Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by increasing fibrosis, which can enhance tumor progression and spread. Here, we undertook an unbiased temporal assessment of the matrisome of the highly metastatic KPC (Pdx1-Cre, LSL-KrasG12D/+, LSL-Trp53R172H/+) and poorly metastatic KPflC (Pdx1-Cre, LSL-KrasG12D/+, Trp53fl/+) genetically engineered mouse models of pancreatic cancer using mass spectrometry proteomics. Our assessment at early-, mid-, and late-stage disease reveals an increased abundance of nidogen-2 (NID2) in the KPC model compared to KPflC, with further validation showing that NID2 is primarily expressed by cancer-associated fibroblasts (CAFs). Using biomechanical assessments, second harmonic generation imaging, and birefringence analysis, we show that NID2 reduction by CRISPR interference (CRISPRi) in CAFs reduces stiffness and matrix remodeling in three-dimensional models, leading to impaired cancer cell invasion. Intravital imaging revealed improved vascular patency in live NID2-depleted tumors, with enhanced response to gemcitabine/Abraxane. In orthotopic models, NID2 CRISPRi tumors had less liver metastasis and increased survival, highlighting NID2 as a potential PDAC cotarget.

Time to Diagnosis and Treatment for Ovarian Cancer and Associations with Outcomes: A Systematic Review.

Background: Ovarian cancer is commonly diagnosed symptomatically at an advanced stage. Better survival for early disease suggests improving diagnostic pathways may increase survival. This study examines literature assessing diagnostic intervals and their association with clinical and psychological outcomes. Methods: Medline, EMBASE, and EmCare databases were searched for studies including quantitative measures of at least one interval, published between January 1, 2000 and August 9, 2022. Interval measures and associations (interval, outcomes, analytic strategy) were synthesized. Risk of bias of association studies was assessed using the Aarhus Checklist and ROBINS-E tool. Results: In total, 65 papers (20 association studies) were included and 26 unique intervals were identified. Interval estimates varied widely and were impacted by summary statistic used (mean or median) and group focused on. Of Aarhus-defined intervals, patient (symptom to presentation, n = 23; range [median]: 7-168 days) and diagnostic (presentation to diagnosis, n = 22; range [median]: 7-270 days) were most common. Nineteen association studies examined survival or stage outcomes with most, including five low risk-of-bias studies, finding no association. Conclusions: Studies reporting intervals for ovarian cancer diagnosis are limited by inconsistent definitions and reporting. Greater utilization of the Aarhus statement to define intervals and appropriate analytic methods is needed to strengthen findings from future studies.

Correlation between cognitive changes and neuroradiological changes over time in multiple sclerosis: a systematic review and meta-analysis.

BACKGROUND: While many studies have examined relationships of neuroimaging variables to cognitive measures in multiple sclerosis (MS), longitudinal studies are lacking. The relationship of cognitive changes to neuroradiological changes in MS is thus incompletely understood. The present study systematically reviews all studies reporting a relationship between MRI changes and cognitive changes after at least one year of follow-up. METHOD: An extensive and methodical search of online databases was conducted to identify qualified studies until August 2023. Among various cognitive tests and magnetic resonance imaging (MRI) measures, Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), verbal fluency, T2 lesion volume (T2LV), white matter lesion volume (WML), and grey matter volume (GMV) qualified for inclusion in a meta-analysis investigating the association of cognitive changes to neuroradiological changes. RESULTS: We identified 35 studies that explored the link between MRI changes and changes in cognitive outcomes. Of these, twenty studies (57.14%) investigated the association between SDMT/PASAT and MRI metrics. Eleven studies (31.42%) focused on the relationship between MRI metrics and verbal learning and memory, while ten studies (28.57%) reported associations with visuospatial learning and memory. Furthermore, eight studies (22.85%) analyzed the correlation between verbal fluency and MRI measures. Only 5 were eligible for inclusion in the meta-analysis. The meta-analysis evaluated correlations between SDMT/PASAT and GMV (rs = 0.67, 95% CI 0.44-0.91), and verbal fluency and T2LV (rs = 0.35, 95% CI 0.09-0.60). CONCLUSION: In this rigorously conducted systematic review, we found a significant association of cognitive changes, specifically SDMT/PASAT and verbal fluency, to changes in T2LV and atrophy in individuals with MS. Findings should be interpreted cautiously due to the limited amount of high-quality research, small sample sizes, and variability in study methodologies.

Rapid, DNA-induced interface swapping by DNA gyrase.

DNA gyrase, a ubiquitous bacterial enzyme, is a type IIA topoisomerase formed by heterotetramerisation of 2 GyrA subunits and 2 GyrB subunits, to form the active complex. DNA gyrase can loop DNA around the C-terminal domains (CTDs) of GyrA and pass one DNA duplex through a transient double-strand break (DSB) established in another duplex. This results in the conversion from a positive (+1) to a negative (-1) supercoil, thereby introducing negative supercoiling into the bacterial genome by steps of 2, an activity essential for DNA replication and transcription. The strong protein interface in the GyrA dimer must be broken to allow passage of the transported DNA segment and it is generally assumed that the interface is usually stable and only opens when DNA is transported, to prevent the introduction of deleterious DSBs in the genome. In this paper, we show that DNA gyrase can exchange its DNA-cleaving interfaces between two active heterotetramers. This so-called interface 'swapping' (IS) can occur within a few minutes in solution. We also show that bending of DNA by gyrase is essential for cleavage but not for DNA binding per se and favors IS. Interface swapping is also favored by DNA wrapping and an excess of GyrB. We suggest that proximity, promoted by GyrB oligomerization and binding and wrapping along a length of DNA, between two heterotetramers favors rapid interface swapping. This swapping does not require ATP, occurs in the presence of fluoroquinolones, and raises the possibility of non-homologous recombination solely through gyrase activity. The ability of gyrase to undergo interface swapping explains how gyrase heterodimers, containing a single active-site tyrosine, can carry out double-strand passage reactions and therefore suggests an alternative explanation to the recently proposed 'swivelling' mechanism for DNA gyrase (Gubaev et al., 2016).

Trajectory-based global sensitivity analysis in multiscale models.

This research introduces a novel global sensitivity analysis (GSA) framework for agent-based models (ABMs) that explicitly handles their distinctive features, such as multi-level structure and temporal dynamics. The framework uses Grassmannian diffusion maps to reduce output data dimensionality and sparse polynomial chaos expansion (PCE) to compute sensitivity indices for stochastic input parameters. To demonstrate the versatility of the proposed GSA method, we applied it to a non-linear system dynamics model and epidemiological and economic ABMs, depicting different dynamics. Unlike traditional GSA approaches, the proposed method enables a more general estimation of parametric sensitivities spanning from the micro level (individual agents) to the macro level (entire population). The new framework encourages the use of manifold-based techniques in uncertainty quantification, enhances understanding of complex spatio-temporal processes, and equips ABM practitioners with robust tools for detailed model analysis. This empowers them to make more informed decisions when developing, fine-tuning, and verifying models, thereby advancing the field and improving routine practice for GSA in ABMs.

Building a National Standard for Outreach and Assistance to At-Risk Patients During Large-Scale Disasters.

Health care institutions play an essential role in community resilience. As one of the largest health care systems in the United States, the Veterans Health Administration (VHA) plays a critical role in supporting medically vulnerable Veterans during disasters. Disasters require large-scale outreach to individuals in affected areas, including the capability to identify patients, establish contact, determine needs, and deliver required services. Here we describe the development and implementation of VHA's Vulnerable Patient Care, Access, and Response in Emergencies (VP CARE) program, a data-driven system of outreach to preidentified medically vulnerable patients, which seeks to streamline this process. VP CARE was inspired by the VHA's Home-Based Primary Care (HBPC) program and the US Department of Health and Human Services' emPOWER program. It seeks to enhance Veteran patients' well-being and continuity of care during disasters using 3 components: (1) improving the readiness and resilience of vulnerable patients and their caregivers; (2) establishing an organization, policies, procedures, and competency-based training exercises to guide outreach and assistance; and (3) creating and implementing standardized 1- and 2-way outreach technology and reporting. Using Geographic Information Systems embedded in VP CARE, VHA can generate a list of high-risk patients and deploy a 2-way texting capability to contact and receive responses from them. VP CARE automatically tracks patient contact and responses, reducing duplication of effort and freeing up VA staff to focus on patients with immediate needs. Patients and their caregivers benefit from the reassurance of knowing that VHA is focused on their well-being and available to support them. The technologies deployed in VP CARE improve the efficiency of outreach efforts and reduce the risk of life-threatening harm, while reducing the cost and demands on VA staff. This article concludes with lessons learned that may be instructive for other health care systems seeking to establish similar outreach capabilities.

A STATISTICAL FRAMEWORK FOR THE MODELING OF THE CONTINUOUS PROGRESSION OF ALZHEIMER'S DISEASE.

Throughout an organism's life, a multitude of biological systems transition through complex biophysical processes. These processes serve as indicators of the underlying biological states. Inferring these latent unobserved states is a key problem in modern biology and neuroscience. Unfortunately, in many experimental setups we can at best obtain snapshots of the system at different times for different individuals, and one major challenge is the one of reconciling those measurements. This formalism is particularly relevant in the study of Alzheimer's Disease (AD) progression, in which we observe in brain donors the aggregation of pathological proteins but the underlying disease state is unknown. The progression of AD can be modeled by assigning a latent score - termed pseudotime - to each pathological state, creating a pseudotemporal ordering of donors based on their pathological burden. This paper proposes a hierarchical Bayesian framework to model AD progression using detailed quantification of multiple AD pathological proteins from the Seattle AD Brain Cell Atlas consortium (SEA-AD). Inspired by biophysical models, we model pathological burden as an exponential process. Theoretical properties of the model are studied, by using linearization to reveal convergence and identifiability properties. We provide Markov chain Monte Carlo estimation algorithms, and show the effectiveness of our approach with multiple simulation studies across data conditions. Applying the methodology to SEA-AD brain data, we infer pseudotime for each donor and order them by pathological burden. Finally, we analyze the information within each pathological feature and utilize it to refine the model by focusing on the most informative pathologies. This lays the groundwork for suggesting future experimental design approaches.

Corrigendum: Editorial: Targeting DNA damage response to enhance antitumor innate immunity in radiotherapy.

[This corrects the article DOI: 10.3389/fonc.2023.1257622.].

Meaningful consumer involvement in cancer care: a systematic review on co-design methods and processes.

OBJECTIVE: Although the benefits of consumer involvement in research and health care initiatives are known, there is a need to optimize this for all people with cancer. This systematic review aimed to synthesize and evaluate the application of co-design in the oncology literature and develop recommendations to guide the application of optimal co-design processes and reporting in oncology research, practice, and policy. METHODS: A systematic review of co-design studies in adults with cancer was conducted, searching MEDLINE, CINAHL, Embase, and PsycINFO databases and included studies focused on 2 concepts, co-design and oncology. RESULTS: A total of 5652 titles and abstracts were screened, resulting in 66 eligible publications reporting on 51 unique studies. Four frameworks were applied to describe the co-design initiatives. Most co-design initiatives were designed for use in an outpatient setting (n = 38; 74%) and were predominantly digital resources (n = 14; 27%) or apps (n = 12; 23%). Most studies (n = 25; 49%) used a co-production approach to consumer engagement. Although some studies presented strong co-design methodology, most (n = 36; 70%) did not report the co-design approach, and 14% used no framework. Reporting was poor for the participant level of involvement, the frequency, and time commitment of co-design sessions. Consumer participation level was predominantly collaborate (n = 25; 49%). CONCLUSIONS: There are opportunities to improve the application of co-design in oncology research. This review has generated recommendations to guide 1) methodology and frameworks, 2) recruitment and engagement of co-design participants, and 3) evaluation of the co-design process. These recommendations can help drive appropriate, meaningful, and equitable co-design, leading to better cancer research and care.

Psychosocial burden of autoimmune blistering diseases: A comprehensive survey study.

BACKGROUND: Autoimmune blistering diseases (AIBDs) are severe dermatologic disorders known for their debilitating physical impact. Recent research has reported that AIBDs lead to psychosocial impairment, including depression and anxiety. Missing from the extant literature is an examination of the impact of AIBDs on body image and related psychological constructs. OBJECTIVES: The current study seeks to characterize the psychological and social consequences of AIBD diagnosis, with particular attention to body image dissatisfaction. METHODS: We conducted a survey study of adults with AIBDs. The survey was open from February 2023 to March 2023. Validated self-report questionnaires assessed depressive symptomatology, body image disturbance and quality of life. Demographic information and self-reported psychiatric history before and after AIBD diagnosis were collected via self-report. Participants were 451 adults with AIBDs, recruited through the International Pemphigus and Pemphigoid Foundation newsletters, email distribution lists and social media. RESULTS: Participants reported increased incidence of psychiatric disorders following AIBD diagnosis. Participants reported high levels of depressive symptomatology and impairments to quality of life compared to other patient groups. The sample reported extremely high levels of body image disturbance, more so than other patients with disfiguring diseases or injury. Correlation analyses revealed significant relationships between body image variables and quality of life, even after controlling for depression. CONCLUSIONS: Current treatment guidelines for AIBDs focus primarily on the management of disease flares and the consequences of immunosuppression, without consideration of the psychosocial consequences of the disease. The current study underscores the need for mental health support for patients with AIBDs.

Harnessing open science practices to teach ecology and evolutionary biology using interactive tutorials.

Open science skills are increasingly important for a career in ecology and evolutionary biology (EEB) as efforts to make data and analyses publicly available continue to become more commonplace. While learning core concepts in EEB, students are also expected to gain skills in conducting open science to prepare for future careers. Core open science skills like programming, data sharing, and practices that promote reproducibility can be taught to undergraduate students alongside core concepts in EEB. Yet, these skills are not always taught in biology undergraduate programs, and a major challenge in developing open science skills and learning EEB concepts simultaneously is the high cognitive load associated with learning multiple disparate concepts at the same time. One solution is to provide students with easily digestible, scaffolded, pre-formatted code in the form of vignettes and interactive tutorials. Here, we present six open source teaching tutorials for undergraduate students in EEB. These tutorials teach fundamental ecological concepts, data literacy, programming (using R software), and analysis skills using publicly available datasets while introducing students to open science concepts and tools. Spanning a variety of EEB topics and skill levels, these tutorials serve as examples and resources for educators to integrate open science tools, programming, and data literacy into teaching EEB at the undergraduate level.

Fecal Microbiota Transplantation in a Domestic Ferret Suffering from Chronic Diarrhea and Maldigestion-Fecal Microbiota and Clinical Outcome: A Case Report.

This case report describes the effects of fecal microbiota transplantation (FMT) administered via enema in a 4-year-old spayed, champagne Domestic Ferret (Mustela putorius furo) with chronic diarrhea, maldigestion and weight loss. We aimed to establish a protocol for FMT as a novel therapeutic treatment for chronic diarrhea in domestic ferrets. We mapped the fecal microbiome by 16S rRNA gene amplicon sequencing to track the patient's fecal microbiota throughout the treatment and observation period. Initial oral FMTs were associated with temporary weight improvement but subsequent treatments, via enema and oral delivery, showed varied outcomes. Molecular analysis highlighted distinct gut microbiota composition profiles between the healthy donor and the diseased ferret. The diseased ferret initially exhibited high abundance of Enterobacteriaceae, Escherichia, and Enterobacter, which ultimately normalized to level like those found in the donor ferret. Overall, the gut microbiota of the recipient became more similar to the donor microbiota using a Yue-Clayton theta coefficients analysis. After a restoration of the gut microbiota and clinical improvement, the recipient's symptoms returned indicating that repeated FMTs might be required for long-term resolution of symptoms and complete restructuring of the gut microbiota. Future studies are warranted to map the microbiome of a larger population of domestic ferrets to investigate a potential correlation between fecal microbiota profiles and chronic/acute gastrointestinal disorders.

Giant root-rat engineering and livestock grazing activities regulate plant functional trait diversity of an Afroalpine vegetation community in the Bale Mountains, Ethiopia.

Disturbances from rodent engineering and human activities profoundly impact ecosystem structure and functioning. Whilst we know that disturbances modulate plant communities, comprehending the mechanisms through which rodent and human disturbances influence the functional trait diversity and trait composition of plant communities is important to allow projecting future changes and to enable informed decisions in response to changing intensity of the disturbances. Here, we evaluated the changes in functional trait diversity and composition of Afroalpine plant communities in the Bale Mountains of Ethiopia along gradients of engineering disturbances of a subterranean endemic rodent, the giant root-rat (Tachyoryctes macrocephalus Rüppell 1842) and human activities (settlement establishment and livestock grazing). We conducted RLQ (co-inertia analysis) and fourth-corner analyses to test for trait-disturbance (rodent engineering/human activities) covariation. Overall, our results show an increase in plant functional trait diversity with increasing root-rat engineering and increasing human activities. We found disturbance specific association with traits. Specifically, we found strong positive association of larger seed mass with increasing root-rat fresh burrow density, rhizomatous vegetative propagation negatively associated with increasing root-rat old burrow, and stolonifereous vegetative propagation positively associated with presence of root-rat mima mound. Moreover, both leaf size and leaf nitrogen content were positively associated with livestock dung abundance but negatively with distance from settlement. Overall, our results suggest that disturbances by rodents filter plant traits related to survival and reproduction strategies, whereas human activities such as livestock grazing act as filters for traits related to leaf economics spectrum along acquisitive resource-use strategy.

A Case Series Study Assessing an Equity-Focused Implementation of Self-Monitoring Blood Pressure Programs Using Telehealth.

CONTEXT: Self-monitoring blood pressure (SMBP) programs are an evidence-based hypertension management intervention facilitated through telehealth. SMBP programs can provide a continuum of care beyond a clinical setting by facilitating hypertension management at home; however, equitable access to SMBP is a concern. OBJECTIVES: To evaluate the implementation of telehealth SMBP programs using an equity lens in 5 federally qualified health centers (FQHCs) in Massachusetts (MA). DESIGN: A prospective case series study. SETTING: Five FQHCs. PARTICIPANTS: The MA Department of Public Health (MDPH) selected 5 FQHCs to implement SMBP programs using telehealth. FQHCs were selected if their patient population experiences inequities due to social determinants of health and has higher rates of cardiovascular disease. Each of the 5 FQHCs reported data on patients enrolled in their SMBP programs totaling 241 patients examined in this study. INTERVENTION: SMBP programs implemented through telehealth. MAIN OUTCOME MEASURE: Systolic blood pressure and diastolic blood pressure. RESULTS: Approximately 53.5% of SMBP participants experienced a decrease in blood pressure. The average blood pressure decreased from 146/87 to 136/81 mm Hg. Among all patients across the 5 FQHCs, the average blood pressure decreased by 10.06/5.34 mm Hg (P < .001). Blood pressure improved in all racial, ethnic, and language subgroups. CONCLUSIONS: Five MA FQHCs successfully implemented equitable telehealth SMBP programs. SMBP participants enrolled in the programs demonstrated notable improvements in their blood pressure at the conclusion of the program. A flexible, pragmatic study design that was adjusted to meet unique patient needs; engaging nonphysician team members, particularly community health workers; adapting health information technology; and partnerships with community-based organizations were critical facilitators to program success.

Novel Mouse Model of Myocardial Infarction, Plaque Rupture, and Stroke Shows Improved Survival With Myeloperoxidase Inhibition.

BACKGROUND: Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of death worldwide. Although most mouse models of atherosclerosis develop lesions in the aorta and carotid arteries, they do not develop advanced coronary artery lesions. Moreover, they do not undergo spontaneous plaque rupture with MI and stroke or do so at such a low frequency that they are not viable experimental models to study late-stage thrombotic events or to identify novel therapeutic approaches for treating atherosclerotic disease. This has stymied the development of more effective therapeutic approaches for reducing these events beyond what has been achieved with aggressive lipid lowering. Here, we describe a diet-inducible mouse model that develops widespread advanced atherosclerosis in coronary, brachiocephalic, and carotid arteries with plaque rupture, MI, and stroke. METHODS: We characterized a novel mouse model with a C-terminal mutation in the scavenger receptor class B, type 1 (SR-BI), combined with Ldlr knockout (designated SR-BI∆CT/∆CT/Ldlr-/-). Mice were fed Western diet (WD) for 26 weeks and analyzed for MI and stroke. Coronary, brachiocephalic, and carotid arteries were analyzed for atherosclerotic lesions and indices of plaque stability. To validate the utility of this model, SR-BI∆CT/∆CT/Ldlr-/- mice were treated with the drug candidate AZM198, which inhibits myeloperoxidase, an enzyme produced by activated neutrophils that predicts rupture of human atherosclerotic lesions. RESULTS: SR-BI∆CT/∆CT/Ldlr-/- mice show high (>80%) mortality rates after 26 weeks of WD feeding because of major adverse cardiovascular events, including spontaneous plaque rupture with MI and stroke. Moreover, WD-fed SR-BI∆CT/∆CT/Ldlr-/- mice displayed elevated circulating high-sensitivity cardiac troponin I and increased neutrophil extracellular trap formation within lesions compared with control mice. Treatment of WD-fed SR-BI∆CT/∆CT/Ldlr-/- mice with AZM198 showed remarkable benefits, including >90% improvement in survival and >60% decrease in the incidence of plaque rupture, MI, and stroke, in conjunction with decreased circulating high-sensitivity cardiac troponin I and reduced neutrophil extracellular trap formation within lesions. CONCLUSIONS: WD-fed SR-BI∆CT/∆CT/Ldlr-/- mice more closely replicate late-stage clinical events of advanced human atherosclerotic disease than previous models and can be used to identify and test potential new therapeutic agents to prevent major adverse cardiac events.

Sex differences in brain resilience of individuals with multiple sclerosis.

BACKGROUND: Brain resilience allows maintenance of neurocognitive function in the face of age or disease-related neural changes. OBJECTIVE: Test the hypothesis that women and men with MS differ in brain resilience. METHODS: This cross-sectional analysis of prospective cohort data included 11,297 patients. Linear mixed effects models predicted performance outcomes on tasks of fine motor dexterity and cognitive processing speed for MRI proxies of disease burden: brain parenchymal fraction (BPF), T2 lesion volume, volumes of deep gray, thalamus, white and cortical gray matter. Covariates were age, sex, age-by-sex, current disease-modifying therapy, disease phenotype, education, total brain volume, and total brain volume-by-sex. Sex-by-MRI metric terms tested primary hypothesis of differential brain-behavior relationships between men and women. RESULTS: Final sample included 10,286 participants. Lower BPF was associated with worse performance (p's<0.001) in men and women; association was smaller for women than men for processing speed (ßetaWomen-Men=-0.044, 95 % CI=[-0.087, -0.002], p = 0.041) and manual dexterity (ßetaWomen-Men=-0.073, 95 % CI=[-0.124, -0.023], p = 0.005). For each MRI variable, women demonstrated better neurocognitive function controlling for disease burden. DISCUSSION: Sex differences in brain metric-neurofunctional performance relationships of people with MS suggest women have higher resilience than men in the face of increased disease burden. Future work exploring mechanism is warranted.

Diagnosis concealment behaviors and disclosure beliefs are associated with health and quality of life in people with multiple sclerosis.

BACKGROUND: People with multiple sclerosis (pwMS) struggle with whether, how, and how much to disclose their diagnosis. They often expend resources to conceal their diagnosis, and hold beliefs that it may negatively affect their personal relationships and/or professional opportunities. To better understand these effects, we developed a measure to quantify concealment behaviors and disclosure beliefs. Our main objective is to evaluate relationships of DISCO-MS responses to health and quality of life in a multinational cohort. METHODS: Survey responses were obtained for DISCO-MS and PROMIS-MS scales: global health, communication, social roles participation, anxiety, depression, emotional / behavioral dyscontrol, fatigue, lower extremity function, positive affect / well-being, social roles satisfaction, sleep, stigma, upper extremity function, cognitive function, bladder control, bowel control, visual function. Simple linear regression assessed associations. RESULTS: 263 pwMS were include. Higher concealment was associated with higher anxiety (beta= 0.15 [0.07, 0.23]), depression (beta = 0.13 [0.05, 0.21]), emotional dyscontrol (beta = 0.12 [0.04, 0.20]), lower affect / well-being (beta = -0.13 [-0.21, - 0.05]). Higher anticipation of negative consequences of disclosure was associated with lower self-reported physical (beta = -0.15) and mental health (beta = -0.14), lower positive affect / well-being, social roles satisfaction, higher anxiety, depression, emotional dyscontrol, sleep disturbance, and higher perceived stigma. DISCUSSION: These results reveal potential consequences of diagnosis concealment for physical and mental health and quality of life. Raising awareness and implementing interventions may mitigate negative repercussions of concealment.

Metabolomic Analysis and Antiviral Screening of a Marine Algae Library Yield Jobosic Acid (2,5-Dimethyltetradecanoic Acid) as a Selective Inhibitor of SARS-CoV-2.

Current small-molecule-based SARS-CoV-2 treatments have limited global accessibility and pose the risk of inducing viral resistance. Therefore, a marine algae and cyanobacteria extract library was screened for natural products that could inhibit two well-defined and validated COVID-19 drug targets, disruption of the spike protein/ACE-2 interaction and the main protease (Mpro) of SARS-CoV-2. Following initial screening of 86 extracts, we performed an untargeted metabolomic analysis of 16 cyanobacterial extracts. This approach led to the isolation of an unusual saturated fatty acid, jobosic acid (2,5-dimethyltetradecanoic acid, 1). We confirmed that 1 demonstrated selective inhibitory activity toward both viral targets while retaining some activity against the spike-RBD/ACE-2 interaction of the SARS-CoV-2 omicron variant. To initially explore its structure-activity relationship (SAR), the methyl and benzyl ester derivatives of 1 were semisynthetically accessed and demonstrated acute loss of bioactivity in both SARS-CoV-2 biochemical assays. Our efforts have provided copious amounts of a fatty acid natural product that warrants further investigation in terms of SAR, unambiguous determination of its absolute configuration, and understanding of its specific mechanisms of action and binding site toward new therapeutic avenues for SARS-CoV-2 drug development.

Guiding the Implementation of Wastewater-based Surveillance for Carceral Infection Control with Perspectives from People with Lived Experience of Incarceration during the COVID-19 Pandemic.

Background: Little guidance exists on best practices for implementing and sustaining wastewater-based surveillance (WBS) for SARS-CoV-2 in carceral settings. To ensure alignment with priorities of stakeholders, we aimed to understand the perspectives of persons with lived experience (PLE) of jail who were incarcerated during the height of the COVID-19 pandemic on infection control. Methods: We recruited two PLE at each of four jails: Cook County (IL), Fulton County (GA), Middlesex County (MA), and Washington DC. Focus Group Discussion (FGD) guides followed the Consolidated Framework for Implementation Research (CFIR). Two FGDs focusing on lived experience with jail infection control protocol and WBS were conducted, and six Key Informant (KI) interviews followed to gain insights on communicating WBS results. We used a combination of deductive thematic analysis based on CFIR constructs and inductive analysis to capture emergent themes. Results: Themes from FGDs included: (1) variable experiences with COVID-19 infection control protocols including intake processes, individual testing, isolation and quarantine, (2) the perceived attitudes of fellow residents and staff surrounding COVID-19 mitigation in a carceral setting; and (3) perceived benefits and challenges involving WBS implementation and messaging. KIs emphasized 1) The importance of straightforward health messaging and trustworthiness in the communication of WBS results, 2) Support for enhanced health education around outbreaks, and 3) Receptiveness to WBS being used as a tool to measure common infectious agents (i.e., influenza) but hesitancy regarding its application to conditions such as HIV and illicit drug use. PLE articulated support of robust infection control programs and receptiveness to expanding WBS if conducted in a non-stigmatizing manner. Conclusion: Perspectives from PLE can help shape the infection control programs for future outbreaks and inform the expansion of WBS implementation in carceral facilities. It will be important to consider the voices of current and former residents, as receivers of care, to promote an environment conducive to comprehensive infection control. In addition to having infection control programs consistently execute set protocols and educate all stakeholders, PLE identified collaboration between jail staff and residents, and clear communication around program expectations as priorities. Findings from this qualitative study can be shared with jail decision makers and the perceived engagement of stakeholders can be measured.