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Background: Pancreatic ductal adenocarcinoma (PDAC) represent an unmet clinical need. Approximately 90% of PDACs express high levels of αvβ6 integrin. We have previously described Ad5NULL-A20, an adenovirus vector with ablated native means of cell entry and retargeted to αvβ6 integrin by incorporation of an A20 peptide. Methods: Here, we incorporate suicide genes FCY1 and FCU1 encoding for cytosine deaminase (CDase) or a combination of CDase and UPRTase, capable of catalysing a non-toxic prodrug, 5-FC into the chemotherapeutic 5-FU and downstream metabolites, into replication-deficient Ad5 and Ad5NULL-A20. Results: We show that Ad5NULL-A20 enables the transfer of suicide genes to αvβ6 integrin-positive PDAC cells which, in combination with 5-FC, results in cell death in vitro which is further mediated by a bystander effect in non-transduced cells. Intratumoural delivery of Ad5NULL-A20.FCU1 in combination with intraperitoneal delivery of 5-FC further results in tumour growth inhibition in a cell line xenograft in vivo. Using clinically-relevant 3D organoid models, we show selective transduction and therapeutic efficacy of FCU1 transgenes in combination with 5-FC. Conclusion: Taken together these data provide the preclinical rationale for combined Ad5NULL-A20.FCU1 plus 5-FC as a promising targeted therapy to mediate "in-tumour chemotherapy" and merits further investigation for the treatment of PDAC patients. [ABSTRACT FROM AUTHOR]

BRCA2 is essential for DNA repair by homologous recombination in mitosis and meiosis. It interacts with recombinases RAD51 and DMC1 to facilitate the formation of nucleoprotein filaments on resected DNA ends that catalyse recombination-mediated repair. BRCA2's BRC repeats bind and disrupt RAD51 and DMC1 filaments, whereas its PhePP motifs bind recombinases and stabilise their nucleoprotein filaments. However, the mechanism of filament stabilisation has hitherto remained unknown. Here, we report the crystal structure of a BRCA2-DMC1 complex, revealing how core interaction sites of PhePP motifs bind to recombinases. The interaction mode is conserved for RAD51 and DMC1, which selectively bind to BRCA2's two distinct PhePP motifs via subtly divergent binding pockets. PhePP motif sequences surrounding their core interaction sites protect nucleoprotein filaments from BRC-mediated disruption. Hence, we report the structural basis of how BRCA2's PhePP motifs stabilise RAD51 and DMC1 nucleoprotein filaments for their essential roles in mitotic and meiotic recombination. This study presents the crystal structure of a BRCA2-DMC1 complex revealing how BRCA2's PhePP motifs stabilise RAD51 and DMC1 nucleoprotein filaments during DNA double-strand break repair by mitotic and meiotic recombination. [ABSTRACT FROM AUTHOR]

Background: The current gold standard for postoperative analgesia following a pancreaticoduodenectomy (PD) is a thoracic epidural analgesia (TEA). Spinal analgesia with continuous wound infusion (CWI) of local anaesthetic is an emerging alternative modality. This non-inferiority study aimed to compare CWI with spinal analgesia to TEA and assess its impact on clinical outcomes. Methods: A retrospective observational analysis of patients undergoing open pancreatoduodenectomy through a midline laparotomy. A total of 74 patients were included in the study forming two groups: CWI (n = 33) and TEA (n = 41). Results: TEA resulted in lower median pain scores at rest (p = 0.002) and with coughing (p = 0.005) on postoperative day 2. CWI was non-inferior to TEA for all other pain outcomes measures from days 0–5. Patients in the CWI group had a shorter time to first bowel motion (p = 0.001), commencement of a liquid diet (p = 0.04), earlier removal of nasogastric tube (p = 0.005), abdominal drain (p = 0.003) and indwelling catheter (p < 0.001). Analgesic failure and postoperative nausea and vomiting were also less frequent (p = 0.001 and p < 0.001 respectively). Conclusion: Local CWI with spinal analgesia was non-inferior to TEA for pain management in open pancreaticoduodenectomy. CWI demonstrated advantages in measures associated with enhanced recovery after surgery programs without disadvantages in terms of analgesia requirements. [ABSTRACT FROM AUTHOR]

The teratogenic potential of valproate in pregnancy is well established; however, evidence regarding the long-term safety of other antiseizure medications (ASMs) during pregnancy remains limited. Using routinely collected primary care data from the UK and nationwide Swedish registries to create a cohort of 3,182,773 children, of which 17,495 were exposed to ASMs in pregnancy, we show that those exposed to valproate were more likely to receive a diagnosis of autism, intellectual disability, and ADHD, when compared to children not exposed to ASMs. Additionally, children exposed to topiramate were 2.5 times more likely to be diagnosed with intellectual disability (95% CI: 1.23–4.98), and those exposed to carbamazepine were 1.25 times more likely to be diagnosed with autism (95% CI: 1.05–1.48) and 1.30 times more likely to be diagnosed with intellectual disability (95% CI: 1.01–1.69). There was little evidence that children exposed to lamotrigine in pregnancy were more likely to receive neurodevelopmental diagnoses. While further research is needed, these findings may support considering safer treatment alternatives well before conception when clinically appropriate. Some antiseizure medications including valporate are associated with neurodevelopmental conditions in children exposed in utero but evidence is less clear for other drugs. Here the authors investigate associations between antiseizure medication use in pregnancy and neurodevelopmental conditions using electronic health record data from the UK and Sweden. [ABSTRACT FROM AUTHOR]

My Kidneys & Me (MK&M), a digital health intervention delivering specialist health and lifestyle education for people with CKD, was developed and its effects tested (SMILE-K trial, ISRCTN18314195, 18/12/2020). 420 adult patients with CKD stages 3–4 were recruited and randomised 2:1 to intervention (MK&M) (n = 280) or control (n = 140) groups. Outcomes, including Patient Activation Measure (PAM-13), were collected at baseline and 20 weeks. Complete case (CC) and per-protocol (PP) analyses were conducted. 210 (75%) participants used MK&M more than once. PAM-13 increased at 20 weeks compared to control (CC: +3.1 (95%CI: −0.2 to 6.4), P = 0.065; PP: +3.6 (95%CI: 0.2 to 7.0), P = 0.041). In those with low activation at baseline, significant between-group differences were observed (CC: +6.6 (95%CI: 1.3 to 11.9), P = 0.016; PP: +9.2 (95%CI: 4.0 to 14.6), P < 0.001) favouring MK&M group. MK&M improved patient activation in those who used the resource compared to standard care, although the overall effect was non-significant. The greatest benefits were seen in those with low activation. [ABSTRACT FROM AUTHOR]

Miscommunication in the OR is a threat to patient safety and surgical efficiency. Our objective was to measure the frequency and causes of communication interference between robotic team members. We observed 78 robotic surgeries over 215 h. 65.4% were General Surgery, most commonly cholecystectomy, identifying Speech Communication Interference (SCI) events, defined as "surgery-related group discourse that is disrupted according to the goals of the communication or the physical and situational context of the exchange". We noted the causes and strategies to correct the miscommunication, near misses, and case delays associated with each SCI event. Post-surgery interviews supported observations and were analyzed thematically. Overall, we observed 687 SCI events (mean 8.8 ± 6.5 per case, 3.2 per hour), ranging from one to 28 per case. 48 (7.0%) occurred during docking and 136 (19.8%) occurred during a critical moment. The most common causes were concurrent tasks (66.1%); loud noises (10.8%) from patient cart, lightbox fan, and suction machine; and overlapping conversations (4.2%). 94.8% resulted in a case delay. These events distracted from monitoring patient safety and resulted in near misses. Mitigating strategies included leaning out of the surgeon console to repeat the message and employing a messenger. These findings help characterize miscommunication in robotic surgery. Possible interventions include microphones and headsets, positioning the surgeon console closer to the bedside, moving loud equipment further away, and upgrading the patient cart speaker. [ABSTRACT FROM AUTHOR]

Breast cancer-related lymphedema (BCRL) remains a challenging condition impacting function and quality of life. Complete decongestive therapy (CDT) is the current standard of care, necessitating a comprehensive review of its impact. This paper presents a systematic review (SR) of SRs on CDT's efficacy in BCRL, and the components of manual lymph drainage (MLD) and exercise. A literature search yielded 13 SRs published between January 2018 and March 2023 meeting inclusion criteria, with varied quality ratings based on the AMSTAR II. A sub-analysis of CDT investigated the within group effect size estimations on volume in different stages of lymphedema. While a moderate quality SR indicated support for CDT in volume reduction, other SRs on the topic were of critically low quality. Larger effect sizes for CDT were found for later stage BCRL. The impact of MLD as a component of CDT demonstrated no additional volume benefit in a mix of moderate to low quality SRs. Similarly, exercise's role in volume reduction in CDT was limited, although it demonstrated some benefit in pain and quality of life. A rapid review of trials published January 2021–March 2023 reinforced these findings. Variability in CDT delivery and outcomes remained. These findings underscore the need to standardize staging criteria and outcome measures in research and practice. Future research should focus on refining interventions, determining clinically important differences in outcomes, and standardizing measures to improve evidence-based BCRL management. Current evidence supports CDT's efficacy in BCRL. MLD and exercise as components of CDT have limited support for volume reduction. [ABSTRACT FROM AUTHOR]

Background: Recurrence of focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) after kidney transplant leads to significant morbidity and potentially earlier allograft loss. To date however, reported rates, risk factors and treatment outcomes have varied widely. Methods: We applied computational phenotypes to a multicenter aggregation of electronic health records data from 7 large pediatric health systems in the USA, to identify recurrence rates, risk factors, and treatment outcomes. We refined the data collection by chart review. Results: From > 7 million patients, we compared children with primary FSGS/SRNS who received a kidney transplant between 2009 and 2020 and who either developed recurrence (n = 67/165; 40.6%) or did not (n = 98/165). Serum albumin level at time of transplant was significantly lower and recipient HLA DR7 presence was significantly higher in the recurrence group. By 36 months post-transplant, complete remission occurred in 58.2% and partial remission in 17.9%. Through 6 years post-transplant, no remission after recurrence was associated with an increased risk of allograft loss over time (p < 0.0001), but any remission showed similar allograft survival and function decline to those with no recurrence. Since treatments were used in non-random fashion, using spline curves and multivariable non-linear analyses, complete + partial remission chance was significantly higher with greater plasmapheresis sessions, CTLA4-Ig doses or LDL-apheresis sessions. Only treatment with anti-CD20, CTLA4-Ig agents, or LDL-apheresis sessions were associated with complete remission. Excluding 25 patients with mutations did not significantly change our results. Conclusions: Our contemporary high-risk cohort had higher favorable response rates than most prior reports, from combinations of agents. [ABSTRACT FROM AUTHOR]

Context: Nomadic waterbirds are highly mobile across a range of spatial and temporal scales, which makes it difficult to monitor, quantify, and predict their habitat use with traditional methods, especially between breeding events when individuals and flocks can move over vast areas. Objectives: This study aimed to provide accurate information on habitat use to improve strategic conservation management of these species, particularly the provisioning of environmental water. Methods: To overcome the challenges of distance and remoteness, we analysed a 7-year GPS satellite telemetry dataset from 141 individuals. We quantified habitat selection post-dispersal from breeding sites, and predicted habitat preference for two wading waterbird species of the Threskiornithidae family that frequently nest together at the same sites: straw-necked ibis (Threskiornis spinicollis) and royal spoonbill (Platalea regia). Results: Both long-term and short-term landscape-scale habitat associations differed between species. Royal spoonbills used fewer and more restricted habitat types than straw-necked ibis. Spoonbills displayed strong preferences for reservoirs, marshes and permanent wetlands, while ibis used both aquatic and terrestrial habitat, including areas of intensive animal production, modified pasture, and woodlands. Analysis of nocturnal versus diurnal space use showed that roosting and foraging habitat requirements for both species are distinct. Conclusions: Analysing over 1 million telemetry points revealed species-level variability in habitat use, informing resource allocation for environmental water management. Royal spoonbills are more vulnerable to habitat change due to water regime alterations, highlighting the need for focused conservation management. Differences in day and night habitat use indicate the necessity of considering roosting habitats alongside foraging habitats for effective conservation. This comprehensive understanding of waterbirds' spatiotemporal interactions with their environment is crucial for long-term management aimed at increasing waterbird numbers and maintaining diversity. [ABSTRACT FROM AUTHOR]

Purpose: To report on the recovery of strength and functional capacity symmetry following multiligament knee surgical reconstruction (MLKR), as well as the capacity of athletes to return to sport. Methods: This prospective cohort study recruited 47 patients undergoing MLKR between February 2018 and July 2021. Forty patients had full outcome assessment postoperatively at 6, 12 and 24 months and were included in the analysis, 75% were knee dislocation one injuries and 60% were injured playing sport. Patient‐reported outcome measures (PROMs) assessed included the International Knee Documentation Committee score, the Knee Outcome Survey, the Lysholm Knee Score and the Tegner Activity Scale (TAS). Patient satisfaction was also assessed. Objective assessment included assessment of active knee flexion and extension range of motion (ROM), the single (single horizontal hop for distance [SHD]) and triple (triple horizontal hop for distance [THD]) hop tests for distance and peak isokinetic knee flexor/extensor torque. Results: All PROMs significantly improved (p < 0.001) from presurgery to 24 months postsurgery. At 24 months, 70% of patients were satisfied with their sports participation. Active knee flexion (p < 0.0001) and extension (p < 0.0001) ROM significantly improved over time, as did the limb symmetry indices (LSIs) for the SHD (p < 0.0001), THD (p < 0.0001), peak knee extensor (p < 0.0001) and flexor (p = 0.012) torque. While LSIs for the SHD, THD and knee flexor strength tended to plateau by 12 months, knee extensor strength continued to improve from 12 to 24 months. Conclusions: The majority of patients undergoing modern MLKR surgical techniques and rehabilitation can achieve excellent knee function, with low complication rates. Level of Evidence: Level IV. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The temporal suppression of insulin clearance after glucose ingestion is a key determinant of glucose tolerance for people without type 2 diabetes. Whether similar adaptations are observed after the ingestion of a mixed-macronutrient meal is unclear. Methods: In a secondary analysis of data derived from two randomised, controlled trials, we studied the temporal responses of insulin clearance after the ingestion of a standardised breakfast meal consisting of cereal and milk in lean normoglycaemic individuals (n=12; Lean-NGT), normoglycaemic individuals with central obesity (n=11; Obese-NGT) and in people with type 2 diabetes (n=19). Pre-hepatic insulin secretion rates were determined by the deconvolution of C-peptide, and insulin clearance was calculated using a single-pool model. Insulin sensitivity was measured by an oral minimal model. Results: There were divergent time course changes in insulin clearance between groups. In the Lean-NGT group, there was an immediate post-meal increase in insulin clearance compared with pre-meal values (p<0.05), whereas insulin clearance remained stable at baseline values in Obese-NGT or declined slightly in the type 2 diabetes group (p<0.05). The mean AUC for insulin clearance during the test was ~40% lower in the Obese-NGT (1.3 ± 0.4 l min−1 m−2) and type 2 diabetes (1.4 ± 0.7 l min−1 m−2) groups compared with Lean-NGT (1.9 ± 0.5 l min−1 m−2; p<0.01), with no difference between the Obese-NGT and type 2 diabetes groups. HOMA-IR and glucagon AUC emerged as predictors of insulin clearance AUC, independent of BMI, age or insulin sensitivity (adjusted R2=0.670). Individuals with increased glucagon AUC had a 40% reduction in insulin clearance AUC (~ −0.75 l min−1 m−2; p<0.001). Conclusions/interpretation: The ingestion of a mixed-macronutrient meal augments differing temporal profiles in insulin clearance among individuals without type 2 diabetes, which is associated with HOMA-IR and the secretion of glucagon. Further research investigating the role of hepatic glucagon signalling in postprandial insulin kinetics is warranted. Trial registration: ISRCTN17563146 and ISRCTN95281775 [ABSTRACT FROM AUTHOR]

Biobanks aim to improve our understanding of health and disease by collecting and analysing diverse biological and phenotypic information in large samples. So far, biobanks have largely pursued a population-based sampling strategy, where the individual is the unit of sampling, and familial relatedness occurs sporadically and by chance. This strategy has been remarkably efficient and successful, leading to thousands of scientific discoveries across multiple research domains, and plans for the next wave of biobanks are underway. In this Perspective, we discuss the strengths and limitations of a complementary sampling strategy for future biobanks based on oversampling of close genetic relatives. Such family-based samples facilitate research that clarifies causal relationships between putative risk factors and outcomes, particularly in estimates of genetic effects, because they enable analyses that reduce or eliminate confounding due to familial and demographic factors. Family-based biobank samples would also shed new light on fundamental questions across multiple fields that are often difficult to explore in population-based samples. Despite the potential for higher costs and greater analytical complexity, the many advantages of family-based samples should often outweigh their potential challenges.This Perspective discusses the strengths and limitations of future biobank sampling strategies based on oversampling close relatives as opposed to the current population-based approach. [ABSTRACT FROM AUTHOR]

Recent works have demonstrated that the optical excitation of crystalline materials with intense narrow-band infrared pulses, tailored to match the frequencies at which the crystal's permittivity approaches close to zero, can drive a permanent reversal of magnetic and ferroelectric ordering. However, the physical mechanism that microscopically underpins this effect remains unclear, as well as the precise role of laser-induced heating and macroscopic strains. Here, we explore how infrared pulses can simultaneously give rise to strong temperature-dependent birefringence and strain in ferroelectric barium titanate. We develop a model of these two coexisting effects, allowing us to use polarization microscopy to disentangle them through their spatial distributions, temporal evolutions and spectral dependencies. We experimentally observe strain-induced patterns that are an order of magnitude larger than that which can be accounted for by laser-induced heating alone, suggesting that non-thermal effects must also play a role. Our results reveal the distinct fingerprints of heat- and strain-induced birefringence, shedding new light on the process of all-optical switching of order parameters in the epsilon-near-zero regime. [ABSTRACT FROM AUTHOR]

With increased globalisation supply chain (SC) disruption significantly affects people, organisations and society. Supply chain network design (SCND) reduces the effects of disruption, employing mitigation strategies such as extra capacity and flexibility to make SCs resilient. Currently, no systematic literature review classifies mitigation strategies for SCND. This paper systematically reviews the literature on SCND, analysing proposed mitigation strategies and the methods used for their integration into quantitative models. First to understand the key failure drivers SCND literature is categorised using geography, with local, regional or global disruptions linked to vulnerable sections of a SC. Second, the strategies used in mathematical models to increase SC resilience are categorized as proactive, reactive, or SC design quality capabilities. Third, the relative performance of mitigation strategies is analysed to provide a comparison, identifying the most effective strategies in given contexts. Forth, mathematical modelling techniques used in resilient SCND are reviewed, identifying how strategies are integrated into quantitative models. Finally, gaps in knowledge, key research questions and future directions for researchers are described. [ABSTRACT FROM AUTHOR]

Purpose: Agriculture and food production contribute to climate change. There is mounting pressure to transition to diets with less environmental impact while maintaining nutritional adequacy. MyPlanetDiet aimed to reduce diet-related greenhouse gas emissions (GHGE) in a safe, nutritionally adequate, and acceptable manner. This paper describes the trial protocol, development, and testing of personalised nutrition feedback in the MyPlanetDiet randomised controlled trial (RCT). Methods: MyPlanetDiet was a 12-week RCT that provided standardised personalised nutrition feedback to participants based on new sustainable healthy eating guidelines (intervention) or existing healthy eating guidelines (control) using decision trees and corresponding feedback messages. To test the personalised nutrition feedback, we modelled a sample of 20 of the MyPlanetDiet participants baseline diets. Diets were modelled to adhere to control and intervention decision trees and feedback messages. Modelled nutrient intakes and environmental metrics were compared using repeated measure one-way analysis of covariance. Results: Intervention diets had significantly lower (p < 0.001) diet-related GHGE per 2500 kilocalories (kcal) (4.7 kg CO2-eq) relative to control (6.6 kg CO2-eq) and baseline (7.1 kg CO2-eq). Modelled control and intervention diets had higher mean daily intakes of macronutrients (carbohydrates, fibre, and protein) and micronutrients (calcium, iron, zinc, and iodine). Modelled control and intervention diets had lower percent energy from fat and saturated fat relative to baseline. Conclusions: Adherence to the MyPlanetDiet personalised nutrition feedback would be expected to lead to better nutrient intakes and reduced diet-related GHGE. The MyPlanetDiet RCT will test the effectiveness and safety of personalised feedback for a more sustainable diet. Trial registration number and date of registration: Clinical trials registration number: NCT05253547, 23 February 2022 [ABSTRACT FROM AUTHOR]

Offshore windfarms are a potential threat to seabirds, partly due to collision risk with turbine blades. Wind influences the mode, height and speed of seabird flight, and therefore the risk of collision with turbines. We investigated how wind influences the flight of black-legged kittiwakes Rissa tridactyla, a gull of conservation concern, in order to incorporate these findings into collision risk estimates and identify mitigation measures. We used GPS telemetry data (23rd June to 10th August 2021) from 20 kittiwakes breeding in Aberdeenshire, UK (57.385°N, 1.868°W) to estimate the effect of wind on behavioural state, proportion of flight at collision risk height, probability of collision when within the rotor-swept zone, and overall collision risk. We found that as windspeed increased, kittiwakes commuted less and rested more. With increasing windspeed, kittiwakes spent a considerably smaller proportion of their flight time in the rotor-swept zone, but had a slightly higher probability of collision while in it. Uncertainty was high for most relationships between windspeed and kittiwake flight metrics. The overall effect of increasing windspeed on collision risk was negative, although we did not model avoidance rate. Effects of windspeed on collision risk were largely mediated through effects on commuting flight, and contingent on wind direction. Collision risk estimates incorporating the effects of windspeed may have greater precision and accuracy, but considerable uncertainty in windspeed-flight parameter relationships remains. Therefore although kittiwake collision risk may be mitigated by raising the 'cut-in' windspeed above which wind turbines generate power, the magnitude of this effect is uncertain. [ABSTRACT FROM AUTHOR]

Purpose: The objectives of the study were to determine the prevalence of (uncontrolled) OIC, relevant medications / interventions employed by healthcare professionals, and the additional strategies utilised by patients, amongst European patients with cancer pain. Methods: This study was a prospective observational study conducted at 24 research sites in ten European countries. Cancer patients receiving opioid analgesics for at least a week were recruited, and asked to complete a questionnaire including background information, single question (Are you constipated?), Rome IV diagnostic criteria for OIC, Bowel Function Index (BFI), and Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL). Participants were characterised as having / not having OIC on the basis of the Rome IV diagnostic criteria. Results: 1200 participants completed the study. 59.5% met the Rome IV diagnostic criteria for OIC: only 61.5% that met these criteria self-reported constipation. 72% participants were prescribed a regular conventional laxative / peripherally acting mu-opioid receptor antagonist (PAMORA). However, only 66% took their prescribed laxatives every day. Many participants had utilised other strategies / interventions to manage their OIC. Furthermore, 27% had needed to use suppositories, 26.5% had needed to use an enema, and 8% had had a manual evacuation. The use of PAMORAs, and other novel effective medications, was relatively uncommon. Conclusion: The results of this study suggest that management in Europe is often inadequate, and this undoubtedly relates to a combination of inadequate assessment, inappropriate treatment, and inadequate reassessment. [ABSTRACT FROM AUTHOR]

The Mapping Imaging Spectrometer for Europa (MISE) is an infrared compositional instrument that will fly on NASA's Europa Clipper mission to the Jupiter system. MISE is designed to meet the Level-1 science requirements related to the mission's composition science objective to "understand the habitability of Europa's ocean through composition and chemistry" and to contribute to the geology science and ice shell and ocean objectives, thereby helping Europa Clipper achieve its mission goal to "explore Europa to investigate its habitability." MISE has a mass of 65 kg and uses an energy per flyby of 75.2 W-h. MISE will detect illumination from 0.8 to 5 μm with 10 nm spectral resolution, a spatial sampling of 25 m per pixel at 100 km altitude, and 300 cross-track pixels, enabling discrimination among the two principal states of water ice on Europa, identification of the main non-ice components of interest: salts, acids, and organics, and detection of trace materials as well as some thermal signatures. Furthermore, the spatial resolution and global coverage that MISE will achieve will be complemented by the higher spectral resolution of some Earth-based assets. MISE, combined with observations collected by the rest of the Europa Clipper payload, will enable significant advances in our understanding of how the large-scale structure of Europa's surface is shaped by geological processes and inform our understanding of the surface at microscale. This paper describes the planned MISE science investigations, instrument design, concept of operations, and data products. [ABSTRACT FROM AUTHOR]

Hexaflumuron (HEX) insecticide is widely used in agriculture practices to fight crop insects. The toxicological effect of HEX on Nile tilapia (Oreochromis niloticus) was investigated in this study. Two hundred and forty fish (35.50 ± 1.45 g) were divided into six groups in four replicates (40 fish/group; 10 fish/replicate) and were exposed to six distinct HEX concentrations (0, 2, 4, 6, 8, and 10 mg L−1) for 96-h. The 96-h lethal concentration 50 (96-h LC50) of HEX was calculated to be 7.19 mg L−1. The fish exhibited reduced surface and middle swimming, aggressiveness, and tail-spreading behaviors with increasing bottom swimming and resting patterns after HEX exposure. HEX exposure resulted in body bleeding and fin rot. The erythrogram (red blood cell count, hemoglobin, and packed cell volume %) was significantly reduced with increased mean corpuscular volume by HEX exposure. HEX exposure decreased the white blood cells (WBCs) and differential WBC counts. Acute HEX exposure raised 8-hydroxy-2-deoxyguanosine level while lowering brain acetylcholine esterase activity. HEX exposure caused hepato-renal dysfunction and increased stress-related parameters (glucose and cortisol). Exposure to HEX reduced the immune responses (lysozyme, nitric oxide, immunoglobulin M, and complement 3). A substantial decrease in the antioxidant variables (reduced glutathione content and catalase) with increasing the malondialdehyde was noted by HEX exposure. Moreover, histopathological changes resulted from HEX exposure in the gills, liver, kidney, and spleen. These results indicate that HEX exposure induced behavioral changes, hepato-renal dysfunction, and immune-antioxidant disruption, indicating a possible physiological disruption in O. niloticus. [ABSTRACT FROM AUTHOR]

Usutu virus (USUV) and West Nile virus (WNV) are two closely related emerging mosquito-borne flaviviruses. Their natural hosts are wild birds, but they can also cause severe neurological disorders in humans. Both viruses are efficiently suppressed by type I interferon (IFN), which interferes with viral replication, dissemination, pathogenesis and transmission. Here, we show that the replication of USUV and WNV are inhibited through a common set of IFN–induced genes (ISGs), with the notable exception of ISG20, which USUV is resistant to. Strikingly, USUV was the only virus among all the other tested mosquito-borne flaviviruses that demonstrated resistance to the 3′–5′ exonuclease activity of ISG20. Our findings highlight that the intrinsic resistance of the USUV genome, irrespective of the presence of cellular or viral proteins or protective post-transcriptional modifications, relies on a unique sequence present in its 3′ untranslated region. Importantly, this genomic region alone can confer ISG20 resistance to a susceptible flavivirus, without compromising its infectivity, suggesting that it could be acquired by other flaviviruses. This study provides new insights into the strategy employed by emerging flaviviruses to overcome host defense mechanisms. Here, the authors identify in the 3′ untranslated region of the genome of Usutu virus, an emerging mosquito-borne flavivirus, a sequence that confers a unique capacity to resist degradation by the ISG20 exonuclease. [ABSTRACT FROM AUTHOR]

Effect of sunflower oil (SFO) + linseed oil (LnO) (1:1) blend as a replacement for fish oil (FO) in the diet of Labeo rohita (initial weight 20.37 ± 0.16 g) was evaluated for a 90-day feeding trial. Five isonitrogenous (30% crude protein) and isolipidic (11% crude lipid) experimental diets with different levels of SFO + LnO (0, 25, 50, 75, and 100%) were formulated. Growth performance, survival, and feed utilization were not significantly affected by the dietary treatments. Similarly, FO replacement did significantly influence hepatosomatic index (HSI), viscerosomatic index (VSI), and the whole body proximate composition. However, significant changes were observed in fatty acid composition (P < 0.05). In the muscle and liver, saturated fatty acids (SFA) and n-3 polyunsaturated fatty acids (PUFA) decreased, while monounsaturated fatty acids (MUFA) and n-6 PUFAs increased with the increasing rate of replacement. Despite the reduction in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as a result of the replacement of dietary FO, these fatty acids were still detected in considerable amounts even after total replacement. Hematology parameters, serum biochemistry, serum lipid profile, and plasma stress biomarkers were not significantly influenced by the dietary treatments. Antioxidant enzyme activities did not significantly change; however, lipid peroxidation level was significantly reduced by the FO replacement with SFO + LnO blend. In conclusion, substituting fish oil with SFO + LnO blend demonstrated promising results, maintaining growth, feed efficiency, and overall health status in L. rohita. Replacement of dietary FO with SFO + LnO resulted in a significant reduction in LC-PUFAs such as EPA and DHA in fish; however, these fatty acids were still detected in a considerable amount even at total replacement, which confirmed the capacity of L. rohita to bioconvert dietary LNA to EPA and DHA in fish. [ABSTRACT FROM AUTHOR]

In this study, we investigated the effects of the dietary addition of lavender essential oil (LEO) on mitigating the adverse effects of high stocking densities (HSD) in the Nile tilapia, Oreochromis niloticus. We used 216 fingerlings and randomly distributed them according to a 2 × 3 factorial design, comprising two stocking densities: a low stocking density (LSD, 2.92 kg/m3) and a high stocking density (5.85 kg/m3) and three levels of LEO, 0, 0.5%, and 1%, for 70 days. We evaluated their growth, digestive enzyme activity, blood biochemical parameters, immune/antioxidant indices, and intestinal morphology. All fish were intraperitoneally inoculated with Aeromonas veronii for a bacterial challenge test at the end of the feeding trial and monitored for 14 days. After 14 days, head kidney samples were collected from all fish to assess the level of expression of immune-related and apoptosis-related genes. Additionally, tissue samples were collected from the liver, kidney, and intestine to investigate the immunohistochemistry and histopathological alterations. The results showed that the final body weight and weight gain were lower and the feed conversion ratio was higher in fish cultured under HSD compared to those cultured under LSD. The fish cultured under LSD and HSD had higher final body weight when administered dietary LEO compared to the fish that were fed the non-supplemented diet. Adding 1% LEO increased the intestinal villus height and muscular coat thickness (MT). The MT was lower in fish cultured under HSD compared to those cultured under LSD. The amylase and lipase activities were lower in the fish cultured under HSD than in those cultured under LSD. However, LEO addition increased the lipase activity in fish cultured under LSD and HSD. Fish cultured under HSD showed lower immune/antioxidant indices (lysozymes, nitric oxide, complement 3, catalase, superoxide dismutase, and glutathione-S transferase) than those cultured under LSD. However, LEO addition significantly increased the immune response and antioxidant activity in fish cultured under LSD and HSD (P < 0.01). The level of expression of the IL-1β, IL-6, IL-8, NF-kB, and TLR-4 B genes was upregulated in the LSD + LEO1, LSD + LEO0.5, and HSD + LEO1 groups. The expression of TGF-β and IL-10 was upregulated in fish that received 1% and 0.5% LEO, irrespective of whether they were cultured under LSD or HSD. The level of expression of apoptosis-related genes (caspase 3 and BAX) was upregulated in the HSD + LEO0 group and modified by the addition of LEO in their diet. The immunoexpression of NF-kB and IL-1β after bacterial challenge increased in the tissues of fish cultured under LSD and HSD after LEO was administered. These results indicated that the dietary addition of 1% LEO mitigated the harmful effects of HSD on the growth, immunity, antioxidant activity, and disease resistance of the Nile tilapia. [ABSTRACT FROM AUTHOR]

Assessment of acute toxicity of magnetic nanogel (MNG) is crucial to conclude the safe applicable dose and to warrant its application in aquaculture. Therefore, the current study is a novel step to assess behavior, neuro-stress response, hepato-renal, oxidative, and histopathological variations produced by MNG' acute toxicity in Clarias gariepinus. Two experiments were conducted: the first was a determination of the 96-h lethal concentration 50 (LC50) of MNG in C. gariepinus. Meanwhile, the second was an assessment of the toxicological impacts of three different concentrations of MNG in C. gariepinus following a 10-day exposure period and a subsequent 10-day depuration trial. One hundred and eighty fish were allotted to four groups exposed to 0, 1/10, 1/8, or 1/5 96-h LC50 of MNG. The outcomes exhibited that 96-h LC50 of MNG for C. gariepinus was 44 mg/L. The subjected group to MNG induced a concentration-dependent elevation in the serum values of cortisol, alanine transaminase, aspartate transaminase, urea, and creatinine following MNG exposure. Marked elevation in the oxidative stress indicators (catalase (CAT), glutathione S-transferase activity (GST), and superoxide dismutase (SOD)) was also evident. Meanwhile, the value of the neurological biomarker, acetylcholinesterase (AChE), was markedly reduced in a concentration-dependent way. These biochemical changes were complemented by pathological alterations in the hepato-renal architecture. Interestingly, in response to the 10-day depuration period, most of the tested parameters were eliminated in C. gariepinus exposed to 1/10 of LC50. Conclusively, MNG can induce numerous adverse effects only at higher doses (1/5 and 1/8 of LC50). Meanwhile, the lowest tested concentration of MNG (1/10 of LC50) was safe for application in aquaculture practices with only mild disruptions in the bio-indices. In addition, a retrieval period of 10 days was sufficient to renovate these alterations only in fish exposed to the same concentration. [ABSTRACT FROM AUTHOR]

Background: Polypharmacy is associated with the prescription of inappropriate medications and avoidable medication-related harm. A novel pharmacist-led intervention aims to identify and resolve inappropriate medication prescriptions in older adults with polypharmacy. Aim: To conduct a preliminary feasibility assessment of the intervention in primary care, testing whether specific components of the intervention procedures and processes can be executed as intended. Method: The mixed-methods study was approved by the New Zealand Health and Disability Ethics Committees and public health agency. Patients from a New Zealand general practice clinic were recruited over 4 weeks to receive the intervention. The preliminary feasibility assessment included measures of intervention delivery, patient-reported outcome measures, and perspectives from ten patients and six clinicians. Data were analysed quantitatively and qualitatively to determine if a full-scale intervention trial is warranted. The study's progression criteria were based on established research and guided the decision-making process. Results: The intervention met the study's progression criteria, including patient recruitment, retention, and adherence to the intervention procedures. However, several modifications were identified, including: (1) enhancing patient recruitment, (2) conducting a preliminary meeting between the patient and pharmacist, (3) supporting pharmacists in maintaining a patient-centred approach, (4) reviewing the choice of patient-reported outcome measure, (5) extending the 8-week follow-up period, (6) allocating more time for pharmacists to conduct the intervention. Conclusion: The study found the intervention feasible; however, additional development is required before progressing to a full-scale trial. This intervention has the potential to effectively reduce medication-related harm and improve outcomes for older adults with polypharmacy. Trial registration number: ACTRN12621000268842 Date registered: 11/03/2021 [ABSTRACT FROM AUTHOR]

Trismus commonly arises after surgery for head and neck cancer (HNC) and its severity is potentiated by postoperative radiotherapy. While the benefit of trismus rehabilitation after surgery and radiotherapy is well established, the evidence during radiotherapy is less clear. This may be due to poor adherence to trismus exercises secondary to acute mucositis. This study assessed the feasibility of using a novel trismus device during adjuvant radiotherapy for HNC in patients with acute postoperative trismus. Prospective single-arm cohort feasibility study. Eligible patients had undergone surgery with curative intent for HNC, planned for adjuvant radiotherapy, and were suitable for trismus rehabilitation. Participants completed a 10-week exercise program using a novel jaw stretching device. Study outcomes were adherence, maximal incisal opening (MIO), and trismus-related function and quality of life scores, assessed at baseline, 10 weeks, and 6 months after commencing exercises. Nine patients diagnosed with trismus after primary surgery were recruited. The mean increase in MIO at 10 weeks was 7.8 mm (range −4 to 15 mm, p = 0.03), and at 6 months was 10.6 mm (range 1–26 mm, p = 0.03). Significant improvements were observed in trismus-related quality of life (Gothenburg Trismus Questionnaire; p = 0.04). Adherence to the exercises was 100% in week 1–2, 67% in weeks 3–6, and 100% at 10 weeks (1 month post radiation). This study demonstrates the feasibility of using a novel jaw stretching device during adjuvant radiotherapy. Further evaluation is warranted to assess the effectiveness of early intervention and prevention of trismus during HNC radiotherapy. Level of Evidence: IV [ABSTRACT FROM AUTHOR]

Introduction: Pharmacovigilance (PV), or the ongoing safety monitoring after a medication has been licensed, plays a crucial role in pregnancy, as clinical trials often exclude pregnant people. It is important to understand how pregnancy PV projects operate in low- and middle-income countries (LMICs), where there is a disproportionate lack of PV data yet a high burden of adverse pregnancy outcomes. We conducted a scoping review to assess how exposures and outcomes were measured in recently published pregnancy PV projects in LMICs. Methods: We utilized a search string, secondary review, and team knowledge to review publications focusing on therapeutic or vaccine exposures among pregnant people in LMICs. We screened abstracts for relevance before conducting a full text review, and documented measurements of exposures and outcomes (categorized as maternal, birth, or neonatal/infant) among other factors, including study topic, setting, and design, comparator groups, and funding sources. Results: We identified 31 PV publications spanning at least 24 LMICs, all focusing on therapeutics or vaccines for infectious diseases, including HIV (n = 17), tuberculosis (TB; n = 9), malaria (n = 7), pertussis, tetanus, and diphtheria (n = 1), and influenza (n = 3). As for outcomes, n = 15, n = 31, and n = 20 of the publications covered maternal, birth, and neonatal/infant outcomes, respectively. Among HIV-specific publications, the primary exposure-outcome relationship of focus was exposure to maternal antiretroviral therapy and adverse outcomes. For TB-specific publications, the main exposures of interest were second-line drug-resistant TB and isoniazid-based prevention therapeutics for pregnant people living with HIV. For malaria-specific publications, the primary exposure-outcome relationship of interest was antimalarial medication exposure during pregnancy and adverse outcomes. Among vaccine-focused publications, the exposure was assessed during a specific time during pregnancy, with an overall interest in vaccine safety and/or efficacy. The study settings were frequently from Africa, designs varied from cohort or cross-sectional studies to clinical trials, and funding sources were largely from high-income countries. Conclusion: The published pregnancy PV projects were largely centered in Africa and concerned with infectious diseases. This may reflect the disease burden in LMICs but also funding priorities from high-income countries. As the prevalence of non-communicable diseases increases in LMICs, PV projects will have to broaden their scope. Birth and neonatal/infant outcomes were most reported, with fewer reporting on maternal outcomes and none on longer-term child outcomes; additionally, heterogeneity existed in definitions and ascertainment of specific measures. Notably, almost all projects covered a single therapeutic exposure, missing an opportunity to leverage their projects to cover additional exposures, add scientific rigor, create uniformity across health services, and bolster existing health systems. For many publications, the timing of exposure, specifically by trimester, was crucial to maternal and neonatal safety. While currently published pregnancy PV literature offer insights into the PV landscape in LMICs, further work is needed to standardize definitions and measurements, integrate PV projects across health services, and establish longer-term monitoring. [ABSTRACT FROM AUTHOR]

Recently, DNA methylation clocks have been proven to be precise age predictors, and the application of these clocks in cancer tissue has revealed a global age acceleration in a majority of cancer subtypes when compared to normal tissue from the same individual. The polycomb repressor complex 2 plays a pivotal role in the aging process, and its targets have been shown to be enriched in CpG sites that gain methylation with age. This complex is further regulated by the chromatin remodeling complex SWItch/Sucrose Non-Fermentable and its core subunit, notably the tumor suppressor gene SMARCB1, which under physiological conditions inhibits the activity of the polycomb repressor complex 2. Hence, the loss of function of core members of the SWItch/sucrose non-fermentable complex, such as the tumor suppressor gene SMARCB1, results in increased activity of polycomb repressor complex 2 and interferes with the aging process. SMARCB1-deficient neoplasms represent a family of rare tumors, including amongst others malignant rhabdoid tumors, atypical teratoid and rhabdoid tumors, and epithelioid sarcomas. As aging pathways have recently been proposed as therapeutic targets for various cancer types, these tumors represent candidates for testing such treatments. Here, by deriving epigenetic age scores from more than 1000 tumor samples, we identified epigenetic age acceleration as a hallmark feature of epithelioid sarcoma. This observation highlights the potential of targeting aging pathways as an innovative treatment approach for patients with epithelioid sarcoma. [ABSTRACT FROM AUTHOR]

Leading theories of the recent history of sexuality have pointed to trends toward detraditionalization and precarity in intimate relations, but also to democratization and innovation. This study grounded in 79 qualitative interviews with men seeking men online considers their experiences in light of these theories. The rise of dating apps has generated sexual fields that have shaped the sexual subjectivities of the current era in multiple ways. The narratives of study participants show much more than the hook-up culture that dating apps are best known for. They speak to experiences of superficiality, unmet expectations, and sometimes bruising intersections with hierarchies defined by age, race, body type, gender expression, and serostatus. Yet at the same time, they show a strong aspiration to sociability, social network building, and reach for a language of affiliation beyond the kin and friendship terms of the larger society. Generational comparisons indicate the shifting sexual subjectivities that dating apps have shaped by constituting virtual sexual fields. [ABSTRACT FROM AUTHOR]

Intracoronary continuous thermodilution has been recently proposed as an invasive method to quantify absolute coronary flow (Qabs) and resistance (Rabs) in vivo. The aim of the present study is to develop and validate of a novel pressure-wire- and microcatheter-free surrogate of coronary flow and resistance derived from a standard coronary angiogram. Angiography derived coronary flow (Qangio) and resistance (Rangio) was prospectively validated in a two-center cohort of patients from Oxford Heart Centre and the Essex Cardiothoracic Centre. Qabs and Rabs were measured during resting and hyperemic conditions with continuous thermodilution using the Rayflow microcatheter. Qangio and Rangio were computed from the diagnostic coronary angiogram in a blinded fashion in resting and hyperemic conditions. A total of 62 patients and 115 vessels were included in the present analysis. The median Qabs at rest was 75 ml/min (53–95) and 151 ml/min (105–203) during hyperemia; Qangio at rest was 84 ml/min (66–108) and 154 ml/min (115–195) during hyperemia. There was a strong correlation between Qabs and Qangio (R = 0,72; p < 0.001, R = 0,86; p < 0.001 respectively) with satisfactory interclass correlation (0.841, 95% CI 0.509–0.957; p = 0.0003). The median Rabs was 1111 mmHg/(L/min) (830-1581.4) at rest and 454 mmHg/(L/min) (348–610) during hyperemia; angiographic resistance (Rangio) was 937.4 mmHg/(L/min) (695.4–1261.9) at rest and 492.4 mmHg/(L/min) (406–697) during hyperemia. There was a strong correlation between Rabs and Rangio in both conditions (R = 0,81; p < 0.001 and R = 0,78; p < 0.001 respectively). The was a good correlation between absolute coronary flow reserve (CFR) and angiography-derived CFR (R = 0,61; p < 0.001) and between absolute microvascular resistance reserve (MRR) and angiography-derived MRR (R = 0,49; p < 0.001). We developed and validated a novel non-invasive, fully angiographic, pressure-wire- and microcatheter-free method to quantify coronary flow and resistance in resting and hyperemic conditions. Angiography-derived coronary flow and resistance was prospectively validated in a two-center cohort of 62 patients and 115 vessels against absolute coronary flow and resistance measured with Rayflow microcatheter. We found a strong correlation between angiography-derived flow and resistance and absolute coronary flow and resistance, with satisfactory interclass correlation. There was a good correlation between absolute coronary flow reserve (CFR) and angiography-derived CFR and between absolute microvascular resistance reserve (MRR) and angiography-derived MRR. [ABSTRACT FROM AUTHOR]

Common Reed Phragmites australis, globally one of the mostly widely distributed wetland plants, is important for biodiversity and for humans. However, like most wetland plant communities, reedbed has rarely been mapped at large geographical scales, restricting the information available to study reed’s range dynamics or inform its management. Using Sentinel-2 data and machine learning, we aimed to produce the first published remotely-sensed reedbed map of Britain; however, accuracy as assessed by field validation was relatively low (AUC = 0.671), with many false positives (commission error of 93.4%). A similar workflow carried out in Google Earth Engine, using nearly an order of magnitude more images, gave a lower commission error but a disproportionately higher omission error. Using the known commission and omission error, we estimate that in 2015–2017 ~ 7800 ha of Britain was reedbed. Our study highlights the enduring barriers to accurate land cover classification at large spatial scales. Even with a ‘big data’ approach, reflectance error and ecological factors such as confusion land cover types and geographical variation in temporal reflectance function will probably continue to limit the size of area for which land cover can be classified accurately, therefore limiting the utility of remote sensing for ecologists. [ABSTRACT FROM AUTHOR]

People will make different moral judgments in similar moral dilemmas where one can act to sacrifice some number of lives to save several more. Research has shown that although people can reason that an action would save more lives, automatic processes can overwrite deliberate reasoning. Having participants imagine hypothetical moral dilemmas, researchers have discovered that factors such as action/omission, means/side-effect, and personal/impersonal can affect judgment. Joshua Greene suggests that these features do not affect people’s judgment because they are morally relevant but are instead a result of the myopic nature of the automatic moral process. Greene hypothesizes that there is some myopic module or domain-general process that attaches a negative emotional response to an action when one is contemplating violent actions. In the present research a model of this myopic automatic process is paired with an analytic system to replicate deontological and utilitarian responses to moral dilemmas. Our system, MERDJ, models this in simulated spiking neurons. The system takes in representations of specific moral dilemmas as inputs and outputs judgments of appropriate or inappropriate. [ABSTRACT FROM AUTHOR]

In this study, a plane strain finite element analysis (FEA) was employed to investigate failure mechanisms of a hydrogen storage pipe system made of 316L stainless steel pipe coated with pure and functionally graded (FG) ceramic layers composed of Al2O3 and SiC. The system was studied for different common failure mechanisms, i.e., delamination, surface cracking and buckling delamination, upon cooling from an elevated stress-free temperature. Finally, the composition and thickness of the coating layers were considered as the main controlling factors and investigated for their influence on the studied failure mechanisms. It was observed that the most energetically favourable cracking mechanism for this type of system was surface cracking with the propagation of these cracks eventually leading to different failure paths. Buckling was found to be as less energetically favourable compared to surface cracking with the buckling resistance being enhanced by changing the coating thickness and composition factor. [ABSTRACT FROM AUTHOR]

COVID-19 pandemic brought chemosensory impairment to the forefront of medicine, revealing gaps in the knowledge of pathophysiological mechanisms, true prevalence and preventive/therapeutic alternatives. This is a sub-study of the ORCHESTRA cohort focusing on post-COVID-19 chemosensory symptoms. Risk factors for neurosensorial cluster of post-COVID-19 syndrome (NSc-PCS) were assessed through multivariable analysis. Psychophysical validated tests were applied on a sub-population of 50 patients. Qualitative chemosensory symptoms as well as nasal and oral chemesthesis were evaluated through anamnestic interview and the quality of life through the SF-36 questionnaire. Chemosensory symptoms evolution and olfactory training's outcome were assessed through phone-call interviews. Out of 1187 patients (female, N = 630), 550 (47%) presented NSc-PCS, with a lower risk for older age and monoclonal antibodies treatment, and a higher risk in females (p < 0.001). Out of the 50 patients evaluated with psychophysical tests, 66% showed smell reduction with a qualitative alteration in 50% of hyposmic and 35% of normosmic patients. Hypogeusia was present in 14 (28%) of the patients assessed, with 56% showing a qualitative alteration; 53% of normogeusic patients presented qualitative disorders. NSc-PCS has a complex, fluctuating, multifaceted presentation. Quantifying and characterizing COVID-19-related chemosensory impairment is key to understand underlying mechanisms and to develop preventive and therapeutic treatment. [ABSTRACT FROM AUTHOR]

Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours1–3. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1−/−;Trp53−/− cells, and find that both follow a similar pattern of loss and spread within ducts. Clonal analysis reveals that ducts consist of small repetitive units of self-renewing cells that give rise to short-lived descendants. This offers a first layer of protection as any descendants, including oncogenic mutant cells, are constantly lost, thereby limiting the spread of mutations to a single stem cell-descendant unit. Local tissue remodelling during consecutive oestrous cycles leads to the cooperative and stochastic loss and replacement of self-renewing cells. This process provides a second layer of protection, leading to the elimination of most mutant clones while enabling the minority that by chance survive to expand beyond the stem cell-descendant unit. This leads to fields of mutant cells spanning large parts of the epithelial network, predisposing it for transformation. Eventually, clone expansion becomes restrained by the geometry of the ducts, providing a third layer of protection. Together, these mechanisms act to eliminate most cells that acquire somatic mutations at the expense of driving the accelerated expansion of a minority of cells, which can colonize large areas, leading to field cancerization.The authors use lineage tracing to map the fate of wild-type and Brca1−/−;Trp53−/− cells in the adult mouse mammary gland, identifying three layers of protection that limit the spread of mutant cells at the expense of allowing a minority of mutant cells to expand, which leads to field cancerization. [ABSTRACT FROM AUTHOR]

Conservation, restoration and land management are increasingly implemented at landscape scales1,2. However, because species interaction data are typically habitat- and/or guild-specific, exactly how those interactions connect habitats and affect the stability and function of communities at landscape scales remains poorly understood. We combine multi-guild species interaction data (plant–pollinator and three plant–herbivore–parasitoid communities, collected from landscapes with one, two or three habitats), a field experiment and a modelling approach to show that multi-habitat landscapes support higher species and interaction evenness, more complementary species interactions and more consistent robustness to species loss. These emergent network properties drive improved pollination success in landscapes with more habitats and are not explained by simply summing component habitat webs. Linking landscape composition, through community structure, to ecosystem function, highlights mechanisms by which several contiguous habitats can support landscape-scale ecosystem services.Species interaction data, a field experiment and modelling of plant–insect communities show that landscapes with more habitat types support more even species, more complementary interactions, are more consistently robust to species loss, and confer greater pollination function. [ABSTRACT FROM AUTHOR]

Background: Arachnoid cysts (AC) are associated with a risk of rupture or haemorrhage following head impact and pose a potential predisposing factor for significant complications of sport-related concussion. Despite a recognised association between ACs and intracranial haemorrhage/cyst rupture, the risk profile of participating in contact sports with AC is not well defined. We report a retrospective case series of players presenting to the Birmingham Sports Concussion Clinic between 2017 and 2023 and underwent MRI head, with a comprehensive review of the prior literature. Results: 432 athletes underwent MRI of which 11 were identified to have AC (middle fossa n = 8; posterior fossa n = 2, intraventricular n = 1). Average maximal diameter was 4.1 ± 1.2 cm. 64% had a protracted recovery (≥ 3 months). 9% experienced an AC specific complication (cyst rupture, complete neurological recovery, maximal diameter 6.5 cm, Galassi II, 4 previous concussions). 91% of patients (mean maximal diameter 3.9 ± 1.0 cm) experienced no complications despite multiple previous accumulated sports-related concussions (mean 3.3, range 1–9). Case studies from the literature are summarised (n = 63), with 98% reporting complications, none of which resulted in adverse or unfavourable neurological outcomes. Across prospective and retrospective cohort studies, 1.5% had a structural injury, and (where outcome was reported) all had a favourable outcome. Conclusions: AC is an incidental finding in athletes, with the majority in our cohort having sustained serial concussions without AC complication. The single complication within this cohort occurred in the largest AC, and AC size is proposed as a tentative factor associated with increased risk of contact sports participation. Complications of AC appear to be a rare occurrence. This case series and review has not identified evidence to suggest that participation in sports with AC is of significant risk, though individualised assessment and discussion of the potential risks of contact sports participation should be offered. Key Points: Incidental arachnoid cysts were found to occur in 2.5% of athletes presenting after sports-related concussion. Of 11 athletes with AC and a history of concussion, one (9%) had experienced a prior complication of AC (cyst rupture) and made a full recovery. A comprehensive review of the prior literature suggests an overall risk of complications of 1.5%, with all reported outcomes from cases describing a full neurological recovery. Overall, complications of AC in athletes after sport-related concussion appear to be rare, with no recorded cases of significant neurological consequences. [ABSTRACT FROM AUTHOR]

Objectives: Antenatal education (ANE) is part of National Health Service (NHS) care and is recommended by The National Institute for Health and Care Excellence (NICE) to increase birth preparedness and help pregnant women/birthing people develop coping strategies for labour and birth. We aimed to understand antenatal educator views about how current ANE supports preparedness for childbirth, including coping strategy development with the aim of identifying targets for improvement. Methods: A United Kingdom wide, cross-sectional online survey was conducted between October 2019 and May 2020. Antenatal educators including NHS midwives and private providers were purposively sampled. Counts and percentages were calculated for closed responses and thematic analysis used for open text responses. Results: Ninety-nine participants responded, 62% of these did not believe that ANE prepared women for labour and birth. They identified practical barriers to accessing ANE, particularly for marginalised groups, including financial and language barriers. Educators believe class content is medically focused, and teaching is of variable quality with some midwives being ill-prepared to deliver antenatal education. 55% of antenatal educators believe the opportunity to develop coping strategies varies between location and educators and only those women who can pay for non-NHS classes are able to access all the coping strategies that can support them with labour and birth. Conclusions for Practice: Antenatal educators believe current NHS ANE does not adequately prepare women for labour and birth, leading to disparities in birth preparedness for those who cannot access non-NHS classes. To reduce this healthcare inequality, NHS classes need to be standardised, with training for midwives in delivering ANE enhanced. Significance: What is Already Known on this Subject?: There is no detailed national guidance about the content or quantity of antenatal education that should be delivered by the NHS to patients and, how coping strategies are developed within these sessions is unknown. What this Study Adds?: Antenatal educators believe that quality of antenatal education needs to be improved. Access to coping strategies for labour and birth is hindered by the type of class, the educator's approach and socioeconomic status. This study can be used to support an argument for addressing the inequality in access to antenatal preparation, whilst better preparing all women through higher quality of antenatal education provision in the NHS. [ABSTRACT FROM AUTHOR]

Although it is well established that wildfire smoke exposure can increase cardiovascular morbidity and mortality, the combined effects of non-chemical stressors and wildfire smoke remains understudied. Housing is a non-chemical stressor that is a major determinant of cardiovascular health, however, disparities in neighborhood and social status have exacerbated the cardiovascular health gaps within the United States. Further, pre-existing cardiovascular morbidities, such as atherosclerosis, can worsen the response to wildfire smoke exposures. This represents a potentially hazardous interaction between inadequate housing and stress, cardiovascular morbidities, and worsened responses to wildfire smoke exposures. The purpose of this study was to examine the effects of enriched (EH) versus depleted (DH) housing on pulmonary and cardiovascular responses to a single flaming eucalyptus wildfire smoke (WS) exposure in male and female apolipoprotein E (ApoE) knockout mice, which develop an atherosclerosis-like phenotype. The results of this study show that cardiopulmonary responses to WS exposure occur in a sex-specific manner. EH blunts adverse WS-induced ventilatory responses, specifically an increase in tidal volume (TV), expiratory time (Te), and relaxation time (RT) after a WS exposure, but only in females. EH also blunted an increase in isovolumic relaxation time (IVRT) and the myocardial performance index (MPI) 1-week after exposures, also only in females. Our results suggest that housing alters the cardiovascular response to a single WS exposure, and that DH might cause increased susceptibility to environmental exposures that manifest in altered ventilation patterns and diastolic dysfunction in a sex-specific manner. [ABSTRACT FROM AUTHOR]

Objectives: Corner metaphyseal lesions (CMLs) are specific for child abuse but challenging to detect on radiographs. The accuracy of CT for CML detection is unknown. Our aim was to compare diagnostic accuracy for CML detection on post-mortem skeletal surveys (PMSS, plain radiography) versus post-mortem CT (PMCT). Methods: A 10-year retrospective review was performed at a children's hospital for patients having PMSS, PMCT and histopathological correlation (reference standard) for suspected CMLs. Twenty-four radiologists independently reported the presence or absence of CMLs in all cases in a blinded randomised cross-over design across two rounds. Logistic regression models were used to compare accuracy between modalities. Results: Twenty CMLs were reviewed for each of the 10 subjects (200 metaphyses in all). Among them, 20 CMLs were confirmed by bone histopathology. Sensitivity for these CMLs was significantly higher for PMSS (69.6%, 95% CI 61.7 to 76.7) than PMCT (60.5%, 95% CI 51.9 to 68.6). Using PMSS for detection of CMLs would yield one extra correct diagnosis for every 11.1 (95% CI 6.6 to 37.0) fractured bones. In contrast, specificity was higher on PMCT (92.7%, 95% CI 90.3 to 94.5) than PMSS (90.5%, 95% CI 87.6 to 92.8) with an absolute difference of 2.2% (95% CI 1.0 to 3.4, p < 0.001). More fractures were reported collectively by readers on PMSS (785) than on PMCT (640). Conclusion: PMSS remains preferable to PMCT for CML evaluation. Any investigation of suspected abuse or unexplained deaths should include radiographs of the limbs to exclude CMLs. Clinical relevance statement: In order to avoid missing evidence that could indicate child abuse as a contributory cause for death in children, radiographs of the limbs should be performed to exclude CMLs, even if a PMCT is being acquired. Key Points: • Corner metaphyseal lesions (CMLs) are indicative for abuse, but challenging to detect. Skeletal surveys (i.e. radiographs) are standard practice; however, accuracy of CT is unknown. • Sensitivity for CML detection on radiographs is significantly higher than CT. • Investigation of unexplained paediatric deaths should include radiographs to exclude CMLs even if CT is also being performed. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the contributors to self-rated health in people with late-stage Parkinson's disease (PD) and cognitive impairment. Methods: A secondary analysis of baseline data from the international Care of Late-Stage Parkinsonism (CLaSP) cohort study was conducted. Participants with PD and either dementia or mild cognitive impairment or MMSE < 24/30 in the absence of major depression were included if they had completed the EQ-5D-3L assessment (n = 277). Factors associated with self-rated health (EQ-5D-3L Index and Visual Analogue Scale) were investigated through multivariable linear regression. Results: More severe PD (motor and non-motor) was associated with worse self-rated health. The EQ-5D-3L dimensions of Mobility, Self-Care and Usual Activities were almost universally affected; the latter two particularly severely. Being unable to perform usual activities or having moderate to extreme anxiety or depression were significantly associated with EQ-5D-3L Visual Analogue Scale, suggesting these are particularly valued. Worse motor impairment and function and the non-motor symptom domains of mood, perception, sexual function, and miscellaneous (e.g., pain) were associated with worse self-rated health, whereas greater burden of gastrointestinal symptoms was associated with better self-rated health in multivariate analysis. Better self-rated health was associated with recent PD nurse consultation, and higher doses of dopaminergic medication. Conclusion: Improvement of activities of daily living, mood and anxiety should be prioritised in clinical practice, with consideration of perception and sexual function in this population. Recent nurse consultations and higher antiparkinsonian doses are associated with better self-rated health, suggesting there is no room for a therapeutic nihilism in this population of people within a complex phase of PD. [ABSTRACT FROM AUTHOR]

This study analyzed collaborative invention projects by teams of lower-secondary (13–14-year-old) Finnish students. In invention projects, student teams design and make materially embodied collaborative inventions using traditional and digital fabrication technologies. This investigation focused on the student teams' knowledge creation processes by examining how they applied maker practices (i.e., design process, computer engineering, product design, and science practices) in their co-invention projects and the effects of teacher and peer support. In our investigations, we relied on video data and on-site observations, utilizing and further developing visual data analysis methods. Our findings assist in expanding the scope of computer-supported collaborative learning (CSCL) research toward sociomaterially mediated knowledge creation, revealing the open-ended, nonlinear, and self-organized flow of the co-invention projects that take place around digital devices. Our findings demonstrate the practice-based, knowledge-creating nature of these processes, where computer engineering, product design, and science are deeply entangled with design practices. Furthermore, embodied design practices of sketching, practical experimenting, and working with concrete materials were found to be of the essence to inspire and deepen knowledge creation and advancement of epistemic objects. Our findings also reveal how teachers and peer tutor students can support knowledge creation through co-invention. [ABSTRACT FROM AUTHOR]

Signal transducers and activators of transcription (STAT) proteins regulate mammary development. Here we investigate the expression of phosphorylated STAT3 (pSTAT3) in the mouse and cow around the day of birth. We present localised colocation analysis, applicable to other mammary studies requiring identification of spatially congregated events. We demonstrate that pSTAT3-positive events are multifocally clustered in a non-random and statistically significant fashion. Arginase-1 expressing cells, consistent with macrophages, exhibit distinct clustering within the periparturient mammary gland. These findings represent a new facet of mammary STAT3 biology, and point to the presence of mammary sub-microenvironments. [ABSTRACT FROM AUTHOR]

Exposure to alkaline stress is common in aquatic practices. The present research investigated the detrimental impacts of rearing Nile tilapia under alkaline water stress by investigating the liver function indices and transcriptomic profile. A 30-day study was conducted on 160 fish (16.02 ± 0.14 g) split into four groups, each with four replicates. Group 1 (G1) and G2 were fed on a basal diet fortified with 0 and 75 g/kg diet camel whey protein hydrolysates (CWP) and reared in freshwater (carbonate alkalinity = 1.4 mmol/L, pH = 7.19). Moreover, G3 and G4 were fed on a basal diet enriched with 0 and 75 g/kg diet CWP and reared in alkaline water (carbonate alkalinity = 23.8 mmol/L; pH = 8.65). The outcomes revealed elevated lipid indices (triglycerides, cholesterol, low- and high-density lipoproteins) and liver enzymes (alanine and aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase) with lowered protein indices (total protein, albumin, and globulin) in alkaline-reared fish. Moreover, oxidative stress was initiated through lowered antioxidant enzymes (superoxide dismutase, catalase, and reduced glutathione) and higher malondialdehyde in the alkaline-exposed fish. Alkaline stress induced the activation of the mechanistic target of rapamycin and MAPK pathway (mitogen-activated protein kinase, c-Jun NH terminal kinase, and MAPK-1) with down-regulation of the autophagy-related genes (ATG-5, ATG-7, and ATG-13) and cathepsin B expression. Feeding on a CWP-supplemented diet resulted in significant modulation of the lipid profile, liver enzyme activity, and improvement in protein indices and antioxidant enzyme activity. Furthermore, modulation of the transcriptomic profile of the hepatic tissue of the alkaline-exposed fish was noticed due to feeding on a CWP-supplemented diet. Overall, CWP dietary addition at a level of 75 g/kg diet can alleviate the alkaline stress exposure in Nile tilapia. These outcomes could contribute to understanding the physiological circumstances of Nile tilapia when reared in alkaline water as well as provide a novel dietary additive for mitigating the bad consequences due to alkaline-stress exposure. [ABSTRACT FROM AUTHOR]

In this study, Moringa oleifera seed protein hydrolysate (MSPH) was included in the diet of Nile tilapia, Oreochromis niloticus, as a protein supplement for 90 days. Fish (n = 250, weighing 30.37 ± 0.05 g) were received diets with five inclusion levels of MSPH: 0, 33, 66, 99, and 132 g kg−1 diet (MSPH0, MSPH33, MSPH66, MSPH99, and MSPH132), respectively, with MSPH0 serving as the control diet. Compared to MSPH0, a pronounced improvement in the final body weight (FBW), total weight gain (TWG), specific growth rate % (SGR %), feed conversion ratio (FCR), protein efficacy ratio (PER), and average daily weight gain (ADWG) was noticed in all MSPH groups, with MSPH132 showing the highest values. The improvement was by 6.41, 18.18, 34.22, and 47.05% for FBW, 9.87, 27.40, 51.39, and 70.46% for TWG, and 4.80, 15.20, 34.40, and 38.40% for FCR in the MSPH33, MSPH66, MSPH99, and MSPH132 groups, respectively. The intestinal histo-morphometric and hematological indices of O. niloticus were significantly improved by MSPH levels. The total proteins and albumin were enhanced considerably by dietary MSPH (66 to 132 g kg−1 diet), while the globulin was enhanced by MSPH (99 to 132 g kg−1 diet). MSPH diets significantly enhanced the hepatic antioxidant enzymes and serum total antioxidant capacity and reduced malondialdehyde level. MSPH dietary inclusion did not alter the hepatorenal functions and their tissue integrity except for mild tubular adenomatous regenerative changes in the kidney of the MSPH132 group. In conclusion, the MSPH at a level up to 99 g kg−1 diet could be used as a dietary inclusion in O. niloticus. These findings contribute to the sustainability of the Nile tilapia culture sector. [ABSTRACT FROM AUTHOR]

Background: Timely diagnosis of heart failure (HF) and rapid optimisation of guideline-directed medication therapy (GDMT) improves patients qualities of life, reducing mortality and morbidity. Previous papers describe the role of pharmacists in medication optimisation, but not in the diagnosis of HF. Aim: To describe the development, implementation, and evaluation of pharmacist-led heart failure clinics with respect to time from referral to diagnosis, time from diagnosis to first review with a specialist, and the proportion receiving optimal GDMT 180 days after diagnosis. Setting: Community outpatient clinics in rural west Wales, United Kingdom. Development: Two experienced non-medical prescribing pharmacists, one of whom had additional diagnostic qualifications in cardiology, delivered the clinic. Implementation: Patients referred with suspected HF were risk-stratified to urgent (within 14 days of referral) or routine (within 42 days) review, based on natriuretic peptide levels. Patients attended the clinic for assessment, including physical examination, electrocardiogram, and echocardiogram. Those with HF with reduced ejection fraction were initiated on drug treatment and referred to the follow-up pharmacist-led GDMT clinic. Evaluation: A sample of 100 patients was evaluated (50 from pre-existing and 50 from new service). Median time from referral to diagnosis reduced from 61 days (IQR 47–115) to 16 days (IQR 10.5–27.5) for urgent and 19 days (IQR 11.5–33) for routine. Median time to first appointment following diagnosis reduced from 54 days (IQR 36–60.5) to 14 days (IQR 9.75–28.75) (p value < 0.0001), and proportion of patients achieving GDMT at 180 days following diagnosis improved from 24 to 86% (p value < 0.0001). Conclusion: This pharmacist HF diagnostic clinic and medication optimisation clinic improved time to diagnosis, time to first specialist review, and proportion of patients' achieving GDMT optimisation in a rural healthcare setting. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is a deadly cancer. Early diagnosis and access to timely treatment are essential to maximizing the likelihood of survival. Indigenous peoples experience enduring disparities in lung cancer survival, and disparities in access to and through lung cancer services is one of the important drivers of these disparities. In this manuscript, we aimed to examine the current evidence on disparities in Indigenous access to services along the lung cancer treatment pathway. Methods: A narrative literature review was conducted for all manuscripts and reports published up until July 20, 2022, using Medline, Scopus, Embase, and Web of Science. Following the identification of eligible literature, full-text versions were scanned for relevance for inclusion in this review, and relevant information was extracted. After scanning 1,459 documents for inclusion, our final review included 36 manuscripts and reports that included information on lung cancer service access for Indigenous peoples relative to non-Indigenous peoples. These documents included data from Aotearoa New Zealand, Australia, Canada, and the USA (including Hawai'i). Results: Our review found evidence of disparities in access to, and the journey through, lung cancer care for Indigenous peoples. Disparities were most obvious in access to early detection and surgery, with inconsistent evidence regarding other components of the pathway. Conclusion: These observations are made amid relatively scant data in a global sense, highlighting the need for improved data collection and monitoring of cancer care and outcomes for Indigenous peoples worldwide. Access to early detection and guideline-concordant treatment are essential to addressing enduring disparities in cancer survival experienced by Indigenous peoples globally. [ABSTRACT FROM AUTHOR]

Primary reflexes are highly stereotypical, automatic movements comprising much of the motor repertoire of newborns. The current study examined rates of presence of five primary reflexes (snout, visual rooting, sucking, tactile rooting, and grasp) and variables predictive of their persistence for children with ASD (n = 35), developmental disability (n = 30), and typically developing children matched to participants with ASD on chronological age (n = 30). There was a higher prevalence of snout and visual rooting reflex among children with ASD. These data suggest that the persistence of primary reflexes holds promise as a biomarker for autism spectrum disorder (ASD). [ABSTRACT FROM AUTHOR]