Search

Abstract Background Advance Care Planning via Group Visits (ACP-GV) is a patient-centered intervention facilitated by a clinician using a group modality to promote healthcare decision-making among veterans. Participants in the group document a “Next Step” to use in planning for their future care needs. The next step may include documentation of preferences in an advance directive, discussing plans with family, or anything else to fulfill their ACP needs. This evaluation seeks to determine whether there are identifiable subgroups of group participants with differing needs prior to delivery of the ACP-GV program and, if so, to use information about the subgroups to enhance the program offered to veterans in United States Department of Veterans Affairs (VA) healthcare settings. Methods We conducted a secondary analysis of national data from a quality improvement evaluation. Patient- and provider-level data from administrative healthcare records for VA users in all 50 states, territories, and the District of Columbia provides data on veterans attending ACP-GV during federal fiscal years 2018–2022 (N = 26,857). Latent class analysis seeks to identify the various subgroups of veterans based on their level of ACP self-efficacy before attending ACP-GV and any demographic differences across the resulting subgroups of veterans attending ACP-GV. ACP self-efficacy is derived from seven items obtained from a participant worksheet used during the group. Results Analysis revealed two distinct groups of veterans, distinguishable by their pre-ACP-GV levels of one aspect of ACP self-efficacy: prior knowledge of ACP. Veterans with higher prior knowledge of ACP are associated with an identified next step focused on checking their current AD status and updating it, and veterans with lower ACP prior knowledge are associated with identifying a next step to discuss ACP more fully with family. Differences in age, sex, race, ethnicity, and marital status exist across subgroups of veterans. Conclusion Greater attention must be paid to ACP and veterans’ prior knowledge of ACP to consistently encourage annual review and status updates.

Abstract Within the healthcare settings of the United States Department of Veterans Affairs (VA), one patient-centered intervention, Advance Care Planning via Group Visits (ACP-GV), engages veterans and those they trust in advance care planning (ACP) by facilitating a discussion that encourages participants to plan for future healthcare needs. ACP-GV is a one-hour, single session group intervention facilitated by a trained clinical professional (e.g., physician, nurse, social worker, psychologist, chaplain) and delivered in a healthcare or community-based setting. Using reporting guidelines for group-based and educational interventions, this paper aims to describe the ACP-GV Facilitator Training used to prepare clinical professionals to offer the ACP-GV intervention to participants. We provide health professional students and early career health professionals with an overview of the training and key tips for using group modalities in the clinical setting. Although the training is initially directed towards health professionals who are learning to offer ACP-GV for the first time, our tips for teaching also focus on and extend to facilitating ACP-GV directly with veterans, caregivers, and those they trust. The ACP-GV Facilitator Training is sequential in that it expects clinicians to first learn the required educational content and how to plan a group, then it engages clinicians in practicing group facilitation skills. At the conclusion of the training, clinicians are then instructed to use the training materials to transfer the information and skills they learned about ACP-GV to patients they encounter in their respective work settings. The culmination of the ACP-GV Facilitator Training is, therefore, when the clinician is able to facilitate their own group, guide discussions and activities, actively use training materials, and encourage veterans and those they trust to participate in a discussion regarding ACP in a group setting. Finally, we share key resources for publicly available and accessible online trainings to promote spread outside of VA. ACP-GV’s Facilitator Training can assist healthcare professionals in implementing ACP-GV in a variety of care settings.

Objective Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases. Establishing autoimmunity in ILD impacts prognosis and treatment. Patients with ILD are screened for autoimmunity by measuring antinuclear autoantibodies, rheumatoid factors, and other nonspecific tests. However, this approach may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. Methods We use Phage Immunoprecipitation‐Sequencing (PhIP‐Seq) to conduct an autoantibody discovery screen of patients with ILD and controls. We screened for novel autoantigen candidates using PhIP‐Seq. We next developed a radio‐labeled binding assay and validated the leading candidate in 398 patients with ILD recruited from two academic medical centers and 138 blood bank individuals that formed our reference cohort. Results PhIP‐Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among the 17 candidates, we validated CDHR5 and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, patients not previously diagnosed with autoimmunity. Using survival and transplant free–survival data available from one of the two centers, patients with CDHR5 autoantibodies showed worse survival compared with other patients with connective tissue disease ILD. Conclusion We used PhIP‐Seq to define a novel CDHR5 autoantibody in a subset of select patients with ILD. Our data complement a recent study showing polymorphisms in the CDHR5‐IRF7 gene locus strongly associated with titer of anticentromere antibodies in systemic sclerosis, creating a growing body of evidence suggesting a link between CDHR5 and autoimmunity.

Abstract Ryugu is the C-type asteroid from which material was brought to Earth by the Hayabusa2 mission. A number of individual grains and fine-grained samples analysed so far for noble gases have indicated that solar wind and planetary (known as P1) noble gases are present in Ryugu samples with concentrations higher than those observed in CIs, suggesting the former to be more primitive compared to the latter. Here we present results of analyses of three fine-grained samples from Ryugu, in one of which Xe concentration is an order of magnitude higher than determined so far in other samples from Ryugu. Isotopically, this Xe resembles P1, but with a much stronger isotopic fractionation relative to solar wind and significantly lower 36Ar/132Xe ratio than in P1. This previously unknown primordial noble gas component (here termed P7) provides clues to constrain how the solar composition was fractionated to form the planetary components.

Medicinal plants have long been used to treat various diseases in both indigenous and non-indigenous populations of Mindanao, Philippines. Here, we extracted data from ethnobotanical studies to compile a comprehensive list of these medicinal plants and identify how and for what purpose they are most commonly used. We identified 530 verified medicinal plant species across 372 genera in 118 families. The two most frequently cited species were Euphorbia hirta and Psidium guajava. The most represented family was Fabaceae and the most represented genus was Ficus. A total of 28 medicinal plant species are designated as threatened at the national or global level; of these, 11 are endemic to the Philippines. Medicinal plant preparations most commonly use leaves for oral administration to treat various diseases such as digestive issues, including diarrhea. This study underscores the need for further ethnobotanical investigations, particularly in areas lacking records. It also emphasizes the need for conservation of threatened and endemic medicinal plants to ensure sustainable utilization of this valuable resource.

Abstract The SARS-CoV-2 outbreak has provoked more than 6 million deaths worldwide. The scarcity of effective treatments and its virulence converted the vaccines into an essential tool to face it. The most used vaccines were the mRNA, adenovirus vector, and inactivated whole-virus. However, nowadays, infants aged

Abstract Background Ehrlichiosis is a potentially fatal tick-borne disease that can progress to involve the central nervous system (CNS) (i.e., neuro-ehrlichiosis), particularly in cases where diagnosis and treatment are delayed. Despite a six-fold national increase in the incidence of ehrlichiosis over the past 20 years, recent data on the prevalence and manifestations of neuro-ehrlichiosis are lacking. Methods We conducted a retrospective chart review of all patients tested for ehrlichiosis at University of North Carolina Health facilities between 2018 and 2021 and identified patients who met epidemiological criteria for ehrlichiosis as established by the Council of State and Territorial Epidemiologists and employed by the Centers for Disease Control and Prevention. We estimated the prevalence of neurological symptoms and described the spectrum of neurological manifestations in acute ehrlichiosis, documenting select patient cases in more detail in a case series. Results Out of 55 patients with confirmed or probable ehrlichiosis, five patients (9.1%) had neurologic symptoms, which is notably lower than previous estimates. Neurological presentations were highly variable and included confusion, amnesia, seizures, focal neurological deficits mimicking ischemic vascular events, and an isolated cranial nerve palsy, though all patients had unremarkable neuroimaging at time of presentation. All but one patient had risk factors for severe ehrlichiosis (i.e., older age, immunosuppression). Conclusions Neuro-ehrlichiosis may lack unifying patterns in clinical presentation that would otherwise aid in diagnosis. Clinicians should maintain a high index of suspicion for neuro-ehrlichiosis in patients with acute febrile illness, diverse neurological symptoms, and negative neuroimaging in lone star tick endemic regions.

Abstract Background Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an inhibitory cell surface protein that functions through homophilic and heterophilic ligand binding. Its expression on immune cells in human tumors is poorly understood. Methods An antibody that distinguishes human CEACAM1 from other highly related CEACAM family members was labeled with 159Tb and inserted into a panel of antibodies that included specificity for programmed cell death protein 1 (PD1) and PD-L1, which are targets of immunotherapy, to gain a data-driven immune cell atlas using cytometry by time-of-flight (CyTOF). A detailed inventory of CEACAM1, PD1, and PD-L1 expression on immune cells in metastatic lesions to lymph node or soft tissues and peripheral blood samples from patients with treatment-naive and -resistant melanoma as well as peripheral blood samples from healthy controls was performed. Results CEACAM1 is absent or at low levels on healthy circulating immune cells but is increased on immune cells in peripheral blood and tumors of melanoma patients. The majority of circulating PD1-positive NK cells, innate T cells, B cells, monocytic cells, dendritic cells, and CD4+ T cells in the peripheral circulation of treatment-resistant disease co-express CEACAM1 and are demonstrable as discrete populations. CEACAM1 is present on distinct types of cells that are unique to the tumor microenvironment and exhibit expression levels that are highest in treatment resistance; this includes tumor-infiltrating CD8+ T cells. Conclusions To the best of our knowledge, this work represents the first comprehensive atlas of CEACAM1 expression on immune cells in a human tumor and reveals an important correlation with treatment-resistant disease. These studies suggest that agents targeting CEACAM1 may represent appropriate partners for PD1-related pathway therapies.

Objective: To review the program and patient metrics for ovarian tissue cryopreservation (OTC) within a comprehensive pediatric fertility preservation program in its first 12 years of development. Design: Retrospective review. Setting: A tertiary children’s hospital in a large urban center between March 2011 and February 2023. Patients: Pediatric patients who underwent OTC. Interventions: Unilateral oophorectomy for OTC. Main Outcome Measures: Patient demographics and clinical course information were collected for analysis. Results: A total of 184 patients underwent OTC in the first 12 years. One hundred fifteen patients were prepubertal at the time of OTC, and 69 were postpubertal. In total, 128 patients (69.6%) received part of their planned therapy before OTC. Starting in 2018, 104 participants (92.0%) donated tissue to research, 99 participants (87.6%) donated blood, and 102 (90.2%) donated media to research. There was a decrease in the median age of patients who underwent OTC from 16.4–6.6 years and an overall increase in the proportion of patients per year that were prepubertal. Forty-eight (26.0%) patients who underwent OTC were outside referrals and traveled from as far as Seattle, Washington. Conclusion: During the first 12 years of this program, oncofertility research increased, annual tissue cryopreservation cases increased, and the median age of those who underwent OTC decreased. The program was adapted to build a stand-alone gonadal tissue processing suite and specialized in prepubertal ovarian tissue processing. The program will continue to adapt to patient needs in the upcoming decades because restoration technologies advance through research supported by this and collaborating programs.

IntroductionRegulatory CD8 T cells (CD8 Treg) are responsible for the selective killing of self-reactive and pathogenic CD4 T cells. In autoimmune disease, CD8 Treg may accumulate in the peripheral blood but fail to control the expansion of pathogenic CD4 T cells that subsequently cause tissue destruction. This CD8 Treg dysfunction is due in part to the expression of inhibitory killer immunoglobulin-like receptors (KIR; KIR2DL isoforms [KIR2DL1, KIR2DL2, and KIR2DL3]); these molecules serve as autoimmune checkpoints and limit CD8 Treg activation.MethodsHere we describe the pre-clinical characterization of MTX-101, a bispecific antibody targeting inhibitory KIR and CD8. Using human peripheral blood mononuculear cells (PBMC) derived from healthy donors and autoimmune patients, humanized mouse models, and human derived tissue organoids, we evaluated the molecular mechanisms and functional effects of MTX-101.ResultsBy binding to KIR, MTX-101 inhibited KIR signaling that can restore CD8 Treg ability to eliminate pathogenic CD4 T cells. MTX-101 bound and activated CD8 Treg in human peripheral blood mononuclear cells (PBMC), resulting in increased CD8 Treg cytolytic capacity, activation, and prevalence. Enhancing CD8 Treg function with MTX-101 reduced pathogenic CD4 T cell expansion and inflammation, without increasing pro-inflammatory cytokines or activating immune cells that express either target alone. MTX-101 reduced antigen induced epithelial cell death in disease affected tissues, including in tissue biopsies from individuals with autoimmune disease (i.e., celiac disease, Crohn’s disease). The effects of MTX-101 were specific to autoreactive CD4 T cells and did not suppress responses to viral and bacterial antigens. In a human PBMC engrafted Graft versus Host Disease (GvHD) mouse model of acute inflammation, MTX-101 bound CD8 Treg and delayed onset of disease. MTX-101 induced dose dependent binding, increased prevalence and cytolytic capacity of CD8 Treg, as well as increased CD4 T cell death. MTX-101 selectively bound CD8 Treg without unwanted immune cell activation or increase of pro-inflammatory serum cytokines and exhibited an antibody-like half-life in pharmacokinetic and exploratory tolerability studies performed using IL-15 transgenic humanized mice with engrafted human lymphocytes, including CD8 Treg at physiologic ratios.ConclusionCollectively, these data support the development of MTX-101 for the treatment of autoimmune diseases.

Summary: Goals of care (Goals-of-care) discussions and palliative care (PC) are crucial to providing comprehensive healthcare, particularly for acute neurological conditions requiring admission to a neurological intensive care unit. We identified gaps in the literature and describe insight for future research on end-of-life discussions and PC for U.S. Latinos with acute neurological conditions. We searched 10 databases including peer-reviewed abstracts and manuscripts of hospitalized U.S. Latinos with acute neurological and non-neurological conditions. We included 44 of 3231 publications and identified various themes: PC utilization, pre-established advanced directives in Goals-of-care discussions, Goals-of-care discussion outcomes, tracheostomy or percutaneous gastrostomy tube placement rates among hospitalized Latinos. Our review highlights that Latinos appear to have lower palliative care utilization compared with non-Latino Whites and may be less likely to have pre-established advanced directives, more likely to have gastrostomy or tracheostomy placement and less likely to have do-not-resuscitate status.

Three senior figures at the US National Institutes of Health explain why the agency remains committed to supporting basic science and research.

To determine antimicrobial susceptibility of Neisseria gonorrhoeae, we analyzed phenotypes and genomes of 72 isolates collected in Cambodia in 2023. Of those, 9/72 (12.5%) were extensively drug resistant, a 3-fold increase from 2022. Genomic analysis confirmed expansion of newly emerging resistant clones and ongoing resistance emergence across new phylogenetic backbones.

Purpose: The purpose of this study was to determine the association between lens thickness and cataract in participants aged 0 to 5 years. Design: This was a prospective, multicenter, case–control study. Participants: We enrolled 118 participants (171 eyes) aged 0 to 5 years, mean age 14.6 ± 17.0 months, range 0 to 60 months. Methods: Lens thickness was measured on 342 ultrasound biomicroscopy (UBM) images. Main Outcome Measures: Lens thickness; feasibility of lens thickness measurement from UBM images. Results: The mean lens thickness among noncataracts was 3.60 ± 0.17 mm, compared with 3.16 ± 0.61 mm among cataracts (P < 0.0001). Lens thickness

Skin melanoma is considered the most dangerous form of skin cancer due to its association with high risk of metastasis, high mortality rate and high resistance to different treatment options. Genistein is a natural isoflavonoid with known chemotherapeutic activity. Unfortunately, it has low bioavailability due to its poor aqueous solubility and excessive metabolism. In the current study, genistein was incorporated into transferosomal hydrogel to improve its bioavailability. The prepared transferosomal formulations were characterized regarding: particle size; polydispersity index; zeta potential; encapsulation efficiency; TEM; FTIR; DSC; XRD; in vitro drug release; viscosity; pH; ex vivo anti-tumor activity on 3D skin melanoma spheroids and 1-year stability study at different storage temperatures. The optimized formulation has high encapsulation efficiency with an excellent particle size that will facilitate its penetration through the skin. The transfersomes have a spherical shape with sustained drug release profile. The anti-tumor activity evaluation of genistein transfersome revealed that genistein is a potent chemotherapeutic agent with enhanced penetration ability through the melanoma spheroids when incorporated into transfersomes. Stability study results demonstrate the high physical and chemical stability of our formulations. All these outcomes provide evidence that our genistein transferosomal hydrogel is a promising treatment option for skin melanoma.

Objective: To examine longitudinal associations between self-reported sleep disturbances and mobility disability progression among women, including subgroups with multiple sclerosis (MS), diabetes, and osteoarthritis (OA). Methods: Prospective cohort study using data from Nurses’ Health Study long-form questionnaires (2008, 2012, 2014, 2016). Logistic regression was used to quantify associations between sleep-related variables at baseline and subsequent increase in mobility disability. Results: Of 70,303 women (mean age 73), 392 had MS, 7,302 had diabetes, and 24,099 had OA. Between 2008–2016, mobility disability increased by 16.9 % overall, 27.8 % in the MS subgroup, 27.0 % in the diabetes subgroup, and 23.7 % in the OA subgroup. Known/suspected obstructive sleep apnea was significantly associated with an increase in mobility disability between 2008 and 2016, overall (OR:1.4, 95 %CI:1.2,1.5), and in the diabetes (OR:1.5, 95 %CI:1.2,1.9) and OA subgroups (OR:1.2, 95 %CI:1.0,1.4), but not in the MS subgroup (OR:2.3, 95 %CI:0.6,8.9); however, across 2012–2016, this association was significant for MS (OR:4.0, 95 %CI:1.0,16.1). Suboptimal sleep duration was significantly associated with increased odds of mobility disability progression overall, but not in disease subgroups. Perception of adequate sleep was associated with lower odds of mobility disability progression overall (OR:0.82, 95 %CI:0.78,0.87) and for the OA subgroup (OR:0.83, 95 %CI:0.76,0.91). Excessive daytime sleepiness was associated with mobility disability progression overall (OR:1.2, 95 %CI:1.1,1.4) and for the OA subgroup (OR:1.2, 95 %CI:1.0,1.4). Conclusions: Prevalent sleep disturbances could increase disability progression among women. Chronic disease populations may be uniquely vulnerable. Informed by these data, future research could offer new insight into sleep-based strategies to ameliorate mobility decline.

Introduction Depression is prevalent among aging people living with HIV (PLWH) worldwide. We sought to identify depression risk factors among a group of middle-aged and older PLWH in Lima, Peru. Materials and Methods We assessed risk factors for depression among PLWH over age 40 receiving care in an HIV clinic in Lima, Peru. The Patient Health Questionnaire-9 (PHQ-9) was administered. We performed descriptive statistics and logistic regression analyses. Results Mean age was 51.7 ± 7.7 years with 15.3% females. One-quarter of participants had depression with higher frequency in females. Risk factors that significantly increased the risk of depression included female sex (adjusted prevalence ratio [aPR] = 2.19 [95%CI 1.07-4.49]), currently smoking (aPR = 2.25 [95%CI 1.15-4.43]), and prior opportunistic infection (aPR = 2.24 [95%CI 1.05-4.76]). Discussion Our study demonstrates that PLWH who are female, current smokers, or had an opportunistic infection have higher risk of depression. Identifying PLWH at-risk for depression is key to early mental health interventions.

Introduction: Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure for portal hypertension complications. However, regional geographical differences pose a particular challenge. This study analyzed the indications and the hemodynamic and technical outcomes of TIPS in patients with liver cirrhosis in a private medical setting in northern Mexico. Material and Methods: Three interventional radiologists conducted this cross-sectional study in two private Mexican hospitals between March 2004 and March 2024. Age, gender, etiology of cirrhosis, indications for TIPS, Child–Pugh score, and model for end-stage liver disease (MELD) were recorded electronically. The hemodynamic and technical outcomes of the TIPS were also recorded. Results: In total, 85 TIPS procedures were performed, 76.5% (n = 65) were performed in the last 10 years. The indications for TIPS were mainly secondary prevention of recurrent variceal bleeding in 47 (55.3%) patients, followed by refractory ascites in 35 (41.1%). Hemodynamic success was achieved in 73.7% from 2004 to 2013 and increased to 95.2% from 2014 to 2024, with a mean final portosystemic pressure gradient (PSPG) of 9 mmHg. Technical success, completing the shunt on the first attempt, was 100% over two decades. The most common etiology of cirrhosis was metabolic-associated fatty liver disease (MAFLD) (n = 29 patients, 34.1%). Conclusion: The main indication for TIPS in our study was secondary prevention of recurrent variceal bleeding, and hemodynamic and technical success was high. This study is the first in Mexico to analyze the indications and hemodynamic and technical outcomes of patients undergoing TIPS.

Parasympathetic activation in the anterior eye segment regulates various physiological functions. This process, mediated by muscarinic acetylcholine receptors, also impacts intraocular pressure (IOP) through the trabecular meshwork. While FDA-approved M3 muscarinic receptor (M3R) agonists exist for IOP reduction, their systemic cholinergic adverse effects pose limitations in clinical use. Therefore, advancing our understanding of the cholinergic system in the anterior segment of the eye is crucial for developing additional IOP-reducing agents with improved safety profiles. Systems genetics analyses were utilized to explore correlations between IOP and the five major muscarinic receptor subtypes. Molecular docking and dynamics simulations were applied to human M3R homology model using a comprehensive set of human M3R ligands and 1,667 FDA-approved or investigational drugs. Lead compounds from the modeling studies were then tested for their IOP-lowering abilities in mice. Systems genetics analyses unveiled positive correlations in mRNA expressions among the five major muscarinic receptor subtypes, with a negative correlation observed only in M3R with IOP. Through modeling studies, rivastigmine and edrophonium emerged as the most optimally suited cholinergic drugs for reducing IOP via a potentially distinct mechanism from pilocarpine or physostigmine. Subsequent animal studies confirmed comparable IOP reductions among rivastigmine, edrophonium, and pilocarpine, with longer durations of action for rivastigmine and edrophonium. Mild cholinergic adverse effects were observed with pilocarpine and rivastigmine but absent with edrophonium. These findings advance ocular therapeutics, suggesting a more nuanced role of the parasympathetic system in the anterior eye segment for reducing IOP than previously thought.

BackgroundCoronavirus disease 2019 (COVID-19) infection has been associated with severe neurological consequences, including stroke or seizures, and less severe neurological sequelae, including headaches, dizziness, and anosmia. Earlier COVID-19 variants were associated with high morbidity and mortality; however, knowledge of the impact of neurological conditions in the setting of COVID-19 on healthcare outcomes is limited. We sought to determine the impact of acute neurological conditions and acute COVID-19 infection on inpatient hospitalization outcomes.MethodsThis was a retrospective, observational study of adult patients who were admitted to a large academic medical center in the Southeastern US between April 2020 and December 2021 with acute COVID-19 infection and a neurological diagnosis. Patient demographics, medical history, neurological diagnoses, and hospitalization outcomes were obtained from the medical record. Descriptive statistics and unadjusted and adjusted logistic regression analyses were performed.ResultsOf the 1,387 patients included in this study, 27% died and 23% were kept under ventilation during hospitalization. The mean +/− standard deviation (SD) age was 64.6+/−16.9 years, with 52.8% women and 30.1% identifying as Black/African American. The most common neurological conditions included ischemic stroke (35.0%), movement disorder (12.0%), and hemorrhagic stroke (10.7%). In-hospital death was most common among those with epilepsy (p = 0.024), headache (p = 0.026), and dementia (p

Objective: Explore the roles of humility in healthcare delivery from perspectives of active doctors and nurses. Background: Although the concept of humility has gained attention in the healthcare and health professions education fields, previous literature has primarily been anecdotal reflections or conceptual explorations, leaving a gap of empirical approaches to what humility “looks like” in healthcare. Methods: Three hundred and five active U.S.-based doctors and nurses completed a survey containing close- and open-ended questions examining their experiences with and perceptions of humility in the clinical care setting. Results: The findings from this study echo previous literature touting the value of humility in regard to patient care, but also spotlight the connections between humility and status, how humility acts as a leveling mechanism, and humility's roles regarding facilitating collaborative, team-based care. We also find evidence of the effects of intellectual humility, as well as the tenets of the professional humility concept. Conclusion: According to doctors and nurses, humility is essential to high quality team-based, patient-centered care, but there is an explicit connection between humility and status – specifically related to the occupational status embedded within healthcare delivery. Future research should investigate not only how humility may facilitate interprofessionalism, but also the roles and impact of humility regarding uncertainty, and the processes related to feedback and decision making.

Abstract This study investigates correlates of anti-S1 antibody response following COVID-19 vaccination in a U.S. population-based meta-cohort of adults participating in longstanding NIH-funded cohort studies. Anti-S1 antibodies were measured from dried blood spots collected between February 2021-August 2022 using Luminex-based microsphere immunoassays. Of 6245 participants, mean age was 73 years (range, 21-100), 58% were female, and 76% were non-Hispanic White. Nearly 52% of participants received the BNT162b2 vaccine and 48% received the mRNA-1273 vaccine. Lower anti-S1 antibody levels are associated with age of 65 years or older, male sex, higher body mass index, smoking, diabetes, COPD and receipt of BNT16b2 vaccine (vs mRNA-1273). Participants with a prior infection, particularly those with a history of hospitalized illness, have higher anti-S1 antibody levels. These results suggest that adults with certain socio-demographic and clinical characteristics may have less robust antibody responses to COVID-19 vaccination and could be prioritized for more frequent re-vaccination.

Abstract Background Early and exclusive breastfeeding may reduce neonatal and post-neonatal mortality in low-resource settings. However, prelacteal feeding (PLF), the practice of giving food or liquid before breastfeeding is established, is still a barrier to optimal breastfeeding practices in many South Asian countries. We used a prospective cohort study to assess the association between feeding non-breastmilk food or liquid in the first three days of life and infant size at 3–5 months of age. Methods The analysis used data from 3,332 mother-infant pairs enrolled in a randomized controlled trial in northwestern rural Bangladesh conducted from 2018 to 2019. Trained interviewers visited women in their households during pregnancy to collect sociodemographic data. Project staff were notified of a birth by telephone and interviewers visited the home within approximately three days and three months post-partum. At each visit, interviewers collected data on breastfeeding practices and anthropometric measures. Infant length and weight measurements were used to produce length-for-age (LAZ), weight-for-age (WAZ), and weight-for-length (WLZ) Z-scores. We used multiple linear regression to assess the association between anthropometric indices and PLF practices, controlling for household wealth, maternal age, weight, education, occupation, and infant age, sex, and neonatal sizes. Results The prevalence of PLF was 23%. Compared to infants who did not receive PLF, infants who received PLF may have a higher LAZ (Mean difference (MD) = 0.02 [95% CI: -0.04, 0.08]) score, a lower WLZ (MD=-0.06 [95% CI: -0.15, 0.03]) score, and a lower WAZ (MD=-0.02 [95% CI: -0.08, 0.05]) score at 3–5 months of age, but none of the differences were statistically significant. In the adjusted model, female sex, larger size during the neonatal period, higher maternal education, and wealthier households were associated with larger infant size. Conclusion PLF was a common practice in this setting. Although no association between PLF and infant growth was identified, we cannot ignore the potential harm posed by PLF. Future studies could assess infant size at an earlier time point, such as 1-month postpartum, or use longitudinal data to assess more subtle differences in growth trajectories with PLF. Trial registration ClinicalTrials.gov: NCT03683667 and NCT02909179.

Abstract Despite the availability of live-attenuated oral vaccines, rotavirus remains a major cause of severe childhood diarrhea worldwide. Due to the growing demand for parenteral rotavirus vaccines, we developed mRNA-based vaccine candidates targeting the viral spike protein VP8*. Our monomeric P2 (universal T cell epitope)-VP8* mRNA design is equivalent to a protein vaccine currently in clinical development, while LS (lumazine synthase)-P2-VP8* was designed to form nanoparticles. Cyro-electron microscopy and western blotting-based data presented here suggest that proteins derived from LS-P2-VP8* mRNA are secreted in vitro and self-assemble into 60-mer nanoparticles displaying VP8*. mRNA encoded VP8* was immunogenic in rodents and introduced both humoral and cellular responses. LS-P2-VP8* induced superior humoral responses to P2-VP8* in guinea pigs, both as monovalent and trivalent vaccines, with encouraging responses detected against the most prevalent P genotypes. Overall, our data provide evidence that trivalent LS-P2-VP8* represents a promising mRNA-based next-generation rotavirus vaccine candidate.

Metal nanoparticles have been tested for therapeutic and imaging applications in pre-clinical models of cancer, but fears of toxicity have limited their translation. An emerging concept in nanomedicine is to exploit the inherent drug-like properties of unmodified nanomaterials for cancer therapy. To be useful clinically, there must be a window between the toxicity of the nanomaterial to cancer and toxicity to normal cells. This necessitates identification of specific vulnerabilities in cancers that can be targeted using nanomaterials without inducing off-target toxicity. Previous studies point to proteotoxic stress as a driver of silver nanoparticle (AgNPs) toxicity. Two key cell stress responses involved in mitigating proteotoxicity are the heat shock response (HSR) and the integrated stress response (ISR). Here, we examine the role that these stress responses play in AgNP-induced cytotoxicity in triple-negative breast cancer (TNBC) and immortalized mammary epithelial cells. Furthermore, we investigate HSR and ISR inhibitors as potential drug partners to increase the anti-cancer efficacy of AgNPs without increasing off-target toxicity. We showed that AgNPs did not strongly induce the HSR at a transcriptional level, but instead decreased expression of heat shock proteins (HSPs) at the protein level, possibly due to degradation in AgNP-treated TNBC cells. We further showed that the HSR inhibitor, KRIBB11, synergized with AgNPs in TNBC cells, but also increased off-target toxicity in immortalized mammary epithelial cells. In contrast, we found that salubrinal, a drug that can sustain pro-death ISR signaling, enhanced AgNP-induced cell death in TNBC cells without increasing toxicity in immortalized mammary epithelial cells. Subsequent co-culture studies demonstrated that AgNPs in combination with salubrinal selectively eliminated TNBCs without affecting immortalized mammary epithelial cells grown in the same well. Our findings provide additional support for proteotoxic stress as a mechanism by which AgNPs selectively kill TNBCs and will help guide future efforts to identify drug partners that would be beneficial for use with AgNPs for cancer therapy.

Introduction The effectiveness of antibiotics for treating gonococcal infections is compromised due to escalating antibiotic resistance; and the development of an effective gonococcal vaccine has been challenging. Emerging evidence suggests that the licensed meningococcal B (MenB) vaccine, 4CMenB is effective against gonococcal infections due to cross-reacting antibodies and 95% genetic homology between the two bacteria, Neisseria meningitidis and Neisseria gonorrhoeae, that cause the diseases. This project aims to undertake epidemiological and genomic surveillance to evaluate the long-term protection of the 4CMenB vaccine against gonococcal infections in the Northern Territory (NT) and South Australia (SA), and to determine the potential benefit of a booster vaccine doses to provide longer-term protection against gonococcal infections.Methods and analyses This observational study will provide long-term evaluation results of the effectiveness of the 4CMenB vaccine against gonococcal infections at 4–7 years post 4CMenB programme implementation. Routine notifiable disease notifications will be the basis for assessing the impact of the vaccine on gonococcal infections. Pathology laboratories will provide data on the number and percentage of N. gonorrhoeae positive tests relative to all tests administered and will coordinate molecular sequencing for isolates. Genome sequencing results will be provided by SA Pathology and Territory Pathology/New South Wales Health Pathology, and linked with notification data by SA Health and NT Health. There are limitations in observational studies including the potential for confounding. Confounders will be analysed separately for each outcome/comparison.Ethics and dissemination The protocol and all study documents have been reviewed and approved by the SA Department for Health and Well-being Human Research Ethics Committee (HREC/2022/HRE00308), and the evaluation will commence in the NT on receipt of approval from the NT Health and Menzies School of Health Research Human Research Ethics Committee. Results will be published in peer-reviewed journals and presented at scientific meetings and public forums.

ABSTRACTCase studies present students with an opportunity to learn and apply course content through problem solving and critical thinking. Supported by the High-throughput Discovery Science & Inquiry-based Case Studies for Today’s Students (HITS) Research Coordination Network, our interdisciplinary team designed, implemented, and assessed two case study modules entitled “You Are What You Eat.” Collectively, the case study modules present students with an opportunity to engage in experimental research design and the ethical considerations regarding microbiome research and society. In this manuscript, we provide instructors with tools for adopting or adapting the research design and/or the ethics modules. To date, the case has been implemented using two modalities (remote and in-person) in three courses (Microbiology, Physiology, and Neuroscience), engaging over 200 undergraduate students. Our assessment data demonstrate gains in content knowledge and students’ perception of learning following case study implementation. Furthermore, when reflecting on our experiences and student feedback, we identified ways in which the case study could be modified for different settings. In this way, we hope that the “You Are What You Eat” case study modules can be implemented widely by instructors to promote problem solving and critical thinking in the traditional classroom or laboratory setting when discussing next-generation sequencing and/or metagenomics research.

Introduction Gonorrhoea, the sexually transmissible infection caused by Neisseria gonorrhoeae, has a substantial impact on sexual and reproductive health globally with an estimated 82 million new infections each year worldwide. N. gonorrhoeae antimicrobial resistance continues to escalate, and disease control is largely reliant on effective therapy as there is no proven effective gonococcal vaccine available. However, there is increasing evidence from observational cohort studies that the serogroup B meningococcal vaccine four-component meningitis B vaccine (4CMenB) (Bexsero), licensed to prevent invasive disease caused by Neisseria meningitidis, may provide cross-protection against the closely related bacterium N. gonorrhoeae. This study will evaluate the efficacy of 4CMenB against N. gonorrhoeae infection in men (cis and trans), transwomen and non-binary people who have sex with men (hereafter referred to as GBM+).Methods and analysis This is a double-blind, randomised placebo-controlled trial in GBM+, either HIV-negative on pre-exposure prophylaxis against HIV or living with HIV (CD4 count >350 cells/mm3), who have had a diagnosis of gonorrhoea or infectious syphilis in the last 18 months (a key characteristic associated with a high risk of N. gonorrhoeae infection). Participants are randomised 1:1 to receive two doses of 4CMenB or placebo 3 months apart. Participants have 3-monthly visits over 24 months, which include testing for N. gonorrhoeae and other sexually transmissible infections, collection of demographics, sexual behaviour risks and antibiotic use, and collection of research samples for analysis of N. gonorrhoeae-specific systemic and mucosal immune responses. The primary outcome is the incidence of the first episode of N. gonorrhoeae infection, as determined by nucleic acid amplification tests, post month 4. Additional outcomes consider the incidence of symptomatic or asymptomatic N. gonorrhoeae infection at different anatomical sites (ie, urogenital, anorectum or oropharynx), incidence by N. gonorrhoeae genotype and antimicrobial resistance phenotype, and level and functional activity of N. gonorrhoeae-specific antibodies.Ethics and dissemination Ethical approval was obtained from the St Vincent’s Hospital Human Research Ethics Committee, St Vincent’s Hospital Sydney, NSW, Australia (ref: 2020/ETH01084). Results will be disseminated in peer-reviewed journals and via presentation at national and international conferences.Trial registration number NCT04415424.

IntroductionTo support rigorous evaluation across a national portfolio of grants, the United States Department of Veterans Affairs (VA) Office of Rural Health (ORH) adopted an analytic framework to guide their grantees' evaluation of initiatives that reach rural veterans and to standardize the reporting of outcomes and impacts. Advance Care Planning via Group Visits (ACP-GV), one of ORH's Enterprise-Wide Initiatives, also followed the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. ACP-GV is a national patient-centered intervention delivered in a large, veterans integrated healthcare system. This manuscript describes how RE-AIM was used to evaluate this national program and lessons learned from ORH's annual reporting feedback to ACP-GV on their use of the framework to describe evaluation impacts.MethodsWe used patient, provider, and site-level administrative health care data from the VA Corporate Data Warehouse and national program management databases for federal fiscal years (FY) spanning October 1, 2018–September 30, 2023. Measures included cumulative and past FY metrics developed to assess program impacts.ResultsRE-AIM constructs included the following cumulative and annual program evaluation results. ACP-GV reached 54,167 unique veterans, including 19,032 unique rural veterans between FY 2018 to FY 2023. During FY 2023, implementation adherence to the ACP-GV model was noted in 91.7% of program completers, with 55% of these completers reporting a knowledge increase and 14% reporting a substantial knowledge increase (effectiveness). As of FY 2023, 66 ACP-GV sites were active, and 1,556 VA staff were trained in the intervention (adoption). Of the 66 active sites in FY 2023, 27 were sites previously funded by ORH and continued to offer ACP-GV after the conclusion of three years of seed funding (maintenance).DiscussionLessons learned developing RE-AIM metrics collaboratively with program developers, implementers, and evaluators allowed for a balance of clinical and scientific input in decision-making, while the ORH annual reporting feedback provided specificity and emphasis for including both cumulative, annual, and rural specific metrics. ACP-GV's use of RE-AIM metrics is a key step towards improving rural veteran health outcomes and describing real world program impacts.

Alzheimer's disease (AD) involves a complex pathological process that evolves over years, and its etiology is understood as a classic example of gene-environment interaction. The notion that exposure to microbial organisms may play some role in AD pathology has been proposed and debated for decades. New evidence from model organisms and -omic studies, as well as epidemiological data from the recent COVID-19 pandemic and widespread use of vaccines, offers new insights into the “germ hypothesis” of AD. To review new evidence and identify key research questions, the Duke/University of North Carolina (Duke/UNC) Alzheimer's Disease Research Center hosted a virtual symposium and workshop: “New Approaches for Understanding the Potential Role of Microbes in Alzheimer's disease.” Discussion centered around the antimicrobial protection hypothesis of amyloid accumulation, and other mechanisms by which microbes could influence AD pathology including immune cell activation, changes in blood-brain barrier, or direct neurotoxicity. This summary of proceedings reviews the content presented in the symposium and provides a summary of major topics and key questions discussed in the workshop.

The increasing availability of novel therapies highlights the importance of screening newborns for rare genetic disorders so that they may benefit from early therapy, when it is most likely to be effective. Pilot newborn screening (NBS) studies are a way to gather objective evidence about the feasibility and utility of screening, the accuracy of screening assays, and the incidence of disease. They are also an optimal way to evaluate the complex ethical, legal and social implications (ELSI) that accompany NBS expansion for disorders. ScreenPlus is a consented pilot NBS program that aims to enroll over 100,000 infants across New York City. The initial ScreenPlus panel includes 14 disorders and uses an analyte-based, multi-tiered screening platform in an effort to enhance screening accuracy. Infants who receive an abnormal result are referred to a ScreenPlus provider for confirmatory testing, management, and therapy as needed, along with longitudinal capture of outcome data. Participation in ScreenPlus requires parental consent, which is obtained in active and passive manners. Patient-facing documents are translated into the ten most common languages spoken at our nine pilot hospitals, all of which serve diverse communities. At the time of consent, parents are invited to receive a series of online surveys to capture their opinions about specific ELSI-related topics, such as NBS policy, residual dried blood spot retention, and the types of disorders that should be on NBS panels. ScreenPlus has developed a stakeholder-based, collective funding model that includes federal support in addition to funding from 14 advocacy and industry sponsors, all of which have a particular interest in NBS for at least one of the ScreenPlus disorders. Taken together, ScreenPlus is a model, multi-sponsored pilot NBS program that will provide critical data about NBS for a broad panel of disorders, while gathering key stakeholder opinions to help guide ethically sensitive decision-making about NBS expansion.

Abstract The genetic diversity of the human leukocyte antigen (HLA) system was shaped by evolutionary constraints exerted by environmental factors. Analyzing HLA diversity may allow understanding of the underlying pathways and offer useful tools in transplant setting. The aim of this study was to investigate the HLA haplotype diversity in patients with sickle cell disease (SCD, N = 282) or β‐thalassemia (β‐Thal, N = 60), who received hematopoietic cell transplantation (HCT) reported to Eurocord and the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM‐TC). We identified 405 different HLA‐A‐B‐DRB1 haplotypes in SCD and 108 in β‐Thal patients. Using data from African and European populations of the “1000 Genomes Project” for comparison with SCD and β‐Thal, respectively, we found that the haplotypes HLA‐A*30‐B*14‐DRB1*15 (OR 7.87, 95% CI: 1.66–37.3, pb = 0.035), HLA‐A*23‐B*08 (OR 6.59, 95% CI: 1.8–24.13, pb = 0.023), and HLA‐B*14‐DRB1*15 (OR 10.74, 95% CI: 3.66–31.57, pb = 0.000) were associated with SCD, and the partial haplotypes HLA‐A*30‐B*13 and HLA‐A*68‐B*53 were associated with β‐Thal (OR 4.810, 95% CI: 1.55–14.91, pb = 0.033, and OR 17.52, 95% CI: 2.81–184.95, pb = 0.011). Our results confirm the extreme HLA genetic diversity in SCD patients likely due to their African ancestry. This diversity seems less accentuated in patients with β‐Thal. Our findings emphasize the need to expand inclusion of donors of African descent in HCT donor registries and cord blood banks.

The long-term sustainability of ex situ animal populations requires coordination across facilities through cooperative breeding programs. Here, we investigate the reasons for inconsistent reproductive success in the zoo-based North American Asian small-clawed otter (ASCO; Aonyx cinereus) population. Reproductive viability analysis (RVA) was used to identify which characteristics of ASCOs in breeding pairs were most predictive of reproductive success. The RVA identified pair type, contraception history, and age as the most significant predictors of offspring production. The use of deslorelin in males and long-term deslorelin use in females hinder future reproductive potential and should, therefore, be considered carefully in genetically valuable individuals and potential breeders. Moreover, genetically valuable animals should be paired with younger mates, as advancing male and female age decreases the likelihood of success. The lack of reproductive success observed after 1 year of attempted breeding among new pairs provides evidence of potential mate incompatibility, therefore, population managers should consider splitting up pairs that remain unsuccessful over time, because the likelihood of offspring production is low. Lastly, the inclusion of dens and/or caves and pools designed with ample shallow water areas in ASCO habitats may improve breeding success.

The only fertility preservation and subsequent restoration option for many patients facing gonadotoxic treatments is ovarian tissue cryopreservation and transplantation. While this process is successful for some, there is significant room for improvement to extend the life of the transplant and to make it safe for patients that may have metastatic disease within their ovarian tissue. We need a deeper understanding of how the physical properties of the ovarian microenvironment may affect folliculogenesis to engineer an environment that supports isolated follicles and maintains primordial follicle quiescence. Bovine ovaries were used here as a monovulatory model of folliculogenesis to examine the effects of primordial follicle activation and growth under different physical conditions. We found that there were no differences in activation, growth or survival when primordial follicles were cultured in isolation or in situ (remaining in the tissue) under two significantly differently rigid alginate gels. To determine if the extra rigid environment did not affect activation in isolated follicles due to an immediate activation event, we used 5-ethynyl-2′-deoxyuridine (EdU) to track follicle activation during the isolation process. We identified EdU incorporation in granulosa cells after primordial follicles were isolated from the surrounding extracellular matrix (ECM). These findings support that isolation of primordial follicles from the ECM is an activating event and that the differentially rigid environments assessed here had no effect on follicle growth. Further work is needed to suppress activation in primordial follicles to maintain the ovarian reserve and extend the life of an ovarian tissue transplant.

Fibromyalgia (FM) is a chronic central sensitivity syndrome characterized by augmented pain processing at diffuse body sites and presents as a multimorbid clinical condition. Long COVID (LC) is a heterogenous clinical syndrome that affects 10–20% of individuals following COVID-19 infection. FM and LC share similarities with regard to the pain and other clinical symptoms experienced, thereby posing a challenge for accurate diagnosis. This research explores the feasibility of using surface-enhanced Raman spectroscopy (SERS) combined with soft independent modelling of class analogies (SIMCAs) to develop classification models differentiating LC and FM. Venous blood samples were collected using two supports, dried bloodspot cards (DBS, n = 48 FM and n = 46 LC) and volumetric absorptive micro-sampling tips (VAMS, n = 39 FM and n = 39 LC). A semi-permeable membrane (10 kDa) was used to extract low molecular fraction (LMF) from the blood samples, and Raman spectra were acquired using SERS with gold nanoparticles (AuNPs). Soft independent modelling of class analogy (SIMCA) models developed with spectral data of blood samples collected in VAMS tips showed superior performance with a validation performance of 100% accuracy, sensitivity, and specificity, achieving an excellent classification accuracy of 0.86 area under the curve (AUC). Amide groups, aromatic and acidic amino acids were responsible for the discrimination patterns among FM and LC syndromes, emphasizing the findings from our previous studies. Overall, our results demonstrate the ability of AuNP SERS to identify unique metabolites that can be potentially used as spectral biomarkers to differentiate FM and LC.

OBJECTIVES/GOALS: There is an interest in developing a bioprosthetic ovary for ovarian tissue transplantation. The properties of the ovarian extracellular matrix need to be better understood in order to replicate the human ovary. We tested the effects of an encapsulating hydrogel at different rigidities on bovine primordial follicle activation, growth, and survival. METHODS/STUDY POPULATION: Bovine primordial follicles were isolated from ovarian cortex. A mean of 9.9 follicles (range 3-24) were encapsulated per bead in either 1% or 5 % alginate across 4 experiments. The encapsulated follicles were subsequently crosslinked in a calcium sulfate solution. Follicles were then cultured for 8 days with light microscopy imaging taken every other day along with media exchanges. Follicles were then examined using immunofluorescence. Growth and survival curves were constructed and all statistical analyses were performed using Graph Pad Prism 9. RESULTS/ANTICIPATED RESULTS: A total of 372 follicles were encapsulated across 32 beads (16 in 1% alginate and 16 in 5% alginate). There were no differences in initial follicle size between the two conditions (33.53 µm vs. 32.45 µm, p=0.47). At the end of 8 days, there was no difference between follicle size (59.55 vs. 56.06, p=0.48). Additionally, there was no difference in survival between 1% and 5% alginate encapsulation (57.75% vs. 52.43%. p=0.40). Immunofluorescence is being performed on encapsulated follicles to confirm the presence of DDX4, a molecular marker of oocytes, after 8 days in culture. Additional encapsulated follicles have also been submitted for histologic sectioning and hematoxylin and eosin staining to better characterize the viability and health of these follicles after 8 days in culture. DISCUSSION/SIGNIFICANCE: There was no significant difference in growth or survival between primordial follicles cultured in 1% or 5% alginate gels. Immunofluorescent analysis confirmed the presence of viable follicles at the end of 8 days of culture. Future work needs to further explore how factors in the ovarian extracellular matrix impact follicle maintenance and growth.

This research aims to uncover which life events (if any) might increase young consumers’ tendencies toward compulsive shopping. Existing literature suggests that stressful events can trigger addictive behaviors, including compulsive buying, with consequences on wellbeing and finances. Our study examines an array of transitional events (e.g., getting the first-time job, moving out of parents’ home, family member’s death), events that mark life changes or role transitions and are stressful while the individual adjusts to new circumstances. Their impact on the development of maladaptive shopping habits is explored in an experimental study with 146 Canadian university students (average age = 20). Overspending and debt accumulation is particularly problematic for young consumers: negative habits developed early in their career can last a lifetime, so understanding compulsive tendencies at this stage is vital. Participants reported their shopping habits on a paper-and-pencil questionnaire, using the compulsive buying scales of Faber and O’Guinn (1992) and Ridgeway et al. (2008). Then, respondents indicated if they experienced any of the transitional events from a listed inventory, when the event occurred, and the intensity of their felt experience (1= not bad at all; 7 = very bad). Other psychological measures were collected, including self-esteem (Heatherton and Polivy, 1991), materialism (Richins and Dawson, 1992), and optimism (Scheier et al., 1994). ANOVA results showed that the type of event, timing, and emotional intensity of the life event influence compulsive buying outcomes. Notably impactful are romantic relationship breakups, deaths of friends, deaths of loved pets, incurring serious injuries/surgeries, moving out of parents’ home, job losses, and working again after a period without work. State self-esteem and materialism are significant factors, but not mediators between transitional life events and compulsive shopping. This research highlights paths through which compulsive buying can develop in early adulthood, offering actionable implications and novel theoretical insights.

Objective: To study ovarian gross morphologic and subanatomic features across pubertal development. Design: Prospective cohort study. Setting: An academic medical center with specimens collected from 2018–2022. Patient(s): Tissue was obtained from prepubertal and postpubertal participants (0.19–22.96 years) undergoing ovarian tissue cryopreservation before treatment that put them at a significantly or high increased risk of developing premature ovarian insufficiency. Most participants (64%) had not received chemotherapy at tissue collection. Intervention(s): None. Main Outcome Measure(s): Ovaries procured for fertility preservation were weighed and measured. Ovarian tissue fragments released during processing, biopsies used for pathology, and hormone panels were analyzed for gross morphology, subanatomic features, and reproductive hormones. Graphical analysis of best-fit lines determined age at maximum growth velocity. Result(s): Prepubertal ovaries were significantly (1.4-fold and 2.4-fold) smaller than postpubertal ovaries by length and width and 5.7-fold lighter on average. Length, width, and weight grew in a sigmoidal pattern with age. Prepubertal ovaries were less likely to display a defined corticomedullary junction (53% vs. 77% in postpubertal specimens), less likely to have a tunica albuginea (22% vs. 93% in postpubertal specimens), contained significantly more (9.8-fold) primordial follicles, and contained primordial follicles at significantly deeper depths (2.9-fold) when compared with postpubertal ovaries. Conclusion(s): Ovarian tissue cryopreservation is a resource to study human ovarian biology and pubertal development. Maximum growth velocity occurs late within the pubertal transition (Tanner 3+) after changes in subanatomic features. This ovarian morphology model adds to foundational knowledge of human ovarian development and supports ongoing transcriptomics research.

Abstract Metachronal propulsion is widespread in aquatic swarming organisms to achieve performance and maneuverability at intermediate Reynolds numbers. Studying only live organisms limits our understanding of the mechanisms driving these abilities. Thus, we present the design, manufacture, and validation of the Pleobot—a unique krill-inspired robotic swimming appendage constituting the first platform to study metachronal propulsion comprehensively. We combine a multi-link 3D printed mechanism with active and passive actuation of the joints to generate natural kinematics. Using force and fluid flow measurements in parallel with biological data, we show the link between the flow around the appendage and thrust. Further, we provide the first account of a leading-edge suction effect contributing to lift during the power stroke. The repeatability and modularity of the Pleobot enable the independent manipulation of particular motions and traits to test hypotheses central to understanding the relationship between form and function. Lastly, we outline future directions for the Pleobot, including adapting morphological features. We foresee a broad appeal to a wide array of scientific disciplines, from fundamental studies in ecology, biology, and engineering, to developing new bio-inspired platforms for studying oceans across the solar system.

The duration and maximum combustion temperature of vegetation fires are important fire properties with implications for ecology, hydrology, hazard potential, and many other processes. Directly measuring maximum combustion temperature during vegetation fires is difficult. However, chemical transformations associated with temperature are reflected in the chemical properties of charcoals (a by-product of fire). Therefore, charcoal could be used indirectly to determine the maximum combustion temperature of vegetation fires with application to palaeoecological charcoal records. To evaluate the reliability of charcoal chemistry as an indicator of maximum combustion temperature, we studied the chemical properties of charcoal formed through two laboratory methods at measured temperatures. Using a muffle furnace, we generated charcoal from the woody material of ten different tree and shrub species at seven distinct peak temperatures (from 200°C to 800°C in 100°C increments). Additionally, we simulated more natural combustion conditions by burning woody material and leaves of four tree species in a combustion facility instrumented with thermocouples, including thermocouples inside and outside of tree branches. Charcoal samples generated in these controlled settings were analyzed using Fourier Transform Infrared (FTIR) spectroscopy to characterize their chemical properties. The Modern Analogue Technique (MAT) was employed on FTIR spectra of muffle furnace charcoal to assess the accuracy of inferring maximum pyrolysis temperature. The MAT model temperature matching accuracy improved from 46% for all analogues to 81% when including ±100°C. Furthermore, we used MAT to compare charcoal created in the combustion facility with muffle furnace charcoal. Our findings indicate that the spectra of charcoals generated in a combustion facility can be accurately matched with muffle furnace-created charcoals of similar temperatures using MAT, and the accuracy improved when comparing the maximum pyrolysis temperature from muffle furnace charcoal with the maximum inner temperature of the combustion facility charcoal. This suggests that charcoal produced in a muffle furnace may be representative of the inner maximum temperatures for vegetation fire-produced charcoals.

Abstract Background Neurodegenerative diseases lead to difficulties with functional activities. In Peru, most caregivers are family members. Little is known about the COVID‐19 pandemic's effect on caregivers in Peru. Methods This was a cross‐sectional, prospective study of family caregivers of dependent patients with dementia or Parkinson's Disease in Lima, Peru. A caregiver burden and mental health questionnaire was administered to the caregiver. Results We enrolled 48 caregivers (65% females, mean ± SD age 49.0 ± 12.3 years); 70% of patients had dementia. Nearly 40% of caregivers reported having full‐time jobs, and 82% felt overwhelmed with almost 75% dedicating more time to caregiving during the pandemic. Caregivers perceived patients felt lonelier (52%), had an increase in hallucinations (50%), or forgetfulness (71%) compared to pre‐pandemic. Conclusions Our study highlights that perceived caregiver burden and patient behavioral symptoms may have been exacerbated during the pandemic. In countries such as Peru, more caregiving resources and interventions are needed.

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma-associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging- and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissues from 38 SSc-ILD and 18 healthy controls and found that markers (GDF15, COMP, and CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found that epithelial and fibroblast senescence signatures had a 3.6- and 3.7-fold enrichment, respectively, in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, and NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in the lung tissue and found that, independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.

Abstract Background Central nervous system (CNS) active medications have been consistently linked to falls in older people. However, few randomized trials have evaluated whether CNS-active medication reduction reduces falls and fall-related injuries. The objective of the Reducing CNS-active Medications to Prevent Falls and Injuries in Older Adults (STOP-FALLS) trial is to test the effectiveness of a health-system-embedded deprescribing intervention focused on CNS-active medications on the incidence of medically treated falls among community-dwelling older adults. Methods We will conduct a pragmatic, cluster-randomized, parallel-group, controlled clinical trial within Kaiser Permanente Washington to test the effectiveness of a 12-month deprescribing intervention consisting of (1) an educational brochure and self-care handouts mailed to older adults prescribed one or more CNS-active medications (aged 60 + : opioids, benzodiazepines and Z-drugs; aged 65 + : skeletal muscle relaxants, tricyclic antidepressants, and antihistamines) and (2) decision support for their primary health care providers. Outcomes are examined over 18–26 months post-intervention. The primary outcome is first incident (post-baseline) medically treated fall as determined from health plan data. Our sample size calculations ensure at least 80% power to detect a 20% reduction in the rate of medically treated falls for participants receiving care within the intervention (n = 9) versus usual care clinics (n = 9) assuming 18 months of follow-up. Secondary outcomes include medication discontinuation or dose reduction of any target medications. Safety outcomes include serious adverse drug withdrawal events, unintentional overdose, and death. We will also examine medication signetur fields for attempts to decrease medications. We will report factors affecting implementation of the intervention. Discussion The STOP-FALLS trial will provide new information about whether a health-system-embedded deprescribing intervention that targets older participants and their primary care providers reduces medically treated falls and CNS-active medication use. Insights into factors affecting implementation will inform future research and healthcare organizations that may be interested in replicating the intervention. Trial registration ClinicalTrial.gov NCT05689554. Registered on 18 January 2023, retrospectively registered.

While ovarian tissue cryopreservation (OTC) is an important fertility preservation option, it has its limitations. Improving OTC and ovarian tissue transplantation (OTT) must include extending the function of reimplanted tissue by reducing the extensive activation of primordial follicles (PMFs) and eliminating the risk of reimplanting malignant cells. To develop a more effective OTT, we must understand the effects of the ovarian microenvironment on folliculogenesis. Here, we describe a method for producing decellularized extracellular matrix (dECM) hydrogels that reflect the protein composition of the ovary. These ovarian dECM hydrogels were engineered to assess the effects of ECM on in vitro follicle growth, and we developed a novel method for selectively removing proteins of interest from dECM hydrogels. Finally, we validated the depletion of these proteins and successfully cultured murine follicles encapsulated in the compartment-specific ovarian dECM hydrogels and these same hydrogels depleted of EMILIN1. These are the first, optically clear, tailored tissue-specific hydrogels that support follicle survival and growth comparable to the “gold standard” alginate hydrogels. Furthermore, depleted hydrogels can serve as a novel tool for many tissue types to evaluate the impact of specific ECM proteins on cellular and molecular behavior.

This visual essay focuses on the visual documentation of the reconstruction of the archaeological site of Tajín from the late 1930s to the 1970s. During this period, the Mexican post-revolutionary state, motivated by the desire to forge a coherent nationality and boost mass tourism, actively supported and funded the monumental reconstruction of the Tajín pyramid and other pre-Hispanic structures across Mexico. Although the workers involved in the reconstruction of the pyramid appear in several on-site photographs, their labor remained ‘underexposed:’ their presence is rarely acknowledged in image labels, they are depicted in subordinated positions vis-à-vis the figure of the archaeologist or used as human scales or ethnic markers. Finally, these photographs, once consigned and buried in the archives, have rarely come into view. As a result, labor-related images are missing from the prevailing visual economy, which tends to prioritize and celebrate grandiose representations of pre-Hispanic ruins while overlooking the monumental process of their physical reconstruction. To counter this ‘underexposure’ of workers and labor, I unearth a selection of images from the archives and altered them by adding my own captions and descriptions, drawing from limited yet valuable information found in technical reports that shed light on the labor conditions at the site. This approach serves a dual purpose. Firstly, it aims to emphasize the significant role that Totonac workers played in the nation-building process by physically constructing Mexico’s ancient heritage. Secondly, it aims to bring attention to the persistent inequalities perpetuated, reinforced, and concealed by the field of archaeology throughout the construction process.

Distal sensory polyneuropathy (DSP) is a disabling, chronic condition in people with HIV (PWH), even those with viral suppression of antiretroviral therapy (ART), and with a wide range of complications, such as reduced quality of life. Previous studies demonstrated that DSP is associated with inflammatory cytokines in PWH. Adhesion molecules, essential for normal vascular function, are perturbed in HIV and other conditions linked to DSP, but the link between adhesion molecules and DSP in PWH is unknown. This study aimed to determine whether DSP signs and symptoms were associated with a panel of plasma biomarkers of inflammation (d-dimer, sTNFRII, MCP-1, IL-6, IL-8, IP-10, sCD14) and vascular I integrity (ICAM-1, VCAM-1, uPAR, MMP-2, VEGF, uPAR, TIMP-1, TIMP-2) and differed between PWH and people without HIV (PWoH). A cross-sectional study was conducted among 143 participants (69 PWH and 74 PWoH) assessed by studies at the UC San Diego HIV Neurobehavioral Research Program. DSP signs and symptoms were clinically assessed for all participants. DSP was defined as two or more DSP signs: bilateral symmetrically reduced distal vibration, sharp sensation, and ankle reflexes. Participant-reported symptoms were neuropathic pain, paresthesias, and loss of sensation. Factor analyses reduced the dimensionality of the 15 biomarkers among all participants, yielding six factors. Logistic regression was used to assess the associations between biomarkers and DSP signs and symptoms, controlling for relevant demographic and clinical covariates. The 143 participants were 48.3% PWH, 47 (32.9%) women, and 47 (33.6%) Hispanics, with a mean age of 44.3 ± 12.9 years. Among PWH, the median (IQR) nadir and current CD4+ T-cells were 300 (178–448) and 643 (502–839), respectively. Participants with DSP were older but had similar distributions of gender and ethnicity to those without DSP. Multiple logistic regression showed that Factor 2 (sTNFRII and VCAM-1) and Factor 4 (MMP-2) were independently associated with DSP signs in both PWH and PWoH (OR [95% CI]: 5.45 [1.42–21.00], and 15.16 [1.07–215.22]), respectively. These findings suggest that inflammation and vascular integrity alterations may contribute to DSP pathogenesis in PWH, but not PWoH, possibly through endothelial dysfunction and axonal degeneration.

Long COVID (LongC) is associated with a myriad of symptoms including cognitive impairment. We reported at the beginning of the COVID-19 pandemic that neuronal-enriched or L1CAM+ extracellular vesicles (nEVs) from people with LongC contained proteins associated with Alzheimer’s disease (AD). Since that time, a subset of people with prior COVID infection continue to report neurological problems more than three months after infection. Blood markers to better characterize LongC are elusive. To further identify neuronal proteins associated with LongC, we maximized the number of nEVs isolated from plasma by developing a hybrid EV Microfluidic Affinity Purification (EV-MAP) technique. We isolated nEVs from people with LongC and neurological complaints, AD, and HIV infection with mild cognitive impairment. Using the OLINK platform that assesses 384 neurological proteins, we identified 11 significant proteins increased in LongC and 2 decreased (BST1, GGT1). Fourteen proteins were increased in AD and forty proteins associated with HIV cognitive impairment were elevated with one decreased (IVD). One common protein (BST1) was decreased in LongC and increased in HIV. Six proteins (MIF, ENO1, MESD, NUDT5, TNFSF14 and FYB1) were expressed in both LongC and AD and no proteins were common to HIV and AD. This study begins to identify differences and similarities in the neuronal response to LongC versus AD and HIV infection.

Human rotavirus (HRV) is still a leading cause of severe dehydrating gastroenteritis globally, particularly in infants and children. Previously, we demonstrated the immunogenicity of mRNA-based HRV vaccine candidates expressing the viral spike protein VP8* in rodent models. In the present study, we assessed the immunogenicity and protective efficacy of two mRNA-based HRV trivalent vaccine candidates, encoding VP8* of the genotypes P[8], P[6], or P[4], in the gnotobiotic (Gn) pig model of Wa (G1P[8]) HRV infection and diarrhea. Vaccines either encoded VP8* alone fused to the universal T-cell epitope P2 (P2-VP8*) or expressed P2-VP8* as a fusion protein with lumazine synthase (LS-P2-VP8*) to allow the formation and secretion of protein particles that present VP8* on their surface. Gn pigs were randomly assigned into groups and immunized three times with either P2-VP8* (30 µg) or LS-P2-VP8* (30 µg or 12 µg). A trivalent alum-adjuvanted P2-VP8* protein vaccine or an LNP-formulated irrelevant mRNA vaccine served as the positive and negative control, respectively. Upon challenge with virulent Wa HRV, a significantly shortened duration and decreased severity of diarrhea and significant protection from virus shedding was induced by both mRNA vaccine candidates compared to the negative control. Both LS-P2-VP8* doses induced significantly higher VP8*-specific IgG antibody titers in the serum after immunizations than the negative as well as the protein control. The P[8] VP8*-specific IgG antibody-secreting cells in the ileum, spleen, and blood seven days post-challenge, as well as VP8*-specific IFN-γ-producing T-cell numbers increased in all three mRNA-vaccinated pig groups compared to the negative control. Overall, there was a clear tendency towards improved responses in LS-P2-VP8* compared to the P2-VP8*mRNA vaccine. The demonstrated strong humoral immune responses, priming for effector T cells, and the significant reduction of viral shedding and duration of diarrhea in Gn pigs provide a promising proof of concept and may provide guidance for the further development of mRNA-based rotavirus vaccines.

Therapeutic Area: Kidney Disease Background: In March 2022 China imposed strict lockdown measures to contain a COVID-19 outbreak which disrupted the global supply chains of iodine contrast media (ICM). Healthcare systems implemented contrast-saving strategies to maintain their remaining ICM supplies. This study sought to determine the impact of contrast shortage on the incidence of contrast-associated acute kidney injury (CA-AKI). Methods: This was a retrospective study of 265 patients undergoing 278 percutaneous coronary interventions (PCI) during 4-month-periods prior to (9/1/2021 - 12/31/2021) and during (5/1/2022- 8/31/2022) contrast shortage at a single center. We excluded patients with same-day discharge, missing baseline or post-PCI creatinine, and patients on dialysis at the time of their PCI. The primary end point was the incidence of CA-AKI between the study periods. Results: A total of 148 and 130 PCIs were performed before and during contrast shortage, respectively. The incidence of CA-AKI significantly decreased from 11.5% in pre-contrast shortage to 4.6% during contrast shortage (p = 0.038). During the shortage, average contrast volume per PCI was significantly lower (122.8 mL ±62 vs. 88.2 mL ±45.6, p-value