towards the S- and G2/M-phases of the cell cycle; this was indeed confirmed by RNA-Seq analysis. Complementary results were obtained with MDA-MB-231 cells. More specifically, mtDNA-high MDA-MB-231 cells showed increases in stemness features and ATP production, as well as rapid cell cycle progression. Moreover, mtDNA-high MDA-MB-231 cells also exhibited increases in both cell migration and invasion, suggesting a role for mtDNA in distant metastasis. To test this hypothesis more directly, a preclinical in vivo model was utilized. For this purpose, MDA-MB-231 tumour cell grafts were treated with an established mtDNA synthesis inhibitor, namely Alovudine (3’-deoxy-3’-fluorothymidine). As expected, drug-induced depletion of mtDNA led to a shift from mitochondrial to glycolytic metabolism. Interestingly, Alovudine very effectively reduced the formation of spontaneous metastases by nearly 70%, but minimally inhibited tumour growth by approximately 20%. Taken together, these data suggest that high mtDNA content is a key driver of stemness, proliferation, and migration, as well as cancer cell metastasis.

Abstract Background It is challenging to predict long-term outcomes of interventions without understanding how they work. Health economic models of public health interventions often do not incorporate the many determinants of individual and population behaviours that influence long term effectiveness. The aim of this paper is to draw on psychology, sociology, behavioural economics, complexity science and health economics to: (a) develop a toolbox of methods for incorporating the influences on behaviour into public health economic models (PHEM-B); and (b) set out a research agenda for health economic modellers and behavioural/ social scientists to further advance methods to better inform public health policy decisions. Methods A core multidisciplinary group developed a preliminary toolbox from a published review of the literature and tested this conceptually using a case study of a diabetes prevention simulation. The core group was augmented by a much wider group that covered a broader range of multidisciplinary expertise. We used a consensus method to gain agreement of the PHEM-B toolbox. This included a one-day workshop and subsequent reviews of the toolbox. Results The PHEM-B toolbox sets out 12 methods which can be used in different combinations to incorporate influences on behaviours into public health economic models: collaborations between modellers and behavioural scientists, literature reviewing, application of the Behaviour Change Intervention Ontology, systems mapping, agent-based modelling, differential equation modelling, social network analysis, geographical information systems, discrete event simulation, theory-informed statistical and econometric analyses, expert elicitation, and qualitative research/process tracing. For each method, we provide a description with key references, an expert consensus on the circumstances when they could be used, and the resources required. Conclusions This is the first attempt to rigorously and coherently propose methods to incorporate the influences on behaviour into health economic models of public health interventions. It may not always be feasible or necessary to model the influences on behaviour explicitly, but it is essential to develop an understanding of the key influences. Changing behaviour and maintaining that behaviour change could have different influences; thus, there could be benefits in modelling these separately. Future research is needed to develop, collaboratively with behavioural scientists, a suite of more robust health economic models of health-related behaviours, reported transparently, including coding, which would allow model reuse and adaptation.

Abstract Background Stress is today a common feature of patients seeking medical care and a growing public health issue in society. A method has been developed to measure biological chronic stress by Hair Cortisol Concentrations (HCC). This biomarker, for chronic stress, captures information about cumulative cortisol levels over the course of several months. Long-term stress might be one of the factors contributing to the onset of cardiovascular conditions and also affecting different risk factors. The aim of this study was to analyse the association between Hair Cortisol Concentrations and previous cardiovascular diseases and cardiovascular risk factors. Methods The method of measuring chronic stress by Hair Cortisol Concentration was applied in a large Swedish national observational cross-sectional study. A population-based random sample of N = 4,821 Swedish middle-aged men and women was analysed for hair cortisol levels in relation to diagnosed previous cardiovascular diseases and biologically measured cardiovascular risk factors. Results Long-term stress, measured by hair cortisol, was significantly associated with the classical cardiovascular risk factors hypertension and high cholesterol, but not smoking. Those with elevated HCC levels also had a significantly increased pre-history of myocardial infarction, type 2 diabetes, atrial fibrillation and by-pass surgery, but not regarding stroke, angina pectoris or sleep apnoea. Higher HCC was significantly associated (p

Abstract Uropygial gland secretions of birds consist of host and bacteria derived compounds and play a major sanitary and feather-protective role. Here we report on our microbiome studies of the New Guinean toxic bird Pachycephala schlegelii and the isolation of a member of the Amycolatopsis genus from the uropygial gland secretions. Bioactivity studies in combination with co-cultures, MALDI imaging and HR-MS/MS-based network analyses unveil the basis of its activity against keratinolytic bacteria and fungal skin pathogens. We trace the protective antimicrobial activity of Amycolatopsis sp. PS_44_ISF1 to the production of rifamycin congeners, ciromicin A and of two yet unreported compound families. We perform NMR and HR-MS/MS studies to determine the relative structures of six members belonging to a yet unreported lipopeptide family of pachycephalamides and of one representative of the demiguisins, a new hexapeptide family. We then use a combination of phylogenomic, transcriptomic and knock-out studies to identify the underlying biosynthetic gene clusters responsible for the production of pachycephalamides and demiguisins. Our metabolomics data allow us to map molecular ion features of the identified metabolites in extracts of P. schlegelii feathers, verifying their presence in the ecological setting where they exert their presumed active role for hosts. Our study shows that members of the Actinomycetota may play a role in avian feather protection.

Abstract The seventh cholera pandemic started in 1961 in Indonesia and spread across the world in three waves in the decades that followed. Here, we utilised genomic evidence to detail the first wave of the seventh pandemic. Genomes of 22 seventh pandemic Vibrio cholerae isolates from 1961 to 1979 were completely sequenced. Together with 152 publicly available genomes from the same period, they fell into seven phylogenetic clusters (CL1–CL7). By multilevel genome typing (MGT), all were assigned to MGT2 ST1 (Wave 1) except three isolates in CL7 which were typed as MGT2 ST2 (Wave 2). The Wave 1 seventh pandemic expanded in two stages, with Stage 1 (CL1–CL5) spread across Asia and Stage 2 (CL6 and CL7) spread to the Middle East and Africa. Three non-synonymous mutations, one each, in three regulatory genes, csrD (global regulator), acfB (chemotaxis), and luxO (quorum sensing) may have critically contributed to its pandemicity. The three MGT2 ST2 isolates in CL7 were the progenitors of Wave 2 and evolved from within Wave 1 with acquisition of a novel IncA/C plasmid. Our findings provide new insight into the evolution and transmission of the early seventh pandemic, which may aid future cholera prevention and control.

Abstract The neurexin superfamily, consisting of neurexins and Casprs, play important roles in the development, maintenance, function, and plasticity of neuronal circuits. Caspr/CNTNAP genes are linked to alterations in neuronal circuits and associated with neurodevelopmental and neurodegenerative conditions. Casprs are implicated in multiple neuronal signaling pathways, including dopamine; however, the molecular mechanisms by which Casprs differentially alter specific signaling pathways and downstream behaviors are unclear. We find that the C. elegans Caspr nlr-1 functions in neurons to control foraging behaviors, acting in distinct monoamine neurons to modulate locomotor activity in the presence or absence of food. nlr-1 functions in dopamine neurons to reduce activity in the absence of food, similar to the role of dopamine, and regulates dopamine signaling through D2-like receptors. Furthermore, nlr-1 contributes to proper morphology and presynaptic structure of dopamine neurons, dopamine receptor expression and localization, and the behavioral response to dopamine. We find that nlr-1 similarly regulates another dopamine-dependent behavior, the basal slowing response. Therefore, spatial manipulation of a broadly expressed neuronal gene is sufficient to alter neural circuits and behavior and uncovers important functions masked by global manipulation, highlighting the importance of genetic variation and mechanisms that impact spatial expression of genes to behavior.

Abstract Background Sulfate-reducing bacteria (SRB) are frequently encountered in anoxic-to-oxic transition zones, where they are transiently exposed to microoxic or even oxic conditions on a regular basis. This can be marine tidal sediments, microbial mats, and freshwater wetlands like peatlands. In the latter, a cryptic but highly active sulfur cycle supports their anaerobic activity. Here, we aimed for a better understanding of how SRB responds to periodically fluctuating redox regimes. Results To mimic these fluctuating redox conditions, a bioreactor was inoculated with peat soil supporting cryptic sulfur cycling and consecutively exposed to oxic (one week) and anoxic (four weeks) phases over a period of > 200 days. SRB affiliated to the genus Desulfosporosinus (Bacillota) and the families Syntrophobacteraceae, Desulfomonilaceae, Desulfocapsaceae, and Desulfovibrionaceae (Desulfobacterota) successively established growing populations (up to 2.9% relative abundance) despite weekly periods of oxygen exposures at 133 µM (50% air saturation). Adaptation mechanisms were analyzed by genome-centric metatranscriptomics. Despite a global drop in gene expression during oxic phases, the perpetuation of gene expression for energy metabolism was observed for all SRBs. The transcriptional response pattern for oxygen resistance was differentiated across individual SRBs, indicating different adaptation strategies. Most SRB transcribed differing sets of genes for oxygen consumption, reactive oxygen species detoxification, and repair of oxidized proteins as a response to the periodical redox switch from anoxic to oxic conditions. Noteworthy, a Desulfosporosinus, a Desulfovibrionaceaea, and a Desulfocapsaceaea representative maintained high transcript levels of genes encoding oxygen defense proteins even under anoxic conditions, while representing dominant SRB populations after half a year of bioreactor operation. Conclusions In situ-relevant peatland SRB established large populations despite periodic one-week oxygen levels that are one order of magnitude higher than known to be tolerated by pure cultures of SRB. The observed decrease in gene expression regulation may be key to withstand periodically occurring changes in redox regimes in these otherwise strictly anaerobic microorganisms. Our study provides important insights into the stress response of SRB that drives sulfur cycling at oxic-anoxic interphases. Video Abstract

Abstract The use of compounds produced by hosts or symbionts for defence against antagonists has been identified in many organisms, including in fungus-farming termites (Macrotermitinae). The obligate mutualistic fungus Termitomyces plays a pivotal role in plant biomass decomposition and as the primary food source for these termites. Despite the isolation of various specialized metabolites from different Termitomyces species, our grasp of their natural product repertoire remains incomplete. To address this knowledge gap, we conducted a comprehensive analysis of 39 Termitomyces genomes, representing 21 species associated with members of five termite host genera. We identified 754 biosynthetic gene clusters (BGCs) coding for specialized metabolites and categorized 660 BGCs into 61 biosynthetic gene cluster families (GCFs) spanning five compound classes. Seven GCFs were shared by all 21 Termitomyces species and 21 GCFs were present in all genomes of subsets of species. Evolutionary constraint analyses on the 25 most abundant GCFs revealed distinctive evolutionary histories, signifying that millions of years of termite-fungus symbiosis have influenced diverse biosynthetic pathways. This study unveils a wealth of non-random and largely undiscovered chemical potential within Termitomyces and contributes to our understanding of the intricate evolutionary trajectories of biosynthetic gene clusters in the context of long-standing symbiosis.

Recent years have seen increasing public attention and, indeed, concern regarding Unidentified Anomalous Phenomena (UAP). Hypotheses for such phenomena tend to fall into two classes: a conventional terrestrial explanation (e.g., human-made technology) or an extraterrestrial explanation (i.e., advanced civilizations from elsewhere in the cosmos). However, there is also a third minority class of hypothesis: an unconventional terrestrial explanation, outside the prevailing consensus view of the universe. This is the ultraterrestrial hypothesis, which includes as a subset the “cryptoterrestrial” hypothesis, namely the notion that UAP may reflect activities of intelligent beings concealed in stealth here on Earth (e.g., underground), and/or its near environs (e.g., the moon), and/or even “walking among us” (e.g., passing as humans). Although this idea is likely to be regarded sceptically by most scientists, such is the nature of some UAP that we argue this possibility should not be summarily dismissed, and instead deserves genuine consideration in a spirit of epistemic humility and openness.

Objective: To evaluate whether major adverse cardiac events (MACE) continue to be a major causative factor for mortality after noncardiac surgery. Patients and Methods: We performed retrospective study of 75,410 adult noncardiac surgery patients at Mayo Clinic Rochester, between January 1, 2016, and May 4, 2018. Electronic medical records were reviewed and data collected on all deaths within 30 days (n=692 patients) of surgery. The incidence of death due to MACE was calculated. Results: Postoperative MACE occurred in 150 patients (21.4 events per 10,000 patients; 95% CI, 18.2-25.2 events per 10,000 patients) with most occurring within 3 days of surgery (n=113). Postoperative MACE events were associated with atrial fibrillation with rapid rate response in 25 patients (16.7%), sepsis in 15 patients (10%), and bleeding in 15 patients (10%). There were 12 intraoperative deaths of which 9 were due to exsanguination (75%) and the remaining 3 (25%) due to cardiac arrest. Of the 56 deaths on the first 24 hours after surgery, 7 were due to hemorrhage, 17 due to cardiovascular causes, 20 due to sepsis, and 7 due to neurologic disease. The leading cause of total death over 30 days postoperatively was sepsis (28%), followed by malignancy (27%), cardiovascular disease (12%) neurologic disease (12%), and hemorrhage (5%). Conclusion: MACE was not the leading cause of death both intraoperatively and postoperatively.

LoRa technology is a recent technology belonging to the Low Power and Wide Area Networks (LPWANs), which offers distinct advantages for wireless communications and possesses unique features. Among others, it can be used for localization procedures offering minimal energy consumption and quite long-range transmissions. However, the exact capabilities of LoRa localization performance are yet to be employed thoroughly. This article examines the efficiency of the LoRa technology in localization tasks using Time Difference of Arrival (TDoA) measurements. An extensive and concrete experimental study was conducted in a real-world setup on the University of Patras campus, employing both real-world data and simulations to assess the precision of geodetic coordinate determination. Through our experiments, we implemented advanced localization algorithms, including Social Learning Particle Swarm Optimization (PSO), Least Squares, and Chan techniques. The results are quite interesting and highlight the conditions and parameters that result in accurate LoRa-based localization in real-world scenarios in smart cities. In our context, we were able to achieve state-of-the-art localization results reporting localization errors as low as 300 m in a quite complex 8 km × 6 km real-world environment.

Abstract Bilirubin is one of the most frequently used laboratory values to monitor critically ill patients with cholestatic liver dysfunction. Besides bilirubin, toxic bile acids (TBAs), which may cause severe organ damage, are typically elevated. A correlation between both parameters seems plausible, but data are lacking. The aim was to investigate whether there is a correlation between bilirubin and TBAs in patients’ blood and whether a compareable reduction can be observed during the use of the adsorber CytoSorb (CS). As part of the Cyto-SOLVE study (NCT04913298), 16 critically ill patients with cholestatic liver dysfunction, bilirubin concentration > 10 mg/dl, continuous kidney replacement therapy and CS-application were investigated. Bilirubin and TBA concentrations were measured from arterial blood at defined time points (before start, after 6 and 12 h). Relative reduction (RR) was calculated using the formula $$\:\:{\boldsymbol{RR}}\:{\boldsymbol{\left(\%\right)}}=\frac{{\boldsymbol{concentration\left(pre-post\right)}}}{{\boldsymbol{concentration\left(pre\right)}}}*{\boldsymbol{100}}$$ . A moderate to high correlation between bilirubin and TBA concentration at all defined timepoints (rstart=0.64, p = 0.008; r6h = 0.85, p

Abstract Background In recent years, the number of forcibly displaced persons has risen worldwide, with approximately 40% being children and adolescents. Most of them are hosted in low- and middle-income countries (LMICs). Many individuals meet the criteria for mental health issues, which can also be exacerbated by a number of risk factors, including low socioeconomic status, displacement, and stressors linked to conflicts in their country or region of origin. However, the vast majority never receive treatment for their psychological problems due to multiple reasons, including a shortage of mental health professionals in LIMCs, transportation challenges in accessing clinics, and clinic hours conflicting with family commitments. In the current study we investigated whether individual psychotherapy delivered by trained lay counsellors over telephone to Syrian refugee children living in Lebanon is effective and overcomes barriers to treatment access. Methods After adaptation of Common Elements Treatment Approach (CETA) to remote delivery over telephone (t-CETA), preliminary effectiveness of the treatment modality was assessed with a pilot single blind randomised controlled trial including a total sample of 20 refugee children with diagnosed mental health problems. Data was analysed applying a Bayesian approach. Results There was a significant session-by-session decrease in self-reported mental health symptoms over the course of treatment. Independent assessments showed that t-CETA resulted in a greater reduction of symptoms than standard in-person treatment as usual. There was no difference between groups for impairment. Importantly, the majority of children allocated to t-CETA completed treatment whilst no children in the treatment as usual condition were able to do so. Conclusion The study provides preliminary evidence that telephone-delivered psychotherapy in a humanitarian setting, delivered by lay counsellors under supervision, works and significantly increases access to treatment compared to traditional in-person treatment. However, findings remain to be replicated in larger trials. Trial Registration Clinical Trials. gov ID: NCT03887312; registered 22nd March 2019.

Abstract Background Including structural determinants (e.g. criminalisation, stigma, inequitable gender norms) in dynamic HIV transmission models is important to help quantify their population-level impacts and guide implementation of effective interventions that reduce the burden of HIV and inequalities thereof. However, evidence-based modelling of structural determinants is challenging partly due to a limited understanding of their causal pathways and few empirical estimates of their effects on HIV acquisition and transmission. Methods We conducted a scoping review of dynamic HIV transmission modelling studies that evaluated the impacts of structural determinants, published up to August 28, 2023, using Ovid Embase and Medline online databases. We appraised studies on how models represented exposure to structural determinants and causal pathways. Building on this, we developed a new methodological framework and recommendations to support the incorporation of structural determinants in transmission dynamics models and their analyses. We discuss the data and analyses that could strengthen the evidence used to inform these models. Results We identified 17 HIV modelling studies that represented structural determinants and/or interventions, including incarceration of people who inject drugs (number of studies [n] = 5), violence against women (n = 3), HIV stigma (n = 1), and housing instability (n = 1), among others (n = 7). Most studies (n = 10) modelled exposures dynamically. Almost half (8/17 studies) represented multiple exposure histories (e.g. current, recent, non-recent exposure). Structural determinants were often assumed to influence HIV indirectly by influencing mediators such as contact patterns, condom use, and antiretroviral therapy use. However, causal pathways’ assumptions were sometimes simple, with few mediators explicitly represented in the model, and largely based on cross-sectional associations. Although most studies calibrated models using HIV epidemiological data, less than half (7/17) also fitted or cross-validated to data on the prevalence, frequency, or effects of exposure to structural determinants. Conclusions Mathematical models can play a crucial role in elucidating the population-level impacts of structural determinants and interventions on HIV. We recommend the next generation of models reflect exposure to structural determinants dynamically and mechanistically, and reproduce the key causal pathways, based on longitudinal evidence of links between structural determinants, mediators, and HIV. This would improve the validity and usefulness of predictions of the impacts of structural determinants and interventions.

Abstract Background Traditional genomic profiling and mutation analysis of single cells like Circulating Tumor Cells (CTCs) fails to capture post-translational and functional alterations of proteins, often leading to limited treatment efficacy. To overcome this gap, we developed a miniaturized ‘protein analysis on the single cell level’ workflow—baptized ZeptoCTC. It integrates established technologies for single-cell isolation with sensitive Reverse Phase Protein Array (RPPA) analysis, thus enabling the comprehensive assessment of multiple protein expression and activation in individual CTCs. Methods The ZeptoCTC workflow involves several critical steps. Firstly, individual cells are labeled and isolated. This is followed by cell lysis and the printing of true single cell lysate preparations onto a ZeptoChip using a modified micromanipulator, CellCelector™. The printed lysates then undergo fluorescence immunoassay RPPA protein detection using a ZeptoReader. Finally, signal quantification is carried out with Image J software, ensuring precise measurement of multiple protein levels. Results The efficacy of ZeptoCTC was demonstrated through various applications. Initially, it was used for measuring EpCAM protein expression, a standard marker for CTC detection, revealing higher levels in single MCF-7 over MDA-MB-231 tumor cells. Furthermore, in Capivasertib (Akt-inhibitor)-treated MCF-7 single cells, ZeptoCTC detected a 2-fold increase in the pAkt/Akt ratio compared to control cells, and confirmed co-performed bulk-cell western blot analysis results. Notably, when applied to individual CTCs from metastasized breast cancer patients, ZeptoCTC revealed significant differences in protein activation levels, particularly in measured pAkt and pErk levels, compared to patient-matched WBCs. Moreover, it successfully differentiated between CTCs from patients with different Akt1 genotypes, highlighting its potential to determine the activation status of druggable cancer driving proteins for individual and targeted treatment decision making. Conclusions The ZeptoCTC workflow represents a valuable tool in single cell cancer research, crucial for personalized medicine. It permits detailed analysis of key proteins and their activation status of targeted, cancer-driven signaling pathways in single cell samples, aiding in understanding tumor response, progression, and treatment efficacy beyond bulk analysis. The method significantly advances clinical investigations in cancer, improving treatment precision and effectiveness. The workflow will be applicable to protein analysis on other types of single cells like relevant in stem cell, neuropathology and hemopoietic cell research.

Abstract Background Nowhere is optimising healthcare staff retention more important than in primary health care (PHC) settings in remote Australia, where there are unacceptably high rates of staff burnout and turnover. Ensuing consequences for the remote health services and the community are acute – staffing shortfalls in clinics; organisational instability; excessive costs associated with frequent staff recruitment and orientation; diminished access to PHC for patients in need; and lack of continuity of patient care; all of which further entrench poor health outcomes for the community. Optimising remote healthcare staff retention is critical in order to provide high quality and continued PHC. Currently, however, there is paucity of knowledge to inform targeted and effective retention strategies in remote health services. This research program seeks to develop a stronger evidence base to understand (i) what retention strategies are effective in improving morale, job satisfaction, intention to remain in the job, and consequent length of service for remote healthcare staff; (ii) how best to ‘bundle’ these strategies for different health workforce groups; and (iii) how these ‘bundles’ work in different service contexts. Methods This paper describes a five-year implementation research program in partnership with twelve remote Aboriginal and Torres Strait Islander Community Controlled Health Services (ATSICCHS) in the Northern Territory and Queensland, Australia. Overall methodology follows a participatory action research approach which incorporates co-design and realist elements. The program comprises two broad phases involving evidence consolidation and synthesis (Phase 1), and co-design, implementation, and prospective evaluation of ‘bundles’ of retention strategies (Phase 2) to improve retention of healthcare staff in participating ATSICCHSs. Discussion This innovative research program has the potential to develop a comprehensive evidence base required to optimise health workforce retention in remote health services. This new evidence will strengthen understanding of what ‘bundles’ of retention strategies are effective, for which groups of employees, and how they work to improve staff retention.

Abstract Lenvatinib is a multiple receptor tyrosine kinase inhibitor (TKI) approved for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). TKI are suspected of exacerbating muscle loss in patients with cancer. In this study, we analyze the role of muscle loss in patients with advanced HCC treated with lenvatinib. This is a retrospective analysis of a real-life cohort of 25 patients with advanced HCC who were treated with lenvatinib from 2018 to March 2021 in Germany. Patients were stratified for loss of skeletal muscle area during the first three months of lenvatinib therapy. Overall survival (OS), progression-free survival (PFS) and toxicity were analyzed for all patients, especially regarding loss of muscle before and during the first three months of therapy with lenvatinib. Three months after beginning of therapy with lenvatinib, a significant reduction of muscle mass was observed in 60% of patients (p = 0.035). Despite increase of loss of skeletal muscle, patients benefitted from lenvatinib in our cohort of patients in terms of OS and PFS and did not experience increased toxicity. Furthermore, muscle loss was not a negative predictor of survival in the univariate analysis (p = 0.675). Patients with advanced hepatocellular carcinoma experience muscle loss with lenvatinib therapy. However, despite progressive muscle loss, patients benefit from a therapy with lenvatinib in terms of OS and PFS without increased toxicity. However, assessment and prophylaxis of skeletal muscle status should be recommended during a therapy with lenvatinib.

Abstract The best available technology (BAT) for waste plastics relies on their components and the right technology employed, while the quality of waste plastics depends on the original plastics and the source separation processes simultaneously. In this study, the quality of waste plastics and the potential recycling processes, including recycling granulation, pyrolysis to oil, Green-RDF and incineration technology, were co-related from the economic and technical perspective. A database was established for waste plastic components, considering factors such as plastic fraction, waste composition, moisture content, and impurity rate. The corresponding environmental impacts for the typical resource processes were assessed by life cycle analysis (LCA) and cost–benefit analysis combined. It was found that around 23% ± 1% of waste plastics in residual waste had the resource potential if the stricter classification criteria of plastic wastes were adopted, such as the components, moisture content less than 5% or 8% and impurity rate less than 8%. Pyrolysis to oil had the best environmental benefits in GWP100, reaching -1,683.51 kg CO2 equivalent (CO2-eq), determined as the best method for high-value plastics, and incineration depicted poor environmental benefits for low-value plastics. The net income of recycling granulation for middle-value waste plastics would achieve 1383 ± 35 yuan/ton through cost–benefit analysis, which represented the optimal economic benefits. CO2 emissions for waste plastics could be mitigated around 29.74% by matching BATs compared to the current management system, which would provide policymakers with proper recommendations in terms of the adaptability of waste plastic sources and technologies.

Abstract Given the early use of triplet and quadruplet regimens, most patients with multiple myeloma (MM) will be exposed and/or refractory to PIs, IMiDs, and anti-CD38 mAbs after first- or second-line treatment. Effective treatment for this group of triple class exposed/refractory (TCE/R) patients is crucial. Here we present a post-hoc subgroup analysis of TCE/R patients treated on the ALGONQUIN study of belantamab mafodotin plus pomalidomide-dexamethasone (belamaf-Pd) for relapsed MM. Of the 99 patients treated on the ALGONQUIN study, 69 were TCE and 56 were TCR and were included in this analysis. Patients had a median of three prior lines of therapy. The ORR was 86.4% in TCE patients and 84.9% in TCR patients, with ≥ very good partial response rates of 64% and 68% respectively. The median progression free survival was 18.3 months in TCE patients and 19.6 months in TCR patients, with overall survival not yet reached and 34.4 months, respectively for TCE and TCR patients. No new safety signals were identified. The most common Grade ≥ 3 AEs were keratopathy (48%), decreased visual acuity (42%), neutropenia (36%), thrombocytopenia (27%), and infection (25%). In this subgroup analysis of the ALGONQUIN study, patients with TCE/TCR disease treated with belamaf-Pd achieved high clinical response rates with durable remissions, comparable to other novel therapeutics in this space.

Abstract Objective Autism spectrum disorder (ASD) is a neurodevelopmental condition that is associated with atypical brain network organization, with prior work suggesting differential connectivity alterations with respect to functional connection length. Here, we tested whether functional connectopathy in ASD specifically relates to disruptions in long- relative to short-range functional connections. Our approach combined functional connectomics with geodesic distance mapping, and we studied associations to macroscale networks, microarchitectural patterns, as well as socio-demographic and clinical phenotypes. Methods We studied 211 males from three sites of the ABIDE-I dataset comprising 103 participants with an ASD diagnosis (mean ± SD age = 20.8 ± 8.1 years) and 108 neurotypical controls (NT, 19.2 ± 7.2 years). For each participant, we computed cortex-wide connectivity distance (CD) measures by combining geodesic distance mapping with resting-state functional connectivity profiling. We compared CD between ASD and NT participants using surface-based linear models, and studied associations with age, symptom severity, and intelligence scores. We contextualized CD alterations relative to canonical networks and explored spatial associations with functional and microstructural cortical gradients as well as cytoarchitectonic cortical types. Results Compared to NT, ASD participants presented with widespread reductions in CD, generally indicating shorter average connection length and thus suggesting reduced long-range connectivity but increased short-range connections. Peak reductions were localized in transmodal systems (i.e., heteromodal and paralimbic regions in the prefrontal, temporal, and parietal and temporo-parieto-occipital cortex), and effect sizes correlated with the sensory-transmodal gradient of brain function. ASD-related CD reductions appeared consistent across inter-individual differences in age and symptom severity, and we observed a positive correlation of CD to IQ scores. Limitations Despite rigorous harmonization across the three different acquisition sites, heterogeneity in autism poses a potential limitation to the generalizability of our results. Additionally, we focussed male participants, warranting future studies in more balanced cohorts. Conclusions Our study showed reductions in CD as a relatively stable imaging phenotype of ASD that preferentially impacted paralimbic and heteromodal association systems. CD reductions in ASD corroborate previous reports of ASD-related imbalance between short-range overconnectivity and long-range underconnectivity.

Abstract ICVB-1042 is an oncolytic adenovirus containing modifications to enhance replication, lysis, and viral spreading in tumor cells. The anti-tumor activity, immune activation, tropism, selectivity, and mechanism of action were evaluated in preparation for a first-in-human study. ICVB-1042 was at least 100-fold more cytotoxic in A549 cells than in normal primary cells tested, demonstrating its high tumor selectivity and a low likelihood of targeting primary tissues. ICVB-1042 administered to mice intravenously or intratumorally was effective in reducing tumor burden. Its intravenous administration also inhibited tumor growth in orthotopic models. ICVB-1042 was well tolerated in mice compared to HAdV-C5 (Wt Ad5), with reduced liver sequestration, supporting safety of the drug for systemic delivery. These preclinical data demonstrating the safety and potency of ICVB-1042 for treatment of various solid tumors support the ongoing clinical investigation (NCT05904236).

Abstract The development of functional neurons is a complex orchestration of multiple signaling pathways controlling cell proliferation and differentiation. Because the balance of antioxidants is important for neuronal survival and development, we hypothesized that ferroptosis must be suppressed to gain neurons. We find that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids, which is fully restored when ferroptosis is inhibited by ferrostatin-1 or when neuronal differentiation occurs in the presence of vitamin A. Furthermore, iron-overload-induced developmental growth defects in C. elegans are ameliorated by vitamin E and A. We determine that all-trans retinoic acid activates the Retinoic Acid Receptor, which orchestrates the expression of anti-ferroptotic genes. In contrast, retinal and retinol show radical-trapping antioxidant activity. Together, our study reveals an unexpected function of vitamin A in coordinating the expression of essential cellular gatekeepers of ferroptosis, and demonstrates that suppression of ferroptosis by radical-trapping antioxidants or by vitamin A is required to obtain mature neurons and proper laminar organization in cortical organoids.

Abstract Background In 2016, large-scale 20 miles per hour speed limits were introduced in the United Kingdom cities of Edinburgh and Belfast. This paper investigates the role that scientific evidence played in the policy decisions to implement lower speed limits in the two cities. Methods Using a qualitative case study design, we undertook content analysis of a range of documents to explore and describe the evolution of the two schemes and the ways in which evidence informed decision-making. In total, we identified 16 documents for Edinburgh, published between 2006 and 2016, and 19 documents for Belfast, published between 2002 and 2016. Findings In both cities, evidence on speed, collisions and casualties was important for initiating discussions on large-scale 20 mph policies. However, the narrative shifted over time to the idea that 20 mph would contribute to a wider range of aspirations, none of which were firmly grounded in evidence, but may have helped to neutralize opposing discourses. Discussion and conclusions The relationship between evidence and decision-making in Edinburgh and Belfast was neither simple nor linear. Widening of the narrative appears to have helped to frame the idea in such a way that it had broad acceptability, without which there would have been no implementation, and probably a lot more push back from vested interests and communities than there was.

Abstract. Background. Upper tract urothelial carcinoma (UTUC) is an aggressive disease with a high progression rate. The standardmanagement for this disease is nephroureterectomy. Nephron sparing nonradical surgery is an alternative therapeutic approach. In men with limited life expectancy, the potential harm of UTUC progression must be weighed against surgical morbidity and mortality, and thus, more conservative approaches may be selected. This study aims to investigate the comparative benefits of radical and conservative surgical management in patients older than 80 years with localized UTUC. Materials and methods. A search was conducted in the Surveillance, Epidemiology, and End Results database for patients older than 80 years who were diagnosed with localized (T1–2N0M0) cancer in the renal pelvis or ureter as the only malignancy from 2004 to 2015. Patients were divided into 3 therapeutic groups: no surgery, local intervention (ie, local tumor excision or segmented ureterectomy), and radical surgery (nephroureterectomy). Demographic and cancer-related parameter data were collected. Logistic regression analysis was conducted to investigate predictors for surgical treatment. Kaplan-Meier curves and Cox regression were used to analyze survival outcomes. Results. Data from 774 patients were analyzed, including 205 in the no-surgery group, 181 in the local intervention group, and 388 in the radical surgery group. Older, African American patients with T1 stage disease were less likely to receive surgical treatment. Among surgically treated patients, renal pelvic tumors, and high-grade and T2 stage disease were associated with radical resection. Surgically treated patients had a longer median overall survival (OS) than in those treated nonsurgically (13, 35, and 47 months in no-surgery, local intervention, and radical surgery groups, respectively; p < 0.001). Although surgically treated patients demonstrated higher 5-year OS (8.8% [no surgery], 23.2% [local intervention], and 23.5% [radical surgery], p < 0.001) and 5-year disease-specific survival (DSS) (41.0%[no surgery], 69.1%[local intervention], and 72.9%[radical surgery]; p < 0.001) than in those treated nonsurgically, no significant differences were found between the local intervention and radical surgery groups (p > 0.05). Based on multivariate Cox regression analysis, surgical treatments, including both nonradical and radical resection, were independently associated with improved OS and DSS after controlling for age, marital status, tumor grade, and radiation status. Conclusions. Patients older than 80 years with localized UTUC who undergo surgery demonstrate longer survival. Radical and nonradical resections seemto have similar OS and DSS outcomes. Thus, when clinically indicated in this population, a more conservative surgical approach may be reasonable.

Benign adrenal cysts are relatively uncommon variants of all adrenal incidentalomas. When identified, most benign adrenal cysts are asymptomatic, which differentiates them from other functional adrenal lesions. There are various types of adrenal cysts, although the most common being an endothelial cyst. Ultimately, evaluation and management approaches are aimed at ruling out a functional adrenal mass and management of symptoms if present. We present a unique presentation of an otherwise healthy male with a large incidental adrenal cyst, later identified as a benign endothelial cyst, who presented with classic symptoms of catecholamine excess. The patient had a negative hormonal evaluation, and his episodic symptoms were resolved with surgical removal of the adrenal mass. This case report and brief review provides valuable insight into the evaluation and management of a unique clinical scenario, where a benign cystic mass led to compression-related symptoms of catecholamine excess that were resolved after removal of the nonfunctional, cystic, mass.

Agricultural intensification and expansion are regarded as main drivers of biodiversity loss. This conclusion is mainly based on observed declines of local diversity (α-diversity), while effects on community composition homogenization (decrease of β-diversity) at a larger spatial scale are less well understood. Carabid beetles and spiders represent two widespread guilds and are important predators of pest species. Here we surveyed carabid beetles and spiders in 66 winter wheat fields in four northwestern European countries (Germany, the Netherlands, Sweden and UK) and analyzed how their community composition was related to geographic distance (separation distance between any pairwise fields) and three environmental variables: crop yield (proxy for land-use intensity), percentage cropland (proxy for landscape complexity) and soil organic carbon content (proxy for local soil conditions). We further analyzed whether the relationship between carabid beetle and spider community composition and geographic distance was influenced by environmental variables. We found that, 55 % and 75 % of all observed carabid and spider individuals, respectively, belonged to species that occurred in all four countries. However, individuals of species that were unique to a particular country only accounted for 3 % of all collected individuals for both taxa. Furthermore, we found a negative relationship between distance and similarity of spider communities but not for carabid beetle communities. None of the environmental variables were related to similarity of carabid beetle and spider communities, nor moderated the effects of distance. Our study indicates that across a great part of the European continent, arthropod communities (especially carabid beetles) in agricultural landscapes are composed of very similar species that are robust to current variations in environment and land-use.