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Aim: Planning conservation action requires accurate estimates of abundance and distribution of the target species. For many mammals, particularly those inhabiting tropical forests, there are insufficient data to assess their conservation status. We present a framework for predicting species distribution using jaguarundi (Herpailurus yagouaroundi), a poorly known felid for which basic information on abundance and distribution is lacking. Location: Mesoamerica and South America. Time Period: From 2003 to 2021. Taxa: Herpailurus yagouaroundi. Methods: We combined camera‐trap data from multiple sites and used an occupancy modelling framework accounting for imperfect detection to identify habitat associations and predict the range‐wide distribution of jaguarundis. Results: Our model predicted that the probability of jaguarundi occupancy is positively associated with rugged terrain, herbaceous cover, and human night‐time light intensity. Jaguarundi occupancy was predicted to be higher where precipitation was less seasonal, and at intermediate levels of diurnal temperature range. Our camera data also revealed additional detections of jaguarundis beyond the current International Union for Conservation of Nature (IUCN) range distribution, including the Andean foothills of Colombia and Bolivia. Main Conclusion: Occupancy was predicted to be low throughout much of Amazonian lowlands, a vast area at the centre of jaguarundi known range. Further work is required to investigate whether this area represents sub‐optimal conditions for the species. Overall, we estimate a crude global jaguarundi population of 35,000 to 230,000 individuals, covering 4,453,406 km2 of Meso‐ and South America at the 0.5 probability level of occupancy. Our current framework allows for an initially detailed, well‐informed species distribution that should be challenged and refined with improved habitat layers and additional records of jaguarundi detection. We encourage similar studies of lesser‐known mammals, pooling existing by‐catch data from the growing bank of camera‐trap surveys around the world. [ABSTRACT FROM AUTHOR]

Improving access to primary care physicians' services may help reduce hospitalizations due to Ambulatory Care Sensitive Conditions (ACSCs). Ontario, Canada's most populous province, introduced blended payment models for primary care physicians in the early‐ to mid‐2000s to increase access to primary care, preventive care, and better chronic disease management. We study the impact of payment models on avoidable hospitalizations due to two incentivized ACSCs (diabetes and congestive heart failure) and two non‐incentivized ACSCs (angina and asthma). The data for our study came from health administrative data on practicing primary care physicians in Ontario between 2006 and 2015. We employ a two‐stage estimation strategy on a balanced panel of 3710 primary care physicians (1158 blended‐fee‐for‐service (FFS), 1388 blended‐capitation models, and 1164 interprofessional team‐based practices). First, we account for the differences in physician practices using a generalized propensity score based on a multinomial logit regression model, corresponding to three primary care payment models. Second, we use fractional regression models to estimate the average treatment effects on the treated outcome (i.e., avoidable hospitalizations). The capitation‐based model sometimes increases avoidable hospitalizations due to angina (by 7 per 100,000 patients) and congestive heart failure (40 per 100,000) relative to the blended‐FFS‐based model. Switching capitation physicians into interprofessional teams mitigates this effect, reducing avoidable hospitalizations from congestive heart failure by 30 per 100,000 patients and suggesting better access to primary care and chronic disease management in team‐based practices. [ABSTRACT FROM AUTHOR]

Purpose: To develop a biocompatible denture base resin/TiO2 nanocomposite material with antifungal characteristics that is suitable for 3D‐printing denture bases. Materials and Methods: TiO2 nanoparticles (NPs) with a 0.10, 0.25, 0.50, and 0.75 weight percent (wt.%) were incorporated into a commercially available 3D‐printed resin material. The resulting nanocomposite material was analyzed using Lactate dehydrogenase (LDH) and AlamarBlue (AB) assays for biocompatibility testing with human gingival fibroblasts (HGF). The composite material was also tested for its antifungal efficacy against Candida albicans. Fourier transform infrared (FTIR) and Energy Dispersive X‐ray Spectroscopy (EDX) mapping were conducted to assess the surface coating and the dispersion of the NPs. Results: LDH and AB assays confirmed the biocompatibility of the material showing cell proliferation at a rate of nearly 100% at day 10, with a cytotoxicity of less than 13% of the cells at day 10. The concentrations of 0.10, 0.25, and 0.50 wt.% caused a significant reduction (p < 0.05) in the number of candida cells attached to the surface of the specimens (p < 0.05), while 0.75 wt.% did not show any significant difference compared to the control (no TiO2 NPs) (p > 0.05). FTIR and EDX analysis confirmed the presence of TiO2 NPs within the nanocomposite material with a homogenous dispersion for 0.10 and 0.25 wt.% groups and an aggregation of the NPs within the material at higher concentrations. Conclusion: The addition of TiO2 NPs into 3D‐printed denture base resin proved to have an antifungal effect against Candida albicans. The resultant nanocomposite material was a biocompatible material with HGFs and was successfully used for 3D printing. [ABSTRACT FROM AUTHOR]

Values that accompany generic health measures are typically anchored at 1 = full health and 0 = dead. Some health states may then be considered 'worse than dead' (WTD) and assigned negative values, which causes fundamental measurement problems. In this paper, we challenge the assumption that anchoring values at 'dead = 0' is necessary for quality‐adjusted life year (QALY) estimation. We summarise the role of 'dead' in health state valuation and consider three critical questions: (i) whether the measurement properties of health state values require 'dead'; (ii) whether 'dead' needs to be valued relative to health states; and (iii) whether values for states WTD are meaningful or useful. We conclude that anchoring 0 at dead is not a requirement of health status measurement or cost‐effectiveness analysis. This results from reframing QALYs as the relevant unit of measurement and reframing values as being derived from QALYs rather than the reverse. [ABSTRACT FROM AUTHOR]

Aims: Soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt‐1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF. Methods and results: ELISA assays for sFlt‐1, PlGF and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt‐1 or PlGF levels were genotyped. sFlt‐1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All‐cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt‐1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt‐1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt‐1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57–16.1; p < 0.001) in PEOPLE, independent of age, NT‐proBNP, ischaemic aetiology, diabetic status and beta‐blocker therapy. Conclusions: Plasma sFlt‐1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF. [ABSTRACT FROM AUTHOR]

Objective: To identify patients presenting to an acute medical hospital with common signs and symptoms that occur in people with eating disorders (EDs), and determine by retrospective file audit if these are diagnosed cases of an ED. Method: The investigators screened electronic medical records of people 16 years and older for common signs and symptoms of an ED such as hypokalemia, in patients presenting to an acute hospital in Sydney, Australia from 2018 to 2020. Cases where the clinical finding was unexplained had their file audited. Cases with a known ED diagnosis or coded with an ED were also retrieved to audit. Results: Investigators identified 192 definite ED cases with a total of 598 episodes of care from 2018 to 2020 presenting to the hospital. Eighty‐three cases were identified as possible EDs due to unexplained clinical signs consistent with an ED, but were not confirmed cases due to lack of clinical history in the file. Only 19.1% of presentations were diagnostically coded with an ED in the electronic medical record. Discussion: Our study revealed a large number of definite ED cases presenting to an acute medical hospital via the emergency department, who were not recognized as having an ED. Greater awareness of clinical signs and symptoms of an ED, such as unexplained low body mass index and hypokalemia, is necessary among acute care clinicians. Correctly identifying EDs in those seeking somatic care should be a public health priority, to facilitate timely and equitable access to diagnostic assessment and evidence based treatment. Public significance: People with eating disorders (EDs) present to acute care settings and have a relatively high utilization of generalist health services with nonspecific problems such as abdominal pain. An enhanced understanding of healthcare utilization by people with EDs, who may not disclose their symptoms, is crucial for improving access to treatment. [ABSTRACT FROM AUTHOR]

The United States Fish and Wildlife Service in Alaska, USA, conducted a species status assessment for a petition to list the Alexander Archipelago wolf (Canis lupus ligoni) under the Endangered Species Act in 2020‐2022. This federal undertaking could not be adequately prepared without including the knowledge of Indigenous People who have a deep cultural connection with the subspecies. Our objective is to communicate the authoritative expertise and voice of the Indigenous People who partnered on the project by demonstrating how their knowledge contributed to the species status assessment. The Indigenous knowledge applied in the assessment is the cultural and intellectual property of those who have shared it. We employed rapid appraisal research to expeditiously develop a preliminary and qualitative understanding of Indigenous People's cultural and ecological knowledge of Alexander Archipelago wolves. We used semi‐directed interviewing and inductive coding from grounded theory for text analysis. Indigenous knowledge contributed to the agency's understanding of the Alexander Archipelago wolf in Southeast Alaska and helped the agency with their classification decision. Indigenous research partners explained the rich cultural significance and position of wolves in Tlingit society and described human–wolf relationships and ecological interactions. The agency used a single‐species assessment approach based in species ecology and conservation biology, whereas the Indigenous wolf experts applied a multi‐species, community ecology approach based in a sociocultural context of balance and respect. The Indigenous wolf experts successfully addressed knowledge gaps identified by the agency. The partners were challenged by a short regulatory timeframe that did not allow for comprehensive study of Indigenous knowledge and constrained review and feedback by Indigenous experts. The United States Fish and Wildlife Service learned that its assessment framework was not designed to account for an Indigenous worldview. To level the playing field, the agency and Indigenous experts should discuss how to co‐develop an assessment framework that equitably applies both perspectives. [ABSTRACT FROM AUTHOR]

In order processing, consecutive sequences (e.g., 1‐2‐3) are generally processed faster than nonconsecutive sequences (e.g., 1‐3‐5) (also referred to as the reverse distance effect). A common explanation for this effect is that order processing operates via a memory‐based associative mechanism whereby consecutive sequences are processed faster because they are more familiar and thus more easily retrieved from memory. Conflicting with this proposal, however, is the finding that this effect is often absent. A possible explanation for these absences is that familiarity may vary both within and across sequence types; therefore, not all consecutive sequences are necessarily more familiar than all nonconsecutive sequences. Accordingly, under this familiarity perspective, familiar sequences should always be processed faster than unfamiliar sequences, but consecutive sequences may not always be processed faster than nonconsecutive sequences. To test this hypothesis in an adult population, we used a comparative judgment approach to measure familiarity at the individual sequence level. Using this measure, we found that although not all participants showed a reverse distance effect, all participants displayed a familiarity effect. Notably, this familiarity effect appeared stronger than the reverse distance effect at both the group and individual level; thus, suggesting the reverse distance effect may be better conceptualized as a specific instance of a more general familiarity effect. [ABSTRACT FROM AUTHOR]

The field of melt electrowriting (MEW) has seen significant progress, bringing innovative advancements to the fabrication of biomaterial scaffolds, and creating new possibilities for applications in tissue engineering and beyond. Multidisciplinary collaboration across materials science, computational modeling, AI, bioprinting, microfluidics, and dynamic culture systems offers promising new opportunities to gain deeper insights into complex biological systems. As the focus shifts towards personalized medicine and reduced reliance on animal models, the multidisciplinary approach becomes indispensable. This review provides a concise overview of current strategies and innovations in controlling and optimizing cellular responses to MEW scaffolds, highlighting the potential of scaffold material, MEW architecture, and computational modeling tools to accelerate the development of efficient biomimetic systems. Innovations in material science and the incorporation of biologics into MEW scaffolds have shown great potential in adding biomimetic complexity to engineered biological systems. These techniques pave the way for exciting possibilities for tissue modeling and regeneration, personalized drug screening, and cell therapies. [ABSTRACT FROM AUTHOR]

Introduction: Teaching of dental caries diagnostics is an essential part of dental education. Diagnosing proximal caries is a challenging task, and automated systems applying artificial intelligence (AI) have been introduced to assist in this respect. Thus, the implementation of AI for teaching purposes may be considered. The aim of this study was to assess the impact of an AI software on students' ability to detect enamel‐only proximal caries in bitewing radiographs (BWs) and to assess whether proximal tooth overlap interferes with caries detection. Materials and Methods: The study included 74 dental students randomly allocated to either a test or control group. At two sessions, both groups assessed proximal enamel caries in BWs. At the first session, the test group registered caries in 25 BWs using AI software (AssistDent®) and the control group without using AI. One month later, both groups detected caries in another 25 BWs in a clinical setup without using the software. The student's registrations were compared with a reference standard. Positive agreement (caries) and negative agreement (no caries) were calculated, and t‐tests were applied to assess whether the test and control groups performed differently. Moreover, t‐tests were applied to test whether proximal overlap interfered with caries registration. Results: At the first and second sessions, 56 and 52 tooth surfaces, respectively, were detected with enamel‐only caries according to the reference standard. At session 1, no significant difference between the control (48%) and the test (42%) group was found for positive agreement (p =.08), whereas the negative agreement was higher for the test group (86% vs. 80%; p =.02). At session 2, there was no significant difference between the groups. The test group improved for positive agreement from session 1 to session 2 (p <.001), while the control group improved for negative agreement (p <.001). Thirty‐eight per cent of the tooth surfaces overlapped, and the mean positive agreement and negative agreement were significantly lower for overlapping surfaces than non‐overlapping surfaces (p <.001) in both groups. Conclusion: Training with the AI software did not impact on dental students' ability to detect proximal enamel caries in bitewing radiographs although the positive agreement improved over time. It was revealed that proximal tooth overlap interfered with caries detection. [ABSTRACT FROM AUTHOR]

A new method has recently been developed for valuing health states, called 'Online elicitation of Personal Utility Functions' (OPUF). In contrast to established methods, such as time trade‐off or discrete choice experiments, OPUF does not require hundreds of respondents, but allows estimating utility functions for small groups and even at the individual level. In this study, we used OPUF to elicit EQ‐5D‐5L health state preferences from a (not representative) sample of the UK general population, and then compared utility functions on the societal‐, group‐, and individual level. A demo version of the survey is available at: https://eq5d5l.me. Data from 874 respondents were included in the analysis. For each respondent, we constructed a personal EQ‐5D‐5L value set. These personal value sets predicted respondents' choices in three hold‐out discrete choice tasks with an accuracy of 78%. Overall, preferences varied greatly between individuals. However, PERMANOVA analysis showed that demographic characteristics explained only a small proportion of the variability between subgroups. While OPUF is still under development, it has important strengths: it can be used to construct value sets for patient reported outcome instruments such as EQ‐5D‐5L, while also allowing examination of underlying preferences in an unprecedented level of detail. In the future, OPUF could be used to complement existing methods, allowing valuation studies in smaller samples, and providing more detailed insights into the heterogeneity of preferences across subgroups. [ABSTRACT FROM AUTHOR]

Background: During the COVID‐19 pandemic, Ireland implemented a series of stringent public health measures, including lockdowns and suspension of non‐urgent clinical services. Aims: To investigate the impact of the COVID‐19 pandemic on the demand for and delivery of speech and language therapy (SLT) services in Ireland in 2020. Methods & Procedures: Two iterations of a cross‐sectional, mixed‐methods online survey were distributed to speech and language therapists (SLTs) and SLT students in Ireland in the spring and autumn of 2020 using a combination of purposive and snowball sampling. The spring survey yielded 407 responses (including 14 from SLT students), while 197 respondents took part in the autumn (13 students). Survey analysis focused on questions related to the impact of the COVID‐19 pandemic on delivery and demand for SLT services (student responses were excluded from analysis owing to low response rate). The largest group in respect of experience were senior SLTs (58% in both surveys). The work settings most strongly represented were HSE primary care (34.4%) and disability services (26.5%) in the spring, and HSE primary care (39.1%), acute hospitals (22.8%) and disability services (20.8%) in the autumn. We used descriptive statistics, including distribution analysis, to analyse the quantitative data. Free text data were interrogated through a variant of a conventional qualitative content analysis. Outcomes & Results: In the spring, cessation of face‐to‐face services featured prominently (reported by 65.6% versus 14.2% in the autumn), across SLTs' work settings, except acute hospitals. Lower demand was reported by 42.5% in the spring, while in the autumn, 48.7% indicated that demand was higher. SLTs experienced large‐scale redeployment (spring: 45.9%, autumn: 38.4%), with HSE primary care SLTs redeployed most (spring: 71.7%; autumn: 62.3%). The need to suddenly pivot to telehealth was a significant challenge in terms of training, technology and logistics. New ways of working emerged and gradually, telehealth became more embedded. SLTs also had to adapt to working with evolving public health measures, such as space restrictions and personal protective equipment (PPE) requirements. Across the two survey iterations, SLTs reported tensions between demands and capacity: while referrals and demand initially decreased in the spring, this led to increased backlog and longer waiting lists, ongoing and increasing pressure on clinicians and services, and negatively impacted clients and families. Conclusions & Implications: The COVID‐19 pandemic had a significant negative impact on SLT services in Ireland. Going forward, the SLT profession and its services will require sustained support to mitigate long‐term negative consequences, such as increased waiting lists. WHAT THIS PAPER ADDS: What is already known on this subject: The negative impact of the COVID‐19 pandemic on SLT services has been examined in several countries. Ireland imposed more stringent pandemic‐management measures than many other countries, and it was therefore warranted to investigate how SLT services in the country were affected. What this study adds to the existing knowledge: Face‐to‐face SLT services effectively ceased in most non‐urgent contexts in spring 2020. This coincided with large‐scale redeployment of SLTs to non‐SLT contexts. By autumn 2020, demand had increased again, but not all services had recommenced, and redeployment was still a factor. Although SLTs adapted to the ongoing changes imposed by the pandemic, they voiced concern about increasing backlogs and longer waiting lists, ongoing and increasing pressure on both SLTs and services, and negative impacts on clients and families. What are the actual and clinical implications of this work?: The COVID‐19 pandemic had a significant negative impact on SLT services in Ireland. Going forward, the SLT profession and its services will require sustained support to mitigate long‐term negative consequences, such as increased waiting lists. [ABSTRACT FROM AUTHOR]

Prostacyclin therapy is a mainstay of the management of pulmonary arterial hypertension (PAH). Inhaled prostacyclins present safe and effective options for the management of PAH that limit systemic side effects. We describe the first reported case of life‐threatening bronchospasm and acute respiratory failure associated with inhaled prostacyclin administration. [ABSTRACT FROM AUTHOR]

Objective: To investigate incorporating a ready‐to‐use 2.5:1 ratio liquid feed into a ketogenic diet (KD) in children and adults with drug‐resistant epilepsy. Methods: Following a three‐day baseline, patients (n = 19; age: 19 years [SD 13], range: 8–46 years) followed a KD for 28 days (control period), then incorporated ≥200 mL/day of a ready‐to‐use liquid feed, made with a ratio of 2.5 g of fat to 1 g of protein plus carbohydrate and including medium chain triglycerides ([MCTs]; 25.6% of total fat/100 mL) for 28 days as part of their KD (intervention period). Outcome measures (control vs intervention period) included gastrointestinal (GI) tolerance, adherence to KD and intervention feed, dietary intake, blood ß‐hydroxybutyrate (BHB) concentration, seizure outcomes, health‐related quality of life (HRQoL), acceptability and safety. Results: Compared to the control period, during the intervention period, the percentage of patients reporting no GI symptoms increased (+5% [SD 5], p = 0.02); adherence to the KD prescription was similar (p = 0.92) but higher in patients (n = 5) with poor adherence (<50%) to KD during the control period (+33% [SD 26], p = 0.049); total MCT intake increased (+12.1 g/day [SD 14.0], p = 0.002), driven by increases in octanoic (C8; +8.3 g/day [SD 6.4], p < 0.001) and decanoic acid (C10; +5.4 g/day [SD 5.4], p < 0.001); KD ratio decreased (p = 0.047), driven by a nonsignificant increase in protein intake (+11 g/day [SD 44], p = 0.29); seizure outcomes were similar (p ≥ 0.63) but improved in patients (n = 6) with the worst seizure outcomes during the control period (p = 0.04); and HRQoL outcomes were similar. The intervention feed was well adhered to (96% [SD 8]) and accepted (≥88% of patients confirmed). Significance: These findings provide an evidence‐base to support the effective management of children and adults with drug‐resistant epilepsy following a KD with the use of a ready‐to‐use, nutritionally complete, 2.5:1 ratio feed including MCTs. Plain language summary: This study examined the use of a ready‐to‐use, nutritionally complete, 2.5:1 ratio (2.5 g of fat to 1 g of protein plus carbohydrate) liquid feed, including medium chain triglycerides (MCTs), into a ketogenic diet (KD) in children and adults with drug‐resistant epilepsy. The results show that the 2.5:1 ratio feed was well tolerated, adhered to, and accepted in these patients. Increases in MCT intake (particularly C8 and C10) and improvements in seizure outcomes (reduced seizure burden and intensity) and KD adherence also occurred with the 2.5:1 ratio feed in patients with the worst seizures and adherence, respectively. [ABSTRACT FROM AUTHOR]

Heparin and heparan sulfate (HS) are naturally occurring mammalian glycosaminoglycans, and their synthetic and semi‐synthetic mimetics have attracted significant interest as potential therapeutics. However, understanding the mechanism of action by which HS, heparin, and HS mimetics have a biological effect is difficult due to their highly charged nature, broad protein interactomes, and variable structures. To address this, a library of novel single‐entity dendritic mimetics conjugated to BODIPY, Fluorine‐19 (19F), and biotin was synthesized for imaging and localization studies. The novel dendritic scaffold allowed for the conjugation of labeling moieties without reducing the number of sulfated capping groups, thereby better mimicking the multivalent nature of HS‐protein interactions. The 19F labeled mimetics were assessed in phantom studies and were detected at concentrations as low as 5 mM. Flow cytometric studies using a fluorescently labeled mimetic showed that the compound associated with immune cells from tumors more readily than splenic counterparts and was directed to endosomal‐lysosomal compartments within immune cells and cancer cells. Furthermore, the fluorescently labeled mimetic entered the central nervous system and was detectable in brain‐infiltrating immune cells 24 hours after treatment. Here, we report the enabling methodology for rapidly preparing various labeled HS mimetics and molecular probes with diverse potential therapeutic applications. [ABSTRACT FROM AUTHOR]

Background: Providing students with worked out problem solutions is a beneficial instructional technique in STEM disciplines, and studying examples that have been worked out incorrectly may be especially helpful for reducing misconceptions in students with low prior content knowledge. However, past results are inconclusive and the effects of incorrect worked examples alone or in combination with correct examples remains unclear. Objectives: We aim to address whether studying incorrect examples alone or in combination with correct examples can support the reduction of students' fraction misconceptions, operationalized as errors made with high confidence. Methods: After incorrectly solving a sampling problem, 130 students in 4th through 11th grade in the U.S. were randomly assigned to a condition in an online problem set focused on fraction equivalence. Students studied either single‐type worked examples (i.e., correct or incorrect; n = 49) or combination‐type worked examples (correct and incorrect; n = 41) or engaged in a problem‐solving control (n = 50). Results: Studying a combination of correct and incorrect worked examples was as effective as the problem‐solving control with feedback at improving fraction equivalence knowledge and reducing the rate of high‐confidence errors. Students in both the combination condition and the problem‐solving with feedback condition outperformed those who studied either correct or incorrect worked examples alone. Conclusions: Results support the inclusion of a combination of correct and incorrect worked examples when teaching students with low prior content knowledge. Studying a combination of example types within an online tutor helps to reduce misconceptions about fractions, a topic students commonly struggle with. A problem‐solving task with corrective feedback worked equally well. Lay Description: What is already known about this topic: Studying worked examples of mathematical solutions improves student learning.Incorrect examples, either alone or in combination with correct examples, are particularly effective for improving learning for students with low prior knowledge in the target content.Comparing correct and incorrect examples is also effective at improving problem‐solving but this effect may be specific to those with high prior knowledge.Still unknown are the impacts of these different combinations of examples on misconceptions in particular. What this paper adds: We show that studying a combination of correct and incorrect examples reduces math misconceptions.Problem‐solving with corrective feedback within an online tutor also has this effect. Implications for practice and/or policy: Using a combination of example types will help reduce students' misconceptions about fractions. [ABSTRACT FROM AUTHOR]

The article provides information on the Network for Investigation of Delirium: Unifying Scientists (NIDUS) which aims to develop the collaborative network and infrastructure to advance scientific research and train on the causes, mechanisms, outcomes, diagnosis, prevention, and treatment of delirium in older adults. Topics include the renewal of NIDUS as NIDUS II in 2020, structure of NIDUS, and summary of NIDUS-I and NIDUS-II accomplishments.

Summary: Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double‐stranded RNA (dsRNA) formation and MDA5/RIG‐I activation. The HMA‐induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN‐to‐sAML progression, establish the LSC‐to‐IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re‐activating dsRNA‐associated IFN signalling. [ABSTRACT FROM AUTHOR]

This study demonstrates how either a heated flat or cylindrical collector enables defect‐free melt electrowriting (MEW) of complex geometries from high melting temperature polymers. The open‐source "MEWron" printer uses nylon‐12 filament and combined with a heated flat or cylindrical collector, produces well‐defined fibers with diameters ranging from 33 ± 4 to 95 ± 3 µm. Processing parameters for stable jet formation and minimal defects based on COMSOL thermal modeling for hardware design are optimized. The balance of processing temperature and collector temperature is achieved to achieve auxetic patterns, while showing that annealing nylon‐12 tubes significantly alters their mechanical properties. The samples exhibit varied pore sizes and wall thicknesses influenced by jet dynamics and fiber bridging. Tensile testing shows nylon‐12 tubes are notably stronger than poly(ε‐caprolactone) ones and while annealing has limited impact on tensile strength, yield, and elastic modulus, it dramatically reduces elongation. The equipment described and material used broadens MEW applications for high melting point polymers and highlights the importance of cooling dynamics for reproducible samples. [ABSTRACT FROM AUTHOR]

In the near future BabyIAXO will be the most powerful axion helioscope, relying on a custom‐made magnet of two bores of 70 cm diameter and 10 m long, with a total available magnetic volume of more than 7 m3. In this document, it proposes and describe the implementation of low‐frequency axion haloscope setups suitable for operation inside the BabyIAXO magnet. The RADES proposal has a potential sensitivity to the axion‐photon coupling gaγ$g_{a\gamma }$ down to values corresponding to the KSVZ model, in the (currently unexplored) mass range between 1 and 2 μ$\umu$ eV, after a total effective exposure of 440 days. This mass range is covered by the use of four differently dimensioned 5‐meter‐long cavities, equipped with a tuning mechanism based on inner turning plates. A setup like the one proposed will also allow an exploration of the same mass range for hidden photons coupled to photons. An additional complementary apparatus is proposed using LC circuits and exploring the low energy range (≈10−4−10−1μ$\approx \ 10^{-4}-10^{-1} \ \umu$ eV). The setup includes a cryostat and cooling system to cool down the BabyIAXO bore down to about 5 K, as well as an appropriate low‐noise signal amplification and detection chain. [ABSTRACT FROM AUTHOR]

Summary: Comorbidity assessment before allogeneic haematopoietic cell transplantation (allo‐HCT) is essential for estimating non‐relapse mortality (NRM) risk. We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of 'high‐yield' comorbidities and older age. The SCI was predictive of NRM in myeloablative CD34‐selected allo‐HCT. Here, we evaluated the SCI in a single‐centre cohort of 327 patients receiving reduced‐intensity conditioning followed by unmanipulated allografts from HLA‐matched donors. Among the SCI factors, age above 60, mild renal impairment, moderate pulmonary disease and cardiac disease were most frequent. SCI scores ranged from 0 to 8, with 39%, 20%, 20% and 21% having scores of 0–1, 2, 3 and ≥4 respectively. Corresponding cumulative incidences of 3‐year NRM were 11%, 16%, 22% and 27%; p = 0.03. In multivariable models, higher SCI scores were associated with incremental risks of all‐cause mortality and NRM. The SCI had an area under the receiver operating characteristic curve of 65.9%, 64.1% and 62.9% for predicting 1‐, 2‐ and 3‐year NRM versus 58.4%, 60.4% and 59.3% with the haematopoietic cell transplantation comorbidity index. These results demonstrate for the first time that the SCI is predictive of NRM in patients receiving allo‐HCT from HLA‐matched donors after reduced‐intensity conditioning. [ABSTRACT FROM AUTHOR]

Precision medicine is a growing field in critical care. Research increasingly demonstrated pharmacogenomic variability to be an important determinant of analgesic and sedative drug response in the intensive care unit (ICU). Genome‐wide association and candidate gene finding studies suggest analgesic and sedatives tailored to an individual's genetic makeup, environmental adaptations, in addition to several other patient‐ and drug‐related factors, will maximize effectiveness and help mitigate harm. However, the number of pharmacogenetic studies in ICU patients remains small and no prospective studies have been published using pharmacogenomic data to optimize analgesic or sedative therapy in critically ill patients. Current recommendations for treating ICU pain and agitation are based on controlled studies having low external validity, including the failure to consider pharmacogenomic factors affecting response. Use of a precision medicine approach to individualize pharmacotherapy focused on optimizing ICU patient comfort and safety may improve the outcomes of critically ill adults. Additionally, benefits and risks of analgesic and/or sedative therapy in an individual may be informed with large, standardized datasets. The purpose of this review was to describe a precision medicine approach focused on optimizing analgesic and sedative therapy in individual ICU patients to optimize clinical outcomes and reduce safety concerns. [ABSTRACT FROM AUTHOR]

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic–pituitary–adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40 min following the onset of a stress‐inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI‐exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG/S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age. [ABSTRACT FROM AUTHOR]

It is important to consider mechanical, biological, and antibacterial properties of scaffolds when used for tissue engineering applications. This study presents a method to create complex "wavy" architecture polycaprolactone (PCL) scaffolds toward the development of tissue engineered ligament and tendon tissue substitutes, fabricated using melt electrowriting (MEW) and loaded with vancomycin (5, 10, and 25% w/w). Scaffolds are characterized for both mechanical and biological properties. Loading PCL scaffolds with vancomycin with modified solvent evaporation technique achieves a high loading efficiency of maximum 18% w/w and high encapsulation efficiency with over 89%. Vancomycin loaded PCL scaffolds with all three doses (5, 10, and 25% w/w) display antibacterial activity against Gram‐positive Staphylococcus aureus (S. aureus) up to 14 days of release. Initial burst followed by a sustained release is observed on all three vancomycin loaded scaffolds for up to 28 days. Importantly, in addition to antibacterial properties, vancomycin‐loaded PCL scaffolds also display improved mechanical properties compared to traditional crosshatch design MEW scaffolds and are noncytotoxic at all concentrations as demonstrated by live‐dead staining, cell attachment and proliferation assays indicating its potential as an effective treatment option for tissue regeneration in rotator cuff injuries or other tissues undergoing tensile biomechanical loading. [ABSTRACT FROM AUTHOR]

Background: Self‐directed therapy activities are not currently part of routine care during inpatient rehabilitation. Understanding patient and clinician perspectives on self‐directed therapy is key to increasing implementation. The aim of this study was to investigate barriers and facilitators to implementing a self‐directed therapy programme ("My Therapy") in adult inpatient rehabilitation settings. Methods: My Therapy was recommended by physiotherapists and occupational therapists and completed by rehabilitation inpatients independently, outside of supervised therapy sessions. Physiotherapists, occupational therapists, and patients were invited to complete an online questionnaire comprising open‐ended questions on barriers and facilitators to prescribing and participating in My Therapy. A directed content analysis of free‐text responses was undertaken, with data coded using categories of the Capability, Opportunity, and Motivation Model of Behaviour (COM‐B model). Results: Eleven patients and 20 clinicians completed the questionnaire. Patient capability was reported to be facilitated by comprehensive education by clinicians, with mixed attitudes towards the format of the programme booklet. Clinician capability was facilitated by staff collaboration. One benefit was the better use of downtime between the supervised therapy sessions, but opportunities for patients to engage in self‐directed therapy were compromised by the lack of space to complete the programme. Clinician opportunity was reported to be provided via organisational support but workload was a reported barrier. Patient motivation to engage in self‐directed therapy was reported to be fostered by feeling empowered, engaged, and encouraged to participate. Clinician motivation was associated with belief in the value of the programme. Conclusion: Despite some barriers to rehabilitation patients independently practicing therapeutic exercises and activities outside of supervised sessions, both clinicians and patients agreed it should be considered as routine practice. To do this, patient time, ward space, and staff collaboration are required. Further research is needed to scale‐up the implementation of the My Therapy programme and evaluate its effectiveness. [ABSTRACT FROM AUTHOR]

Objectives: Morphological intraspecific variation is due to the balance between skeletal plasticity and genetic constraint on the skeleton. Osteogenic responses to external stimuli, such as locomotion, have been well documented interspecifically across the primate order, but less so at the intraspecific level. Here, we examine the differences in cross‐sectional variability of the femur, humerus, radius, and tibia in Pan troglodytes troglodytes versus Gorilla gorilla gorilla. We investigate whether there are sex, species, bone, and trait differences in response to variable body size and locomotion. Materials and Methods: Adult male and female P. t. troglodytes and G. g. gorilla long bones from the Cleveland Museum of Natural History were scanned with a peripheral quantitative computer tomography system. Scans were taken at the midshaft of each bone according to functional bone length. Coefficients of variation were used to provide a size‐independent measure of variation. We applied a Bonferroni correction to account for the multiple pairwise tests. Results: There were limited significant differences between males and females, however, females tended to be more variable than males. Variation in Gorilla, when significant, was greater than in Pan, although significant differences were limited. There were no differences between bone variability in male and female Gorilla, and female Pan. Discussion: Increased female variability may be due to more variable locomotor behavior, particularly during periods of pregnancy, lactation, and caring for an offspring compared to consistent locomotion over the life course by males. Body size may be a contributing factor to variability; more work is needed to understand this relationship. [ABSTRACT FROM AUTHOR]

Keywords: cancer; couseling; epilepsy; folic acid EN cancer couseling epilepsy folic acid 2239 2243 5 09/21/23 20230901 NES 230901 Key points Serious methodological flaws do not allow conclusions about cancer risks in the offspring of mothers with epilepsy and high-dose folic acid supplementation. It is hard to believe that 60% of patients included in the WWE group were former epilepsy patients, which had benign childhood epilepsy syndromes or other types of epilepsy that are resolved by now, had successful epilepsy surgery, or were misdiagnosed as a person with epilepsy (PWE), which was later revised and the ASMs withdrawn. Unjustified allegation on cancer risks in children of mothers with epilepsy taking high-dose folic acid during pregnancy - No proof of a causal relationship As a consequence, PWWE taking ASM and high-dose folic acid would have to be compared to those taking high-dose folic acid but not taking ASM to explore any effects of the combination of ASM and folic acid. [Extracted from the article]

Objectives: The use of directed observers in high-fidelity simulation education is increasingly common. While evidence suggests similar educational outcomes for directed observers compared to active participants in technical skills, it remains uncertain if this benefit also exists for senior clinicians, especially in mental workload. We sought to compare the workload between active participants and directed observers using an objective measure. Methods: We performed a prospective, repeated-measures observational study during the New South Wales Ambulance Aeromedical Operations induction training from 2019 to 2020. Participants included senior critical care doctors, paramedics, and nurses undergoing high-fidelity simulation of prehospital and interhospital aeromedical missions. Task load was measured using the National Aeronautics and Space Administration task load index (NASA-TLX) administered following each simulation debrief. Prehospital and interhospital simulations were compared separately by building a multilevel model for complete case and all study data. Post hoc comparisons of NASA-TLX score for each group were performed using estimated marginal means (EMMs). Results: We enrolled 70 participants, comprising 49 physicians (70%), 19 paramedics (27%), and two flight nurses (3%). From the complete case analysis, statistically significant differences were observed for total NASA-TLX scores between active participants and directed observers in both prehospital (participant EMM 78, observer EMM 65, estimated difference -13, 95% confidence interval [CI] -20 to -7) and interhospital simulations (participant EMM 69, observer EMM 59, estimated difference -10, 95% CI -16 to -3). When all available data were included, the pattern of results did not change. Conclusions: In our sample of senior clinicians, the task load experienced by both active participants and directed observers in high-fidelity simulation education was high for both prehospital and interhospital simulation exercises. The statistically significant differences we report are unlikely to be practically significant. Our results support the use of directed observers when resource limitations do not allow all course attendees to participate in every simulation. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic brought rapid and major changes to research, and those wishing to carry out Patient and Public Involvement (PPI) activities faced challenges, such as restrictions on movement and contact, illness, bereavement and risks to potential participants. Some researchers moved PPI to online settings during this time but remote consultations raise, as well as address, a number of challenges. It is important to learn from PPI undertaken in this period as face‐to‐face consultation may no longer be the dominant method for PPI. Methods: UK stay‐at‐home measures announced in March 2020 necessitated immediate revisions to the intended face‐to‐face methods of PPI consultation for the ESORT Study, which evaluated emergency surgery for patients with common acute conditions. PPI plans and methods were modified to all components being online. We describe and reflect on: initial plans and adaptation; recruitment; training and preparation; implementation, contextualisation and interpretation. Through first‐hand accounts we show how the PPI processes were developed, experienced and viewed by different partners in the process. Discussion and Conclusions: While concerns have been expressed about the possible limiting effects of forgoing face‐to‐face contact with PPI partners, we found important benefits from the altered dynamic of the online PPI environment. There were increased opportunities for participation which might encourage the involvement of a broader demographic, and unexpected benefits in that the online platform seemed to have a 'democratising' effect on the meetings, to the benefit of the PPI processes and outcomes. Other studies may however find that their particular research context raises particular challenges for the use of online methods, especially in relation to representation and inclusion, as new barriers to participation may be raised. It is important that methodological challenges are addressed, and researchers provide detailed examples of novel methods for discussion and empirical study. Patient and Public Contribution: We report a process which involved people with lived experience of emergency conditions and members of the public. A patient member was involved in the design and implementation, and two patients with lived experience contributed to the manuscript. [ABSTRACT FROM AUTHOR]

This study aimed to understand the views of children and young people (CYP), parents and staff on how staff should respond to incidents of self‐harm carried out by CYP in mental health inpatient settings. Semi‐structured interviews were conducted with CYP (n = 6), parents (n = 5) and mental health professionals (n = 6) with experience of this issue. Data were analysed using reflexive thematic analysis. Two superordinate themes were identified: (1) The threshold for intervening; and (2) Interpersonal attributes of staff. There was general agreement among participants about the interpersonal skills that staff should possess to work safely and effectively with this population. There was disagreement between staff and parent participants about the appropriate threshold for using restrictive interventions to manage incidents of self‐harm for this group. Our findings suggest that further work is needed to develop effective approaches for addressing self‐harm in this population which are considered acceptable to all key stakeholders. The results of this study could be used to inform future intervention development. [ABSTRACT FROM AUTHOR]

BACKGROUND: School nurses are rarely integrated into primary care teams to their full potential. We aimed to characterize school nurses' perceptions related to current and optimal collaboration with primary care providers (PCPs) and identify actionable solutions to improve efficiency, quality, and coordination of pediatric care. METHODS: We conducted and qualitatively analyzed interviews with school nurses to characterize structures, processes, and perceived benefits of optimized school nurse‐PCP collaboration. RESULTS: School nurse interviewees (n = 23) identified factors important to school nurse‐PCP collaboration within 2 domains: information sharing and relationship building. Information sharing themes included health information sharing laws, data sharing systems, and technology‐based communication systems. Relationship building themes included health care sector understanding of the school nurse role, PCP knowledge of school health requirements, shared professional development opportunities, and time and personnel. Perceived benefits of optimized PCP‐school nurse collaboration were identified for children, PCPs, school nurses, and parents. IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY: Needs assessments and action plans guided by the domains of information sharing and relationship building can inform local improvements to optimize school nurse‐PCP collaboration. CONCLUSIONS: School nurses highlighted cross‐sector solutions to enhance school nurse‐PCP collaboration including integrated information sharing systems and intentional relationship building. [ABSTRACT FROM AUTHOR]

Firefighters are at increased risk for developing posttraumatic stress disorder (PTSD) and face numerous barriers to accessing mental health care. Innovative ways to increase access to evidence‐based interventions are needed. This study was a case series testing the acceptability, feasibility, and preliminary effectiveness of a paraprofessional‐delivered, virtual narrative exposure therapy (eNET) intervention for PTSD. Participants were 21 firefighters who met the criteria for clinical or subclinical probable PTSD and completed 10–12 sessions of eNET via videoconference. Participants completed self‐report measures pre‐ and postintervention and at 2‐ and 6‐month follow‐ups as well as a postintervention qualitative interview. Paired samples t tests evidenced statistically significant decreases in PTSD, anxiety, and depressive symptom severity and functional impairment from pre‐ to postintervention, ds = 1.08–1.33, and in PTSD and anxiety symptom severity and functional impairment from preintervention to 6‐month follow‐up, ds = 0.69–1.10. The average PTSD symptom severity score fell from above to below the clinical cutoff for probable PTSD at postintervention and follow‐ups. Qualitative interviews indicated that paraprofessionals were considered central to participants' success and experience with the intervention. No adverse events or safety concerns were raised. This study is an important step in demonstrating that appropriately trained and supervised paraprofessionals can effectively deliver eNET to firefighters with PTSD. [ABSTRACT FROM AUTHOR]

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JNJ‐64264681 is an irreversible covalent inhibitor of Bruton's tyrosine kinase. This phase 1, first‐in‐human, 2‐part (single‐ascending dose [SAD]; multiple‐ascending dose [MAD]) study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD; Bruton's tyrosine kinase occupancy [BTKO]) of JNJ‐64264681 oral solution in healthy participants. For SAD (N = 78), 6 increasing doses of JNJ‐64264681 (4–400 mg) or placebo were evaluated in fasted males. The effects of sex, food, and a capsule formulation were evaluated in separate cohorts. For MAD (N = 27), sequential cohorts of male and female participants received 36/100/200 mg JNJ‐64264681 once daily for 10 days. JNJ‐64264681 exposure (peak concentration; area under the concentration‐time curve) was less than dose proportional from 4 mg to 36 mg. Dose‐normalized area under the concentration‐time curves following the 36 mg and 100 mg doses were generally similar. The mean terminal half‐life was 1.6–13.2 hours. With multiple doses, steady state was achieved by day 2. A semimechanistic PK/PD model was developed using the first 5 SAD cohorts' data to predict %BTKO in MAD cohorts. PK/PD model guided dose‐escalation, and all participants in the 200/400 mg single‐dose cohorts achieved ≥90% BTKO at 4 hours after dosing (peak) with prolonged occupancy. As BTKO data became available from MAD cohorts, it was found that observed BTKO data were consistent with model predictions. JNJ‐64264681 showed no safety signals of concern. Overall, safety, tolerability, PK, BTKO, and PK/PD modeling guided the rationale for dose selection for the subsequent first‐in‐patient lymphoma studies. [ABSTRACT FROM AUTHOR]

Keywords: blood management; RBC transfusion EN blood management RBC transfusion 849 860 12 04/13/23 20230401 NES 230401 Abbreviations ACR American College of Rheumatology CRP C-Reactive Protein EPO Erythropoietin ESA Erythropoiesis stimulating agents ESR Erythrocyte sedimentation rate Hb Hemoglobin HIF 1 alpha Hypoxia Inducible Factor 1 Alpha IL-6 Interleukin-6 PRISMA-Scr Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol Extension for Scoping Review RCT Randomized controlled trial SD Standard Deviation TNF-alpha Tumor necrosis factor alpha INTRODUCTION Anemia contributes substantially to the global burden of disease, affecting approximately one third of the population.[1] Anemia is associated with an array of poor outcomes, and - when coupled with other comorbidities - increased mortality.[[2], [4], [6], [8], [10], [12]] Chronic disease and inflammation retard normal pathways of iron metabolism, leading to iron sequestration and suppression of marrow function.[14] Inflammation induces pro-inflammatory cytokines and mediators which upregulate the iron transport regulatory protein, hepcidin.[[14]] Hepcidin expression downregulates the iron transport protein ferroportin and thus limits iron egress from cells, leading to restricted uptake and reticuloendothelial sequestration of iron.[[14]] While iron deficiency remains the leading cause of anemia worldwide, amongst hospitalized patients the anemia of chronic disease is a common cause of anemia.[14] Both iron deficiency and inflammation contribute to anemia in the peri-operative population, with anemia conferring a heightened risk of complications, readmission, and mortality.[[3], [5], [10], [16], [18]] Given the burden of anemia amongst hospitalized and surgical patients, there has been considerable research interest in the treatment of anemia as a modifiable risk factor to reduce peri-operative complications. [Extracted from the article]

Outer membrane protein (OMP) biogenesis in gram‐negative bacteria is managed by a network of periplasmic chaperones that includes SurA, Skp, and FkpA. These chaperones bind unfolded OMPs (uOMPs) in dynamic conformational ensembles to suppress aggregation, facilitate diffusion across the periplasm, and enhance folding. FkpA primarily responds to heat‐shock stress, but its mechanism is comparatively understudied. To determine FkpA chaperone function in the context of OMP folding, we monitored the folding of three OMPs and found that FkpA, unlike other periplasmic chaperones, increases the folded yield but decreases the folding rate of OMPs. The results indicate that FkpA behaves as a chaperone and not as a folding catalyst to influence the OMP folding trajectory. Consistent with the folding assay results, FkpA binds all three uOMPs as determined by sedimentation velocity (SV) and photo‐crosslinking experiments. We determine the binding affinity between FkpA and uOmpA171 by globally fitting SV titrations and find it to be intermediate between the known affinities of Skp and SurA for uOMP clients. Notably, complex formation steeply depends on the urea concentration, suggesting an extensive binding interface. Initial characterizations of the complex using photo‐crosslinking indicate that the binding interface spans the entire FkpA molecule. In contrast to prior findings, folding and binding experiments performed using subdomain constructs of FkpA demonstrate that the full‐length chaperone is required for full activity. Together these results support that FkpA has a distinct and direct effect on OMP folding that it achieves by utilizing an extensive chaperone‐client interface to tightly bind clients. [ABSTRACT FROM AUTHOR]

Aims: We investigated titration patterns of angiotensin‐converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) and beta‐blockers, quality of life (QoL) over 6 months, and associated 1 year outcome [all‐cause mortality/heart failure (HF) hospitalization] in a real‐world population with HF with reduced ejection fraction (HFrEF). Methods and results: Participants with HFrEF (left ventricular ejection fraction <40%) from a prospective multi‐centre study were examined for use and dose [relative to guideline‐recommended maintenance dose (GRD)] of ACEis/ARBs and beta‐blockers at baseline and 6 months. 'Stay low' was defined as <50% GRD at both time points, 'stay high' as ≥50% GRD, and 'up‐titrate' and 'down‐titrate' as dose trajectories. Among 1110 patients (mean age 63 ± 13 years, 16% women, 26% New York Heart Association Class III/IV), 714 (64%) were multi‐ethnic Asians from Singapore and 396 were from New Zealand (mainly European ethnicity). Baseline use of either ACEis/ARBs or beta‐blockers was high (87%). Loop diuretic was prescribed in >80% of patients, mineralocorticoid receptor antagonist in about half of patients, and statins in >90% of patients. At baseline, only 11% and 9% received 100% GRD for each drug class, respectively, with about half (47%) achieving ≥50% GRD for ACEis/ARBs or beta‐blockers. At 6 months, a large majority remained in the 'stay low' category, one third remained in 'stay high', whereas 10–16% up‐titrated and 4–6% down‐titrated. Patients with lower (vs. higher) N‐terminal pro‐beta‐type natriuretic peptide levels were more likely to be up‐titrated or be in 'stay high' for ACEis/ARBs and beta‐blockers (P = 0.002). Ischaemic aetiology, prior HF hospitalization, and enrolment in Singapore (vs. New Zealand) were independently associated with higher odds of 'staying low' (all P < 0.005) for prescribed doses of ACEis/ARBs and beta‐blockers. Adjusted for inverse probability weighting, ≥100% GRD for ACEis/ARBs [hazard ratio (HR) = 0.42; 95% confidence interval (CI) 0.24–0.73] and ≥50% GRD for beta‐blockers (HR = 0.58; 95% CI 0.37–0.90) (vs. Nil) were associated with lower hazards for 1 year composite outcome. Country of enrolment did not modify the associations of dose categories with 1 year composite outcome. Higher medication doses were associated with greater improvements in QoL. Conclusions: Although HF medication use at baseline was high, most patients did not have these medications up‐titrated over 6 months. Multiple clinical factors were associated with changes in medication dosages. Further research is urgently needed to investigate the causes of lack of up‐titration of HF therapy (and its frequency), which could inform strategies for timely up‐titration of HF therapy based on clinical and biochemical parameters. [ABSTRACT FROM AUTHOR]

Ciliopathies may be classed as primary or motile depending on the underlying ciliary defect and are usually considered distinct clinical entities. Primary ciliopathies are associated with multisystem syndromes typically affecting the brain, kidney, and eye, as well as other organ systems such as the liver, skeleton, auditory system, and metabolism. Motile ciliopathies are a heterogenous group of disorders with defects in specialised motile ciliated tissues found within the lung, brain, and reproductive system, and are associated with primary ciliary dyskinesia, bronchiectasis, infertility and rarely hydrocephalus. Primary and motile cilia share defined core ultra‐structures with an overlapping proteome, and human disease phenotypes can reflect both primary and motile ciliopathies. CEP164 encodes a centrosomal distal appendage protein vital for primary ciliogenesis. Human CEP164 mutations are typically described in patients with nephronophthisis‐related primary ciliopathies but have also been implicated in motile ciliary dysfunction. Here we describe a patient with an atypical motile ciliopathy phenotype and biallelic CEP164 variants. This work provides further evidence that CEP164 mutations can contribute to both primary and motile ciliopathy syndromes, supporting their functional and clinical overlap, and informs the investigation and management of CEP164 ciliopathy patients. [ABSTRACT FROM AUTHOR]

Tobacco use is associated with poor surgical outcomes and is the leading cause of preventable morbidity and mortality in the United States. Because of the risk for postoperative complications, researchers continue to examine the association between surgical patients' smoking status and adverse outcomes. This quantitative integrative review synthesizes evidence on the relationship between smoking status and postoperative outcomes according to information in the American College of Surgeons National Surgical Quality Improvement Program data set. The included studies involved 10 procedures and the evaluated outcomes comprise surgical complications (eg, surgical site infection), medical complications (eg, sepsis), and transitions in care (eg, discharge destination). The review results are mixed and are not generalizable because only two studies specified smoking status as a primary variable of interest. To develop policies for perioperative patient smoking cessation, perioperative nurses require additional research results on the relationships between smoking status and standardized variables. [ABSTRACT FROM AUTHOR]

Protected areas serve as population strongholds for many large carnivores, with multi‐use landscapes along their borders forming the front‐lines of wildlife conservation. Understanding large carnivore population dynamics within working landscapes is difficult where anthropogenic mortality is high and unregulated. This study focused on working ranches, where killing jaguars (Panthera onca) and their prey was prohibited, to gain insight into jaguar population potential across multi‐use landscapes. Faced with forest fragmentation, presence of domestic livestock, and dynamic land‐use practices, we expected jaguar populations in working landscapes to be predominantly male and transient, with low cub production, and inflated population densities in remnant forest patches, versus protected areas where we expected native forest habitat and stable jaguar territories. Using camera traps and spatial‐capture recapture analyses, we observed that male jaguars demonstrated larger‐scale movements and were more detectable than females (0.07 ± 0.01 SE vs. 0.02 ± 0.01 SE) in both working and protected landscapes. Female jaguars in ranches traveled farther than females in parks. Carnivore density increased with forest cover and wild prey activity, decreased with domestic prey activity, and was marginally higher in ranches (4.08 individuals/100 km2 ± 0.73 SE) than in parks (3.59 individuals/100 km2 ± 0.64 SE). Females outnumbered males in both landscapes (2.20–2.60 females/100 km2 vs. ~1.60 males/100 km2), although local male density reached up to 11.00 males/100 km2 in ranches (vs. 3.50 males/100 km2 in parks). While overall jaguar density was patchier in protected areas (x̿ = 0.69 parks, 0.54 ranches), inter‐annual patchiness was higher within ranches (Moran's I = 0.49–0.60 ranches, 0.69–0.70 parks), reflecting changes in cattle management. Despite major habitat alterations, working landscapes can support carnivore densities equivalent to (or exceeding that of) unmodified forest habitat, provided that wildlife‐tolerant ranching practices are maintained. [ABSTRACT FROM AUTHOR]

Background: Inhibition of antiapoptotic B‐cell lymphoma 2 (BCL2) proteins by small molecule Bcl‐2 homology 3 (BH3) mimetics causes rapid induction of apoptosis of human hematological cancers in vitro and in vivo. Objectives: Assess in vitro sensitivity of non‐neoplastic lymphocytes and primary hematological cancer cells from dogs to venetoclax (VEN) or the dual BCL2/ B‐cell lymphoma‐extra‐large (BCLxL) inhibitor, navitoclax (NAV), and evaluate the association between BCL2 protein expression and VEN sensitivity. Animals: Nine client‐owned dogs without cancer and 18 client‐owned dogs with hematological cancer. Methods: Prospective, nonrandomized noncontrolled study. Lymphocytes isolated from peripheral blood, lymph node, or bone marrow from dogs were incubated with BH3 mimetics for 24 hours. Viable cells were counted using flow cytometry and half maximal effective concentration (EC50) was calculated. BCL2 protein from whole cell lysates was assessed via immunoblots. Results: Nodal B and T lymphocytes were more sensitive to VEN than circulating lymphocytes (P =.02). Neoplastic T lymphocytes were sensitive to VEN (mean EC50 ± SD = 0.023 ± 0.018 μM), whereas most non‐indolent B cell cancers were resistant to killing by VEN (mean EC50 ± SD = 288 ± 700 μM). Unclassified leukemias showed variable sensitivity to VEN (mean EC50 ± SD = 0.49 ± 0.66 μM). Detection of BCL2 protein was not associated with VEN sensitivity. Conclusion and Clinical Importance: Neoplastic canine T lymphocytes are sensitive to VEN in vitro. Quantification of BCL2 protein alone is insufficient to predict sensitivity to VEN. [ABSTRACT FROM AUTHOR]

Because decision makers tend to dislike ambiguity, the uncertainty surrounding new products can act as a barrier to retailer acceptance. We propose that by changing the structure of cash flows in the contract offered to a retailer (keeping net payments constant), a manufacturer can shift a retailer from making ambiguity‐averse to ambiguity‐neutral choices, thereby increasing the retailer's willingness to stock new products. In a series of studies, we demonstrate that contracts structured to provide positive cash flows after ambiguity has been resolved can increase the retailer's willingness to choose products with an unknown demand distribution. Thus, contracts with positive postdemand payments to the retailer have the potential to increase acceptance of new products. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies targeting the SARS‐CoV‐2 spike (S) neutralize infection and are efficacious for the treatment of COVID‐19. However, SARS‐CoV‐2 variants, notably sublineages of B.1.1.529/omicron, have emerged that escape antibodies in clinical use. As an alternative, soluble decoy receptors based on the host entry receptor ACE2 broadly bind and block S from SARS‐CoV‐2 variants and related betacoronaviruses. The high‐affinity and catalytically active decoy sACE22.v2.4‐IgG1 was previously shown to be effective against SARS‐CoV‐2 variants when administered intravenously. Here, inhalation of aerosolized sACE22.v2.4‐IgG1 increased survival and ameliorated lung injury in K18‐hACE2 mice inoculated with P.1/gamma virus. Loss of catalytic activity reduced the decoy's therapeutic efficacy, which was further confirmed by intravenous administration, supporting dual mechanisms of action: direct blocking of S and turnover of ACE2 substrates associated with lung injury and inflammation. Furthermore, sACE22.v2.4‐IgG1 tightly binds and neutralizes BA.1, BA.2, and BA.4/BA.5 omicron and protects K18‐hACE2 mice inoculated with a high dose of BA.1 omicron virus. Overall, the therapeutic potential of sACE22.v2.4‐IgG1 is demonstrated by the inhalation route and broad neutralization potency persists against highly divergent SARS‐CoV‐2 variants. Synopsis: SARS‐CoV‐2 infects cells via interactions between the viral Spike and ACE2 on host cells. A soluble derivative of ACE2 that is engineered for tight Spike affinity is effective against newly circulating SARS‐CoV‐2 variants and is efficacious through multiple mechanisms and routes of administration. An engineered decoy receptor, sACE22.v2.4‐IgG1, binds tightly to Spike proteins and blocks replication in vitro and in vivo of SARS‐CoV‐2 omicron variants.Proteolytic activity of the decoy receptor contributes to its therapeutic efficacy to increase survival of SARS‐CoV‐2 infected K18‐hACE2 transgenic mice.The decoy receptor is therapeutically effective via intravenous infusion and inhalation routes. [ABSTRACT FROM AUTHOR]