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As the advantages of course-based undergraduate research experiences (CUREs) become widely accepted as a mainstream high-impact practice for undergraduate STEM education, it is paramount for instructors to be trained in effective practices for CURE development and implementation. The Mentoring the Integration of Research Into the Classroom (MIRIC) Network is a community of practice dedicated to providing current and future instructors with long-term support in implementing CUREs tailored to specific academic environments. Through the use of virtual synchronous all-network discussions as well as participant-selected affinity groups, MIRIC provides instructors with a dynamic and diverse community of educators in which to engage in long-term conversation in best practices in CURE development and implementation. Survey data on MIRIC participants reveals both success in providing instructors with the tools they need to succeed in CURE development and inspiration for evolving network focus and direction in the future.

Elementary teachers (N = 160) from two districts responded to survey questions about inservice professional development and administrator feedback and support for implementing research-based, effective classroom and behavior management (C/BM) strategies. Results indicated slightly more than half (55%) of teachers reported their participation in formal, inservice professional development activities improved their ability to implement research-based C/BM strategies. A higher percentage (77%) of teachers reported they receive adequate feedback from their current school supervisor (e.g., principal, curriculum/instructional coach) on their use of C/BM. Teachers' reported specific ways for school and district administrators to better prepare and support them for challenges related to C/BM. Implications are provided for improving inservice professional development and administrator feedback to promote teachers' use of effective classroom and behavior management practices.

Purpose In this first-in-human dose escalation study, the safety and efficacy of IO-108, a fully human monoclonal antibody targeting leukocyte immunoglobulin-like receptor B2 (LILRB2), was investigated in patients with advanced solid tumors as monotherapy and in combination with pembrolizumab, an anti-programmed cell death protein 1 (PD-1) antibody.Methods The study included patients with histologically or cytologically confirmed advanced and relapsed solid tumors, with measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1. Patients were treated with escalating doses of IO-108 every 3 weeks (Q3W) as monotherapy and in combination with pembrolizumab. Safety and tolerability were the primary objectives. Secondary and exploratory objectives included: pharmacokinetics, clinical efficacy, immunogenicity and biomarkers.Results Of 25 patients enrolled, 12 were treated with IO-108 monotherapy and 13 received combination therapy. IO-108 was well-tolerated up to the maximally administered dose of 1,800 mg every 3 weeks (Q3W) as monotherapy and in combination with pembrolizumab. No dose-limiting toxicity was observed, and a maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 6 (50.0%) patients treated with IO-108 monotherapy and 6 (46.2%) patients treated with IO-108+pembrolizumab. All TRAEs were mild or moderate (Grade 1 or 2), and no TRAEs led to treatment discontinuation or death. IO-108 exhibited a dose-proportional increase in exposure. Full receptor occupancy (RO) in peripheral blood was achieved at doses ≥600 mg. The overall response rate was 9% (1/11) in the monotherapy and 23% (3/13) in the combination therapy. A patient with treatment-refractory Merkel cell carcinoma treated with IO-108 monotherapy achieved a durable complete response (CR) for more than 2 years. Pharmacodynamic gene expression changes reflecting increased tumor infiltration of T cells were associated with clinical benefits in both monotherapy and combination therapy. Additionally, baseline tumor inflammation gene signature (TIS) scores correlated with clinical benefit.Conclusion IO-108 is well tolerated and has led to objective response as monotherapy and in combination with pembrolizumab. The complete response and the pharmacodynamic changes in the monotherapy cohort demonstrate single agent activity of IO-108 and provide proof of concept that targeting myeloid-suppressive pathways through LILRB2 inhibition may potentiate the clinical efficacy of anti-PD-1 immune checkpoint inhibitors.Trial registration number NCT05054348.

Abstract In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels. On-treatment peripheral biomarker changes showed that BEMPEG + NIVO increased all immune cell subset counts interrogated, including regulatory T cells. This was followed by attenuation of the increase in CD8 + T cells, conventional CD4 + T cells, and systemic interferon gamma levels at later treatment cycles in the combination arm. Changes in tumor biomarkers were comparable between arms. These biomarker results help provide a better understanding of the mechanism of action of BEMPEG + NIVO and may help contextualize the clinical observations from PIVOT IO 001.

Abstract Population-representative estimates of SARS-CoV-2 infection prevalence and antibody levels in specific geographic areas at different time points are needed to optimise policy responses. However, even population-wide surveys are potentially impacted by biases arising from differences in participation rates across key groups. Here, we used spatio-temporal regression and post-stratification models to UK’s national COVID-19 Infection Survey (CIS) to obtain representative estimates of PCR positivity (6,496,052 tests) and antibody prevalence (1,941,333 tests) for different regions, ages and ethnicities (7-December-2020 to 4-May-2022). Not accounting for vaccination status through post-stratification led to small underestimation of PCR positivity, but more substantial overestimations of antibody levels in the population (up to 21 percentage points), particularly in groups with low vaccine uptake in the general population. There was marked variation in the relative contribution of different areas and age-groups to each wave. Future analyses of infectious disease surveys should take into account major drivers of outcomes of interest that may also influence participation, with vaccination being an important factor to consider.

Abstract Background Angiolipomas have been well described in patients with HIV exposed to protease inhibitors with possible resolution after switching to non-nucleoside reverse transcriptase inhibitor-based regimens. Resolution of symptoms have occurred with switches to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens; however, little is known regarding the development of angiolipomas when switching from NNRTI- to modern, integrase strand transfer inhibitor-based regimens. We describe a patient who underwent switch therapy from tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/FTC/EFV) to tenofovir alafenamide/FTC/bictegravir (TAF/FTC/BIC) who later developed angiolipomas. Case Presentation A 55-year-old male had been on TDF/FTC/EFV for 8 years before switching to TAF/FTC/BIC. Nineteen months after antiretroviral switch, the patient presented with multiple lesions in the upper extremities and abdomen. Diagnostic biopsies revealed non-encapsulated angiolipomas and HHV-8 and non-alcoholic fatty liver disease was ruled out. New lesions continued to appear 29 months after ART switch, after which now lesions appeared and prior lesions remained stable with no increase in size noted. No surgical intervention or change in antiretroviral therapy was needed. Conclusions Angiogenesis may have been suppressed with TDF/FTC/EFV treatment, however when switched to TAF/FTC/BIC, promoted the growth of angiolipomas. Clinicians should be aware of the impact of switching to modern ART therapies resulting in possible adipogenesis.

Abstract The Gulf of Carpentaria and Torres Strait in north‐eastern Australia support globally significant seagrass ecosystems that underpin fishing and cultural heritage of the region. Reliable data on seagrass distribution are critical to understanding how these ecosystems are changing, while managing for resilience. Spatial data on seagrass have been collected since the early 1980s, but the early data were poorly curated. Some was not publicly available, and some already lost. We validated and synthesized historical seagrass spatial data to create a publicly available database. We include a site layer of 48,612 geolocated data points including information on seagrass presence/absence, sediment, collection date, and data custodian. We include a polygon layer with 641 individual seagrass meadows. Thirteen seagrass species are identified in depths ranging from intertidal to 38 m below mean sea level. Our synthesis includes scientific survey data from 1983 to 2022 and provides an important evidence base for marine resource management.

The concepts of resilience and resistance (R&R) have been used to improve wildland fuel treatment outcomes by identifying parts of the landscape that are more likely to respond well to treatment. This study examined how the economic benefits and costs of fuel treatments in sagebrush (Artemisia spp.) ecosystems varied with the resilience and resistance properties of the treatment site. Generalized ecological models were developed for the economic analysis of fuel treatments that integrated ecological succession, annual grass invasion, pinyon–juniper expansion, and wildfire to simulate ecosystem dynamics over time. The models incorporated resilience and resistance by varying model parameters related to each plant community’s ability to resist annual grass invasion and recover post-disturbance. Simulations produced estimates of the expected (ex ante) benefit–cost ratio for each treatment. The approach also considered the benefits associated with the system remaining in an ecologically favorable condition, allowing us to report a more holistic measure of the net economic benefits of fuel treatments. The results from the simulations indicated fuel treatment was economically efficient in late-successional sagebrush and early-successional juniper in mountain big sagebrush associations. For sagebrush associations where treatment was economically efficient, higher R&R status sites had higher benefit–cost ratios. The results suggested that treatment costs were more determinative of economic efficiency than treatment benefits.

Surgical management of feline extra-hepatic biliary obstruction (EHBO) has poor survival rates with few prognostic factors reported in the literature. The etiology and clinical findings of feline EHBO and their influence on short-(2 weeks–6 months) and long-term (>6 months) survival and prognosis were examined in an observational clinical retrospective study of 26 client-owned cats undergoing surgery for biliary obstruction at one institution between 2012 and 2020. The etiology of EHBO was determined in 21/26 cats, which included inflammatory causes (14/21), neoplastic causes (6/21), and a duodenal foreign body (1/21). Pre-operative hyperbilirubinemia and post-extubation hypotension (mean arterial pressure < 60 mmHg) were statistically associated with reduced short- and long-term survival. Short-term survival was documented in 17/26 cats, and long-term survival in 13/26 cats. Median survival time (MST) was 86 days (range, 0–1497). An MST of 17 days (range, 2–520) in cats with malignancies was found compared to an MST of 1165 days (range, 61–2268) in EHBO resulting from inflammatory complexes. Pre-operative hyperbilirubinemia and immediate post-operative hypotension may represent prognostic factors for cats undergoing surgery for EHBO. Cats with inflammatory causes of EHBO carry a more favorable prognosis than neoplastic causes. Further studies are required to evaluate the validity of the observed associations.

Abstract Climate change‐induced shifts in snow storage and snowmelt patterns pose risks for adverse impacts to people, the environment, and irrigated agriculture. Existing research primarily focuses on evaluating these risks to irrigated agriculture at large scales, overlooking the role of local context in shaping risk dynamics. Consequently, many “at‐risk” areas lack insight into how adaptation strategies for managing risk through water supply augmentation or water conservation vary across contexts and over time. To address this gap, we develop a comprehensive index for evaluating irrigated agriculture's risk and adaptation potential to changes in snow at local scales and apply it throughout the western US. Results confirm trends toward escalating risk for changes in snow storage and snowmelt patterns over the century. However, substantial heterogeneity in the extent and drivers of risk exists due to variability in localized interactions between declines in water supply (approximately −9% ± 13% by 2100) and increased agricultural demand (approximately 7% ± 5% by 2100). Despite an existing focus on supply augmentation as a critical adaptation strategy to reduce risk, we show its effectiveness diminishes for many areas over time, declining to an average of −54% of historical augmentation potential by 2100. Conserving water through historical changes in crop acreage and type emerges as a more stable adaptation measure, reducing demand by 7%–8% regardless of time. While particularly relevant for higher elevation, less intensive agricultural settings in snowmelt‐dependent regions, findings underscore the need for strategies that support local‐scale, context‐appropriate adaptation to effectively manage escalating risk as snow changes.

Carbon fibre reinforced polymers (CFRPs) are an attractive and versatile material, owing to their low weight and high mechanical stability, among other characteristics. This has led to a rapid increase in their use across many industries, particularly the aviation and automotive sectors. However, large quantities of waste are being generated when CFRPs reach their end-of-life (EoL) due to limited recycling and reuse pathways. To create a circular economy for CFRPs, alternative, high-value EoL pathways for recycled carbon fibres (rCFs) are needed. At present, very few studies investigate the activation of rCFs, particularly for applications as adsorbents. Developing on from the authors’ previous study, where rCFs were shown to be a promising precursor for the development of carbonaceous adsorbents, for applications in aqueous-phase, this work has focused on optimising the chemical activation procedure via a Box Behnken design-response surface methodology (BBD-RSM) approach, with an aim to maximise product yield and methylene blue adsorption capacity, using virgin carbon fibres (vCFs) as proof of concept. The optimum activated rCFs achieved an adsorption capacity of 454.55 mg/L; a significant increase of 715 % when compared to the previous study. While the optimum activated vCF counterpart achieved a maximum adsorption capacity 344.83 mg/L.

Objective: Social adjustment, including alcohol use, directly affects the success of college students. Due to an increased reliance on computer-delivered alcohol interventions (CDIs) a need has emerged to further investigate alcohol use and web-based interventions. Methods: In-depth focus group interviews were conducted with 51 undergraduate students to elicit information from students on the shared experience of participating in a CDI. Results: Participants identified the influence of gender, culture, parents, and family on alcohol use behavior. A difference in personal factors, previous exposure, and experiences can affect the attitudes, behaviors, and outcomes of a CDI. Conclusion: Multiple approaches geared towards a wide variety of students from different backgrounds and environments are needed to be truly successful in preventing alcohol misuse.

Abstract Background Post-smoking-cessation weight gain can be a major barrier to quitting smoking; however, adding behavior change interventions for physical activity (PA) and diet may adversely affect smoking cessation outcomes. The “Picking up the PACE (Promoting and Accelerating Change through Empowerment)” study assessed change in PA, fruit/vegetable consumption, and smoking cessation by providing a clinical decision support system for healthcare providers to utilize at the intake appointment, and found no significant change in PA, fruits/vegetable consumption, or smoking cessation. The objective of this qualitative study was to explore the factors affecting the implementation of the intervention and contextualize the quantitative results. Methods Twenty-five semi-structured interviews were conducted with healthcare providers, using questions based on the National Implementation Research Network’s Hexagon Tool. The data were analyzed using the framework’s standard analysis approach. Results Most healthcare providers reported a need to address PA and fruit/vegetable consumption in patients trying to quit smoking, and several acknowledged that the intervention was a good fit since exercise and diet could improve smoking cessation outcomes. However, many healthcare providers mentioned the need to explain the fit to the patients. Social determinants of health (e.g., low income, food insecurity) were brought up as barriers to the implementation of the intervention by a majority of healthcare providers. Most healthcare providers recognized training as a facilitator to the implementation, but time was mentioned as a barrier by many of healthcare providers. Majority of healthcare providers mentioned allied health professionals (e.g., dieticians, physiotherapists) supported the implementation of the PACE intervention. However, most healthcare providers reported a need for individualized approach and adaptation of the intervention based on the patients’ needs when implementing the intervention. The COVID-19 pandemic was found to impact the implementation of the PACE intervention based on the Hexagon Tool indicators. Conclusion There appears to be a need to utilize a flexible approach when addressing PA and fruit/vegetable consumption within a smoking cessation program, based on the context of clinic, the patients’ it is serving, and their life circumstances. Healthcare providers need support and external resources to implement this particular intervention. Name of the registry Clinicaltrials.gov. Trial registration number NCT04223336. Date of registration 7 January 2020 Retrospectively registered. URL of trial registry record https://classic.clinicaltrials.gov/ct2/show/NCT04223336 .

Abstract Background A substantial proportion of people with bipolar disorder (BD) experience persistent cognitive difficulties associated with impairments in psychosocial functioning and a poorer disorder course. Emerging evidence suggests that cognitive remediation (CR), a psychological intervention with established efficacy in people with schizophrenia, can also benefit people with BD. Following a proof-of-concept trial showing that CR is feasible and potentially beneficial for people with BD, we are conducting an adequately powered trial in euthymic people with BD to 1) determine whether an individual, therapist-supported, computerised CR can reduce cognitive difficulties and improve functional outcomes; and 2) explore how CR exerts its effects. Methods CRiB2 is a two-arm, assessor-blind, multi-site, randomised controlled trial (RCT) comparing CR to treatment-as-usual (TAU). Participants are people with a diagnosis of BD, aged between 18 and 65, with no neurological or current substance use disorder, and currently euthymic. 250 participants will be recruited through primary, secondary, tertiary care, and the community. Participants will be block-randomised (1:1 ratio, stratified by site) to continue with their usual care (TAU) or receive a 12-week course of therapy and usual care (CR + TAU). The intervention comprises one-on-one CR sessions with a therapist supplemented with independent cognitive training for 30–40 h in total. Outcomes will be assessed at 13- and 25-weeks post-randomisation. Efficacy will be examined by intention-to-treat analyses estimating between-group differences in primary (i.e., psychosocial functioning at week 25 measured with the Functional Assessment Short Test) and secondary outcomes (i.e., measures of cognition, mood, patient-defined goals, and quality of life). Global cognition, metacognitive skills, affect fluctuation, and salivary cortisol levels will be evaluated as putative mechanisms of CR through mediation models. Discussion This study will provide a robust evaluation of efficacy of CR in people with BD and examine the putative mechanisms by which this therapy works. The findings will contribute to determining the clinical utility of CR and potential mechanisms of action. Trial registration Cognitive Remediation in Bipolar 2 (CRiB2): ISRCTN registry: https://www.isrctn.com/ISRCTN10362331 . Registered 04 May 2022. Overall trial status: Ongoing; Recruitment status: Recruiting.

Abstract Monitoring sleep and activity through wearable devices such as wrist-worn actigraphs has the potential for long-term measurement in the individual’s own environment. Long periods of data collection require a complex approach, including standardized pre-processing and data trimming, and robust algorithms to address non-wear and missing data. In this study, we used a data-driven approach to quality control, pre-processing and analysis of longitudinal actigraphy data collected over the course of 1 year in a sample of 95 participants. We implemented a data processing pipeline using open-source packages for longitudinal data thereby providing a framework for treating missing data patterns, non-wear scoring, sleep/wake scoring, and conducted a sensitivity analysis to demonstrate the impact of non-wear and missing data on the relationship between sleep variables and depressive symptoms. Compliance with actigraph wear decreased over time, with missing data proportion increasing from a mean of 4.8% in the first week to 23.6% at the end of the 12 months of data collection. Sensitivity analyses demonstrated the importance of defining a pre-processing threshold, as it substantially impacts the predictive value of variables on sleep-related outcomes. We developed a novel non-wear algorithm which outperformed several other algorithms and a capacitive wear sensor in quality control. These findings provide essential insight informing study design in digital health research.

Abstract Magnetic resonance imaging (MRI) demonstrates clear advantages over other imaging modalities in neurosurgery with its ability to delineate critical neurovascular structures and cancerous tissue in high‐resolution 3D anatomical roadmaps. However, its application has been limited to interventions performed based on static pre/post‐operative imaging, where errors accrue from stereotactic frame setup, image registration, and brain shift. To leverage the powerful intra‐operative functions of MRI, e.g., instrument tracking, monitoring of physiological changes and tissue temperature in MRI‐guided bilateral stereotactic neurosurgery, a multi‐stage robotic positioner is proposed. The system positions cannula/needle instruments using a lightweight (203 g) and compact (Ø97 × 81 mm) skull‐mounted structure that fits within most standard imaging head coils. With optimized design in soft robotics, the system operates in two stages: i) manual coarse adjustment performed interactively by the surgeon (workspace of ±30°), ii) automatic fine adjustment with precise (

Background Pancreatic cancer is one of the deadliest cancer types and represents a major unmet medical need. CheckMate 032 investigated safety and efficacy of nivolumab monotherapy and nivolumab plus ipilimumab with/without cobimetinib in advanced/metastatic solid tumors, including pancreatic cancer.Methods In the original pancreatic cancer cohort, previously treated patients (≥1 prior regimen) with advanced/metastatic pancreatic adenocarcinoma were assigned to nivolumab 3 mg/kg every 2 weeks (monotherapy arm) or nivolumab 1 mg/kg and ipilimumab 1 mg/kg or 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks (combination arm). A subsequent modified pancreatic cohort (one or two prior regimens) received nivolumab 3 mg/kg every 2 weeks, ipilimumab 1 mg/kg every 6 weeks, and cobimetinib 60 mg orally once daily for 21 days on and 7 days off (triplet arm). The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints were investigator-assessed progression-free survival (PFS), PFS rate, overall survival (OS), OS rate, safety, and tolerability. Additionally, ORR, PFS, and duration of response were assessed by blinded independent central review (BICR) in the triplet arm.Results 18 patients received nivolumab monotherapy, 21 received nivolumab plus ipilimumab, and 30 received nivolumab plus ipilimumab plus cobimetinib. In the triplet arm, partial responses were observed in two patients per investigator (ORR 6.7% (95% CI 0.8% to 22.1%)) and in three patients per BICR (ORR 10% (95% CI 2.1% to 26.5%)); no responses were observed in the other arms. Median (95% CI) PFS per investigator was 1.4 (1.3 to 2.0), 1.4 (1.2 to 2.7), and 3.0 (1.5 to 4.1) months for the monotherapy, nivolumab plus ipilimumab, and triplet arms, respectively. Median (95% CI) OS was 5.1 (2.0 to 9.0) months, 4.0 (1.9 to 5.6) months, and 6.2 (3.9 to 11.4) months, respectively. Most treatment-related adverse events were grade 2 or less.Conclusions Nivolumab with or without ipilimumab did not elicit objective responses in previously treated patients with advanced pancreatic adenocarcinoma, although three confirmed partial responses and manageable safety were observed with cobimetinib-containing triplet therapy. The small sample size and differences in baseline disease-specific characteristics between arms limit interpretation of these results.

Background Lenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma in Study 111/KEYNOTE-146 (NCT02501096). In these exploratory analyses from this study, we evaluated the associations between clinical outcomes and gene expression signature scores and descriptively summarized response in biomarker subpopulations defined by tumor mutational burden (TMB) and DNA variants for individual genes of interest.Methods Patients with histologically confirmed metastatic endometrial carcinoma received oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles. Archived formalin-fixed paraffin-embedded tissue was obtained from all patients. T-cell–inflamed gene expression profile (TcellinfGEP) and 11 other gene signatures were evaluated by RNA sequencing. TMB, hotspot mutations in PIK3CA (oncogene), and deleterious mutations in PTEN and TP53 (tumor suppressor genes) were evaluated by whole-exome sequencing (WES).Results 93 and 79 patients were included in the RNA-sequencing-evaluable and WES-evaluable populations, respectively. No statistically significant associations were observed between any of the RNA-sequencing signature scores and objective response rate or progression-free survival. Area under the receiver operating characteristic curve values for response ranged from 0.39 to 0.54; all 95% CIs included 0.50. Responses were seen regardless of TMB (≥175 or