Design of High Affinity Binders to Convex Protein Target Sites.

While there has been progress in the de novo design of small globular miniproteins (50-65 residues) to bind to primarily concave regions of a target protein surface, computational design of minibinders to convex binding sites remains an outstanding challenge due to low level of overall shape complementarity. Here, we describe a general approach to generate computationally designed proteins which bind to convex target sites that employ geometrically matching concave scaffolds. We used this approach to design proteins binding to TGFßRII, CTLA-4 and PD-L1 which following experimental optimization have low nanomolar to picomolar affinities and potent biological activity. Co-crystal structures of the TGFßRII and CTLA-4 binders in complex with the receptors are in close agreement with the design models. Our approach provides a general route to generating very high affinity binders to convex protein target sites.

Chromatin context-dependent regulation and epigenetic manipulation of prime editing.

We set out to exhaustively characterize the impact of the cis-chromatin environment on prime editing, a precise genome engineering tool. Using a highly sensitive method for mapping the genomic locations of randomly integrated reporters, we discover massive position effects, exemplified by editing efficiencies ranging from ∼0% to 94% for an identical target site and edit. Position effects on prime editing efficiency are well predicted by chromatin marks, e.g., positively by H3K79me2 and negatively by H3K9me3. Next, we developed a multiplex perturbational framework to assess the interaction of trans-acting factors with the cis-chromatin environment on editing outcomes. Applying this framework to DNA repair factors, we identify HLTF as a context-dependent repressor of prime editing. Finally, several lines of evidence suggest that active transcriptional elongation enhances prime editing. Consistent with this, we show we can robustly decrease or increase the efficiency of prime editing by preceding it with CRISPR-mediated silencing or activation, respectively.

Trends in ototoxicity monitoring among cisplatin-treated patients with cancer.

PURPOSE: This study aims to characterize patterns in ototoxicity monitoring and identify potential barriers to audiologic follow-up. METHODS: We performed a single-institution retrospective cohort study on adult (≥ 18 years old) cancer patients treated with cisplatin from January 2014 to September 2021. Our primary outcomes were rates of baseline and post-treatment audiograms at the following time points: 3, 6, 12, and greater than 12 months. Time-to-event analyses were performed to describe additional insights to ototoxicity monitoring patterns. RESULTS: Nine hundred fifty-five patients with cancer were included for analysis. The most common primary cancer sites were head and neck (64%), followed by cervical (24%). Three hundred seventy-three patients (39%) underwent baseline audiometric assessment, 38 patients (4%) received audiologic evaluation during chemotherapy, and 346 patients (36%) obtained at least one post-treatment audiogram. Audiologic follow-up was greatest within 3 months of completing chemotherapy (26%), but this tapered dramatically to less than 10% at every other post-treatment time point. Patients with head and neck cancer achieved higher rates of audiologic follow-up at every time point than patients with non-head and neck cancer except for during treatment. CONCLUSIONS: Ototoxicity monitoring is an inconsistent practice, particularly during chemotherapy and for long-term surveillance of hearing loss. Patients with non-head and neck cancer may be at increased risk for loss of audiologic follow-up. IMPLICATIONS FOR CANCER SURVIVORS: Cisplatin ototoxicity is a common occurrence that can be effectively managed with auditory rehabilitation. Therefore, referrals to audiology and counseling on treatment-related ototoxicity are recommended throughout chemotherapy and cancer survivorship.

Multiplex generation and single cell analysis of structural variants in a mammalian genome.

The functional consequences of structural variants (SVs) in mammalian genomes are challenging to study. This is due to several factors, including: 1) their numerical paucity relative to other forms of standing genetic variation such as single nucleotide variants (SNVs) and short insertions or deletions (indels); 2) the fact that a single SV can involve and potentially impact the function of more than one gene and/or cis regulatory element; and 3) the relative immaturity of methods to generate and map SVs, either randomly or in targeted fashion, in in vitro or in vivo model systems. Towards addressing these challenges, we developed Genome-Shuffle-seq, a straightforward method that enables the multiplex generation and mapping of several major forms of SVs (deletions, inversions, translocations) throughout a mammalian genome. Genome-Shuffle-seq is based on the integration of "shuffle cassettes" to the genome, wherein each shuffle cassette contains components that facilitate its site-specific recombination (SSR) with other integrated shuffle cassettes (via Cre-loxP), its mapping to a specific genomic location (via T7-mediated in vitro transcription or IVT), and its identification in single-cell RNA-seq (scRNA-seq) data (via T7-mediated in situ transcription or IST). In this proof-of-concept, we apply Genome-Shuffle-seq to induce and map thousands of genomic SVs in mouse embryonic stem cells (mESCs) in a single experiment. Induced SVs are rapidly depleted from the cellular population over time, possibly due to Cre-mediated toxicity and/or negative selection on the rearrangements themselves. Leveraging T7 IST of barcodes whose positions are already mapped, we further demonstrate that we can efficiently genotype which SVs are present in association with each of many single cell transcriptomes in scRNA-seq data. Finally, preliminary evidence suggests our method may be a powerful means of generating extrachromosomal circular DNAs (ecDNAs). Looking forward, we anticipate that Genome-Shuffle-seq may be broadly useful for the systematic exploration of the functional consequences of SVs on gene expression, the chromatin landscape, and 3D nuclear architecture. We further anticipate potential uses for in vitro modeling of ecDNAs, as well as in paving the path to a minimal mammalian genome.

Cisplatin drives mitochondrial dysregulation in sensory hair cells.

Cisplatin is a commonly used chemotherapy that causes permanent hearing loss by injuring cochlear hair cells. The underlying mechanisms that drive hair cell loss remain unknown, but mitochondria have emerged as potential mediators of cisplatin ototoxicity. Direct observation of changes in hair cell mitochondrial function are challenging because the mammalian inner ear is optically inaccessible. Here, we perform live in vivo imaging of hair cells within the zebrafish lateral-line organ to evaluate the role of mitochondria in cisplatin ototoxicity. Using a genetically encoded biosensor that measures cumulative mitochondrial activity in hair cells, we demonstrate that greater redox history increases susceptibility to cisplatin. Next, we conduct time-lapse imaging of individual hair cells to understand dynamic changes in mitochondrial homeostasis. We observe spikes in mitochondrial calcium and cytosolic calcium immediately prior to hair cell death. Furthermore, we use a mitochondrially-localized probe that fluoresces in the presence of cisplatin to show that cisplatin accumulates in hair cell mitochondria. Lastly, we demonstrate that this accumulation occurs before mitochondrial dysregulation, Caspase-3 activation, and ultimately, hair cell death. Our findings provide additional evidence that suggest mitochondria are integral to cisplatin ototoxicity and cisplatin directly targets hair cell mitochondria.

When detecting a salient target makes search more effortful.

Prior research has demonstrated two distinct modes of searching a display: singleton detection mode and feature search mode. Due to the explicit template-based attentional control involved in feature search mode, singleton detection mode is often assumed to be less mentally effortful, which can potentially explain why people search using such an inefficient and distraction-prone strategy. However, this assumption remains largely untested. In the present study, we used a hand dynamometer to relate physical effort to perceived mental effort across different search conditions. Surprisingly, across three experiments, participants exerted more effort to avoid singleton detection trials compared to feature search trials, suggesting that they found singleton detection to be the more effortful mode of searching. In a fourth experiment, we removed the physical effort component and simply asked participants to self-report how effortful they perceived each search task to be. Participants robustly indicated that singleton detection trials were more effortful. Lastly, in a fifth experiment, we removed distractor-present trials. Again, participants exerted more effort to avoid singleton detection trials. In contrast to widely held assumptions, our findings suggest that searching for a salient singleton is in fact more mentally effortful than searching for a specific feature in a heterogeneous display, which has broad implications for theories of attentional control and the influence of mental effort on cognition. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling.

Altered myeloid inflammation and lymphopenia are hallmarks of severe infections. We identified the upregulated EN-RAGE gene program in airway and blood myeloid cells from patients with acute lung injury from SARS-CoV-2 or other causes across 7 cohorts. This program was associated with greater clinical severity and predicted future mechanical ventilation and death. EN-RAGEhi myeloid cells express features consistent with suppressor cell functionality, including low HLA-DR and high PD-L1. Sustained EN-RAGE program expression in airway and blood myeloid cells correlated with clinical severity and increasing expression of T cell dysfunction markers. IL-6 upregulated many EN-RAGE program genes in monocytes in vitro. IL-6 signaling blockade by tocilizumab in a placebo-controlled clinical trial led to rapid normalization of EN-RAGE and T cell gene expression. This identifies IL-6 as a key driver of myeloid dysregulation associated with worse clinical outcomes in COVID-19 patients and provides insights into shared pathophysiological mechanisms in non-COVID-19 ARDS.

Common- and rare-variant genetic architecture of heart failure across the allele frequency spectrum.

Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, that affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mendelian forms of disease, where rare genetic variants have been linked to familial cardiomyopathies. More recently, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with risk of HF. However, the relative importance of genetic variants across the allele-frequency spectrum remains incompletely characterized. Here, we report the results of common- and rare-variant association studies of all-cause heart failure, applying recently developed methods to quantify the heritability of HF attributable to different classes of genetic variation. We combine GWAS data across multiple populations including 207,346 individuals with HF and 2,151,210 without, identifying 176 risk loci at genome-wide significance (p < 5×10-8). Signals at newly identified common-variant loci include coding variants in Mendelian cardiomyopathy genes (MYBPC3, BAG3), as well as regulators of lipoprotein (LPL) and glucose metabolism (GIPR, GLP1R), and are enriched in cardiac, muscle, nerve, and vascular tissues, as well as myocyte and adipocyte cell types. Gene burden studies across three biobanks (PMBB, UKB, AOU) including 27,208 individuals with HF and 349,126 without uncover exome-wide significant (p < 3.15×10-6) associations for HF and rare predicted loss-of-function (pLoF) variants in TTN, MYBPC3, FLNC, and BAG3. Total burden heritability of rare coding variants (2.2%, 95% CI 0.99-3.5%) is highly concentrated in a small set of Mendelian cardiomyopathy genes, and is lower than heritability attributable to common variants (4.3%, 95% CI 3.9-4.7%) which is more diffusely spread throughout the genome. Finally, we demonstrate that common-variant background, in the form of a polygenic risk score (PRS), significantly modifies the risk of HF among carriers of pathogenic truncating variants in the Mendelian cardiomyopathy gene TTN. These findings suggest a significant polygenic component to HF exists that is not captured by current clinical genetic testing.

Implications of preferential access to land and clean energy for Sustainable Aviation Fuels.

Aviation is highly dependent on liquid fossil fuel, and the production of 'sustainable aviation fuels' (SAF) is being proposed as a solution to removing the fossil carbon component, especially for long-haul flights. An analysis of 12 aviation roadmaps for net zero 2050 reveals heavy reliance on biogenic SAF in the medium-term and synthetic e-kerosene in the longer term. Realising these roadmaps could require 9 % of global renewable electricity and 30 % of sustainably available biomass in 2050, with significant energy 'losses'. The continued use of hydrocarbon fuel in the roadmaps generates 1.35 GtCO2 in 2050, of which 30 % are still from fossil fuel. The net carbon savings from the 70 % depend on the direct and indirect life cycle emissions of producing SAF. Additional effects that are omitted in most roadmaps relate to decadal time lags in re-sequestering biocarbon in the case of forest biomass and the impact of non-CO2 emissions. Both require greater scrutiny in fully understanding the climate impact of SAF substitution. The scaling up of SAF to not only maintain but grow global aviation is problematic as it competes for land needed for nature-based carbon removal, clean energy that could more effectively decarbonise other sectors, and captured CO2 to be stored permanently. As such, SAF production undermines global goals of limiting warming to 1.5 °C; a conflict that is neither recognised in the roadmaps nor in the public debate.

Responsible Imputation of Missing Speech Perception Testing Data & Analysis of 4,739 Observations and Predictors of Performance.

OBJECTIVE: To address outcome heterogeneity in cochlear implant (CI) research, we built imputation models using multiple imputation by chained equations (MICEs) and K-nearest neighbors (KNNs) to convert between four common open-set testing scenarios: Consonant-Nucleus-Consonant word (CNCw), Arizona Biomedical (AzBio) in quiet, AzBio +5, and AzBio +10. We then analyzed raw and imputed data sets to evaluate factors affecting CI outcome variability. STUDY DESIGN: Retrospective cohort study of a national CI database (HERMES) and a nonoverlapping single-institution CI database. SETTING: Multi-institutional (32 CI centers). PATIENTS: Adult CI recipients (n = 4,046 patients). MAIN OUTCOME MEASURES: Mean absolute error (MAE) between imputed and observed speech perception scores. RESULTS: Imputation models of preoperative speech perception measures demonstrate a MAE of less than 10% for feature triplets of CNCw/AzBio in quiet/AzBio +10 (MICE: MAE, 9.52%; 95% confidence interval [CI], 9.40-9.64; KNN: MAE, 8.93%; 95% CI, 8.83-9.03) and AzBio in quiet/AzBio +5/AzBio +10 (MICE: MAE, 8.85%; 95% CI, 8.68-9.02; KNN: MAE, 8.95%; 95% CI, 8.74-9.16) with one feature missing. Postoperative imputation can be safely performed with up to four of six features missing in a set of CNCw and AzBio in quiet at 3, 6, and 12 months postcochlear implantation using MICE (MAE, 9.69%; 95% CI, 9.63-9.76). For multivariable analysis of CI performance prediction, imputation increased sample size by 72%, from 2,756 to 4,739, with marginal change in adjusted R2 (0.13 raw, 0.14 imputed). CONCLUSIONS: Missing data across certain sets of common speech perception tests may be safely imputed, enabling multivariate analysis of one of the largest CI outcomes data sets to date.

Can inflammation predict social media use? Linking a biological marker of systemic inflammation with social media use among college students and middle-aged adults.

Drawing on recent evidence that inflammation may promote social affiliative motivation, the present research proposes a novel perspective that inflammation may be associated with more social media use. In a cross-sectional analysis of a nationally representative sample, Study 1 (N = 863) found a positive association between C-reactive protein (CRP), a biomarker of systemic inflammation, and the amount of social media use by middle-aged adults. Study 2 (N = 228) showed that among college students CRP was prospectively associated with more social media use 6 weeks later. Providing stronger evidence of the directionality of this effect, Study 3 (N = 171) showed that in college students CRP predicted increased social media use in the subsequent week even after controlling for current week's use. Additionally, in exploratory analyses of CRP and different types of social media use in the same week, CRP was only associated with using social media for social interaction and not for other purposes (e.g., entertainment). The present research sheds light on the social effects of inflammation and highlights potential benefits of using social media as a context for studying the impact of inflammation on social motivation and behavior.

Selection history contributes to suboptimal attention strategies.

Attentional control balances the competing drives of performance maximization and effort minimization. One way the attention system minimizes effort is through a bias to persist in the use of attentional control strategies that have been useful in the past. In the present study, we asked whether such selection history can result in the persistence of an attentional control strategy that is counterproductive, effectively competing with a more optimal strategy. Participants first completed a training in which one color target was encountered more frequently than another, and then completed a test phase in which they could search for one of two targets on any given trial, one of which would be more optimal to search for given the distribution of color stimuli. An attentional bias for the more frequent target color was observed in the training phase and the choice of which target to report was robustly optimal in the test phase, reflecting performance maximization. Importantly, participants also exhibited a tendency to report the target rendered in the previously more frequent target color in the test phase, even when the distribution of non-target colors made it suboptimal to do so. Our findings shed light on the fundamental question of why attentional control is sometimes suboptimal, demonstrating a role for selection history in the perseveration of previously employed attentional strategies even when such strategies produce suboptimal performance.

Audiologic Follow-up in Patients With Head and Neck Cancer Treated With Cisplatin and Radiation.

OBJECTIVES: Evaluate factors associated with adherence to ototoxicity monitoring among patients with head and neck cancer treated with cisplatin and radiation therapy at a tertiary care center. METHODS: We performed a single-institution retrospective cohort study on adults with head and neck cancer treated with cisplatin and radiation therapy who participated in an ototoxicity monitoring program. The primary outcomes were rates of post-treatment audiograms at the following time points: one, three, six, 12, and greater than 12 months. Multivariable logistic regression was performed to identify risk factors associated with complete loss of follow-up after pre-treatment evaluation. RESULTS: Two hundred ninety-four head and neck cancer patients were analyzed. Overall, 220 (74.8%) patients had at least one post-treatment audiogram; 58 (20.0%) patients had more than one audiogram. The time point with the highest follow-up rate was at 3 months (n = 170, 57.8%); rates at the remaining times ranged from 7.1% to 14.3%. When controlling for covariates, patients without insurance and those with stage IV cancers were associated with complete loss of audiologic follow-up (aOR = 7.18, 95% CI = 2.75-19.90; aOR = 1.96, 95% CI = 1.02-3.77, respectively). Among 156 patients recommended for a hearing aid, only 39 (24.8%) patients received one. CONCLUSIONS: Head and neck cancer patients enrolled in an ototoxicity monitoring program demonstrate moderately high follow-up rates for at least one post-treatment audiogram. However, follow-up tapers dramatically after 6 months, and overall hearing aid utilization is low. Further research is needed to understand barriers to long-term audiologic follow-up and hearing aid utilization to decrease untreated hearing loss in cancer survivorship. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 133:3161-3168, 2023.

Hearing Outcomes in a Deintensification Trial of Adjuvant Therapy for HPV-Related Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVE: To explore whether deintensification of adjuvant therapy reduces ototoxicity among patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). STUDY DESIGN: Retrospective cohort study. SETTING: Single academic center. METHODS: The ototoxicity rate among adult patients with HPV-related OPSCC enrolled in the Minimalist Trial (MINT), a prospective phase 2 trial of surgery followed by risk-adjusted deintensified adjuvant therapy (42 Gy radiation given alone or with a single 100 mg/m2 dose of cisplatin), was compared to that among a historical cohort treated with standard adjuvant therapy (60-66 Gy radiation with up to three 100 mg/m2 doses of cisplatin). Ototoxicity was defined as Common Terminology Criteria for Adverse Events v5.0 ≥ Grade 2. Mixed model analysis was performed to investigate the association between deintensified adjuvant therapy and treatment-related hearing loss. RESULTS: A total of 29 patients (58 ears) were analyzed in the MINT cohort, and 27 patients (54 ears) in the historical cohort. The ototoxicity rate was 5% (n = 3/58 ears) in the MINT cohort and 46% (n = 25/54 ears) in the historical cohort (difference, 41%; 95% confidence interval [CI] = 27%-56%). Patients in the MINT cohort demonstrated a 95% decrease in risk of ototoxicity compared to those in the historical cohort (adjusted odds ratio: 0.05, 95% CI = 0.01-0.31). Differences in estimated marginal mean threshold shifts were statistically and clinically significant at frequencies ≥ 3 kHz. CONCLUSION: The deintensified adjuvant therapy given in MINT led to less ototoxicity than standard adjuvant therapy among patients with HPV-related OPSCC.

Outcomes of Mesh Cranioplasty in Scalp-Free Tissue Reconstruction: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically review the literature to determine the prevalence and risk of the free flap and postoperative complications in scalp-free tissue reconstruction with synthetic mesh cranioplasty. DATA SOURCES: Search strategies created with a medical librarian were implemented using multiple databases in May 2021. REVIEW METHODS: Two reviewers independently performed the review, data extraction, and quality assessment. Cohort studies of patients with scalp-free tissue reconstruction with or without mesh cranioplasty were included. Studies that did not report whether mesh was used or did not separate outcomes by mesh use were excluded. The primary outcomes were free flap failure and postoperative complications. A random-effects model was used for the meta-analysis to estimate prevalence and prevalence ratios (PRs). RESULTS: A total of 28 studies and 440 cases of scalp-free tissue reconstruction were included. The pooled prevalence of free flap failures and postoperative complications in patients with mesh cranioplasty was estimated at 7% (95% confidence interval [CI], 3%-17%; p = .85, I2 = 0%) and 21% (95% CI, 14%-31%; p = .44, I2 = 0%), respectively. In a subgroup analysis, mesh cranioplasty was not associated with a significantly increased risk of free flap failure or postoperative complications when compared to cases without mesh cranioplasty; pooled PR 1.21 (95% CI, 0.50-2.88; p = .90, I2 = 0%) for free flap failure and PR 1.85 (95% CI, 0.89-3.85; p = .28, I2 = 19) for postoperative complications. CONCLUSION: Synthetic mesh cranioplasty does not significantly increase the risk of free flap compromise or postoperative complications. A higher prevalence of postoperative recipient site complications was observed in patients with mesh cranioplasty.

Genetics of atrial fibrillation.

PURPOSE OF REVIEW: Atrial fibrillation is the most common cardiac arrhythmia worldwide. There is considerable interest in better understanding the molecular genetics and biology of atrial fibrillation to inform the development of new therapies and improve clinical management. This review summarizes recent advances in our understanding of the genetic basis of atrial fibrillation and new efforts to utilize genetics to inform clinical management. RECENT FINDINGS: Genome-wide association studies in diverse populations have increased the number of genetic loci associated with atrial fibrillation and its specific subtypes. Large-scale biobanks with deep phenotyping have provided invaluable data to study the impact of both common and rare variants on atrial fibrillation, susceptibility, and prognosis. Polygenic risk scores help improve individual atrial fibrillation risk stratification and prognostication. SUMMARY: Our understanding of atrial fibrillation genetics is rapidly improving with larger and more diverse genome-wide association studies. Translating genetic discoveries into molecular pathways and new therapeutic targets remains a bottleneck in the development of new therapies for atrial fibrillation. Genetic risk scores have shown early promise in improving atrial fibrillation risk stratification; however, their broader utility for the general population remains unclear.

The poly(C)-binding protein Pcbp2 is essential for CD4+ T cell activation and proliferation.

The RNA-binding protein Pcbp2 is widely expressed in the innate and adaptive immune systems and is essential for mouse development. To determine whether Pcbp2 is required for CD4+ T cell development and function, we derived mice with conditional Pcbp2 deletion in CD4+ T cells and assessed their overall phenotype and proliferative responses to activating stimuli. We found that Pcbp2 is essential for T conventional cell (Tconv) proliferation, working through regulation of co-stimulatory signaling. Pcbp2 deficiency in the CD4+ lineage did not impact Treg abundance in vivo or function in vitro. In addition, our data demonstrate a clear association between Pcbp2 control of Runx1 exon 6 splicing in CD4+ T cells and a specific role for Pcbp2 in the maintenance of peripheral CD4+ lymphocyte population size. Last, we show that Pcbp2 function is required for optimal in vivo Tconv cell activation in a T cell adoptive transfer colitis model system.

Visual search as effortful work.

Tasks that involve more demanding cognitive operations, such as working memory maintenance and rule switching, tend to be perceived as effortful. People will make choices that minimize the need to perform such tasks and will even accept some measure of physical pain in exchange for the ability to avoid them. Nearly all tasks require that people find and extract relevant perceptual information from their environment, but demands of this nature are often ignored in the study of mental effort. Visual search is sometimes described as "difficult" or "easy" on the basis of search slopes or other performance-based metrics, but how such performance differences map onto conceptions of cognitive demand is unclear. In the present study, we examined whether people would be willing to exert physical effort in exchange for the opportunity to minimize the number of items they needed to search through in a visual search task and whether they would be more willing to endure physical effort demands if it resulted in fewer items needing to be searched. Our results are broadly consistent with the idea that the performance of visual search constitutes effortful work that can trade-off with physical effort demands, which has broad implications for theories of visual information processing and practical considerations for professions that tax peoples' ability to search. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

From whom do people seek what type of support? A regulatory scope perspective.

From whom do people seek what type of support? Although people regularly seek support from close and distant others, little work has systematically investigated when and why people approach different people in their support network for different types of support. The present research introduces a novel distinction of social support and explores its relationship to the scope or range of support providers people would consider asking for support. Based on a recent extension of construal level theory (Trope et al., 2021), five experiments tested the bidirectional relation between levels of support and scope-the latter assessed by the social distance of potential support providers. Experiment 1 demonstrated that people can categorize supportive behaviors into low-level support (i.e., addressing the effect of a problem) and high-level support (i.e., addressing the cause of a problem). Experiments 2 and 4 showed that being prompted to seek low-level (vs. high-level) support-oriented people toward support providers who are socially proximal (vs. distal). In Experiment 3, thinking about interacting with a socially proximal (vs. distal) support provider led to a greater focus on receiving low-level (vs. high-level) support. Testing the implication of the link between levels of support and scope, Experiment 5 demonstrated that support recipients reported they would feel more gratitude when they imagined receiving low-level (vs. high-level) support from socially proximal (vs. distal) support providers. Broader implications for social support, interpersonal relationships, and construal level theory research are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Feasibility study of student-led fall prevention care management: Reducing fall risks in assisted living facilities.

Falls are common in Assisted Living Facilities (ALFs). We evaluated the feasibility, acceptability, and preliminary impact of student-led Fall Prevention Care Management (FPCM) on reducing fall risks in ALFs. Residents who were age ≥65, had a fall in the previous year Or considered high fall risk at the facility, and who had a MoCA cognition score>15 were enrolled. The FPCM interventions were semi-structured to facilitate students' learning while addressing participants' unique fall risks. Twenty-five older adults in the U.S. completed the study (recruitment rate: 55%; retention rate: 64%). Participants rated the study as 87.16 (100 = excellent), and likelihood to recommend the study to others was 80.85 (100 = most likely). Participants were 84% female, mean age 88.6 years old. Fall risks such as fear of falling decreased from 16.05 to 15.12 (p = .022), fall prevention behaviors increased from 2.94 to 3.07 (p = .048), and the level of confidence to prevent falls increased from 63.38 to 78.35 (p = .015). Students commonly provided education and coaching on fall prevention strategies, and addressed emotional and behavioral aspects of fall prevention. With improvement with recruitment and retention, student-led FPCM intervention is a promising approach for fall prevention in ALF.