At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. DESIGN: Phase 2, open-label, single arm study. SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-ß antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Data-driven determination of zooplankton bioregions and robustness analysis.

Identifying biogeographic regions through cluster analysis of species distribution data is a common method for partitioning ecosystems. Selecting the appropriate cluster analysis method requires a comparison of multiple algorithms. In this study, we demonstrate a data-driven process to select a method for bioregionalization based on community data and test its robustness to data variability following these steps: •We aggregated and curated zooplankton community observations from expeditions in the Northeast Pacific.•We determined the best bioregionalization approach by comparing nine cluster analysis methods using ten goodness of clustering indices.•We evaluated the robustness of the bioregionalization to different sources of sampling and taxonomic variability by comparing the bioregionalization of the overall dataset with bioregionalizations of subsets of the data. The K-means clustering of the log-chord transformed abundance was selected as the optimal method for bioregionalization of the zooplankton dataset. This clustering resulted in the emergence of four bioregions along the cross-shelf gradient: the Offshore, Deep Shelf, Nearshore, and Deep Fjord bioregions. The robustness analyses demonstrated that the bioregionalization was consistent despite variability in the spatial and temporal frequency of sampling, sampling methodology, and taxonomic coverage.

Domoic acid in Canadian Pacific waters, from 2016 to 2021, and relationships with physical and chemical conditions.

Domoic acid, a phycotoxin produced by species of the marine diatom Pseudo-nitzschia, can cause deleterious impacts to marine food webs and human health. Domoic acid and Pseudo-nitzschia spp. were surveyed from 2016 to 2021 in the Pacific waters of Canada to assess their occurrences, concentrations, and relationships with physical and chemical conditions. Domoic acid was common, occurring in measurable concentrations in 73 % of the 454 samples. It occurred in all regions (west coast of Vancouver Island, Salish Sea, Queen Charlotte Sound / Hecate Strait, deep oceanic NE Pacific), in all years and all seasons. Median concentrations were highest along the west coast of Vancouver Island, and lowest in the oceanic waters of the NE Pacific. Winter had the lowest concentrations; no significant differences occurred between spring, summer, and autumn. High domoic acid concentrations equal to or above 100 ng/L were not common, occurring in about 5 % of samples, but in all seasons and all years except 2019. All six Pseudo-nitzschia taxa identified had similar median concentrations, but different frequencies of occurrence. P. cf. australis appeared to be the major contributor to high concentrations of domoic acid. Physico-chemical conditions were described by ten variables: temperature, salinity, density difference between 30 m and the surface (a proxy for vertical stability), chlorophyll a, nitrate, phosphate, silicate, and the ratios nitrate:phosphate, nitrate:silicate, and silicate:phosphate. Statistical analyses, using general linear models, of their relationships with the absence/presence of Pseudo-nitzschia spp. found silicate (negative) to be the most influential variable common in both the west coast of Vancouver Island and Salish Sea regions. Temperature and chlorophyll a were the most influential variables which determined the log10 abundance of Pseudo-nitzschia spp. in both regions. Analyses of the absence/presence of particulate domoic acid per Pseudo-nitzschia cell (excluding P. americana) found chlorophyll a to be the most influential variable common in both regions, whereas no common influential variable determined the log10 concentration of particulate domoic acid per Pseudo-nitzschia cell (excluding P. americana). These results were generally similar to those of other studies from this area, although this study extends these findings to all seasons and all regions of Canada's Pacific waters. The results provide important background information against which major outbreaks and unusual events can be compared. A domoic acid surveillance program during synoptic oceanographic surveys can help to understand where and when it reaches high concentrations at sea and the potential impacts to the marine ecosystem.

Strain control of a bandwidth-driven spin reorientation in Ca3Ru2O7.

The layered-ruthenate family of materials possess an intricate interplay of structural, electronic and magnetic degrees of freedom that yields a plethora of delicately balanced ground states. This is exemplified by Ca3Ru2O7, which hosts a coupled transition in which the lattice parameters jump, the Fermi surface partially gaps and the spins undergo a 90∘ in-plane reorientation. Here, we show how the transition is driven by a lattice strain that tunes the electronic bandwidth. We apply uniaxial stress to single crystals of Ca3Ru2O7, using neutron and resonant x-ray scattering to simultaneously probe the structural and magnetic responses. These measurements demonstrate that the transition can be driven by externally induced strain, stimulating the development of a theoretical model in which an internal strain is generated self-consistently to lower the electronic energy. We understand the strain to act by modifying tilts and rotations of the RuO6 octahedra, which directly influences the nearest-neighbour hopping. Our results offer a blueprint for uncovering the driving force behind coupled phase transitions, as well as a route to controlling them.

A new test method for biochemical analysis of plasmalogens in dried blood spots and erythrocytes from patients with peroxisomal disorders.

Measurement of plasmalogens is useful for the biochemical diagnosis of rhizomelic chondrodysplasia punctata (RCDP) and is also informative for Zellweger spectrum disorders (ZSD). We have developed a test method for the simultaneous quantitation of C16:0, C18:0, and C018:1 plasmalogen (PG) species and their corresponding fatty acids (FAs) in dried blood spots (DBS) and erythrocytes (RBC) by using capillary gas chromatography-mass spectrometry. Normal reference ranges for measured markers and 10 calculated ratios were established by the analysis of 720 and 473 unaffected DBS and RBC samples, respectively. Determination of preliminary disease ranges was made by using 45 samples from 43 unique patients: RCDP type 1 (DBS: 1 mild, 17 severe; RBC: 1 mild, 6 severe), RCDP type 2 (DBS: 2 mild, 1 severe; RBC: 2 severe), RCDP type 3 (DBS: 1 severe), RCDP type 4 (RBC: 2 severe), and ZSD (DBS: 3 severe; RBC: 2 mild, 7 severe). Postanalytical interpretive tools in Collaborative Laboratory Integrated Reports (CLIR) were used to generate an integrated score and a likelihood of disease. In conjunction with a review of clinical phenotype, phytanic acid, and very long-chain FA test results, the CLIR analysis allowed for differentiation between RCDP and ZSD. Data will continue to be gathered to improve CLIR analysis as more samples from affected patients with variable disease severity are analyzed. The addition of DBS analysis of PGs may allow for at-home specimen collection and second-tier testing for newborn screening programs.

A survey in the West Midlands of the United Kingdom of current practice in managing hypotension in lower segment caesarean section under spinal anaesthesia.

BACKGROUND: Spinal anaesthesia, the most common form of anaesthesia for caesarean section, leads to sympathetic blockade and profound maternal hypotension resulting in adverse maternal and neonatal outcomes. Hypotension, nausea and vomiting remain common but until the publication of the National Institute of Health and Care Excellence (NICE) 2021 guidance, no national guideline existed on how best to manage maternal hypotension following spinal anaesthesia for caesarean section. A 2017 international consensus statement recommended prophylactic vasopressor administration to maintain a systolic blood pressure of >90% of an accurate pre-spinal value, and to avoid a drop to <80% of this value. This survey aimed to assess regional adherence to these recommendations, the presence of local guidelines for management of hypotension during caesarean section under spinal anaesthesia, and the individual clinician's treatment thresholds for maternal hypotension and tachycardia. METHODS: The West Midlands Trainee-led Research in Anaesthesia and Intensive Care Network co-ordinated surveys of obstetric anaesthetic departments and consultant obstetric anaesthetists across 11 National Health Service Trusts in the Midlands, England. RESULTS: One-hundred-and-two consultant obstetric anaesthetists returned the survey and 73% of sites had a policy for vasopressor use; 91% used phenylephrine as the first-line drug but a wide range of recommended delivery methods was noted and target blood pressure was only listed in 50% of policies. Significant variation existed in both vasopressor delivery methods and target blood pressures. CONCLUSIONS: Although NICE has since recommended prophylactic phenylephrine infusion and a target blood pressure, the previous international consensus statement was not adhered to routinely.

Network Preservation Analysis Reveals Dysregulated Metabolic Pathways in Human Vascular Smooth Muscle Cell Phenotypic Switching.

BACKGROUND: Vascular smooth muscle cells are key players involved in atherosclerosis, the underlying cause of coronary artery disease. They can play either beneficial or detrimental roles in lesion pathogenesis, depending on the nature of their phenotypic changes. An in-depth characterization of their gene regulatory networks can help better understand how their dysfunction may impact disease progression. METHODS: We conducted a gene expression network preservation analysis in aortic smooth muscle cells isolated from 151 multiethnic heart transplant donors cultured under quiescent or proliferative conditions. RESULTS: We identified 86 groups of coexpressed genes (modules) across the 2 conditions and focused on the 18 modules that are least preserved between the phenotypic conditions. Three of these modules were significantly enriched for genes belonging to proliferation, migration, cell adhesion, and cell differentiation pathways, characteristic of phenotypically modulated proliferative vascular smooth muscle cells. The majority of the modules, however, were enriched for metabolic pathways consisting of both nitrogen-related and glycolysis-related processes. Therefore, we explored correlations between nitrogen metabolism-related genes and coronary artery disease-associated genes and found significant correlations, suggesting the involvement of the nitrogen metabolism pathway in coronary artery disease pathogenesis. We also created gene regulatory networks enriched for genes in glycolysis and predicted key regulatory genes driving glycolysis dysregulation. CONCLUSIONS: Our work suggests that dysregulation of vascular smooth muscle cell metabolism participates in phenotypic transitioning, which may contribute to disease progression, and suggests that AMT (aminomethyltransferase) and MPI (mannose phosphate isomerase) may play an important role in regulating nitrogen and glycolysis-related metabolism in smooth muscle cells.

Ulnar Nerve Translocation Following a Routine Distal Radius Fracture.

A 35-year-old right hand dominant male sustained a high energy closed right distal radius fracture with associated generalized paresthesias. Following closed reduction, the patient was found to have an atypical low ulnar nerve palsy upon outpatient follow-up. After continued symptoms and an equivocal wrist MRI the patient underwent surgical exploration. Intraoperatively, the ulnar nerve as well as the ring and small finger flexor digitorum superficialis tendons were found to be translocated around the ulnar head. The nerve and tendons were reduced, the median nerve was decompressed, and the fracture was addressed with volar plating. Post-operatively, the patient continued to have sensory deficits and stiffness of the ring and small fingers. After one year, he reported substantial improvements as demonstrated by full sensation (4.0 mm two-point discrimination) and fixed flexion contractures at the proximal and distal interphalangeal joints of the small finger. The patient returned to work without functional limitations. This case highlights a unique case of ulnar nerve and flexor tendon entrapment following a distal radius fracture. History, physical examination, and a high index of clinical suspicion is essential for proper management of this rare injury. Level of Evidence: V.

FHL5 Controls Vascular Disease-Associated Gene Programs in Smooth Muscle Cells.

BACKGROUND: Genome-wide association studies have identified hundreds of loci associated with common vascular diseases, such as coronary artery disease, myocardial infarction, and hypertension. However, the lack of mechanistic insights for many GWAS loci limits their translation into the clinic. Among these loci with unknown functions is UFL1-four-and-a-half LIM (LIN-11, Isl-1, MEC-3) domain 5 (FHL5; chr6q16.1), which reached genome-wide significance in a recent coronary artery disease/ myocardial infarction GWAS meta-analysis. UFL1-FHL5 is also associated with several vascular diseases, consistent with the widespread pleiotropy observed for GWAS loci. METHODS: We apply a multimodal approach leveraging statistical fine-mapping, epigenomic profiling, and ex vivo analysis of human coronary artery tissues to implicate FHL5 as the top candidate causal gene. We unravel the molecular mechanisms of the cross-phenotype genetic associations through in vitro functional analyses and epigenomic profiling experiments in coronary artery smooth muscle cells. RESULTS: We prioritized FHL5 as the top candidate causal gene at the UFL1-FHL5 locus through expression quantitative trait locus colocalization methods. FHL5 gene expression was enriched in the smooth muscle cells and pericyte population in human artery tissues with coexpression network analyses supporting a functional role in regulating smooth muscle cell contraction. Unexpectedly, under procalcifying conditions, FHL5 overexpression promoted vascular calcification and dysregulated processes related to extracellular matrix organization and calcium handling. Lastly, by mapping FHL5 binding sites and inferring FHL5 target gene function using artery tissue gene regulatory network analyses, we highlight regulatory interactions between FHL5 and downstream coronary artery disease/myocardial infarction loci, such as FOXL1 and FN1 that have roles in vascular remodeling. CONCLUSIONS: Taken together, these studies provide mechanistic insights into the pleiotropic genetic associations of UFL1-FHL5. We show that FHL5 mediates vascular disease risk through transcriptional regulation of downstream vascular remodeling gene programs. These transacting mechanisms may explain a portion of the heritable risk for complex vascular diseases.

Genetic Regulation of SMC Gene Expression and Splicing Predict Causal CAD Genes.

BACKGROUND: Coronary artery disease (CAD) is the leading cause of death worldwide. Recent meta-analyses of genome-wide association studies have identified over 175 loci associated with CAD. The majority of these loci are in noncoding regions and are predicted to regulate gene expression. Given that vascular smooth muscle cells (SMCs) play critical roles in the development and progression of CAD, we aimed to identify the subset of the CAD loci associated with the regulation of transcription in distinct SMC phenotypes. METHODS: We measured gene expression in SMCs isolated from the ascending aortas of 151 heart transplant donors of various genetic ancestries in quiescent or proliferative conditions and calculated the association of their expression and splicing with ~6.3 million imputed single-nucleotide polymorphism markers across the genome. RESULTS: We identified 4910 expression and 4412 splicing quantitative trait loci (sQTLs) representing regions of the genome associated with transcript abundance and splicing. A total of 3660 expression quantitative trait loci (eQTLs) had not been observed in the publicly available Genotype-Tissue Expression dataset. Further, 29 and 880 eQTLs were SMC-specific and sex-biased, respectively. We made these results available for public query on a user-friendly website. To identify the effector transcript(s) regulated by CAD loci, we used 4 distinct colocalization approaches. We identified 84 eQTL and 164 sQTL that colocalized with CAD loci, highlighting the importance of genetic regulation of mRNA splicing as a molecular mechanism for CAD genetic risk. Notably, 20% and 35% of the eQTLs were unique to quiescent or proliferative SMCs, respectively. One CAD locus colocalized with a sex-specific eQTL (TERF2IP), and another locus colocalized with SMC-specific eQTL (ALKBH8). The most significantly associated CAD locus, 9p21, was an sQTL for the long noncoding RNA CDKN2B-AS1, also known as ANRIL, in proliferative SMCs. CONCLUSIONS: Collectively, our results provide evidence for the molecular mechanisms of genetic susceptibility to CAD in distinct SMC phenotypes.

Role of Dynamic Stabilizers of the Elbow in Radiocapitellar Joint Alignment: A Prospective In Vivo Study.

PURPOSE: To investigate the effect of dynamic stabilizers of the elbow on radiocapitellar joint alignment, before and after the administration of regional anesthesia. METHODS: At a single institution, 14 patients were prospectively enrolled in a study using a within-subjects control design. Before performing a supraclavicular regional block, 10 fluoroscopic images (1 anteroposterior and 9 lateral views) of the elbow were obtained for each patient. The lateral images were obtained with the forearm in maximal supination, neutral rotation, and maximal pronation, and these forearm positions were repeated for 3 elbow positions: (1) full extension; (2) flexion to 90°, with 0° of shoulder internal rotation; and (3) flexion to 90°, with 90° of shoulder internal rotation. After obtaining the 10 initial images, a block was performed to achieve less than 3/5 motor strength of the imaged extremity, followed by obtaining the same 10 images in each patient. Radiocapitellar ratio, defined as the minimal distance between the right bisector of the radial head and the center of the capitellum divided by the diameter of the capitellum, was measured in each image. RESULTS: The 14 patients had a mean age of 47.8 ± 15.7 years, and 10 (71.4%) patients were women. A difference between radiocapitellar ratios measured before and after the regional block administration was observed for all lateral images (-1.0% ± 7.2% to -2.2% ± 8.0%), although this difference was less than the minimum clinically important difference. CONCLUSIONS: Paralysis of the dynamic stabilizers of the elbow produces a difference in the radiocapitellar joint alignment, but this did not reach the minimum clinically important difference. CLINICAL RELEVANCE: Paralysis of the dynamic stabilizers of the elbow via a supraclavicular nerve block produces no clinically relevant effect on the radiocapitellar alignment of uninjured elbows.

Mobile Health Apps for Patient-Centered Care: Review of United States Rheumatoid Arthritis Apps for Engagement and Activation.

BACKGROUND: Rheumatoid arthritis (RA) is a highly dynamic and individualized disease in terms of its patterns of symptomatic flare-ups and periods of remission. Patient-centered care (PCC) aligns patients' lifestyle goals with their preferences for managing symptoms and side effects through the selection of therapies appropriate for disease management. Mobile health (mHealth) apps have the potential to engage and activate patients in PCC. mHealth apps can provide features that increase disease knowledge, collect patient-generated health indicators and behavioral metrics, and highlight goals for disease management. However, little evidence-based guidance exists as to which apps contain functionality essential for supporting the delivery of PCC. OBJECTIVE: The objective of this study was to evaluate the patient-centeredness of United States-based rheumatoid arthritis mobile apps in terms of patient engagement and activation. METHODS: A search of mobile apps on 2 major United States app stores (Apple App Store and Google Play) was conducted from June 2020 to July 2021 to identify apps designed for use by patients with RA by adapting the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines for mobile health app screening based on the literature. Reviewers conducted a content analysis of mobile app features to evaluate their functionality for patient engagement and activation. Engagement and activation were assessed using the Mobile Application Rating Scale (MARS) and social cognitive theory, respectively. Apps were ranked by their ability to facilitate PCC care along 2 dimensions: engagement and activation. RESULTS: A total of 202 mobile apps were initially identified, and 20 remained after screening. Two apps emerged with the greatest ability to facilitate PCC. Both apps were scored as having acceptable or good patient engagement according to the MARS. These 2 apps also had high patient activation according to social cognitive theory, with many features within those apps representing theoretical constructs such as knowledge, perceived self-efficacy, and expectations about outcomes that support behavioral management of RA. CONCLUSIONS: We found very few mobile apps available within the United States that have functionality that both engages and activates the patient to facilitate PCC. As the prevalence of mobile apps expands, the design of mobile apps needs to integrate patients to ensure that their functionality promotes engagement and activation. More research is needed to understand how mobile app use impacts patient engagement and activation, and ultimately, treatment decisions and disease trajectory.

Effective practices during emergency school lockdowns: shared experiences of four Australian schools.

This study investigates common features of a set of diverse schools' responses to the initial school lockdown period during the pandemic in 2020, with a focus on practices supporting learning, inclusion and wellbeing. It comprises a collective case study of four Australian schools that were selected based on their reputation for impactful support of students and teachers during the emergency remote teaching period. Methods included interviews and focus groups with school leaders, teachers and students. The schools had widely differing contexts, technology access and student needs. Despite these varied contexts, the findings provided important insights into common practices supporting effective remote teaching. Emerging principles of effective practice illuminate ways forward to mitigate the significant risks accompanying emergency remote teaching, and guide practices in a variety of school contexts.

Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality.

The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Previously, we used the gene-breaking transposon to create 1200 transgenic zebrafish strains tagging protein-coding genes (Ichino et al., 2020), including the lrpprc locus. Here, we present and characterize a new genetic revertible animal model that recapitulates components of Leigh Syndrome French Canadian Type (LSFC), a mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic variations in the LRPPRC gene, involved in mitochondrial mRNA polyadenylation and translation. lrpprc zebrafish homozygous mutants displayed biochemical and mitochondrial phenotypes similar to clinical manifestations observed in patients, including dysfunction in lipid homeostasis. We were able to rescue these phenotypes in the disease model using a liver-specific genetic model therapy, functionally demonstrating a previously under-recognized critical role for the liver in the pathophysiology of this disease.

Evaluating a Global Assessment Measure Created by Standardized Patients for the Multiple Mini Interview in Medical School Admissions: Mixed Methods Study.

BACKGROUND: Standardized patients (SPs) are essential stakeholders in the multiple mini interviews (MMIs) that are increasingly used to assess medical school applicants' interpersonal skills. However, there is little evidence for their inclusion in the development of instruments. OBJECTIVE: This study aimed to describe the process and evaluate the impact of having SPs co-design and cocreate a global measurement question that assesses medical school applicants' readiness for medical school and acceptance status. METHODS: This study used an exploratory, sequential, and mixed methods study design. First, we evaluated the initial MMI program and determined the next quality improvement steps. Second, we held a collaborative workshop with SPs to codevelop the assessment question and response options. Third, we evaluated the created question and the additional MMI rubric items through statistical tests based on 1084 applicants' data from 3 cohorts of applicants starting in the 2018-2019 academic year. The internal reliability of the MMI was measured using a Cronbach α test, and its prediction of admission status was tested using a forward stepwise binary logistic regression. RESULTS: Program evaluation indicated the need for an additional quantitative question to assess applicant readiness for medical school. In total, 3 simulation specialists, 2 researchers, and 21 SPs participated in a workshop leading to a final global assessment question and responses. The Cronbach α's were >0.8 overall and in each cohort year. The final stepwise logistic model for all cohorts combined was statistically significant (P<.001), explained 9.2% (R2) of the variance in acceptance status, and correctly classified 65.5% (637/972) of cases. The final model consisted of 3 variables: empathy, rank of readiness, and opening the encounter. CONCLUSIONS: The collaborative nature of this project between stakeholders, including nonacademics and researchers, was vital for the success of this project. The SP-created question had a significant impact on the final model predicting acceptance to medical school. This finding indicates that SPs bring a critical perspective that can improve the process of evaluating medical school applicants.

z+: Neutron cross section separation from wide-angle uniaxial polarization analysis.

We introduce a simple method to extract the nuclear coherent and isotope incoherent, spin incoherent, and magnetic neutron scattering cross section components from powder scattering data measured using a single neutron beam polarization direction and a position-sensitive detector with large out-of-plane coverage. The method draws inspiration from polarized small-angle neutron scattering and contrasts with conventional so-called "xyz" polarization analysis on wide-angle instruments, which requires measurements with three orthogonal polarization directions. The viability of the method is demonstrated on both simulated and experimental data for the classical "spin ice" system Ho2Ti2O7, the latter from the LET direct geometry spectrometer at the ISIS facility. The cross section components can be reproduced with good fidelity by either fitting the out-of-plane angle dependence around a Debye-Scherrer cone or grouping the data by angle and performing a matrix inversion. The limitations of the method and its practical uses are discussed.

Patient-reported outcomes predict survival and adverse events following anticancer treatment initiation in advanced HER2-positive breast cancer.

BACKGROUND: The prognostic value of patient-reported outcomes (PROs) has been minimally explored in advanced breast cancer (BC), and their comparative prognostic performance against Eastern Cooperative Oncology Group performance status (ECOG PS) is largely unknown. PATIENTS AND METHODS: This study pooled individual participant data from clinical trials CLEOPATRA, EMILIA, and MARIANNE. Pre-treatment PRO associations with overall survival (OS), progression-free survival (PFS), and grade ≥3 adverse events were evaluated via Cox proportional hazards regression. Prognostic performance was assessed with the C-statistic (c). PRO values were collected via the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. All analyses were stratified by study and treatment arms. Analyses adjusted for known prognostic variables were conducted. Exploratory analysis of the prognostic performance of PROs compared to ECOG PS was undertaken. RESULTS: The study included data from 2894 patients initiated on contemporary therapies including pertuzumab (n = 765), trastuzumab (n = 1173), trastuzumab emtansine (n = 1225), taxanes (n = 1173), lapatinib (n = 496), and capecitabine (n = 496). On univariable and adjusted analysis, patient-reported physical well-being, functional well-being, and BC subscale were all identified to be associated with OS, PFS, and grade ≥3 adverse events (P < 0.05). Patient-reported physical well-being was the most prognostic PRO for all assessed outcomes. The OS prognostic performance of physical well-being (c = 0.58) was superior to ECOG PS (c = 0.56) (P < 0.05), with multivariable analysis indicating that both provide independent information (P < 0.0001). CONCLUSIONS: PROs were identified as independent prognostic factors for OS, PFS, and grade ≥3 adverse events in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced BC initiating contemporary treatment options. Further, patient-reported physical well-being was more prognostic of OS than ECOG PS and contained independent information. PROs have value as prognostic and stratification factors for clinical use and research trials of anticancer treatment in HER2-positive ABC.