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Career counselors practicing in rural communities must understand and address social determinants of mental health (SDOMH). This conceptual article details the relationships between SDOMH domains and employment and provides evidence-based recommendations for integrating SDOMH into practice through a rural community health and well-being framework. Description of the adaptation of the framework for career counselors in rural communities, SDOMH assessment strategies and tools, and workflow adjustments are included. Conclusions suggest next steps for practice and research.

Addressing non-medical factors that adversely impact mental health, wellness, and academic persistence is important to increasing access to college for vulnerable college students. This systematic review synthesized 63 articles on interventions to address college student SDOMH challenges. Researchers found that SDOMH themes were addressed in intervention studies at different rates, specifically, healthcare access and quality (n = 27, 42.3%), education access and quality (n = 24; 37.5%), social and community context (n = 11; 17.4%), economic stability (n = 3; 4.7%), and neighborhood and built environment (n = 1; 1.6%). Implications for higher education stakeholders conclude.

In light of the ongoing COVID-19 pandemic, the health disparities plaguing our communities are highlighted more than ever. Community-based learning (CBL) and community-based participatory research (CBPR) provide a highly relevant framework in addressing health problems, especially those related to the Social Determinants of Health (AHRQ, 2020). Throughout the COVID-19 pandemic, the team at the Community Health Division (CHD) within the Family Medicine Department of Georgetown University School of Medicine (GUSOM) maintained and deepened relationships with community partners through engagement activities, which not only actively addressed community needs but also acted as an educational tool for a growing number of interdisciplinary students. This paper explores the effectiveness of CBL and CBPR as a framework, even when presented with challenges of the COVID-19 pandemic. It further underscores how students at Georgetown University have become more intimately involved in community health engagement during the pandemic. This serves as an encouraging model for establishing a student-based research learning community.

Background SL-172154 is a hexameric fusion protein adjoining the extracellular domain of SIRPα to the extracellular domain of CD40L via an inert IgG4-derived Fc domain. In preclinical studies, a murine equivalent SIRPα-Fc-CD40L fusion protein provided superior antitumor immunity in comparison to CD47- and CD40-targeted antibodies. A first-in-human phase I trial of SL-172154 was conducted in patients with platinum-resistant ovarian cancer.Methods SL-172154 was administered intravenously at 0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg. Dose escalation followed a modified toxicity probability interval-2 design. Objectives included evaluation of safety, dose-limiting toxicity, recommended phase II dose, pharmacokinetic (PK) and pharmacodynamic (PD) parameters, and antitumor activity.Results 27 patients (median age 66 years (range, 33–85); median of 4 prior systemic therapies (range, 2–9)) with ovarian (70%), fallopian tube (15%), or primary peritoneal (15%) cancer received SL-172154. Treatment-emergent adverse events (TEAEs) were reported for 27 patients (100%), with 24 (88.9%) having a drug-related TEAE and infusion-related reactions being the most common. 12 patients (44.4%) had grade 3/4 TEAEs, and half of these patients (22.2%) had a drug-related grade 3/4 TEAE. There were no fatal adverse events, and no TEAEs led to drug discontinuation. SL-172154 Cmax and area under the curve increased with dose with greater than proportional exposure noted at 3.0 and 10.0 mg/kg. CD47 and CD40 target engagement on CD4+ T cells and B cells, respectively, approached 100% by 3.0 mg/kg. Dose-dependent responses in multiple cytokines (eg, interleukin 12 (IL-12), IP-10) approached a plateau at ≥3.0 mg/kg. Paired tumor biopsies demonstrated a shift in macrophages from an M2- to an M1-dominant phenotype and increased infiltration of CD8 T cells. PK/PD modeling showed near maximal margination of B cells and a dose-dependent production of IL-12 nearing a plateau at >3.0 mg/kg. The best response was stable disease in 6/27 (22%) patients.Conclusions SL-172154 was tolerable as monotherapy and induced, dose-dependent, and cyclical immune cell activation, increases in multiple serum cytokines, and trafficking of CD40-positive B cells and monocytes following each infusion. The safety, PK, and PD activity support 3.0 mg/kg as a safe and pharmacologically active dose.Trial registration number NCT04406623.

Targeted nanoparticles offer potential to selectively deliver therapeutics to cells; however, their subcellular fate following endocytosis must be understood to properly design mechanisms of drug release. Here we describe a nanoparticle platform and associated cell-based assay to observe lysosome trafficking of targeted nanoparticles in live cells. The nanoparticle platform utilizes two fluorescent dyes loaded onto PEG-poly(glutamic acid) and PEG-poly(Lysine) block co-polymers that also comprise azide reactive handles on PEG termini to attach antibody-based targeting ligands. Fluorophores were selected to be pH-sensitive (pHrodo Red) or pH-insensitive (Alexafluor 488) to report when nanoparticles enter low pH lysosomes. Dye-labelled block co-polymers were further assembled into polyion complex micelle nanoparticles and crosslinked through amide bond formation to form stable nano-scaffolds for ligand attachment. Cell binding and lysosome trafficking was determined in live cells by fluorescence imaging in 96-well plates and quantification of red- and green-fluorescence signals over time. The platform and assay was validated for selection of optimal antibody-derived targeting ligands directed towards CD22 for nanoparticle delivery. Kinetic analysis of uptake and lysosome trafficking indicated differences between ligand types and the ligand with the highest lysosome trafficking efficiency translated into effective DNA delivery with nanoparticles bearing the optimal ligand.

Joseph D. Brain, a leading light in environmental and occupational health at the Harvard T.H. Chan School of Public Health, passed away on 29 January 2024, just 9 days after [...]

Objectives: A decline in mitochondrial function and increased susceptibility to oxidative stress is a hallmark of ageing. Exercise endogenously generates reactive oxygen species (ROS) in skeletal muscle and promotes mitochondrial remodelling resulting in improved mitochondrial function. It is unclear how exercise induced redox signalling results in alterations in mitochondrial dynamics and morphology. Methods: In this study, a Caenorhabditis elegans model of exercise and ageing was used to determine the mechanistic role of Peroxiredoxin 2 (PRDX-2) in regulating mitochondrial morphology. Mitochondrial morphology was analysed using transgenic reporter strains and transmission electron microscopy, complimented with the analysis of the effects of ageing and exercise on physiological activity. Results: The redox state of PRDX-2 was altered with exercise and ageing, hyperoxidised peroxiredoxins were detected in old worms along with basally elevated intracellular ROS. Exercise generated intracellular ROS and rapid mitochondrial remodelling, which was disrupted with age. The exercise intervention promoted mitochondrial ER contact sites (MERCS) assembly and increased DAF-16/FOXO nuclear localisation. The prdx-2 mutant strain had a disrupted mitochondrial network as evidenced by increased mitochondrial fragmentation. In the prdx-2 mutant strain, exercise did not activate DAF-16/FOXO, mitophagy or increase MERCS assembly. The results demonstrate that exercise generated ROS increased DAF-16/FOXO transcription factor nuclear localisation required for activation of mitochondrial fusion events that were blunted with age. Conclusions: The data demonstrate the critical role of PRDX-2 in orchestrating mitochondrial remodelling in response to a physiological stress by regulating redox dependent DAF-16/FOXO nuclear localisation.

The race to take advantage of the numerous economic, security, and social opportunities made possible by artificial intelligence (AI) is on—with states, intergovernmental organizations, cities, and firms publishing an array of AI strategies. Simultaneously, there are various efforts to identify and distill an array of AI norms. Thus far, there has been limited effort to mine existing AI strategies to see whether common AI norms such as transparency, human-centered design, accountability, awareness, and public benefit are entering into these strategies. Such data is vital to identify areas of convergence and divergence that could highlight opportunities for further norm development in this space by crystallizing State practice.This Article analyzes more than forty existing national AI strategies paying particular attention to the US context, comparing those strategies with private-sector efforts, and addressing common criticisms of this process within a polycentric framework. Our findings support the contention that State practices are converging around certain AI principles, focusing primarily upon public benefit. AI is a critical component of international peace, security, and sustainable development in the twenty-first century, and as such, reaching consensus on AI governance will become vital to help build bridges and trust.

This paper focusses on how careers advice provided to Australian secondary school students varies according to students' socio-economic background. National data for students in Years 11 and 12 from five cohorts of the Longitudinal Surveys of Australian Youth initiated between 1998 and 2015 are analysed. Students from higher socio-economic backgrounds are found to be more likely to access multiple forms of careers information, particularly information relating to university entrance, compared to students from low-SES backgrounds. Conversely, students from lower socio-economic backgrounds are more likely to receive information on pathways to non-professional vocations. This socioeconomic divide has become more pronounced over time. Importantly, access to nonprofessional careers information appears to have declined over time, while there is evidence to suggest this form of advice is more highly valued by students of low-socioeconomic background relative to those of high-socioeconomic background.

Tom Kornhauser,1 Christian M Ponder,1 Philip W Dockery,1 Anna B Sharabura,2 Wade Brock,2,3 John Nguyen,4 John D Pemberton1 1Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 2College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 3Arkansas Oculoplastic Surgery, PLLC, Little Rock, AR, USA; 4West Virginia University, Department of Ophthalmology and Visual Sciences, Department of Otolaryngology and Head and Neck Cancer, Morgantown, WV, USACorrespondence: Tom Kornhauser, Jones Eye Institute, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR, 72207, USA, Tel +501-686-5822, Fax +501-686-7037, Email tkornhauser@uams.eduPurpose: To elicit, from a survey of oculoplastic surgeons, the timing and reason for delaying Jones tube placement after the excision of nasal or lacrimal drainage system malignancy.Methods: The authors reviewed current literature and distributed an anonymous survey to 627 members of the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) to determine the length of time members wait to perform a Jones tube placement after the removal of nasal or lacrimal drainage system malignancy. The survey also included questions about the rationale for this waiting period.Results: Fifty-eight members of ASOPRS (9.3%) responded to our survey, 49 (84.4%) of whom had performed Jones tube placement on patients who had an excision of a nasal or lacrimal drainage system malignancy. Nearly 52% of respondents waited one year for Jones tube placement. However, a sizeable number of respondents opted to wait five years (15.1%). The most common rationale for waiting was a concern for tumor recurrence (42 responses).Conclusion: There is no consensus on when to perform Jones tube placement after the excision of nasal or lacrimal drainage system malignancy. This survey demonstrates a broad array of waiting periods between operations, although most surgeons wait 12 months.Keywords: Conjunctivodacryocystorhinostomy, cDCR, Jones Tube, Malignant Neoplasm

Abstract The first conference of the Vaccination Acceptance Research Network, VARN2022: Shaping Global Vaccine Acceptance with Localized Knowledge, was held virtually, from March 1st to 3rd 2022. This inaugural event brought together a global representation of experts to discuss key priorities and opportunities emerging across the ecosystem of vaccine acceptance and demand, from policies to programs and practice. Convened by the Sabin Vaccine Institute, VARN aims to support dialogue among multidisciplinary stakeholders to enhance the uptake of social and behavioral science-based solutions for vaccination decision-makers and implementers. The conference centered around four key themes: 1) Understanding vaccine acceptance and its drivers; 2) One size does not fit all: community- and context-specific approaches to increase vaccine acceptance and demand; 3) Fighting the infodemic and harnessing social media for good; and 4) Frameworks, data integrity and evaluation of best practices. Across the conference, presenters and participants considered the drivers of and strategies to increase vaccine acceptance and demand relating to COVID-19 vaccination and other vaccines across the life-course and across low-, middle- and high-income settings. VARN2022 provided a wealth of evidence from around the world, highlighting the need for human-centered, multi-sectoral and transdisciplinary approaches to improve vaccine acceptance and demand. This report summarizes insights from the diverse presentations and discussions held at VARN2022, which will form a roadmap for future research, policy making, and interventions to improve vaccine acceptance and demand globally.

The role of parental expectations in determining children's higher education participation is important in understanding both participation and potential policy responses. Using a nationally representative longitudinal survey of Australian households, providing repeat observations on expectations for individual children, this study extends the literature in several respects. First, it examines the adaptation of parental expectations over a 4-year time frame. Second, it looks at how parental expectations for school children are associated with actual higher education outcomes in the future. Third, the longitudinal aspect of the dataset permits more robust analyses of factors that shape parental expectations. The findings indicate that parental expectations of their children's attendance at university are generally stable across time. Perceptions of children's academic achievement at school are shown to be the key influence in shaping parents' expectations, and behavioural issues at school adversely affect expectations. Australian parents from non-English-speaking backgrounds were more likely to form positive expectations of university participation by their children, consistent with studies from other countries. A more nuanced picture of the formation of expectations for sole-parent mothers is also presented. Positive effects of parental education and children's enrolment in a private school on parents' expectations, over and above any effect on school achievement, highlight these socioeconomic factors as potential causal channels for the intergenerational transmission of socioeconomic outcomes.

Abstract Over 15% of probands in a large cohort of more than 1500 inherited retinal degeneration patients present with a clinical diagnosis of Stargardt disease (STGD1), a recessive form of macular dystrophy caused by biallelic variants in the ABCA4 gene. Participants were clinically examined and underwent either target capture sequencing of the exons and some pathogenic intronic regions of ABCA4, sequencing of the entire ABCA4 gene or whole genome sequencing. ABCA4 c.4539 + 2028C > T, p.[= ,Arg1514Leufs*36] is a pathogenic deep intronic variant that results in a retina-specific 345-nucleotide pseudoexon inclusion. Through analysis of the Irish STGD1 cohort, 25 individuals across 18 pedigrees harbour ABCA4 c.4539 + 2028C > T and another pathogenic variant. This includes, to the best of our knowledge, the only two homozygous patients identified to date. This provides important evidence of variant pathogenicity for this deep intronic variant, highlighting the value of homozygotes for variant interpretation. 15 other heterozygous incidents of this variant in patients have been reported globally, indicating significant enrichment in the Irish population. We provide detailed genetic and clinical characterization of these patients, illustrating that ABCA4 c.4539 + 2028C > T is a variant of mild to intermediate severity. These results have important implications for unresolved STGD1 patients globally with approximately 10% of the population in some western countries claiming Irish heritage. This study exemplifies that detection and characterization of founder variants is a diagnostic imperative.

A patient with a neuroendocrine tumor and history of coronary artery disease underwent PET with 68Ga-DOTATATE PET tracer for tumor visualization. Analysis of the scan showed uptake of 68Ga-DOTATATE in the left ventricle corresponding to previous myocardial infarct. 68Ga-DOTATATE binds by somatostatin receptors (SSTR) and it has been proposed that it may be useful for the detection of cardiac inflammatory lesions. We aimed to test whether SSTR could be upregulated in cardiac fibrotic scar. We analyzed SSTR in cardiac samples from patients with end-stage ischemic cardiomyopathy (ICM, n = 8) and control hearts (n = 5). In mature ICM tissue, SSTR1 and SSTR2 expression was unchanged and SSTR5 expression was significantly decreased in ICM samples vs. control. Immunohistochemistry showed increased SSTR1 and SSTR2 in ICM. Areas with SSTR1 or SSTR2 staining were often adjacent to fibrotic areas. The majority of SSTR1 and SSTR2 staining localized in cardiomyocytes in fibrotic scar-rich areas where CD68 macrophage staining was not present. SSTR are occasionally upregulated in cardiac fibrotic areas. When using 68Ga-DOTATATE PET tracer to detect cardiac sarcoidosis or atherosclerotic plaque, the possibility of tracer uptake in fibrotic areas should be considered.

Conclusion: Endogenous fungal endophthalmitis is most commonly seen in immunocompromised patients, and oral corticosteroid therapy for such patients should be used with caution as it can worsen an infection. In cases of fusarial endophthalmitis, visual prognosis is poor.