A Phase II, Open-Label, Randomized Trial of Durvalumab With Olaparib or Cediranib in Patients With Mismatch Repair-Proficient Colorectal or Pancreatic Cancer.

BACKGROUND: The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib). METHODS: PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing. RESULTS: A total of 31 metastatic pMMR-CRC patients were randomized to arm A (n = 16) or B (n = 15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab + olaparib and 1 patient treated with durvalumab + cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n = 19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab + cediranib, 1 patient had SD with durvalumab + olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes. CONCLUSIONS: In patients with pMMR-CRC or PDAC, durvalumab + olaparib and durvalumab + cediranib showed limited antitumor activity. Different immune components of the TME were associated with treatment outcomes.

Evaluation of Aav Capsids and Delivery Approaches for Hereditary Hemorrhagic Telangiectasia Gene Therapy.

Nosebleeds and intracranial hemorrhage from brain arteriovenous malformations (bAVMs) are among the most devastating symptoms of patients with hereditary hemorrhagic telangiectasis (HHT). All available managements have limitations. We showed that intravenous delivery of soluble FMS-related tyrosine kinase 1 using an adeno-associated viral vector (AAV9-sFLT1) reduced bAVM severity of endoglin deficient mice. However, minor liver inflammation and growth arrest in young mice were observed. To identify AAV variants and delivery methods that can best transduce brain and nasal tissue with an optimal transduction profile, we compared 3 engineered AAV capsids (AAV.cc47, AAV.cc84 and AAV1RX) with AAV9. A single-stranded CBA promoter driven tdTomato transgene was packaged in these capsids and delivered intravenously (i.v.) or intranasally (i.n.) to wild-type mice. A CMV promoter driven Alk1 transgene was packaged into AAV.cc84 and delivered to PdgfbiCre; Alk1 f/f mice through i.v. injection followed by brain AVM induction. Transduced cells in different organs, vessel density and abnormal vessels in the bAVMs, and liver inflammation were analyzed histologically. Liver and kidney function were measured enzymatically. Compared to other viral vectors, AAV.cc84, after i.v. delivery, transduced a high percentage of brain ECs and few hepatocytes; whereas after i.n. delivery, AAV.cc84 transduced ECs and perivascular cells in the brain, and ECs, epithelial cells, and skeletal muscles in the nose with minimum hepatocyte transduction. No changes to liver or kidney function were detected. Delivery of AAV.cc84-Alk1 through i.v. to PdgfbiCre; Alk1 f/f mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.

Acute psychological symptom profiles in high school athletes following sport-related concussion.

OBJECTIVE: Psychological symptoms following a sport-related concussion may affect recovery in adolescent athletes. Therefore, the aims of this study were to 1) describe the proportion of athletes with acute psychological symptoms, 2) identify potential predictors of higher initial psychological symptoms, and 3) determine whether psychological symptoms affect recovery in a cohort of concussed high school athletes. METHODS: A retrospective cohort study of high school athletes (14-18 years of age) who sustained a sport-related concussion from November 2017 to April 2022 and presented to a multidisciplinary concussion center was performed. The main independent variable was psychological symptom cluster score, calculated by summing the four affective symptoms on the initial Post-Concussion Symptom Scale (PCSS) (i.e., irritability, sadness, nervousness, feeling more emotional). The psychological symptom ratio was defined as the ratio of the psychological symptom cluster score divided by the total initial PCSS score. The outcomes included time to return to learn (RTL), symptom resolution, and time to return to play (RTP). Univariable and multivariable regressions were performed to adjust for demographic factors and health history. RESULTS: A total of 431 athletes (58.0% female, mean age 16.2 ± 1.3 years) were included. Nearly half of the sample (45%) reported at least one psychological symptom, with a mean psychological symptom cluster score of 4.2 ± 5.2 and psychological symptom cluster ratio of 0.10 ± 0.11. Irritability was the most commonly endorsed psychological symptom (38.1%), followed by feeling more emotional (30.2%), nervousness (25.3%), and sadness (22.0%). Multivariable regression showed that female sex (B = 2.15, 95% CI 0.91-3.39; p < 0.001), loss of consciousness (B = 1.91, 95% CI 0.11-3.72; p = 0.037), retrograde/anterograde amnesia (B = 1.66, 95% CI 0.20-3.11; p = 0.026), and psychological history (B = 2.96, 95% CI 1.25-4.70; p < 0.001) predicted an increased psychological symptom cluster score. Female sex (B = 0.03, 95% CI 0.00-0.06; p = 0.031) and psychological history (B = 0.06, 95% CI 0.02-0.10; p = 0.002) predicted an increased psychological symptom ratio. Multivariable linear regression showed that both higher psychological symptom cluster score and ratio were associated with longer times to RTL, symptom resolution, and RTP. CONCLUSIONS: In a cohort of high school athletes, 45% reported at least one psychological symptom, with irritability being most common. Female sex, loss of consciousness, amnesia, and a psychological history were significantly associated with an increased psychological symptom cluster score. Higher psychological symptom cluster score and psychological symptom ratio independently predicted longer recovery. These results reinforce the notion that psychological symptoms after concussion are common and may negatively impact recovery.

High-Density Lipoprotein Particle Concentration and Size Predict Incident Coronary Artery Disease Events in a Cohort With Type 1 Diabetes.

BACKGROUND: The cholesterol efflux capacity of high density lipoprotein (HDL) is negatively associated with cardiovascular risk. Small HDL particles account almost quantitatively for cholesterol efflux capacity, perhaps mediated through efflux of cholesterol and outer leaflet plasma membrane phospholipids by ABCA1 (ATP binding cassette subfamily A member 1). People with type 1 diabetes are at increased coronary artery disease (CAD) risk despite normal HDL-cholesterol concentrations. We therefore tested the hypothesis that small HDL particles (HDL-P)-rather than HDL-cholesterol-predict incident CAD in type 1 diabetes. METHODS AND RESULTS: Incident CAD (CAD death, myocardial infarction, or coronary revascularization) was determined in 550 individuals with childhood-onset type 1 diabetes. HDL-P was quantified by calibrated ion mobility analysis and cholesterol efflux capacity was quantified with validated assays. During a median follow-up of 26 years, 36.5% of the participants developed incident CAD, for an incidence density of 181.3 per 10 000 person-years. In multivariable Cox models, neither HDL-cholesterol nor apolipoprotein A1 concentration was significantly associated with CAD risk. In contrast, higher extra-small HDL-P concentrations were significantly associated with decreased CAD risk (hazard ratio [HR], 0.26 [95% CI, 0.14-0.50]). Weaker associations were observed for total HDL-P (HR, 0.88 [95% CI, 0.83-0.93]), small HDL (HR, 0.83 [95% CI, 0.68-1.02]), medium HDL (HR, 0.79 [95% CI, 0.71-0.89]), and large HDL (HR, 0.72 [95% CI, 0.59-0.89]). Although cholesterol efflux capacity was negatively associated with incident CAD, this association was no longer significant after adjustment for total HDL-P. CONCLUSIONS: Lower concentrations of total HDL-P and HDL subpopulations were positively associated with incident CAD independently of HDL-cholesterol, apolipoprotein A1, and other common CVD risk factors. Extra-small HDL was a much stronger predictor of risk than the other HDLs. Our data are consistent with the proposal that extra-small HDL plays a critical role in cardioprotection in type 1 diabetes, mediated by macrophage cholesterol efflux by the ABCA1 pathway.

Postoperative Infection Following Hip Arthroscopy in Patients Receiving Preoperative Intra-articular Injections: A Systematic Review and Meta-Analysis.

Intra-articular injections prior to hip arthroscopy are often used to diagnose and conservatively manage hip pathologies, such as femoroacetabular impingement, labral tears, and chondral lesions. As a diagnostic tool, the relief of hip pain following an intra-articular injection helps pinpoint the primary source of pain and assists surgeons in recommending arthroscopic intervention for underlying intra-articular pathologies. However, when injections are not sufficiently spaced apart in time prior to hip arthroscopy, there is an elevated risk of postoperative infection. This systematic review aims to assess whether preoperative intra-articular injections prior to hip arthroscopy are associated with an increased risk of postoperative infection and to determine the safety timeframe for administering such injections prior to the procedure. A comprehensive search was conducted in the PubMed, Embase, and Cochrane Library databases to identify studies examining the relationship between preoperative intra-articular injections and postoperative infection following hip arthroscopy. A meta-analysis was conducted to compare the risk of infection between patients who received injections prior to hip arthroscopy at varying intervals and those who did not receive any preoperative injections. Five studies were included (four level III and one level IV), which consisted of 58,576 patients (58.4% female). Injections administered anytime prior to hip arthroscopy posed a significantly higher risk of infection compared to no history of prior injections (risk ratio: 1.45, 95% confidence interval: 1.14-1.85, P = 0.003). However, upon subanalysis, the risk of infection was significantly higher among patients who received injections within three months prior to hip arthroscopy compared to those who did not receive injections (risk ratio: 1.55, 95% confidence interval: 1.19-2.01, P = 0.001). Additionally, no significant difference in infection risk was observed when injections were administered more than three months before hip arthroscopy compared to no injections (risk ratio: 1.05, 95% confidence interval: 0.56-1.99, P = 0.87). The findings suggest that patients undergoing hip arthroscopy who have previously received intra-articular injections may face a statistically higher risk of postoperative infection, particularly when the injection is administered within three months prior to hip arthroscopy. Consequently, surgeons should exercise caution and avoid administering intra-articular injections to patients scheduled for hip arthroscopy within the subsequent three months to mitigate the increased risk of infection.

Cost Removed! Do Different Factors Influence Motivation for Vasectomy Reversal When Cost Is Not an Issue?

INTRODUCTION: Vasectomy is a relatively common procedure performed for the purposes of sterilization; however, up to 6% of men that undergo vasectomy wish for its reversal at some point. Few studies have examined the motivation behind vasectomy reversal (VR), especially within special populations, such as the U.S. Military. The aim of this study was to examine the motivations of U.S. Military service members (SMs) who opted for VR surgery, considering their unique access to free health care. MATERIALS AND METHODS: We conducted a retrospective record review of microsurgical VRs performed by a single surgeon (DJH) between January 2020 and May 2023. We evaluated patient's age at which vasectomy was performed, age at VR, reasons for seeking VR surgical care, number of children fathered before the vasectomy, and the age of the current partner. RESULTS: A total of 106 patients underwent VR during the study period, and 102 of them had their medical records available for review. The average age at the time of vasectomy was 31.3 years, while the average age at VR was 40.2 years. The average spousal age at the time of seeking VR was 34.8 years. Before undergoing vasectomy, the men had fathered an average of 2.7 children. Most men were enlisted members of the military (68) and of all service branches, Army represented the greatest number (50). The vast majority of men (76) cited having a new partner after divorce as the primary motivation for seeking VR. Within this group, 57 were remarried, 15 were in a new relationship, 3 were newly engaged, and 1 desired fertility for future relationships. Additionally, 21 sought VR to have more children with the same spouse. Among them, motivating factors included changes to financial status and improvement in partner's health condition. A minority of patients (2) desired VR due to post vasectomy pain syndrome or religious beliefs. CONCLUSIONS: Our study demonstrates that the primary driver for seeking VR surgical care among SMs was the desire for fertility with a new partner, which correlates with trends in the civilian sector. Approximately 20% of the men cited the wish to have more children with the same partner as their motivation. Non-fertility reasons, such as religious beliefs and post vasectomy pain syndrome, were also observed, albeit less frequently.

Active E. coli heteromeric acetyl-CoA carboxylase forms polymorphic helical tubular filaments.

The Escherichia coli heteromeric acetyl-CoA carboxylase (ACC) has four subunits assumed to form an elusive catalytic complex and are involved in allosteric and transcriptional regulation. The E. coli ACC represents almost all ACCs from pathogenic bacteria making it a key antibiotic development target to fight growing antibiotic resistance. Furthermore, it is a model for cyanobacterial and plant plastid ACCs as biofuel engineering targets. Here we report the catalytic E. coli ACC complex surprisingly forms tubes rather than dispersed particles. The cryo-EM structure reveals key protein-protein interactions underpinning efficient catalysis and how transcriptional regulatory roles are masked during catalysis. Discovering the protein-protein interaction interfaces that facilitate catalysis, allosteric and transcriptional regulation provides new routes to engineering catalytic activity and new targets for drug discovery.

Degradation of the mechanical properties of cortical bone due to long duration storage.

Understanding the behaviour and material properties of bone is critical in predicting the failure and fracture of bones in humans. To address this, mechanical tests have traditionally been conducted to characterize bone material and this has resulted in large body of literature. However, there appears to be a lack of complete information regarding the storage protocols used for bone specimens prior to conducting mechanical tests. For example, while storage methods are well described, parameters such as the time between donor death and bone retrieval, as well as time between specimen machining and testing, are seldom reported. As biological materials undergo degradation in storage after being removed from the donor, a clear understanding of this degradation behaviour would identify critical time frames in which previously stored cortical bone specimens should be tested such that they can still be considered representative of an in-vivo condition. In this paper, the results of an investigation to determine the effects of long duration storage on the measured mechanical properties of bovine cortical bone are reported. Three different storage protocols are compared; namely machined-refrigerated, machined-frozen and frozen-machined-frozen. Degradation effects are evident for both refrigerated and frozen specimens and the results demonstrate that testing bone specimens after more than one week in storage may not provide representative in-vivo properties. In addition, specimens exhibit severe degradation after six months in storage regardless of the storage protocol.

Community-Based Cluster-Randomized Trial to Reduce Opioid Overdose Deaths.

BACKGROUND: Evidence-based practices for reducing opioid-related overdose deaths include overdose education and naloxone distribution, the use of medications for the treatment of opioid use disorder, and prescription opioid safety. Data are needed on the effectiveness of a community-engaged intervention to reduce opioid-related overdose deaths through enhanced uptake of these practices. METHODS: In this community-level, cluster-randomized trial, we randomly assigned 67 communities in Kentucky, Massachusetts, New York, and Ohio to receive the intervention (34 communities) or a wait-list control (33 communities), stratified according to state. The trial was conducted within the context of both the coronavirus disease 2019 (Covid-19) pandemic and a national surge in the number of fentanyl-related overdose deaths. The trial groups were balanced within states according to urban or rural classification, previous overdose rate, and community population. The primary outcome was the number of opioid-related overdose deaths among community adults. RESULTS: During the comparison period from July 2021 through June 2022, the population-averaged rates of opioid-related overdose deaths were similar in the intervention group and the control group (47.2 deaths per 100,000 population vs. 51.7 per 100,000 population), for an adjusted rate ratio of 0.91 (95% confidence interval, 0.76 to 1.09; P = 0.30). The effect of the intervention on the rate of opioid-related overdose deaths did not differ appreciably according to state, urban or rural category, age, sex, or race or ethnic group. Intervention communities implemented 615 evidence-based practice strategies from the 806 strategies selected by communities (254 involving overdose education and naloxone distribution, 256 involving the use of medications for opioid use disorder, and 105 involving prescription opioid safety). Of these evidence-based practice strategies, only 235 (38%) had been initiated by the start of the comparison year. CONCLUSIONS: In this 12-month multimodal intervention trial involving community coalitions in the deployment of evidence-based practices to reduce opioid overdose deaths, death rates were similar in the intervention group and the control group in the context of the Covid-19 pandemic and the fentanyl-related overdose epidemic. (Funded by the National Institutes of Health; HCS ClinicalTrials.gov number, NCT04111939.).

A clathrin mediated endocytosis scaffolding protein, Intersectin 1, changes in an isoform, brain region, and sex specific manner in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by the accumulation of amyloid-beta (Aß) plaques and neurofibrillary Tau tangles in the brain. We previously identified a set of candidate AD microRNAs (miRNAs) in human cerebrospinal fluid (CSF) and used a target prediction pipeline to identify mRNAs and pathways that could potentially be regulated by the miRNAs. Of these pathways, clathrin mediated endocytosis (CME) was selected for further investigation. CME is altered in multiple brain cell types in AD and is implicated in early cellular phenotypes such as enlarged early endosomes and pathogenic processing of Aß. However, a comprehensive evaluation of major CME hub proteins in humans with AD across multiple brain regions is lacking. Thus, we used immunoblots to evaluate human post-mortem AD and control (CTL) frontal cortex (FC; AD n = 22, CTL n = 23) and hippocampus (HP; AD n = 34, CTL n = 22) for changes in Intersectin 1 (ITSN1), Phosphatidylinositol Binding Clathrin Assembly Protein gene (PICALM), Clathrin Light Chain (CLT), FCH and Mu Domain Containing Endocytic Adaptor 1 (FCHO1), Adaptor Related Protein Complex 2 (AP2) Subunit Alpha 1 (AP2A1), and Dynamin 2 (DNM2). Of these, we found that in AD, ITSN1-long (ITSN1-L) was decreased in the FC of males and HP of females, while ITSN1-short was increased in the HP of both males and females. We further evaluated ITSN1-L levels in cortex (CTX) and HP of the 5xFAD mouse model of Aß pathology at different timepoints during aging and disease progression by immunoblot (n = 5-8 per group). At 3 months, female 5xFAD exhibited an increase of ITSN1-L in CTX but a decrease at 6 and 9 months. Additionally, immunofluorescent staining of 5xFAD primary HP neurons showed an increase of ITSN1-L in matured 5xFAD neurons at 21 and 28 days in vitro. Together, our studies show that in AD, isoforms of ITSN1 change in a brain region-and sex-dependent manner. Further, changes in ITSN1-L are transient with levels increasing during early Aß accumulation and decreasing during later progression. These findings suggest that ITSN1 expression, and consequently CME activity, may change depending on the stage of disease progression.

Treed Gaussian processes for animal movement modeling.

Wildlife telemetry data may be used to answer a diverse range of questions relevant to wildlife ecology and management. One challenge to modeling telemetry data is that animal movement often varies greatly in pattern over time, and current continuous-time modeling approaches to handle such nonstationarity require bespoke and often complex models that may pose barriers to practitioner implementation. We demonstrate a novel application of treed Gaussian process (TGP) modeling, a Bayesian machine learning approach that automatically captures the nonstationarity and abrupt transitions present in animal movement. The machine learning formulation of TGPs enables modeling to be nearly automated, while their Bayesian formulation allows for the derivation of movement descriptors with associated uncertainty measures. We demonstrate the use of an existing R package to implement TGPs using the familiar Markov chain Monte Carlo algorithm. We then use estimated movement trajectories to derive movement descriptors that can be compared across individuals and populations. We applied the TGP model to a case study of lesser prairie-chickens (Tympanuchus pallidicinctus) to demonstrate the benefits of TGP modeling and compared distance traveled and residence times across lesser prairie-chicken individuals and populations. For broad usability, we outline all steps necessary for practitioners to specify relevant movement descriptors (e.g., turn angles, speed, contact points) and apply TGP modeling and trajectory comparison to their own telemetry datasets. Combining the predictive power of machine learning and the statistical inference of Bayesian methods to model movement trajectories allows for the estimation of statistically comparable movement descriptors from telemetry studies. Our use of an accessible R package allows practitioners to model trajectories and estimate movement descriptors, facilitating the use of telemetry data to answer applied management questions.

Tear Proteins Altered in Patients with Persistent Eye Pain after Refractive Surgery: Biomarker Candidate Discovery.

Some patients develop persistent eye pain after refractive surgery, but factors that cause or sustain pain are unknown. We tested whether tear proteins of patients with pain 3 months after surgery differ from those of patients without pain. Patients undergoing refractive surgery (laser in situ keratomileusis or photorefractive keratectomy ) were recruited from 2 clinics, and tears were collected 3 months after surgery. Participants rated their eye pain using a numerical rating scale (NRS, 0-10; no pain-worst pain) at baseline, 1 day, and 3 months after surgery. Using tandem mass tag proteomic analysis, we examined tears from patients with pain [NRS ≥ 3 at 3 months (n = 16)] and patients with no pain [NRS ≤ 1 at 3 months (n = 32)] after surgery. A subset of proteins (83 of 2748 detected, 3.0%) were associated with pain 3 months after surgery. High-dimensional statistical models showed that the magnitude of differential expression was not the only important factor in classifying tear samples from pain patients. Models utilizing 3 or 4 proteins had better classification performance than single proteins and represented differences in both directions (higher or lower in pain). Thus, patterns of protein differences may serve as biomarkers of postsurgical eye pain as well as potential therapeutic targets.

Phylogenomics and biogeography of the small carpenter bees (Apidae: Xylocopinae: Ceratina).

Small carpenter bees in the genus Ceratina are behaviourally diverse, species-rich, and cosmopolitan, with over 370 species and a range including all continents except Antarctica. Here, we present the first comprehensive phylogeny of the genus based on ultraconserved element (UCE) phylogenomic data, covering a total of 185 ingroup specimens representing 22 of the 25 current subgenera. Our results support most recognized subgenera as natural groups, but we also highlight several groups in need of taxonomic revision - particularly the nominate subgenus Ceratina sensu stricto - and several clades that likely need to be described as new subgenera. In addition to phylogeny, we explore the evolutionary history of Ceratina through divergence time estimation and biogeographic reconstruction. Our findings suggest that Ceratinini split from its sister tribe Allodapini about 72 million years ago. The common ancestor of Ceratina emerged in the Afrotropical realm approximately 42 million years ago, near the Middle Eocene Climatic Optimum. Multiple subsequent dispersal events led to the present cosmopolitan distribution of Ceratina, with the majority of transitions occurring between the Afrotropics, Indomalaya, and the Palearctic. Additional movements also led to the arrival of Ceratina in Madagascar, Australasia, and a single colonization of the Americas. Dispersal events were asymmetrical overall, with temperate regions primarily acting as destinations for migrations from tropical source regions.

The Utility of Heartrate and Heartrate Variability Biofeedback for the Improvement of Interoception across Behavioural, Physiological and Neural Outcome Measures: A Systematic Review.

Interoceptive dysfunctions are increasingly implicated in a number of physical and mental health conditions. Accordingly, there is a pertinent need for therapeutic interventions which target interoceptive deficits. Heartrate and heartrate variability biofeedback therapy (HR(V)-BF), interventions which train individuals to regulate their cardiovascular signals and constrain these within optimal parameters through breathing, could enhance the functioning of interoceptive pathways via stimulation of the vagus nerve. Consequently, this narrative systematic review sought to synthesise the current state of the literature with regard to the potential of HR(V)-BF as an interoceptive intervention across behavioural, physiological and neural outcome measures related to interoception. In total, 77 papers were included in this review, with the majority using physiological outcome measures. Overall, findings were mixed with respect to improvements in the outcome measures after HR(V)-BF. However, trends suggested that effects on measures related to interoception were stronger when resonance frequency breathing and an intense treatment protocol were employed. Based on these findings, we propose a three-stage model by which HR(V)-BF may improve interoception which draws upon principles of interoceptive inference and predictive coding. Furthermore, we provide specific directions for future research, which will serve to advance the current knowledge state.

The inhibitory effect of a recent distractor: singleton vs. multiple distractors.

In the complex interplay between sensory and cognitive processes, the brain must sift through a flood of sensory data to pinpoint relevant signals. This selective mechanism is crucial for the effective control of behaviour, by allowing organisms to focus on important tasks and blocking out distractions. The Inhibition of a Recent Distractor (IRD) Task examines this selection process by exploring how inhibiting distractors influences subsequent eye movements towards an object in the visual environment. In a series of experiments, research by Crawford et al. (2005a) demonstrated a delayed response to a target appearing at the location that was previously occupied by a distractor, demonstrating a legacy inhibition exerted by the distractor on the spatial location of the upcoming target. This study aimed to replicate this effect and to investigate any potential constraints when multiple distractors are presented. Exploring whether the effect is observed in more ecologically relevant scenarios with multiple distractors is crucial for assessing the extent to which it can be applied to a broader range of environments. Experiment 1 successfully replicated the effect, showing a significant IRD effect only with a single distractor. Experiments 2-5 explored a number of possible explanations for this phenomenon.

Nondestructive quantification of internal raster path for additively manufactured components via ultrasonic testing.

This work investigates the viability of discerning the raster pattern of additively manufactured components using high frequency ultrasonic nondestructive testing. Test coupons were fabricated from poly cyclohexylenedimethylene terephthalate glycol using the fused filament fabrication process, in which layers were deposited at various predetermined raster angles. Each printed part was scanned using spherically focused, high-resolution, ultrasonic transducers of various peak frequencies between 7.5 and 15 MHz. From the captured waveform data, images are extracted to observe the raster pattern in a layer-by-layer manner, with the results from the 10 MHz element yielding the best performance. An in-house MATLAB script was developed to analyze the transducer signal to investigate C-scan images at various depths throughout the component. From the resulting C-scan images, one can consistently identify the proper raster orientation within 2°-4° in each of the first 10 deposited layers, with the accuracy decreasing as a function of depth into the component. Due to signal attenuation, there is insufficient data at depths beyond the 11th and 12th layer, to properly analyze the present data sets accurately. Validation was performed using X-ray computed tomography scans to demonstrate the accuracy of the ultrasonic inspection method.

Poor Bone Mineral Density Is Associated With Increased Risk of Urological Bone Metastases.

OBJECTIVE: To investigate whether a diagnosis of precancer poor bone mineral density (PBMD) is associated with higher risk of urological cancer bone metastasis. METHODS: The PearlDiver Database was utilized to conduct a retrospective, propensity-matched cohort analysis of adult patients diagnosed with kidney, bladder, prostate, and testicular cancer with and without a prior diagnosis of PBMD, defined as osteopenia or osteoporosis. Unadjusted and adjusted odds ratios (OR) and 95% confidence intervals are used to compare the rate of newly diagnosed bone metastases between 6months and 3years of the initial cancer diagnosis between the experimental and control cohorts. RESULTS: Among 685,066 patients with urological cancers, precancer PBMD was associated with increased odds of bone metastasis at various time periods (1week, 6months, 1, 2, and 3years). The strongest association was appreciated within 1week of cancer diagnosis (kidney: adjusted odds ratio [aOR], 2.37, P <.001; bladder: [aOR], 2.37, P <.001; prostate: [aOR], 2.84, P <.001; testicular: [aOR], 4.45, P <.001). Bisphosphonates were associated with reduced risk of kidney ([aOR], 0.46, P <.001), bladder ([aOR], 0.61, P <.001), and prostate ([aOR], 0.66, P <.001) cancer bone metastasis. CONCLUSION: Our findings suggest urology patients with PBMD may be predisposed to forming bone metastases as well as presenting with metastatic disease at time of cancer diagnosis. As such, further studies are needed to elucidate whether PBMD plays a role in bone tropism and whether bone health pertains to prolonging bone-free metastasis.

Management of Anticoagulation and Antifibrinolytics in Catastrophic Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disorder that presents with hypercoagulability and results in a lab artifact of prolonged PTT. The most severe form is catastrophic antiphospholipid antibody syndrome (CAPS), which manifests as rapidly progressing thromboses in multiple organ systems leading to multi-organ ischemia. The mainstay management CAPS is anticoagulation and systemic corticosteroids. Antifibrinolytic agents have previously been thought to be relatively contraindicated in CAPS due to the pro-thrombotic nature of the disease; the complex coagulation profile of CAPS can make it difficult to assess the risks and benefits of antifibrinolytic therapy. Also, should a patient with CAPS require cardiopulmonary bypass (CPB) for surgery, it poses a unique challenge in providing appropriate anticoagulation in the setting of prolonged ACT. We present a case of a 32-year-old postpartum female with CAPS requiring heart transplant who safely received intraoperative antifibrinolytic therapy and was successfully anticoagulated during CPB after perioperative plasmapheresis.

Broadening Eligibility Criteria and Diversity among Patients for Cancer Clinical Trials.

BACKGROUND: Certain populations have been historically underrepresented in clinical trials. Broadening eligibility criteria is one approach to inclusive clinical research and achieving enrollment goals. How broadened trial eligibility criteria affect the diversity of eligible participants is unknown. METHODS: Using a nationwide electronic health record-derived deidentified database, we identified a retrospective cohort of patients diagnosed with 22 cancer types between April 1, 2013 and December 31, 2022 who received systemic therapy (N=235,234) for cancer. We evaluated strict versus broadened eligibility criteria using performance status and liver, kidney, and hematologic function around first line of therapy. We performed logistic regression to estimate odds ratios for exclusion by strict criteria and their association with measures of patient diversity, including sex, age, race or ethnicity, and area-level socioeconomic status (SES); estimated the impact of broadening criteria on the number and distribution of eligible patients; and performed Cox regression to estimate hazard ratios for real-world overall survival (rwOS) comparing patients meeting strict versus broadened criteria. RESULTS: When applying common strict cutoffs for eligibility criteria to patients with complete data and weighting each cancer type equally, 48% of patients were eligible for clinical trials. Female (odds ratio, 1.30; 95% confidence interval [CI], 1.25 to 1.35), older (age 75+ vs. 18 to 49 years old: odds ratio, 3.04; 95% CI, 2.85 to 3.24), Latinx (odds ratio, 1.46; 95% CI, 1.39 to 1.54), non-Latinx Black (odds ratio, 1.11; 95% CI, 1.06 to 1.16), and lower-SES patients were more likely to be excluded using strict eligibility criteria. Broadening criteria increased the number of eligible patients by 78%, with the strongest impact for older, female, non-Latinx Black, and lower-SES patients. Patients who met only broadened criteria had worse rwOS versus those with strict criteria (hazard ratio, 1.31; 95% CI, 1.27 to 1.34). CONCLUSIONS: Data-driven evaluation of clinical trial eligibility criteria may optimize the eligibility of certain historically underrepresented groups and promote access to more inclusive trials. (Sponsored by Flatiron Health.).