Social isolation, depression, and anxiety among young adult cancer survivors: The mediating role of social connectedness.

BACKGROUND: Social isolation and social connectedness are health determinants and aspects of social well-being with strong associations with psychological distress. This study evaluated relationships among social isolation, social connectedness, and psychological distress (i.e., depression, anxiety) over 1 year in young adult (YA) cancer survivors 18-39 years old. METHODS: Participants were YAs in a large cohort study that completed questionnaires every 2 months for 1 year. Social isolation, aspects of social connectedness (i.e., companionship, emotional support, instrumental support, and informational support), depression, and anxiety were assessed with Patient-Reported Outcomes Measurement Information System short form measures. Mixed-effect models were used to evaluate changes over time. Confirmatory factor analysis and multilevel structural equation modeling were used to define social connectedness as a latent construct and determine whether relationships between social isolation and psychological distress were mediated by social connectedness. RESULTS: Participants (N = 304) were mean (M) = 33.5 years old (SD = 4.7) and M = 4.5 years (SD = 3.5) post-initial cancer diagnosis. Most participants were female (67.4%) and non-Hispanic White (68.4%). Average scores for social well-being and psychological distress were within normative ranges and did not change (p values >.05). However, large proportions of participants reported at least mild social isolation (27%-30%), depressive symptoms (36%-37%), and symptoms of anxiety (49%-51%) at each time point. Across participants, more social isolation was related to less social connectedness (p values <.001), more depressive symptoms (p < .001), and more symptoms of anxiety (p < .001). Social connectedness mediated the relationship between social isolation and depression (p = .004), but not anxiety (p > .05). CONCLUSIONS: Social isolation and connectedness could be intervention targets for reducing depression among YA cancer survivors.

Open-source hardware and software for the measurement, characterization, reporting, and correction of geometric distortion in MRI.

BACKGROUND: Geometric distortion is a serious problem in MRI, particularly in MRI guided therapy. A lack of affordable and adaptable tools in this area limits research progress and harmonized quality assurance. PURPOSE: To develop and test a suite of open-source hardware and software tools for the measurement, characterization, reporting, and correction of geometric distortion in MRI. METHODS: An open-source python library was developed, comprising modules for parametric phantom design, data processing, spherical harmonics, distortion correction, and interactive reporting. The code was used to design and manufacture a distortion phantom consisting of 618 oil filled markers covering a sphere of radius 150 mm. This phantom was imaged on a CT scanner and a novel split-bore 1.0 T MRI magnet. The CT images provide distortion-free dataset. These data were used to test all modules of the open-source software. RESULTS: All markers were successfully extracted from all images. The distorted MRI markers were mapped to undistorted CT data using an iterative search approach. Spherical harmonics reconstructed the fitted gradient data to 1.0 ± 0.6% of the input data. High resolution data were reconstructed via spherical harmonics and used to generate an interactive report. Finally, distortion correction on an independent data set reduced distortion inside the DSV from 5.5 ± 3.1 to 1.6 ± 0.8 mm. CONCLUSION: Open-source hardware and software for the measurement, characterization, reporting, and correction of geometric distortion in MRI have been developed. The utility of these tools has been demonstrated via their application on a novel 1.0 T split bore magnet.

Novel therapeutic regimens in previously untreated metastatic urothelial carcinoma: A systematic review and bayesian network meta-analysis.

Metastatic urothelial carcinoma (muC) has historically had few effective therapeutic options. Recently, immune checkpoint inhibitors (ICIs), were introduced as therapeutic options for cisplatin-ineligible patients, however, direct head-to-head trials comparing these treatments are lacking. To address this gap, this study employs a Bayesian framework to indirectly compare the performance of ICIs as first-line agents for muC. A systematic review was performed to identify randomized controlled trials evaluating different ICI for mUC. Data was inputted into Review Manager 5.4 for pairwise meta-analysis. Data was then used to build a network in R Studio. These networks were used to model 200,000 Markov Chains via MonteCarlo sampling. The results are expressed as hazard ratios (HR) with 95% credible intervals (CrI). Six studies with 5,449 patients were included, 3,255 received ICI monotherapy or combination. Moreover, a total of 3,006 had PD-L1 positive tumors and 2,362 were PD-L1 negative. Median overall survival (OS) ranged from 12.1 to 31.5 months across the studies, with the combination of enfortumab vedotin and pembrolizumab demonstrating the most substantial reduction in the risk of death (HR 0.47 [95% CrI: 0.38, 0.58]), followed by avelumab monotherapy (HR 0.69 [95% CrI: 0.56, 0.86]). The limitations of this network meta-analysis include variability in study follow-up duration, lack of standardized methods for assessing PD-L1 positivity, and potential bias introduced by control arms with poorer survival outcomes across included trials. The enfortumab vedotin/pembrolizumab combination significantly improved survival and response rates. Avelumab showed notable single-agent activity. These findings provide a valuable framework to guide clinical decision-making and highlight priority areas for future research, including biomarker refinement and novel combination strategies to enhance antitumor immunity in this challenging malignancy.

BRCA1/BRC-1 and SMC-5/6 regulate DNA repair pathway engagement during C. elegans meiosis.

The preservation of genome integrity during sperm and egg development is vital for reproductive success. During meiosis, the tumor suppressor BRCA1/BRC-1 and structural maintenance of chromosomes 5/6 (SMC-5/6) complex genetically interact to promote high fidelity DNA double strand break (DSB) repair, but the specific DSB repair outcomes these proteins regulate remain unknown. Using genetic and cytological methods to monitor resolution of DSBs with different repair partners in Caenorhabditis elegans, we demonstrate that both BRC-1 and SMC-5 repress intersister crossover recombination events. Sequencing analysis of conversion tracts from homolog-independent DSB repair events further indicates that BRC-1 regulates intersister/intrachromatid noncrossover conversion tract length. Moreover, we find that BRC-1 specifically inhibits error prone repair of DSBs induced at mid-pachytene. Finally, we reveal functional interactions of BRC-1 and SMC-5/6 in regulating repair pathway engagement: BRC-1 is required for localization of recombinase proteins to DSBs in smc-5 mutants and enhances DSB repair defects in smc-5 mutants by repressing theta-mediated end joining (TMEJ). These results are consistent with a model in which some functions of BRC-1 act upstream of SMC-5/6 to promote recombination and inhibit error-prone DSB repair, while SMC-5/6 acts downstream of BRC-1 to regulate the formation or resolution of recombination intermediates. Taken together, our study illuminates the coordinate interplay of BRC-1 and SMC-5/6 to regulate DSB repair outcomes in the germline.

Quantitative Computed Tomography Angiography for the Evaluation of Valvular Fibrocalcific Volume in Aortic Stenosis.

BACKGROUND: Aortic stenosis (AS) is characterized by calcification and fibrosis. The ability to quantify these processes simultaneously has been limited with previous imaging methods. OBJECTIVES: The purpose of this study was to evaluate the aortic valve fibrocalcific volume by computed tomography (CT) angiography in patients with AS, in particular, to assess its reproducibility, association with histology and disease severity, and ability to predict/track progression. METHODS: In 136 patients with AS, fibrocalcific volume was calculated on CT angiograms at baseline and after 1 year. CT attenuation distributions were analyzed using Gaussian-mixture-modeling to derive thresholds for tissue types enabling the quantification of calcific, noncalcific, and fibrocalcific volumes. Scan-rescan reproducibility was assessed and validation provided against histology and in an external cohort. RESULTS: Fibrocalcific volume measurements took 5.8 ± 1.0 min/scan, demonstrating good correlation with ex vivo valve weight (r = 0.51; P < 0.001) and excellent scan-rescan reproducibility (mean difference -1%, limits of agreement -4.5% to 2.8%). Baseline fibrocalcific volumes correlated with mean gradient on echocardiography in both male and female participants (rho = 0.64 and 0.69, respectively; both P < 0.001) and in the external validation cohort (n = 66, rho = 0.58; P < 0.001). The relationship was driven principally by calcific volume in men and fibrotic volume in women. After 1 year, fibrocalcific volume increased by 17% and correlated with progression in mean gradient (rho = 0.32; P = 0.003). Baseline fibrocalcific volume was the strongest predictor of subsequent mean gradient progression, with a particularly strong association in female patients (rho = 0.75; P < 0.001). CONCLUSIONS: The aortic valve fibrocalcific volume provides an anatomic assessment of AS severity that can track disease progression precisely. It correlates with disease severity and hemodynamic progression in both male and female patients.

Organizational and patient factors associated with positive primary care experiences for veterans with current or recent homelessness.

OBJECTIVE: To identify organizational service features associated with positive patient ratings of primary care within primary care clinics tailored to accommodate persons with ongoing and recent experiences of homelessness (PEH). DATA SOURCES AND STUDY SETTING: PEH receiving primary care in 29 United States Veterans Health Administration homeless-tailored clinics were surveyed about their primary care experience using the validated Primary Care Quality-Homeless (PCQ-H) survey. Characteristics of the clinics were assessed through surveys of clinic staff using a new organizational survey developed through literature review, site visits, statistical analysis, and consensus deliberation. STUDY DESIGN: Cross-sectional examination of patients' ratings of care based on surveys of patients, and of clinic characteristics, analyzed with Classification and Regression Tree (CART) analysis, a form of machine learning. DATA COLLECTION METHODS: Patient surveys (n = 3394) were obtained from a random sample of enrolled patients by both mail and telephone by an external survey contractor. Staff (n = 52 from 29 clinics) were interviewed by telephone. PRINCIPAL FINDINGS: This analysis identified service features that impact patient experience favorably, including aspects of patient-centeredness, team identity, strong external leadership support, and service that reach beyond traditional primary care clinic confines. Results varied according to the patient experience scale analyzed. Individual characteristics of PEH, such as degree of social support, general health, and unsheltered status, were also correlated with how they rate care. CONCLUSIONS: Organizational characteristics correlate with ratings of primary care from patients with recent and ongoing homelessness. Primary care programs serving homeless individuals can assure better care based on who they hire, how they foster team identity, what services they provide, and the strength of leadership support to protect a homeless-focused mission.

Innovative techniques for combating a common enemy forever chemicals: A comprehensive approach to mitigating per- and polyfluoroalkyl substances (PFAS) contamination.

The pervasive presence of per and polyfluoroalkyl substances (PFAS), commonly referred to as "forever chemicals," in water systems poses a significant threat to both the environment and public health. PFAS are persistent organic pollutants that are incredibly resistant to degradation and have a tendency to accumulate in the environment, resulting in long-term contamination issues. This comprehensive review delves into the primary impacts of PFAS on both the environment and human health while also delving into advanced techniques aimed at addressing these concerns. The focus is on exploring the efficacy, practicality, and sustainability of these methods. The review outlines several key methods, such as advanced oxidation processes, novel materials adsorption, bioremediation, membrane filtration, and in-situ chemical oxidation, and evaluates their effectiveness in addressing PFAS contamination. By conducting a comparative analysis of these techniques, the study aims to provide a thorough understanding of current PFAS remediation technologies, as well as offer insights into integrated approaches for managing these persistent pollutants effectively. While acknowledging the high efficiency of adsorption and membrane filtration in reducing persistent organic pollutants due to their relatively low cost, versatility, and wide applicability, the review suggests that the integration of these methods could result in an overall enhancement of removal performance. Additionally, the study emphasizes the need for researcher attention in key areas and underscores the necessity of collaboration between researchers, industry, and regulatory authorities to address this complex challenge.

Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma.

Sonic hedgehog subgroup of medulloblastoma (SHH-MB) is characterized by aberrant activation of the SHH signaling pathway. An inhibition of the positive SHH regulator Smoothened (SMO) has demonstrated promising clinical efficacy. Yet, primary and acquired resistance to SMO inhibitors limit their efficacy. An understanding of underlying molecular mechanisms of resistance to therapy is warranted to bridge this unmet need. Here, we make use of genome-wide CRISPR-Cas9 knockout screens in murine SMB21 and human DAOY cells, in order to unravel genetic dependencies and drug-related genetic interactors that could serve as alternative therapeutic targets for SHH-MB. Our screens reinforce SMB21 cells as a faithful model system for SHH-MB, as opposed to DAOY cells, and identify members of the epigenetic machinery including DNA methyltransferase 1 (DNMT1) as druggable targets in SHH-dependent tumors. We show that Dnmt1 plays a crucial role in normal murine cerebellar development and is required for SHH-MB growth in vivo. Additionally, DNMT1 pharmacological inhibition alone and in combination with SMO inhibition effectively inhibits tumor growth in murine and human SHH-MB cell models and prolongs survival of SHH-MB mouse models by inhibiting SHH signaling output downstream of SMO. In conclusion, our data highlight the potential of inhibiting epigenetic regulators as a novel therapeutic avenue in SMO-inhibitor sensitive as well as resistant SHH-MBs.

Affective Sensitivity to Air Pollution (ASAP): Person-specific associations between daily air pollution and affective states.

Individuals' sensitivity to climate hazards is a central component of their vulnerability to climate change. In this paper, we introduce and outline the utility of a new intraindividual variability construct, affective sensitivity to air pollution (ASAP)-defined as the extent to which an individual's affective states fluctuate in accordance with daily changes in air quality. As such, ASAP pushes beyond examination of differences in individuals' exposures to air pollution to examination of differences in individuals' sensitivities to air pollution. Building on known associations between air pollution exposure and adverse mental health outcomes, we empirically illustrate how application of Bayesian multilevel models to intensive repeated measures data obtained in an experience sampling study (N = 150) over one year can be used to examine whether and how individuals' daily affective states fluctuate with the daily concentrations of outdoor air pollution in their county. Results indicate construct viability, as we found substantial interindividual differences in ASAP for both affect arousal and affect valence. This suggests that repeated measures of individuals' day-to-day affect provides a new way of measuring their sensitivity to climate change. In addition to contributing to discourse around climate vulnerability, the intraindividual variability construct and methodology proposed here can help better integrate affect and mental health in climate adaptation policies, plans, and programs.

Regulated induced proximity targeting chimeras-RIPTACs-A heterobifunctional small molecule strategy for cancer selective therapies.

We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.

One-Month Dual Antiplatelet Therapy in High Bleeding Risk Asian Patients Undergoing Percutaneous Coronary Intervention　- Onyx ONE Clear 2-Year Results.

Background: One-month dual antiplatelet therapy (DAPT) in high bleeding risk (HBR) patients undergoing percutaneous coronary intervention (PCI) with the Resolute OnyxTM zotarolimus-eluting stents (ZES) is safe and effective. Asian patients have a unique ischemia/bleeding risk profile. Here, we compare the outcomes between Asian and non-Asian patients after PCI and 1-month DAPT. Methods and Results: Onyx ONE Clear was a prospective, multicenter study enrolling HBR patients undergoing PCI with the Resolute Onyx ZES (ClinicalTrials.gov identifier NCT03647475). Event-free patients after 1-month DAPT transitioned to single antiplatelet therapy. Clinical outcomes between 1 month and 2 years were compared between patients from Asian and non-Asian countries after 1 : 1 propensity score matching accounting for baseline differences. Patients from Asian countries represented 18% (n=273) of the study group (n=1,507). Non-Asian patients had greater clinical complexity; however, these differences were minimal after matching. There were no significant differences in ischemic outcomes between matched cohorts from 1 month to 2 years, including the primary composite endpoint of cardiac death or myocardial infarction (12% vs. 12%; P>0.99). However, there were significantly fewer Bleeding Academic Research Consortium types 3-5 bleeding events in the Asian vs. non-Asian cohort (4% vs. 9%; P=0.007), despite similar bleeding risk profiles after matching. Conclusions: After propensity score matching, HBR patients from Asian countries undergoing PCI treated with 1-month DAPT had similar ischemic outcomes but fewer bleeding events between 1 month and 2 years compared with patients from non-Asian countries.

Cluster effect for SNP-SNP interaction pairs for predicting complex traits.

Single nucleotide polymorphism (SNP) interactions are the key to improving polygenic risk scores. Previous studies reported several significant SNP-SNP interaction pairs that shared a common SNP to form a cluster, but some identified pairs might be false positives. This study aims to identify factors associated with the cluster effect of false positivity and develop strategies to enhance the accuracy of SNP-SNP interactions. The results showed the cluster effect is a major cause of false-positive findings of SNP-SNP interactions. This cluster effect is due to high correlations between a causal pair and null pairs in a cluster. The clusters with a hub SNP with a significant main effect and a large minor allele frequency (MAF) tended to have a higher false-positive rate. In addition, peripheral null SNPs in a cluster with a small MAF tended to enhance false positivity. We also demonstrated that using the modified significance criterion based on the 3 p-value rules and the bootstrap approach (3pRule + bootstrap) can reduce false positivity and maintain high true positivity. In addition, our results also showed that a pair without a significant main effect tends to have weak or no interaction. This study identified the cluster effect and suggested using the 3pRule + bootstrap approach to enhance SNP-SNP interaction detection accuracy.

Select Dietary Components Are Associated With Better Global Cognition in Adults With HIV.

ABSTRACT: People with HIV (PWH) are at an increased risk for cognitive impairment. Lifestyle factors can have protective effects on cognition; little work has examined diet and cognitive function in PWH. In this cross-sectional pilot study, 86 PWH (mean age 56 years) completed diet recalls and a neurocognitive assessment. Correlations were conducted between diet and cognitive function, adjusting for total calories, sex, and education (multiple comparison correction p values are reported). Diet quality of the sample was poor. Greater calories per day (r = 0.28, p =.08) and greater percentage of calories from saturated fatty acids (SFAs; r = 0.26, p = 0.08) were associated with better cognition. Higher intake of SFAs (rs 0.30-0.31, ps = 0.07), amino acids (rs = 0.27, ps = 0.08), and phosphorus (r = 0.29, p = .07) and magnesium (r = 0.25, p = .08) were associated with better cognition. A diet reflecting higher protein and fat relative to carbohydrates was associated with better cognition. Targeting individual nutrients, improving diet quality, and adequate caloric intake may preserve cognition in PWH.

Older Caregivers With HIV: Their Story of Caregiving.

ABSTRACT: As people with HIV live longer and healthier, it has become more likely that they will assume a caregiver role for their families and/or friends. Yet, there is a significant gap in the literature that older caregivers with HIV (OCWH) have not received attention from practitioners and researchers. To fill the gap, our qualitative study was conducted with OCWH (N = 19) to explore various themes such as adjustment to caregiving, caregiving responsibilities, HIV and other health issues, support systems, caregiving outcomes, needs assessment, cognitive health, and the impact of COVID-19. Results indicated that each OCWH faced their own unique challenges (e.g., severity of health conditions, intense caregiving responsibilities, caregiving situation, lack of social support/transportation/financial means), but they expressed positive and fulfilling caregiving outcomes. Understanding the lived experiences of OCWH is requisite to develop holistic service programs to meet their caregiving needs while supporting their HIV health and co-occurring health conditions.

Parametrically guided design of beta barrels and transmembrane nanopores using deep learning.

Francis Crick's global parameterization of coiled coil geometry has been widely useful for guiding design of new protein structures and functions. However, design guided by similar global parameterization of beta barrel structures has been less successful, likely due to the deviations required from ideal beta barrel geometry to maintain extensive inter-strand hydrogen bonding without introducing considerable backbone strain. Instead, beta barrels and other protein folds have been designed guided by 2D structural blueprints; while this approach has successfully generated new fluorescent proteins, transmembrane nanopores, and other structures, it requires considerable expert knowledge and provides only indirect control over the global barrel shape. Here we show that the simplicity and control over shape and structure provided by global parametric representations can be generalized beyond coiled coils by taking advantage of the rich sequence-structure relationships implicit in RoseTTAFold based inpainting and diffusion design methods. Starting from parametrically generated idealized barrel backbones, both RFjoint inpainting and RFdiffusion readily incorporate the backbone irregularities necessary for proper folding with minimal deviation from the idealized barrel geometries. We show that for beta barrels across a broad range of global beta sheet parameterizations, these methods achieve high in silico and experimental success rates, with atomic accuracy confirmed by an X-ray crystal structure of a novel beta barrel topology, and de novo designed 12, 14, and 16 stranded transmembrane nanopores with conductances ranging from 200 to 500 pS. By combining the simplicity and control of parametric generation with the high success rates of deep learning based protein design methods, our approach makes the design of proteins where global shape confers function, such as beta barrel nanopores, more precisely specifiable and accessible.

IL-1 receptor antagonism reveals a yin-yang relationship between NFκB and interferon signaling in chronic lymphocytic leukemia.

Nuclear factor kappa B (NFκB) is a pathogenic factor in chronic lymphocytic leukemia (CLL) that is not addressed specifically by current therapies. NFκB is activated by inflammatory factors that stimulate toll-like receptors (TLRs) and receptors for interleukin-1 (IL-1) family members. IL-1 is considered a master regulator of inflammation, and IL-1 receptor signaling is inhibited by the IL-1 receptor antagonist anakinra. These considerations suggested that anakinra might have a role in the treatment of CLL. Consistent with this idea, anakinra inhibited spontaneous and TLR7-mediated activation of the canonical NFκB pathway in CLL cells in vitro. However, CLL cells exhibited only weak signaling responses to IL-1 itself, and anakinra was found to inhibit NFκB along with oxidative stress in an IL-1 receptor-independent manner. Anakinra was then administered with minimal toxicity to 11 previously untreated CLL patients in a phase I dose-escalation trial (NCT04691765). A stereotyped clinical response was observed in all patients. Anakinra lowered blood lymphocytes and lymph node sizes within the first month that were associated with downregulation of NFκB and oxidative stress in the leukemia cells. However, inhibition of NFκB was accompanied by upregulation of type 1 interferon (IFN) signaling, c-MYC-regulated genes and proteins, and loss of the initial clinical response. Anakinra increased IFN signaling and survival of CLL cells in vitro that were, respectively, phenocopied by mitochondrial antioxidants and reversed by IFN receptor blocking antibodies. These observations suggest that anakinra has activity in CLL and may be a useful adjunct for conventional therapies as long as compensatory IFN signaling is blocked at the same time.

Pollinator response to livestock grazing: implications for rangeland conservation in sagebrush ecosystems.

World food supplies rely on pollination, making this plant-animal relationship a highly valued ecosystem service. Bees pollinate flowering plants in rangelands that constitute up to half of global terrestrial vegetation. Livestock grazing is the most widespread rangeland use and can affect insect pollinators through herbivory. We examined management effects on bee abundance and other insect pollinators on grazed and idle sagebrush rangelands in central Montana, USA. From 2016 to 2018, we sampled pollinators on lands enrolled in rest-rotation grazing, unenrolled grazing lands, and geographically separate idle lands without grazing for over a decade. Bare ground covered twice as much area (15% vs. 7) with half the litter (12% vs. 24) on grazed than idle regardless of enrollment. Bee pollinators were 2-3 times more prevalent in grazed than idle in 2016-2017. In 2018, bees were similar among grazed and idled during an unseasonably wet and cool summer that depressed pollinator catches; captures of secondary pollinators was similar among treatments 2 of 3 study years. Ground-nesting bees (94.6% of total bee abundance) were driven by periodic grazing that maintained bare ground and kept litter accumulations in check. In contrast, idle provided fewer nesting opportunities for bees that were mostly solitary, ground-nesting genera requiring unvegetated spaces for reproduction. Managed lands supported higher bee abundance that evolved with bison grazing on the eastern edge of the sagebrush ecosystem. Our findings suggest that periodic disturbance may enhance pollinator habitat, and that rangelands may benefit from periodic grazing by livestock.