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Background: Atrial fibrillation (AF) is associated with increased morbidity and mortality and exerts an increasingly significant burden on global healthcare resources, with its prevalence rising with an ageing population. Despite a substantial thromboembolic risk, particularly in the period immediately following diagnosis, oral anti-coagulation is frequently not initiated or is delayed. The aim of this study was to evaluate healthcare costs in people with AF, comparing those who were commenced on oral anti-coagulation in the immediate period following the index diagnosis date with those in whom initiation was late and those who never started anti-coagulation. Methods: This retrospective cost analysis used linked Scottish health data to identify adults newly diagnosed with AF between January 1st 2012 and April 30th 2019 with a baseline CHA2DS2-VASc score of ≥ 2. This AF population was sub-divided according to timing of the first prescription of oral anti-coagulant (OAC) during a 2-year follow-up period: never started (OAC never initiated), immediate OAC (OAC prescribed within 60 days of incident AF diagnosis), and delayed OAC (OAC prescribed more than 60 days after incident AF diagnosis). A two-part model was developed, adjusted for key covariates, including age, sex, and frailty, to estimate costs for inpatient admissions, outpatient care, prescriptions, and care home admissions, and overall costs. Results: Of an overall AF population of 54,385, 26,805 (49.3%) never commenced OAC, 7654 (14.1%) initiated an OAC late, and 19,926 (36.6%) were prescribed anti-coagulation immediately. The mean adjusted cost for the overall AF population was £7807 per person per year (unadjusted: £8491). Delayed OAC initiation was associated with the greatest adjusted estimated mean annual cost (unadjusted: £13,983; adjusted: £9763), compared to those that never started (unadjusted: £10,433; adjusted: £7981) and those that received an immediate OAC prescription (unadjusted: £3976; adjusted: £6621). Increasing frailty, mortality, and female sex were associated with greater healthcare costs. Conclusion: AF is associated with significant healthcare resource utilisation and costs, particularly in the context of delayed or non-initiation of anti-coagulation. Indeed, there exists substantial opportunity to improve the utilisation and prompt initiation in people newly diagnosed with AF in Scotland. Interventions to mitigate against the growing economic burden of AF should focus on reducing admissions to hospitals and care homes, which are the principal drivers of costs; prescriptions and outpatient appointments account for a relatively small proportion of overall costs for AF. [ABSTRACT FROM AUTHOR]

Introduction: Intravenous (IV) iron is the recommended treatment for patients with iron deficiency anemia (IDA) unresponsive to oral iron treatment, in whom oral iron is contraindicated, or where rapid iron replenishment is required. Ferric derisomaltose (FDI) and ferric carboxymaltose (FCM) are high-dose, rapid-infusion, IV iron formulations that have recently been compared in three head-to-head randomized controlled trials (RCTs), which showed significantly higher incidence of hypophosphatemia after administration of FCM than FDI. The present study objective was to evaluate the cost–utility of FDI versus FCM in a population of patients with IDA in China. Methods: A previously-published patient-level simulation model was used to model the cost–utility of FDI versus FCM in China. The number of infusions of FDI and FCM was modeled based on the approved posology of the respective formulations using simplified tables of iron need in a population of patients with body weight and hemoglobin levels informed by a Chinese RCT of FCM. Data on the incidence of hypophosphatemia was obtained from the PHOSPHARE-IDA RCT, while data on disease-related quality of life were obtained from SF-36v2 data from the PHOSPHARE-IBD RCT. Results: Over the 5-year time horizon, patients received 3.98 courses of iron treatment on average, requiring 0.90 fewer infusions of FDI than FCM (7.69 vs. 6.79). This resulted in iron procurement and administration cost savings of renminbi (RMB) 206 with FDI (RMB 3,519 vs. RMB 3,312). Reduced incidence of hypophosphatemia-related fatigue resulted in an increase of 0.07 quality-adjusted life years and further cost savings of RMB 782 over 5 years, driven by reduced need for phosphate testing and replenishment. FDI was therefore the dominant intervention. Conclusions: The results showed that FDI would improve patient quality of life and reduce direct healthcare expenditure versus FCM in patients with IDA in China. [ABSTRACT FROM AUTHOR]

Background: Adults with bipolar disorder (BD) commonly present with cognitive deficits. Many also report subjective or perceived cognitive failures. For this study, we identified four distinct clusters of adults with BD on the basis of both BD symptoms (depression and hypo/mania) and perceived cognitive errors (i.e., forgetfulness, distractibility, false triggering). We hypothesized that participants reporting more BD symptoms and cognitive errors would report lower psychological well-being (i.e., self-efficacy, life scheme, life satisfaction). A second objective was to determine if and how clusters differed in terms of BD related factors (e.g., subtypes, sleep, medications) and sociodemographic differences such as age of participants. From the BADAS (Bipolar Affective Disorder and older Adults) Study, we identified 281adults with BD (M = 44.27 years of age, range 19–81), recruited via social media. Results: All clusters significantly differed across all grouping variables except symptoms of hypo/mania due to low frequency. Across clusters, perceived cognitive failures and BD symptoms increased in lockstep; that is, those reporting more cognitive errors also reported significantly higher symptoms of both depression and hypo/mania. As hypothesized, they also reported significantly lower psychological well-being. Conclusions: Age did not significantly differ across clusters in contrast to existing research in which cognitive loss is objectively measured. That is, perceived cognitive errors are significantly associated with lower psychological well-being for both young and older adults with BD. [ABSTRACT FROM AUTHOR]

We report the case of a cochlear implant patient who developed multiple infections with device extrusion necessitating explanation and reimplantation twice. An approach using a vancomycin washout followed by a temporalis muscle rotation and scalp rotation flap was utilized to salvage the device. [ABSTRACT FROM AUTHOR]

Emulating the Ni-base superalloy γ + γ ′ microstructure in BCC–B2 refractory alloys is a promising design strategy to achieve high temperature strength and ductility. Ru-base B2 precipitates have shown exceptional thermal stability but can be difficult to solutionize, making high cooling rate solidification pathways like additive manufacturing (AM) a promising approach for synthesis of more homogeneous microstructures. Using single track laser experiments on aged bulk substrates, five representative refractory alloys with varying Ru-base B2 precipitates (AlRu, HfRu, TiRu) and matrix constituents (Mo, Nb) were investigated for their solidification behavior and defect susceptibility under laser melting conditions. Susceptibility to solidification cracking, solid-state cracking, and keyhole formation was found to be highly dependent on the matrix composition. Characterization of the melt pools by scanning and transmission electron microscopy shows evidence for disordered BCC upon solidification, enabling tailoring of the B2 precipitates that are thermodynamically stable above 1300 °C. The B2 precipitate morphologies in the melt tracks after aging treatments are influenced by the partitioning behavior of Ru from laser melting. Results from these single track experiments provide guidance toward design strategies for fabricable refractory BCC–B2 alloys. [ABSTRACT FROM AUTHOR]

Increasingly ambitious space missions rely upon the advancement of propulsion systems, and innovations in electric propulsion represent a vital step toward potential solutions. Electric propulsion research has indicated improved thruster performance at higher magnetic fields, but real-world implementations have been encumbered by available magnet technology. In this study, a new class of superconducting magnet designed for such space applications is demonstrated. A central cathode electrostatic thruster was paired with a conduction cooled high temperature superconducting magnet operated in non-pulsed mode. Using Xe propellant, thrust of 38–73 mN was measured at a central bore magnetic field of 1.13 T and on-anode field of 1.28 T, and the thruster's specific impulse was throttled between 1050s and 1450s. The peak thruster efficiency was 18.7%, inclusive of the power consumption of the magnet subsystems. This was performed without the onset of plasma instabilities, and is the first case in the literature of a high temperature superconducting plasma thruster operating at >1 T. [ABSTRACT FROM AUTHOR]

Microglia are resident immune cells in the central nervous system, including the retina that surveil the environment for damage and infection. Following retinal damage, microglia undergo morphological changes, migrate to the site of damage, and express and secrete pro-inflammatory signals. In the zebrafish retina, inflammation induces the reprogramming and proliferation of Müller glia and the regeneration of neurons following damage or injury. Immunosuppression or pharmacological ablation of microglia reduce or abolish Müller glia proliferation. We evaluated the retinal architecture and retinal regeneration in adult zebrafish irf8 mutants, which have significantly depleted numbers of microglia. We show that irf8 mutants have normal retinal structure at 3 months post fertilization (mpf) and 6 mpf but fewer cone photoreceptors by 10 mpf. Surprisingly, light-induced photoreceptor ablation induced Müller glia proliferation in irf8 mutants and cone and rod photoreceptor regeneration. Light-damaged retinas from both wild-type and irf8 mutants show upregulated expression of mmp-9, il8, and tnfβ pro-inflammatory cytokines. Our data demonstrate that adult zebrafish irf8 mutants can regenerate normally following acute retinal injury. These findings suggest that microglia may not be essential for retinal regeneration in zebrafish and that other mechanisms can compensate for the reduction in microglia numbers. [ABSTRACT FROM AUTHOR]

Violence, poor mental health, and harmful substance use are commonly experienced by female sex workers (FSWs) in sub-Saharan Africa, all of which are associated with increased HIV susceptibility. We aimed to investigate the associations between violence, poor mental health and harmful alcohol/substance use with hair cortisol concentration (HCC) levels as a potential biological pathway linking the experiences of these stressors and HIV vulnerability. We used the baseline data of the Maisha Fiti study of FSWs in Nairobi, Kenya. Participants reported recent violence, poor mental health, and harmful alcohol/substance use. Hair samples proximal to the scalp were collected to measure cortisol levels determined by ELISA. We analysed the data of 425 HIV-negative respondents who provided at least 2 cm of hair sample. The prevalence of recent violence was 89.3% (physical 54.6%; sexual 49.4%; emotional 77.0% and financial 66.5%), and 29.1% had been arrested due to sex work. 23.7% of participants reported moderate/severe depression, 11.6% moderate/severe anxiety, 13.5% PTSD and 10.8% recent suicidal thoughts and/or attempts. About half of the participants (48.8%) reported recent harmful alcohol and/or other substance use. In multivariable linear regression analyses, both physical and/or sexual violence (adjusted geometric mean ratio (aGMR) = 1.28; 95% CI 1.01–1.62) and harmful alcohol and/or other substance use (aGMR = 1.31; 95% CI 1.03–1.65) were positively and independently associated with increased HCC levels. Findings suggest a role of violence and substance use in elevated HCC levels, which could increase HIV risk due to cortisol-related T cell activation. However, longitudinal and mechanistic studies are needed to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Purpose: Iron deficiency anemia is common in people with inflammatory bowel disease (IBD), causing deterioration in quality of life, which can be reversed by treatment that increases iron stores and hemoglobin levels. The present post hoc analyses estimate health state utility values for patients with IBD after treatment with ferric derisomaltose or ferric carboxymaltose and evaluate the health domains driving the changes. Methods: SF-36v2 responses were recorded at baseline and day 14, 35, 49, and 70 from 97 patients enrolled in the randomized, double-blind, PHOSPHARE-IBD trial (ClinicalTrials.gov ID: NCT03466983), in which patients with IBD across five European countries were randomly allocated to either ferric derisomaltose or ferric carboxymaltose. Changes in SF-36v2 scale scores and SF-6Dv2 health utility values were analyzed by mixed models. Results: In both treatment arms, SF-6Dv2 utility values and all SF-36v2 scale scores, except Bodily Pain, improved significantly (p = < 0.0001). The improvement in SF-6Dv2 utility values showed no significant treatment group difference. The improvement in utility values was completely explained by improvement in Vitality scores. Vitality scores showed significantly larger improvement with ferric derisomaltose versus ferric carboxymaltose (p = 0.026). Patients with the smallest decrease in phosphate had significantly larger improvements in Vitality scores at each time point (p = < 0.05 for all comparisons) and overall (p = 0.0006). Conclusions: Utility values improved significantly with intravenous iron treatment. Improvement in utility values was primarily driven by Vitality scores, which showed significantly greater improvement in the ferric derisomaltose arm. Smaller decreases in phosphate were associated with significantly higher Vitality scores, suggesting that quality of life improvement is attenuated by hypophosphatemia. The utility values can inform future cost-utility analysis. [ABSTRACT FROM AUTHOR]

Introduction: This analysis examined the baseline characteristics and clinical outcomes of patients with chronic kidney disease (CKD) and rapid or non-rapid estimated glomerular filtration rate (eGFR) decline, using retrospective data from DISCOVER CKD (ClinicalTrials.gov, NCT04034992). Methods: Data (2008–2020) were extracted from UK Clinical Practice Research Datalink, US TriNetX, US Limited Claims and Electronic Health Record Dataset, and Japan Medical Data Vision. Patients with CKD (two consecutive eGFR measures < 75 mL/min/1.73 m2 recorded 90–730 days apart) were included. Rapid eGFR decline was defined as an annual decline of > 4 mL/min/1.73 m2 at 2 years post-index; non-rapid eGFR decline was defined as an annual decline of ≤ 4 mL/min/1.73 m2. Clinical outcomes assessed included all-cause mortality, kidney outcomes (composite risk of kidney failure [progression to CKD stage 5] or > 50% eGFR decline, and kidney failure alone), cardiovascular events—including major adverse cardiovascular events (MACE; non-fatal myocardial infarction/stroke and cardiovascular death)—and all-cause hospitalization. Results: Across databases, rapid eGFR decline occurred in 13.7% of 804,237 eligible patients. Mean annual eGFR decline ranged between − 6.21 and − 6.86 mL/min/1.73 m2 in patients with rapid eGFR decline versus between − 0.11 and − 0.77 mL/min/1.73 m2 in patients with non-rapid eGFR decline. Rapid eGFR decline was associated with increased comorbidity burden and medication prescriptions. Across databases, the composite risk of kidney failure or > 50% decline in eGFR was significantly greater in patients with rapid versus non-rapid eGFR decline (P < 0.01); all-cause mortality, kidney failure alone, MACE, and all-cause hospitalization each significantly increased in two databases (P < 0.01–0.05). Conclusion: Understanding patient factors associated with rapid eGFR decline in patients with CKD may help identify individuals who would benefit from proactive management to minimize the risk of adverse outcomes. Trial Registration: ClinicalTrials.gov identifier, NCT04034992. [ABSTRACT FROM AUTHOR]

The microstructure and temperature dependence of linear thermal expansion and elastic properties of a two-phase, A2 + B2, Al10Nb20Ta15Ti30V5Zr20 refractory superalloy (RSA) and its constituent phases are reported. After slow cooling from 1400 °C, this alloy has a nanometer-sized, two-phase microstructure consisting of Nb-rich BCC (A2 crystal structure) cuboidal precipitates at the volume fraction of 0.63 and continuous channels of a Zr-rich ordered B2 matrix phase. This two-phase microstructure forms by spinodal decomposition of a high-temperature BCC phase. Differential scanning calorimetry shows that the order–disorder transformation in the Zr-rich phase occurs in the temperature range of 550 °C to 850 °C. The coefficient of thermal expansion (CTE) of the Nb-rich BCC phase increases slightly from 8.9 × 10−6 to 9.1 × 10−6 K−1 with increasing temperature from 20 °C to 1200 °C. The Zr-rich phase has CTE of 9.1 × 10−6 K−1 in the ordered (B2) state, at 20 °C to 550 °C, and 12.2 × 10−6 K−1 in the disordered (A2) state, at 900 °C to 1200 °C. The Nb-rich phase has higher Young's and shear moduli, but lower bulk modulus and Poisson's ratio, as compared to the Zr-rich phase, at 20 °C to 600 °C. The CTE and elastic properties of the two-phase RSA approximately follow the rule of mixtures of the constituent phases in the studied temperature ranges. Correlations between the morphology of the spinodally decomposed microstructure in the two-phase RSA and the thermal and elastic properties of the constituent A2 and B2 phases are established. [ABSTRACT FROM AUTHOR]

Obesity increases the risk of chronic kidney disease. We have previously demonstrated the benefits of preconception maternal weight loss on fertility and pregnancy outcomes in a mouse model of maternal obesity. Here, we elucidate if preconception weight loss, either by diet modification or the glucose-like peptide 1 agonist liraglutide, used in the treatment of diabetes and obesity, improves maternal kidney outcomes in late gestation. C57BL/6 female mice were fed either a high-fat-diet (HFD) or a chow (control) diet for 8 weeks. To induce pre-pregnancy weight loss, HFD-fed dams were switched to chow diet (HFD-C) or administered liraglutide (0.3 mg/kg subcutaneous) whilst continuing on HFD (HFD-L). Liraglutide was discontinued one week prior to mating. HFD-V mice continued on HFD, with saline injections. A group of HFD-fed dams were 'diet switched' to chow after conception (post-conception, HFD-PC). Maternal body weight and glucose tolerance were measured: (1) preconception and (2) during late gestation followed by blood, urine and kidney collection. Serum creatinine, urinary creatinine and albumin, kidney tissue gene expression and protein were measured. In the preconception period, HFD-L and HFD-C mothers have lower urine albumin:creatinine ratios (UACR) and fatty acid synthase (FAS) protein expression (P < 0.005 vs. HFD-V). At late gestation, kidneys of HFD-V and HFD-PC dams have increased gene expression of insulin receptor and FAS (P < 0.05) and higher UACR compared to controls (P < 0.01). In the HFD-PC group, kidneys show increased mRNA and protein expression of metabolic and oxidative stress markers (FAS, 8-OHdG vs. control, P < 0.05, P < 0.0001 respectively). The preconception intervention groups with liraglutide, or diet change show reduced oxidative stress (protein expression of 8-OHdG, P < 0.05 vs. HFD), mRNA and protein expression of FAS (P < 0.05 vs. HFD), protein expression of fibrosis markers (collagen IV, fibronectin vs. HFD, P < 0.05), and UACR (P < 0.05 vs. HFD). This study suggests that preconception weight loss benefits maternal kidney health during pregnancy, superior to diet intervention once already pregnant. [ABSTRACT FROM AUTHOR]

Objectives: To investigate whether a history of traumatic brain injury (TBI) is associated with greater long-term grey-matter loss in patients with mild cognitive impairment (MCI). Methods: 85 patients with MCI were identified, including 26 with a previous history of traumatic brain injury (MCI[TBI-]) and 59 without (MCI[TBI+]). Cortical thickness was evaluated by segmenting T1-weighted MRI scans acquired longitudinally over a 2-year period. Bayesian multilevel modelling was used to evaluate group differences in baseline cortical thickness and longitudinal change, as well as group differences in neuropsychological measures of executive function. Results: At baseline, the MCI[TBI+] group had less grey matter within right entorhinal, left medial orbitofrontal and inferior temporal cortex areas bilaterally. Longitudinally, the MCI[TBI+] group also exhibited greater longitudinal declines in left rostral middle frontal, the left caudal middle frontal and left lateral orbitofrontal areas sover the span of 2 years (median = 1–2%, 90%HDI [−0.01%: −0.001%], probability of direction (PD) = 90–99%). The MCI[TBI+] group also displayed greater longitudinal declines in Trail-Making-Test (TMT)-derived ratio (median: 0.737%, 90%HDI: [0.229%: 1.31%], PD = 98.8%) and differences scores (median: 20.6%, 90%HDI: [−5.17%: 43.2%], PD = 91.7%). Conclusions: Our findings support the notion that patients with MCI and a history of TBI are at risk of accelerated neurodegeneration, displaying greatest evidence for cortical atrophy within the left middle frontal and lateral orbitofrontal frontal cortex. Importantly, these results suggest that long-term TBI-mediated atrophy is more pronounced in areas vulnerable to TBI-related mechanical injury, highlighting their potential relevance for diagnostic forms of intervention in TBI. [ABSTRACT FROM AUTHOR]

Theta–gamma coupling (TGC) is a neurophysiological process that supports working memory. Working memory is associated with other clinical and biological features. The extent to which TGC is associated with these other features and whether it contributes to working memory beyond these features is unknown. Two-hundred-and-three older participants at risk for Alzheimer's dementia—98 with mild cognitive impairment (MCI), 39 with major depressive disorder (MDD) in remission, and 66 with MCI and MDD (MCI + MDD)—completed a clinical assessment, N-back-EEG, and brain MRI. Among them, 190 completed genetic testing, and 121 completed [11C] Pittsburgh Compound B ([11C] PIB) PET imaging. Hierarchical linear regressions were used to assess whether TGC is associated with demographic and clinical variables; Alzheimer's disease-related features (APOE ε4 carrier status and β-amyloid load); and structural features related to working memory. Then, linear regressions were used to assess whether TGC is associated with 2-back performance after accounting for these features. Other than age, TGC was not associated with any non-neurophysiological features. In contrast, TGC (β = 0.27; p = 0.006), age (β = − 0.29; p = 0.012), and parietal cortical thickness (β = 0.24; p = 0.020) were associated with 2-back performance. We also examined two other EEG features that are linked to working memory—theta event-related synchronization and alpha event-related desynchronization—and found them not to be associated with any feature or performance after accounting for TGC. Our findings suggest that TGC is a process that is independent of other clinical, genetic, neurochemical, and structural variables, and supports working memory in older adults at risk for dementia. [ABSTRACT FROM AUTHOR]

Chemical exposures from consumer products are a major concern in modern society. To address the need for accurate health risk estimation, particularly for chronic chemical hazards that may be less evident such as those contained in consumer products, this study reports on the development of the Population Attributable Risk Screening Tool (PAR Tool) Version 1.0. The PAR Tool was designed for the use of professional staff at the Consumer Product Safety Commission (CPSC), and assumes some prior knowledge of chemical risk assessment. This tool provides reasonable estimates of potential acute and chronic health impacts and mortality resulting from exposure to chemicals in consumer products. The PAR Tool provides the ability to integrate diverse data sources, including consumer product composition, user exposures, chemical toxicity data, consumer use patterns, and other pertinent factors to estimate the Population Attributable Risk associated with exposures to chemical components in consumer products. By generating PAR estimates on a chemical-by-chemical basis, the tool will assist the CPSC in assessing potential health risks and prioritizing efforts for risk reduction. Output from the tool provides an estimate of the number of specific health outcomes that may occur in the population of users of a specific consumer product. Interim steps produce exposure percentiles that are used along with dose–response data for a selected chemical and exposure pathway to calculate the proportion of the population at risk. The output is an estimated number of cases of an adverse health effect or mortality in a product user population potentially related to exposures to a single chemical in a product. These results are based primarily on user inputs, and the rationale for selection of these inputs is documented. All inputs and calculations within the PAR Tool are traceable and based on accepted practices and resources. The ongoing development of the PAR Tool aims to enhance its functionalities, incorporating features such as uncertainty analysis, increased automation, and user support. For example, future iterations may allow CPSC users to analyze multiple chemicals and health endpoints simultaneously and introduce sensitivity analysis capabilities for exposure and toxicity parameters. Ultimately, the PAR Tool represents a valuable advancement in comprehending product risks related to consumer product exposure, contributing to enhanced consumer protection and improved health outcomes. [ABSTRACT FROM AUTHOR]

Ru-based B2 phases present an opportunity to design two-phase BCC + B2 refractory multi-principal element alloys (RMPEAs) with higher temperature stability compared to B2 phases observed in RMPEAs. In this investigation, seven equiatomic Ru-containing RMPEAs were characterized in the as-cast and annealed conditions. Of the two Hf-free alloys, Mo 25 Nb 25 Ta 25 Ru 25 was determined to be a single-phase B2 alloy and Mo 20 Nb 20 Ta 20 W 20 Ru 20 was single-phase BCC. Within all five Hf-containing alloys, phases formed during solidification included HfRu–B2, disordered BCC, and HfO 2 phases. The Hf-containing alloys also precipitated B2 nanoparticles within the BCC phases after further cooling in the solid. All phases were still present after annealing at 1500 ∘ C to 1600 ∘ C. The HfRu–B2 nanoparticles in as-cast Hf 20 Mo 20 Nb 20 Ta 20 Ru 20 were characterized by transmission electron microscopy (TEM), and a lattice misfit of < 1 pct between the BCC phase and B2 nanoparticles was calculated. Room-temperature micropillar compression tests were performed on BCC + B2 nanoparticle regions in annealed Hf 20 Mo 20 Nb 20 Ta 20 Ru 20 . Post-mortem TEM analysis revealed precipitate shearing by dislocations, resulting in paired dislocations, along with bowing of dislocations around precipitates. Utilizing the insights from this investigation, compositions for RMPEAs with solutionable B2 precipitates stable above 1200 ∘ C are suggested. [ABSTRACT FROM AUTHOR]

WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms1–5. Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214. This compound selectively engages a cysteine (C727) located in a region of the helicase domain subject to interdomain movement during DNA unwinding. VVD-133214 binds WRN protein cooperatively with nucleotide and stabilizes compact conformations lacking the dynamic flexibility necessary for proper helicase function, resulting in widespread double-stranded DNA breaks, nuclear swelling and cell death in MSI-high (MSI-H), but not in microsatellite-stable, cells. The compound was well tolerated in mice and led to robust tumour regression in multiple MSI-H colorectal cancer cell lines and patient-derived xenograft models. Our work shows an allosteric approach for inhibition of WRN function that circumvents competition from an endogenous ATP cofactor in cancer cells, and designates VVD-133214 as a promising drug candidate for patients with MSI-H cancers.VVD-133214, a clinical-stage, covalent allosteric inhibitor of the helicase WRN, was well tolerated in mice and led to robust tumour regression in multiple microsatellite-instability-high colorectal cancer cell lines and patient-derived xenograft models. [ABSTRACT FROM AUTHOR]

Introduction: The goal of this research is to identify the factors that negatively impact the achievement of the minimum clinically significant change (MCID) for the American Shoulder and Elbow Surgeons (ASES) score within the realm of various orthopedic shoulder procedures. Methods: We conducted a comprehensive review of studies published from 2002 to 2023, utilizing OvidMedline and PubMed databases. Our search criteria included terms such as "minimal clinically important difference" or "MCID" along with associated MeSH terms, in addition to "American shoulder and elbow surgeon" or "ASES." We selectively included primary investigations that assessed factors linked to the failure to achieve MCID for the ASES score subsequent to orthopedic shoulder procedures, while excluding papers addressing anatomical, surgical, or injury-related aspects. Results: Our analysis identified 149 full-text articles, leading to the inclusion of 12 studies for detailed analysis. The selected studies investigated outcomes following various orthopedic shoulder procedures, encompassing biceps tenodesis, total shoulder arthroplasty, and rotator cuff repair. Notably, factors, such as gender, body mass index, diabetes, smoking habits, opioid usage, depression, anxiety, workers' compensation, occupational satisfaction, and the preoperative ASES score, were all associated with the inability to attain MCID. Conclusion: In summary, numerous factors exert a negative influence on the attainment of MCID following shoulder procedures, and these factors appear to be irrespective of the specific surgical technique employed. Patients presenting with these factors may perceive their surgical outcomes as less successful when compared to those without these factors. Identifying these factors can enable healthcare providers to provide more effective counseling to patients regarding their expected outcomes and rehabilitation course. Furthermore, these findings can aid in the development of a screening tool to better identify these risk factors and optimize them before surgery. [ABSTRACT FROM AUTHOR]

Hypersonic vehicles must withstand extreme conditions during flights that exceed five times the speed of sound. These systems have the potential to facilitate rapid access to space, bolster defense capabilities, and create a new paradigm for transcontinental earth-to-earth travel. However, extreme aerothermal environments create significant challenges for vehicle materials and structures. This work addresses the critical need to develop resilient refractory alloys, composites, and ceramics. We will highlight key design principles for critical vehicle areas such as primary structures, thermal protection, and propulsion systems; the role of theory and computation; and strategies for advancing laboratory-scale materials to manufacturable flight-ready components. Hypersonic vehicles experience extreme temperatures, high heat fluxes, and aggressive oxidizing environments. Here, the authors highlight key materials design principles for critical vehicle areas and strategies for advancing laboratory-scale materials to flight-ready components. [ABSTRACT FROM AUTHOR]

The past decade has seen an increase in the prevalence of sequence type (ST) 45 methicillin-resistant Staphylococcus aureus (MRSA), yet the underlying drivers for its emergence and spread remain unclear. To better understand the worldwide dissemination of ST45 S. aureus, we performed phylogenetic analyses of Australian isolates, supplemented with a global population of ST45 S. aureus genomes. Our analyses revealed a distinct lineage of multidrug-resistant ST45 MRSA harbouring qacA, predominantly found in Australia and Singapore. Bayesian inference predicted that the acquisition of qacA occurred in the late 1990s. qacA was integrated into a structurally variable region of the chromosome containing Tn552 (carrying blaZ) and Tn4001 (carrying aac(6')-aph(2")) transposable elements. Using mutagenesis and in vitro assays, we provide phenotypic evidence that qacA confers tolerance to chlorhexidine. These findings collectively suggest both antimicrobial resistance and the carriage of qacA may play a role in the successful establishment of ST45 MRSA. A study underscores the emergence of a qacA-harbouring multidrug-resistant sequence type 45 methicillin-resistant Staphylococcus aureus lineage, highlighting the potential impact of biocide tolerance on its recent clonal spread in Australia and Asia. [ABSTRACT FROM AUTHOR]

Despite rapid growth of quantum information science (QIS) workforce development initiatives, perceived lack of agreement among faculty on core content has made prior research-based curriculum and assessment development initiatives difficult to scale. To identify areas of consensus on content coverage, we report findings from a survey of N=63 instructors teaching introductory QIS courses at US institutions of higher learning. We identify a subset of content items common across a large fraction (≥ 80%) of introductory QIS courses that are potentially amenable to research-based curriculum development, with an emphasis on foundational skills in mathematics, physics, and engineering. As a further guide for curriculum development, we also examine differences in content coverage by level (undergraduate/graduate) and discipline. Finally, we briefly discuss the implications of our findings for the development of a research-based QIS assessment at the postsecondary level. [ABSTRACT FROM AUTHOR]

Background: Cancer is common and disproportionately impacts older adults. Moreover, cancer care of older adults is complex, and the current Canadian cancer care system struggles to address all of the dimensions. In this project, our goal was to understand the barriers and facilitators to caring for older adults with cancer from perspectives of healthcare professionals and cancer care allies, which included community groups, seniors’ centers, and other community-based supports. Methods: In collaboration with a patient advisory board, we conducted focus groups and interviews with multiple local healthcare professionals and cancer care allies in British Columbia, Canada. We used a descriptive qualitative approach and conducted a thematic analysis using NVivo software. Results: A total of 71 participants of various disciplines and cancer care allies participated. They identified both individual and system-level barriers. Priority system-level barriers for older adults included space and staffing constraints and disconnections within healthcare systems, and between healthcare practitioners and cancer care allies. Individual-level barriers relate to the complex health states of older adults, caregiver/support person needs, and the needs of an increasingly diverse population where English may not be a first or preferable language. Conclusions: This study identified key barriers and facilitators that demonstrate aligned priorities among a diverse group of healthcare practitioners and cancer care allies. In conjunction with perspectives from patients and caregivers, these findings will inform future improvements in cancer care. Namely, we emphasize the importance of connections among health systems and community networks, given the outpatient nature of cancer care and the needs of older adults. [ABSTRACT FROM AUTHOR]

In Sweden, allergy immunotherapy (AIT) is available as either subcutaneous immunotherapy (SCIT) injections or sublingual immunotherapy (SLIT) tablets and is used to treat moderate-severe allergic rhinitis (AR). This study sought to determine treatment-related CO2 emissions and travel times in Swedish patients receiving either SCIT or SLIT-tablets. A list of specialized Swedish AR clinics that administer AIT was determined, and respective co-ordinates retrieved. Swedish municipality population data were obtained from a national database. The mean distance from each Swedish municipality to the nearest AR clinic was calculated, adjusted using a detour index, and weighted by estimated patient population size. Transport modality data were obtained from a Swedish urban transport study and CO2 emissions were obtained from Government sources. The mean number of annual SLIT-tablets and SCIT doses required were calculated based on product labels and clinical expert input. The annual number of healthcare professional interactions were layered into the model to estimate changes in mean patient travel time, distance, and travel-related CO2 emissions associated with using SCIT versus SLIT-tablets. Mean annual travel-related CO2 emissions were 410 tonnes (to two significant figures [s.f.]; standard deviation [SD] 90) with SLIT-tablets, versus 1700 tonnes (SD 380) for SCIT, resulting in mean annual savings of approximately 1300 tonnes (SD 290) of CO2 if all AIT patients were to receive SLIT-tablets instead of SCIT, over 380 times greater than 2021 average Swedish CO2 emissions per capita. Approximate mean annual travel times for patients taking SLIT-tablets were 66,500 h (three s.f.; SD 14,400), and 278,000 h (SD 60,200) for SCIT, resulting in mean annual savings of 211,000 h (SD 45,800) if all AIT patients were to receive SLIT-tablets instead of SCIT. Compared with SCIT injections, SLIT-tablets led to substantial reductions in treatment-related CO2 emissions and travel times for Swedish patients. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to analyze the treatment outcomes of single-fraction stereotactic radiosurgery (SRS) for adenoid cystic carcinoma patients. Methods: Retrospective analysis was conducted for 55 patients with 66 lesions. SRS intentions were categorized as definitive, adjuvant, salvage, and palliative. Tumor control was defined as local (within 50% isodose line), marginal (outside 50% isodose line), and distant (metastasis outside head/neck). Results: The median age was 60 years (range 21–85), with 53% males. Tumor origin was head/neck for 88% and trachea/lung for 12%. 61% were recurrent lesions. Median interval from diagnosis to SRS was 14 months. Preceding surgery was performed in 30%. SRS was administered as definitive (30 lesions), adjuvant (13), salvage (19), and palliative (4). SRS was used as a boost to external beam radiation therapy (EBRT) in 39%. Concurrent chemotherapy was administered in 26%. 5-, 10-, and 15-year local control rates were 60%, 33%, and 27%, respectively; local/marginal control rates were 29%, 13%, and 10%. For recurrent lesions treated with SRS without EBRT, 5-year local control rate was 14%, and local/marginal control rate was 5%. For recurrent lesions treated with SRS and EBRT, 5-year local control rate was 100%, and local/marginal control rate was 40%. The rate of distant failure after SRS was 40%. Older age and distant metastasis before SRS were negative factors for overall survival. Conclusion: SRS provided a high rate of local tumor control, but marginal failure was frequent. Integrating SRS with added EBRT exhibits potential for enhancing local and local/marginal tumor control, particularly in recurrent cases. [ABSTRACT FROM AUTHOR]

Interplanetary transport of payloads of unprecedented mass, as envisaged beyond the lunar gateway, will require thrusters with high specific impulse as well as high thrust. To achieve this, innovations in propulsion are critical. Many classes of electric thruster utilise a magnetic applied field module to accelerate charged particles. Magnetoplasmadynamic thrusters exhibit improved performance with increasing field, at least up to the limit of around 0.5 T able to be provided by permanent magnets or copper electromagnets. However, superconducting magnets can generate much stronger magnetic fields. In this study, we utilised a space-relevant cryocooled high temperature superconducting magnet as the applied field module for a central cathode electrostatic thruster (CC-EST). A convex anode enabled ignition at high magnetic fields, and in this configuration the thruster's performance was characterised in the power range of 1 kW to 2.5 kW and at steady applied fields ranging from 0.6 T to 0.8 T, representing a significant advance in achievable field strength. In combination, these operating parameters enabled the achievement of a magnet-inclusive thruster efficiency of 19%, while the cryocooled magnet was demonstrated to be thermally stable in the presence of the kW-scale plasma, demonstrating the viability of such a design for space flight applications. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) patients with metastatic/recurrent disease have limited treatment options and poor survival outcomes. Recently, we discovered the FGFR2c splice isoform is associated with poor prognosis in EC patients. Here we report the establishment of 16 EC patient-derived xenografts (PDX)-derived organoids (PDXOs) with or without FGFR2c expression. In vitro treatment of 5 EC PDXOs with BGJ398 showed significant cell death in 3 models with FGFR2c expression. PDXs with high/moderate FGFR2c expression showed significant tumour growth inhibition (TGI) following 21-day treatment with FGFR inhibitors (BGJ398 or pemigatinib) and significantly prolonged survival in 4/5 models. Pemigatinib + cisplatin combination therapy (n = 5) resulted in significant TGI and prolonged survival in one of two p53abn PDXs. All five models treated with cisplatin alone showed de novo resistance and no survival benefit. Seven-day treatment with BGJ398 revealed a significant reduction in angiogenesis and CD206 + M2 macrophages. These data collectively support the evaluation of FGFR inhibitors in a clinical trial. [ABSTRACT FROM AUTHOR]

We introduce a flexible method to simultaneously infer both the drift and volatility functions of a discretely observed scalar diffusion. We introduce spline bases to represent these functions and develop a Markov chain Monte Carlo algorithm to infer, a posteriori, the coefficients of these functions in the spline basis. A key innovation is that we use spline bases to model transformed versions of the drift and volatility functions rather than the functions themselves. The output of the algorithm is a posterior sample of plausible drift and volatility functions that are not constrained to any particular parametric family. The flexibility of this approach provides practitioners a powerful investigative tool, allowing them to posit a variety of parametric models to better capture the underlying dynamics of their processes of interest. We illustrate the versatility of our method by applying it to challenging datasets from finance, paleoclimatology, and astrophysics. In view of the parametric diffusion models widely employed in the literature for those examples, some of our results are surprising since they call into question some aspects of these models. [ABSTRACT FROM AUTHOR]

Background: Hydrocephalus (HC) is common in patients with vestibular schwannoma (VS). This can be managed with a cerebrospinal fluid (CSF) diversion procedure prior to VS resection or with VS resection, keeping CSF diversion in reserve unless required postoperatively. No clear consensus exists as to which approach is superior. This study identifies factors predictive of the development of HC, and analyses outcomes for those managed with primary CSF resection versus tumour resection. Methods: Single-centre retrospective cohort study of 204 consecutive adult patients with a unilateral VS from May 2009 to June 2021. Data was collected on patient and tumour demographics, management, and outcome. Results: 204 patients, with a mean age at presentation of 59.5 (21–83), with 50% female, and a mean follow-up of 7.5 years (1.8–13.9) were included. 119 were managed conservatively, 36 with stereotactic radiosurgery only, and 49 with surgery. 30 (15%) patients had radiological HC, of which 23 (77%) were obstructive, and 7 (23%) were communicating. Maximum intracranial tumour diameter and Koos grade were higher in patients with HC. Of the patients with HC the majority (20, 67%) were managed initially with CSF diversion, with 12 patients undergoing subsequent tumour resection, and three patients avoiding primary resection. Nine (30%) were managed with primary surgical resection, of whom three required subsequent CSF diversion. Complication rates and Modified Rankin Scale (MRS) were comparable or lower in the CSF diversion group (8%, MRS ≤2 = 83%), versus the primary resection group (67%, MRS ≤2 = 67%), and the primary surgical resection without HC group (25%, MRS ≤2 = 86%). Conclusions: CSF diversion prior to tumour resection is a safe and acceptable strategy compared to primary VS resection, with improved outcomes and reduced surgical complications. Randomized studies and national databases are needed to determine the long-term outcomes of patients treated with CSF diversion versus primary resection. [ABSTRACT FROM AUTHOR]

A great many efforts are dedicated to developing noise reduction and mitigation methods. One remarkable achievement in this direction is dynamical decoupling (DD), although its applicability remains limited because fast control is required. Using resource theoretic tools, we show that non-Markovianity is a resource for noise reduction, raising the possibility that it can be leveraged for noise reduction where traditional DD methods fail. We propose a non-Markovian optimisation technique for finding DD pulses. Using a prototypical noise model, we numerically demonstrate that our optimisation-based methods are capable of drastically improving the exploitation of temporal correlations, extending the timescales at which noise suppression is viable by at least two orders of magnitude, compared to traditional DD which does not use any knowledge of the non-Markovian environment. Importantly, the corresponding tools are built on operational grounds and can be easily implemented to reduce noise in the current generation of quantum devices. [ABSTRACT FROM AUTHOR]

Background: Retroperitoneal liposarcomas are locally aggressive and frequently recur following complete surgical resection. Palbociclib, a cyclin-dependent kinase (CDK) 4/CDK6 inhibitor, is effective in the treatment of metastatic or unresectable liposarcoma. Objective: The purpose of this study was to describe our initial experience using adjuvant palbociclib to delay recurrence. Methods: Patients with resected RPS were identified from a prospectively maintained institutional database. In 2017, we began offering adjuvant palbociclib to patients following complete gross resection. Treatment interval, defined as the time between surgical resection and re-resection or change in systemic therapy, was compared between patients selected for adjuvant palbociclib or observation. Results: Between 2017 and 2020, 12 patients underwent a total of 14 operations (14 patient cases) and were selected for adjuvant palbociclib for recurrence prevention. These patients were compared with 14 patients who, since 2010, underwent a total of 20 operations (20 patient cases) and were selected for observation. Histology was primarily dedifferentiated liposarcoma for both groups (observation: 70% [14/20]; adjuvant palbociclib: 64% [9/14]). All patients underwent complete gross resection. Neither age, number of previous surgeries, histologic grade, or Eastern Cooperative Oncology Group (ECOG) performance status differed between groups (p > 0.05 for all). Patients selected for adjuvant palbociclib experienced a longer treatment interval than those selected for observation, although it did not reach statistical significance (20.5 months vs. 13.1 months, p = 0.08, log rank). Conclusion: Adjuvant palbociclib may be associated with a prolonged interval between liposarcoma resection and the need for re-resection or other systemic therapy. Palbociclib may be effective in delaying liposarcoma recurrence, and its use for this indication warrants prospective study. [ABSTRACT FROM AUTHOR]

As a universal structure in space plasma, electron holes represent an obvious signature of nonlinear process. Although the theory has a 60-year history, whether electron hole can finally accelerate ambient electrons (or ions) is quite controversial. Previous theory for one-dimensional holes predicts that net velocity change of passing electrons (or ions) occurs only if the holes have non-zero acceleration. However, the prediction has not yet been demonstrated in observations. Here, we report four electron holes whose acceleration/deceleration is obtained by fitting the spatial separations and detection time delays between different Magnetospheric Multiscale spacecraft. We find that electron hole acceleration/deceleration is related to the ion velocity distribution gradient at the hole's velocity. We observe net velocity changes of ions passing through the accelerating/decelerating holes, in accordance with theoretical predictions. Therefore, we show that electron holes with non-zero acceleration can cause the velocity of passing ions to increase in the acceleration direction. Electron holes with drift speeds comparable to local ion thermal velocity are called slow electron holes. Here, the authors show slow electron holes with non-zero acceleration can cause net velocity change of ions passing through. [ABSTRACT FROM AUTHOR]

Global commitments to protect 30% of land by 2030 present an opportunity to combat the biodiversity crisis, but reducing extinction risk will depend on where countries expand protection. Here, we explore a range of 30×30 conservation scenarios that vary what dimension of biodiversity is prioritized (taxonomic groups, species-at-risk, biodiversity facets) and how protection is coordinated (transnational, national, or regional approaches) to test which decisions influence our ability to capture biodiversity in spatial planning. Using Canada as a model nation, we evaluate how well each scenario captures biodiversity using scalable indicators while accounting for climate change, data bias, and uncertainty. We find that only 15% of all terrestrial vertebrates, plants, and butterflies (representing only 6.6% of species-at-risk) are adequately represented in existing protected land. However, a nationally coordinated approach to 30×30 could protect 65% of all species representing 40% of all species-at-risk. How protection is coordinated has the largest impact, with regional approaches protecting up to 38% fewer species and 65% fewer species-at-risk, while the choice of biodiversity incurs much smaller trade-offs. These results demonstrate the potential of 30×30 while highlighting the critical importance of biodiversity-informed national strategies. Expanding protected areas to meet conservation goals requires careful consideration of potential trade-offs. Here, by simulating conservation scenarios for Canada, the authors report that 30×30 outcomes for biodiversity depend more on how protection is coordinated at different spatial scales than on which biodiversity metrics are prioritized. [ABSTRACT FROM AUTHOR]

Most work in the epistemology of testimony is built upon a simple model of communication according to which, when the speaker asserts that p, the hearer must recover this very content, p. In this paper, I argue that this 'Content Preservation Model' of communication cannot bear the weight placed on it by contemporary work on testimony. It is popularly thought that testimonial exchanges are often successful such that we gain a great deal of knowledge through testimony. In addition, the testimonial knowledge so gained is thought to be informative: it closes off epistemic possibilities for the agent. However, in the literature on truth-conditional content, there is no theory of content that can underpin both of these commitments simultaneously if the Content Preservation Model is true. There is a minimal notion of content, which is commonly preserved in communication, but which is typically uninformative; there is a maximal notion of content, which is often informative, but which is not often preserved in communication; and, although there are moderate positions between these two extremes, these views cannot strike the right balance between informativeness and shareability. Thus, an epistemology of testimony that endorses the Content Preservation Model faces a dilemma: on the first horn, testimonial exchanges are rarely successful; on the second horn, testimonial content is rarely informative. I suggest that this dilemma motivates further exploration of alternative communicative foundations for the epistemology of testimony. [ABSTRACT FROM AUTHOR]

Mechanics is known to play a fundamental role in many cellular and developmental processes. Beyond active forces and material properties, osmotic pressure is believed to control essential cell and tissue characteristics. However, it remains very challenging to perform in situ and in vivo measurements of osmotic pressure. Here we introduce double emulsion droplet sensors that enable local measurements of osmotic pressure intra- and extra-cellularly within 3D multicellular systems, including living tissues. After generating and calibrating the sensors, we measure the osmotic pressure in blastomeres of early zebrafish embryos as well as in the interstitial fluid between the cells of the blastula by monitoring the size of droplets previously inserted in the embryo. Our results show a balance between intracellular and interstitial osmotic pressures, with values of approximately 0.7 MPa, but a large pressure imbalance between the inside and outside of the embryo. The ability to measure osmotic pressure in 3D multicellular systems, including developing embryos and organoids, will help improve our understanding of its role in fundamental biological processes. Osmotic pressure is thought to play a key role in many cellular and developmental processes, but remains challenging to measure it in cells and tissues. Here, the authors present a sensor based on double emulsion droplets that allows quantification of osmotic pressure in situ and in vivo. [ABSTRACT FROM AUTHOR]

Introduction: Intravenous (IV) administration of iron is considered a safe and efficacious treatment for iron deficiency anemia (IDA), recommended in patients requiring rapid replenishment of iron, or intolerant or unresponsive to oral administration of iron. Recent randomized controlled trials (RCTs) have shown high incidence of hypophosphatemia after administration of two IV iron preparations: saccharated ferric oxide (SFO) and ferric carboxymaltose (FCM). The present study aimed to conduct matching-adjusted indirect comparison (MAIC) of hypophosphatemia incidence with these iron formulations and ferric derisomaltose (FDI) based on data from head-to-head RCTs conducted in Japan. Methods: A MAIC of hypophosphatemia incidence was conducted on the basis of data from two head-to-head RCTs. The relative odds of hypophosphatemia with FDI versus SFO were obtained from patient-level data from a recent RCT and adjusted for cumulative iron dose, while parametric models of serum phosphate levels from a separate RCT were used to estimate the relative odds of hypophosphatemia with FCM with SFO. An anchored MAIC was then conducted comparing FDI with FCM. Results: The adjusted odds of experiencing hypophosphatemia were significantly lower with FDI than SFO [odds ratio (OR) of 0.02; 95% confidence interval (CI) 0.01–0.05]. The parametric models of serum phosphate from the RCT comparing FCM with SFO provided an estimated OR of 1.17 for the incidence of hypophosphatemia with FCM versus SFO. Combining the two estimates in the MAIC showed that the odds of experiencing hypophosphatemia would be 52.5 (95% CI 27.7–99.4) times higher with FCM than FDI in patients with IDA associated with heavy menstrual bleeding in Japan. Conclusions: Direct comparison of patient-level data and a MAIC from two RCTs in Japanese patients with heavy menstrual bleeding indicated that hypophosphatemia is less frequent in patients treated with FDI than those with FCM or SFO. Results are in agreement with RCTs comparing FDI and FCM in patients with various etiologies conducted in the USA and Europe. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate endovascular popliteal artery aneurysm repair using a an "off-label" abdominal endograft limb-module with nitinol-ring structure. Materials and Methods: Retrospective observational study of 14 popliteal artery aneurysms in 12 male patients (mean age 76 years and median ASA grade 3) treated electively using the Anaconda™ endograft limb (Terumo Aortic) at a single teaching hospital. Eight limbs were treated percutaneously and 6 limbs required surgical arterial exposure. The mean popliteal artery aneurysm diameter treated was 3.6 cm (range 2.1–5.3 cm). Stent-graft diameters and lengths used were 10–15 and 60–140 mm, respectively. The median covered stented length was 218 mm (range 160–270 mm) and median duration of follow-up was 3.7 years. Outcomes assessed included technically successful aneurysm exclusion, primary patency, re-intervention and survival. Results: All patients had successful stent-graft deployment and aneurysm exclusion, with no early complications or mortality at 30 days. Primary stent-graft patency at 1, 3 and 4 years was 93%, 75%, and 64%. By 8 years, patency had declined with 29% (2/14) stent-grafts patent. 7/14 limbs occluded; 3 underwent re-intervention (2 surgical, 1 endovascular). There were no deaths related to the procedure. Freedom from re-intervention and survival at 1/5 years was 93%/84% and 93%/67%, respectively. Conclusion: The Anaconda™ endograft limb for endovascular popliteal artery aneurysm repair offers good mid-term patency and acceptable long-term patency up to 4 years when compared with other grafts and open surgery. It may be considered in older comorbid patients unfit for surgery and can be performed percutaneously under local anaesthesia when anatomically feasible. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis III (MPSIII, Sanfilippo syndrome) is a devastating lysosomal storage disease that primarily affects the central nervous system. MPSIIIA is caused by loss-of-function mutations in the gene coding for sulfamidase (N-sulfoglucosamine sulfohydrolase/SGSH) resulting in SGSH enzyme deficiency, a buildup of heparin sulfate and subsequent neurodegeneration. There is currently no cure or disease modifying treatment for MPSIIIA. A mouse model for MPSIIIA was characterized in 1999 and later backcrossed onto the C57BL/6 background. In the present study, a novel immune deficient MPSIIIA mouse model (MPSIIIA-TKO) was created by backcrossing the immune competent, C57BL/6 MPSIIIA mouse to an immune deficient mouse model lacking Rag2, CD47 and Il2rg genes. The resulting mouse model has undetectable SGSH activity, exhibits histological changes consistent with MPSIIIA and lacks T cells, B cells and NK cells. This new mouse model has the potential to be extremely useful in testing human cellular therapies in an animal model as it retains the MPSIIIA disease phenotype while tolerating xenotransplantation. [ABSTRACT FROM AUTHOR]

The Healthy Dads, Healthy Kids (HDHK) program was designed to help fathers with BMI ≥ 25 kg/m2 to lose weight and positively influence physical activity and dietary behaviors of their children. There is a need to better understand the broader impact of father-focused, healthy lifestyle programs from the perspectives of other family members. This qualitative study explored the impact of a HDHK by gathering insights from the family unit (fathers, mothers/partners and children). Fathers and children who participated in the HDHK dissemination trial from the Maitland local government area (New South Wales, Australia) (n = 33) and all mothers/partners of participating HDHK were invited to take part in this qualitative study. Eleven focus groups were undertaken with 25 fathers (41.9 ± 6.3 years, 32.4 ± 5.1 kg/m2), 15 mothers/partners' (38.1 ± 6.6 years), and 41 children (51% male, 8.2 ± 2.1 years). Audio recordings were transcribed and analyzed by an independent researcher using a standard general inductive approach to qualitative analysis with thematic analysis applied. Three key themes emerged, demonstrating several personal and family program impacts. These included a positive impact on: (i) the father-child relationship, (ii) new family habits (e.g., lifestyle changes within the family unit) and (iii) fathers' involvement and parenting practices (e.g., increase in fathers' household responsibilities). Improving the knowledge and skills of fathers and children through evidence-based strategies may be a useful approach to strengthen their relationship, enhance parenting strategies, and optimize health behaviors. Notably, findings showed the changes made by the fathers and children positively impacted the wider family unit. Highlights: First qualitative study to explore the impact of a father–child lifestyle program by gathering insights from the whole family unit. Fathers and children embraced program concepts to strengthen their relationship and optimize health behaviors. Fathers improved their parenting practices. Changes made by fathers and children positively impacted the wider family unit. [ABSTRACT FROM AUTHOR]

Purpose: To perform a systematic review of literature specific to single-fraction stereotactic radiosurgery (SRS) for large vestibular schwannomas (VS), maximum diameter ≥ 2.5 cm and/or classified as Koos Grade IV, and to present consensus recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS). Methods: The Medline and Embase databases were used to apply the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach. We considered eligible prospective and retrospective studies, written in the English language, reporting treatment outcomes for large VS; SRS for large post-operative tumors were analyzed in aggregate and separately. Results: 19 of the 229 studies initially identified met the final inclusion criteria. Overall crude rate of tumor control was 89% (93.7% with no prior surgery vs 87.7% with prior surgery). Rates of salvage microsurgical resection, need for shunt, and additional SRS in all series versus those with no prior surgery were 9.6% vs 3.3%, 4.7% vs 6.4% and 1% vs 0.9%, respectively. Rates of facial palsy and hearing preservation in all series versus those with no prior surgery were 1.3% vs 3.4% and 34.2% vs 40.4%, respectively. Conclusions: Upfront SRS resulted in high rates of tumor control with acceptable rates of facial palsy and hearing preservation as compared to the results in those series including patients with prior surgery (level C evidence). Therefore, although large VS are considered classic indication for microsurgical resection, upfront SRS can be considered in selected patients and we recommend a prescribed marginal dose from 11 to 13 Gy (level C evidence). [ABSTRACT FROM AUTHOR]

Greater sensitivity to the cost of effortful engagement has long been implicated in the development of Attention Deficit Hyperactivity Disorder (ADHD). The current study evaluated preferential choice to engage in demanding tasks, and did so in combination with computational methods to interrogate the process of choice. Children aged 8–12 with (n = 49) and without (n = 36) ADHD were administered the cognitive effort discounting paradigm (COG-ED, adapted from Westbrook et al., 2013). Diffusion modelling was subsequently applied to the choice data to allow for a better description of the process of affective decision making. All children showed evidence of effort discounting, but, contrary to theoretical expectations, there was no evidence that children with ADHD judged effortful tasks to be lower in subjective value, or that they maintained a bias towards less effortful tasks. However, children with ADHD developed a much less differentiated mental representation of demand than their non-ADHD counterparts even though familiarity with and exposure to the experience of effort was similar between groups. Thus, despite theoretical arguments to the contrary, and colloquial use of motivational constructs to explain ADHD-related behavior, our findings strongly argue against the presence of greater sensitivity to costs of effort or reduced sensitivity to rewards as an explanatory mechanism. Instead, there appears to be a more global weakness in the metacognitive monitoring of demand, which is a critical precursor for cost–benefit analyses that underlie decisions to engage cognitive control. [ABSTRACT FROM AUTHOR]

Activated macrophages play a critical role in the orchestration of inflammation and inflammatory pain in several chronic diseases. We present here the first perfluorocarbon nanoemulsion (PFC NE) that is designed to preferentially target activated macrophages and can deliver up to three payloads (two fluorescent dyes and a COX-2 inhibitor). Folate receptors are overexpressed on activated macrophages. Therefore, we introduced a folate-PEG-cholesterol conjugate into the formulation. The incorporation of folate conjugate did not require changes in processing parameters and did not change the droplet size or fluorescent properties of the PFC NE. The uptake of folate-conjugated PFC NE was higher in activated macrophages than in resting macrophages. Flow cytometry showed that the uptake of folate-conjugated PFC NE occurred by both phagocytosis and receptor-mediated endocytosis. Furthermore, folate-conjugated PFC NE inhibited the release of proinflammatory cytokines (TNF-α and IL-6) more effectively than nonmodified PFC NE, while drug loading and COX-2 inhibition were comparable. The PFC NEs reported here were successfully produced on multiple scales, from 25 to 200 mL, and by using two distinct processors (microfluidizers: M110S and LM20). Therefore, folate-conjugated PFC NEs are viable anti-inflammatory theranostic nanosystems for macrophage drug delivery and imaging. [ABSTRACT FROM AUTHOR]

Purpose: To examine children’s experiences of chemotherapy-induced cognitive impairment––colloquially “chemobrain”––and the impact on children’s social, academic, and daily living skills via a qualitative systematic review. Experiencing chemotherapy as a child, when the brain is still developing, may cause lifelong detriment to survivors’ lives. There is a significant gap in understanding their lived experience, including the self-identified barriers that children face following treatment. Such a gap can only be fully bridged by listening to the child’s own voice and/or parent proxy report through an exploration of the qualitative research literature. Methods: A search of MEDLINE, Embase, PsycINFO, and CINAHL databases was conducted. Inclusion criteria were qualitative studies with a focus on children (0–18 years) during and/or following chemotherapy treatment and explored children’s experiences of chemobrain. Results: Two synthesized findings were identified from six studies. (1) Chemobrain has an academic and psychosocial impact, which may not be understood by education providers. (2) Children and their parents have concerns about their reintegration and adaptation to school, social lives, and their future selves as independent members of society. Children’s experiences primarily related to changes in their academic and social functioning. Conclusion: This review highlights two important considerations: (1) the lived experiences of pediatric childhood cancer survivors guiding where future interventions should be targeted, and (2) a need to perform more qualitative research studies in this area, as well as to improve the quality of reporting among the existing literature, given that this is a current gap in the field. [ABSTRACT FROM AUTHOR]

Purpose: Many patients prefer an active role in making decisions about their care and treatment, but participating in such decision-making is challenging. The aim of this study was to explore whether patient-reported outcomes (quality of life and patient satisfaction), patients’ coping strategies, and sociodemographic and clinical characteristics were associated with self-efficacy for participation in decision-making among patients with advanced cancer. Methods: We used baseline data from the ACTION trial of patients with advanced colorectal or lung cancer from six European countries, including scores on the decision-making participation self-efficacy (DEPS) scale, EORTC QLQ-C15-PAL questionnaire, and the EORTC IN-PATSAT32 questionnaire. Multivariable linear regression analyses were used to examine associations with self-efficacy scores. Results: The sample included 660 patients with a mean age of 66 years (SD 10). Patients had a mean score of 73 (SD 24) for self-efficacy. Problem-focused coping (B 1.41 (95% CI 0.77 to 2.06)), better quality of life (B 2.34 (95% CI 0.89 to 3.80)), and more patient satisfaction (B 7.59 (95% CI 5.61 to 9.56)) were associated with a higher level of self-efficacy. Patients in the Netherlands had a higher level of self-efficacy than patients in Belgium ((B 7.85 (95% CI 2.28 to 13.42)), whereas Italian patients had a lower level ((B −7.50 (95% CI −13.04 to −1.96)) than those in Belgium. Conclusion: Coping style, quality of life, and patient satisfaction with care were associated with self-efficacy for participation in decision-making among patients with advanced cancer. These factors are important to consider for healthcare professionals when supporting patients in decision-making processes. [ABSTRACT FROM AUTHOR]

Purpose: The incidence of self-harm is an important indicator in suicide surveillance and a target outcome for suicide prevention. Self-harm rates vary by geographic location and rurality appears to be a risk factor. The objectives of this study were to estimate rates of self-harm hospitalization in Canada over a 5-year period by sex and age group, and examine relationships between self-harm and rurality. Methods: Hospitalizations related to self-harm were identified in a national dataset (the Discharge Abstract Database) for all patients aged 10 years or older who were discharged from hospital between 2015 and 2019. Self-harm hospitalization rates were calculated and stratified by year, sex, age group, and level of rurality, as measured using the Index of Remoteness. A Poisson regression was fit to estimate rate ratios for the levels of rurality. Results: Rates of self-harm hospitalization were higher for females than males across all levels of rurality and increased with each level for both sexes, except for among young males. The widest rural-to-urban disparities were observed for the 10–19 and 20–34-year old age groups. Females aged 10–19 in very remote areas had the highest self-harm hospitalization rate. Conclusion: The rate of self-harm hospitalization in Canada varied by sex, age group, and level of rurality. Clinical and community-based interventions for self-harm, such as safety planning and increased access to mental health services, should be tailored to the differential risks across geographic contexts. [ABSTRACT FROM AUTHOR]