Search

Abstract Neuroblastoma is the most common pediatric extracranial solid tumor and is derived from trunk neural crest cells (tNCC) and its progenitor sympathoadrenal (SA) cells. While human pluripotent stem cell (PSC) models of neuroblastoma have been described, the PSC were differentiated using protocols that made neural crest cells, but not specifically the trunk subtype. Here, we compared four recent protocols to differentiate pluripotent stem cells (PSC) toward SA cells and examined their efficiency at generating SA cells along with earlier cell states (neuromesodermal progenitors [NMP], tNCC), as well as generating MYCN-driven tumors. Interestingly, the protocols that created cells with the highest level of NMP markers did not produce cells with the highest tNCC or SA cell markers. We identified a protocol that consistently produced cells with the highest level of SA markers using two PSC lines of different genders. This protocol also generated tumors with the highest level of PHOX2B, a marker of neuroblastoma. Transcriptionally, however, each protocol generates tumors that resemble neuroblastoma. Two of the protocols repeatedly produced adrenergic neuroblastoma whereas the other two protocols were ambiguous. Thus, we identified a protocol that reliably generates adrenergic neuroblastoma.

West Nile virus (WNV) is the most common cause of human arboviral disease in the contiguous United States, where only lineage 1 (L1) WNV had been found. In 2023, an immunocompetent patient was hospitalized in Nebraska with West Nile neuroinvasive disease and multisystem organ failure. Testing at the Centers for Disease Control and Prevention indicated an unusually high viral load and acute antibody response. Upon sequencing of serum and cerebrospinal fluid, we detected lineage 3 (L3) and L1 WNV genomes. L3 WNV had previously only been found in Central Europe in mosquitoes. The identification of L3 WNV in the United States and the observed clinical and laboratory features raise questions about the potential effect of L3 WNV on the transmission dynamics and pathogenicity of WNV infections. Determining the distribution and prevalence of L3 WNV in the United States and any public health and clinical implications is critical.

Abstract Preeclampsia, a pregnancy complication characterized by hypertension after 20 gestational weeks, is a major cause of maternal and neonatal morbidity and mortality. Mechanisms leading to preeclampsia are unclear; however, there is evidence of high heritability. We evaluated the association of polygenic scores (PGS) for blood pressure traits and preeclampsia to assess whether there is shared genetic architecture. Non-Hispanic Black and White reproductive age females with pregnancy indications and genotypes were obtained from Vanderbilt University’s BioVU, Electronic Medical Records and Genomics network, and Penn Medicine Biobank. Preeclampsia was defined by ICD codes. Summary statistics for diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse pressure (PP) PGS were acquired from Giri et al. Associations between preeclampsia and each PGS were evaluated separately by race and data source before subsequent meta-analysis. Ten-fold cross validation was used for prediction modeling. In 3504 Black and 5009 White included individuals, the rate of preeclampsia was 15.49%. In cross-ancestry meta-analysis, all PGSs were associated with preeclampsia (ORDBP = 1.10, 95% CI 1.02–1.17, p = 7.68 × 10−3; ORSBP = 1.16, 95% CI 1.09–1.23, p = 2.23 × 10−6; ORPP = 1.14, 95% CI 1.07–1.27, p = 9.86 × 10−5). Addition of PGSs to clinical prediction models did not improve predictive performance. Genetic factors contributing to blood pressure regulation in the general population also predispose to preeclampsia.

The mechanisms contributing to age-related deterioration of the female reproductive system are complex, however aberrant protein homeostasis is a major contributor. We elucidated exceptionally stable proteins, structures, and macromolecules that persist in mammalian ovaries and gametes across the reproductive lifespan. Ovaries exhibit localized structural and cell-type-specific enrichment of stable macromolecules in both the follicular and extrafollicular environments. Moreover, ovaries and oocytes both harbor a panel of exceptionally long-lived proteins, including cytoskeletal, mitochondrial, and oocyte-derived proteins. The exceptional persistence of these long-lived molecules suggest a critical role in lifelong maintenance and age-dependent deterioration of reproductive tissues.

Objectives: The prevalence and associated adverse effects of obesity on health and healthcare cost make it a primary public health concern. However, individuals with the physiological features of obesity may be underdiagnosed and undertreated. We aimed to determine the prevalence of obesity diagnoses and obesity-related treatments in an integrated health system and determine the factors associated with receiving an obesity diagnosis and treatment for this indication. Methods: This retrospective cross-sectional study of data from the Henry Ford Health electronic health record included adult patients with a body mass index (BMI) indicating clinical evidence of class II and III (severe) obesity in 2017 and who received treatment through 2019. The primary outcome was prevalence of obesity diagnosis and obesity-related treatment. Logistic regression evaluated the patient-level factors associated with odds of having obesity diagnosis and treatment. Results: Among 64,741 patients meeting the clinical definition of definition of severe obesity, only 40.7 % were clinically diagnosed with obesity, and 23.5 % received an obesity-related intervention. Patients with BMI≥40 kg/m2 (class III) were more likely to be diagnosed with obesity than those with BMI 35–39.9 kg/m2 (class II) (odds ratio [OR] 5.84; 95 % CI, 5.62–6.07). Patients with a diagnosis of obesity (OR 2.92; 95 % CI, 2.80–3.05), Black patients (OR 1.46; 95 % CI, 1.40–1.53), and female patients (OR 1.47; 95 % CI, 1.41–1.54) were more likely to be offered obesity-related treatment. Conclusions: Severe obesity may be underdiagnosed in patients who have BMI 35–39.9 kg/m2 and 1 comorbidity.

Key Clinical Message Symmetrical drug‐related intertriginous and flexural exanthema, commonly known as “baboon syndrome” due to its typical involvement of the gluteal area, is an erythematous symmetrical rash associated with systemic drug administration.

Enquadramento: A fenomenologia progressivamente tem conquistado, no contexto internacional, um espaço de destaque na investigação em enfermagem. Objetivo: Mapear e caracterizar as teses de doutoramento em enfermagem de abordagem metodológica fenomenológica. Metodologia: Investigação documental, com acesso a 273 teses de doutoramento, realizadas no período de 2004-2018, disponíveis nos repositórios digitais abertos das universidades portuguesas. Resultados: Identificaram-se 26 teses de doutoramento com estudos de investigação de abordagem metodológica fenomenológica. A análise realizada teve em conta os seguintes aspetos: a) os participantes - maioritariamente adultos e clientes dos cuidados de enfermagem; b) a área de cuidados de saúde - a maioria das teses não se enquadra numa área de saúde específica; c) o contexto - primordialmente hospitalar; d) e o método usado – fenomenológico hermenêutico. Conclusão: As teses de doutoramento, de orientação fenomenológica, embora ainda em percentagem reduzida, ao explicitarem a natureza e o significado da experiência vivida tornam-se relevantes para a construção disciplinar de enfermagem.

OBJECTIVES/GOALS: Uterine fibroids are benign tumors of the uterus with a high disease prevalence and burden, yet there are few multi-ancestry genetic studies. This is the largest and most diverse fibroid GWAS to-date. Our goal is to identify novel genetic variants and gene expression pathways associated with fibroids and characterize their biological relevance. METHODS/STUDY POPULATION: We performed a cross-ancestry meta-analysis of GWAS summary statistics from eight datasets. The total sample size was 74,294 cases and 465,810 controls with participants of European (80% of sample), African (4%), East Asian, and Central South Asian (16%) ancestry. We mapped variants to genes with OpenTarget Genetics and used Functional Mapping and Annotation to conduct tissue expression gene-set enrichment and identify lead variants. We used S-PrediXcan to estimate genetically predicted gene expression (GPGE) associated with fibroid risk. This was with models that predicted gene expression across 49 different tissue types. Ingenuity Pathway Analysis compiled significant GPGE genes and their weights with a scientific literature database to identify overlapping pathways. RESULTS/ANTICIPATED RESULTS: We identified 370 independent significant variants. Among these, we identified variants mapped to three novel genes (PAX2, VIP, FOXO3) and eight genes not previously validated (TEKT1, SLC16A11, RPEL1, RASL11B, ASGR1, SLC12A7, TTC28, POLR2A). Many loci have roles in cell cycle regulation or are associated with fibroid risk factors like blood pressure, BMI, and vitamin D levels. Loci were significantly enriched in DNA damage and cell cycle pathways. Of 588 significant predicted expression gene-tissue pairs, 173 unique genes were novel fibroid associations. These genes are also associated with cancers, estradiol, and endometriosis. Top enriched pathways included p53 signaling, HOTAIR, BRCA1DNA damage response, and pulmonary fibrosis signaling. In uterine tissue there were 15 novel GPGE associations. DISCUSSION/SIGNIFICANCE: Using this large and diverse data, we identified novel loci associated with fibroids that are enriched in hormone-response, DNA damage, and cell-cycle pathways. GPGE loci were in tumorigenesis and fibrosis pathways. These novel genetic loci and uterine gene expression findings may provide translational opportunities for novel fibroid treatments.

Abstract Tissue engineering is a relatively recent research area aimed at developing artificial tissues that can restore, maintain, or even improve the anatomical and/or functional integrity of injured tissues. Otolaryngology, as a leading surgical specialty in head and neck surgery, is a candidate for the use of these advanced therapies and medicinal products developed. Nevertheless, a knowledge-based analysis of both areas together is still needed. The dataset was retrieved from the Web of Science database from 1900 to 2020. SciMAT software was used to perform the science mapping analysis and the data for the biomedical translation identification was obtained from the iCite platform. Regarding the analysis of the cognitive structure, we find consolidated research lines, such as the generation of cartilage for use as a graft in reconstructive surgery, reconstruction of microtia, or the closure of perforations of the tympanic membrane. This last research area occupies the most relevant clinical translation with the rest of the areas presenting a lower translational level. In conclusion, Tissue engineering is still in an early translational stage in otolaryngology, otology being the field where most advances have been achieved. Therefore, although otolaryngologists should play an active role in translational research in tissue engineering, greater multidisciplinary efforts are required to promote and encourage the translation of potential clinical applications of tissue engineering for routine clinical use.

Abstract Familial Alzheimer’s disease (FAD) is a complex neurodegenerative disorder for which there are no therapeutics to date. Several mutations in presenilin 1 (PSEN 1), which is the catalytic component of γ-secretase complex, are causal of FAD. Recently, the p.Ile416Thr (I416T) PSEN 1 mutation has been reported in large kindred in Colombia. However, cell and molecular information from I416T mutation is scarce. Here, we demonstrate that menstrual stromal cells (MenSCs)-derived planar (2D) PSEN 1 I416T cholinergic-like cells (ChLNS) and (3D) cerebral spheroids (CSs) reproduce the typical neuropathological markers of FAD in 4 post-transdifferentiating or 11 days of transdifferentiating, respectively. The models produce intracellular aggregation of APPβ fragments (at day 4 and 11) and phosphorylated protein TAU at residue Ser202/Thr205 (at day 11) suggesting that iAPPβ fragments precede p-TAU. Mutant ChLNs and CSs displayed DJ-1 Cys106-SO3 (sulfonic acid), failure of mitochondria membrane potential (ΔΨm), and activation of transcription factor c-JUN and p53, expression of pro-apoptotic protein PUMA, and activation of executer protein caspase 3 (CASP3), all markers of cell death by apoptosis. Moreover, we found that both mutant ChLNs and CSs produced high amounts of extracellular eAβ42. The I416T ChLNs and CSs were irresponsive to acetylcholine induced Ca2+ influx compared to WT. The I416T PSEN 1 mutation might work as dominant-negative PSEN1 mutation. These findings might help to understanding the recurring failures of clinical trials of anti-eAβ42, and support the view that FAD is triggered by the accumulation of other intracellular AβPP metabolites, rather than eAβ42.

Abstract This study demonstrates a full-color near-eye holographic display capable of superimposing color virtual scenes with 2D, 3D, and multiple objects with extended depth upon a real scene, which also has the ability to present different 3D information depending on the focus of the user’s eyes using a single computer-generated hologram per color channel. Our setup makes use of a hologram generation method based on two-step propagation and the singular value decomposition of the Fresnel transform impulse response function to efficiently generate the holograms of the target scene. Then, we test our proposal by implementing a holographic display that makes use of a phase-only spatial light modulator and time-division multiplexing for color reproduction. We demonstrate the superior quality and computation speed of this approach compared with other hologram generation techniques with both numerical and experimental results.

Background Fibrotic hypersensitivity pneumonitis (fHP) is an immune-mediated interstitial lung disease caused by sensitisation to chronic allergen inhalation. This study aimed to determine prognostic indicators of progression and mortality in fHP. Methods This was a retrospective, multicentre, observational, cross-sectional cohort study of consecutive patients diagnosed with fHP from 1 January 2012 to 31 December 2021. Multivariate Cox regression analyses were used to calculate hazard ratios (HRs) with 95% confidence intervals for predictors of progression and survival. Results A total of 403 patients were diagnosed with fHP: median (interquartile range) age 66.5 (14.0) years, 51.9% females and 55.1% never-smokers. The cause of fHP was mainly fungal (39.7%) or avian (41.4%). Lung biopsy was performed in 269 cases (66.7%). In the whole cohort the variables that were related to mortality or lung transplant were older age (HR 1.08; p

Introduction There are limited longitudinal data on the systemic and mucosal antibody responses to SARS-CoV-2 from Latin America, a region severely affected by COVID-19, and where vaccine strategies have been implemented during the evolving pandemic. Objective To evaluate determinants of seroprevalence and changes in levels of anti-SARS-CoV-2 antibodies longitudinally in adults with different levels of exposure to SARS-CoV-2 (defined a priori as low, medium, and high based on presumed occupational risk), in two Andean cities in Ecuador. Methods Longitudinal cohort study of 1,000 adults aged 18 years and older with questionnaire data and sample collection done at 0, 3, 6, and 12 months during the period 2020-2023. Observations collected included WHO-ISARIC questionnaire and peripheral blood and saliva samples for measurement of IgG and IgA antibodies, respectively. Planned analyses are tailored to the longitudinal nature of the outcomes defined by participants’ antibody levels and aim at estimating their average trends with time since infection in each of the occupational groups, adjusted for demographics and calendar-time levels of SARS-CoV-2 infection in the general population. The latter reflect the impact of the national control measures such as vaccinations and movement restrictions. Importance Understanding the duration and the dynamics of waning immunity to SARS-CoV-2, in the context of exposures to emerging virus variants and immunization, will inform the implementation of targeted public health strategies in the Latin American region. Ethics and Dissemination This study will observe the bioethical principles of the Declaration of Helsinki. Informed written consent will be obtained. Samples from participants will be stored for up to three years after which they will be destroyed. The study protocol was approved by the Ecuadorian Ministry of Public Health Ethics Committee for COVID-19 Research. Antibody results will be provided to participants and participating institutions and to the national health authorities.

Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by ‘brute force’ surveys of all genes within RNA-sequencing measures across tissues within a population. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or high-fat/high-sucrose (HFHS) diet. Variation of genes such as FGF21, ADIPOQ, GCG, and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liver PCSK9) and genes encoding enzymes producing metabolites (adipose PNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource as gene-derived correlations across tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways, and network architectures across metabolic organs.

El uso de la ureteroscopia flexible, se ha convertido en un procedimiento mínimamente invasivo, eficiente y seguro para la exploración de la vía urinaria superior; asociada al uso del láser como método de fragmentación, alcanzando altas tasas libres de cálculos. Objetivo: Presentar la experiencia clínica en la Efectividad del uso del ureterorrenoscopio flexible de unsolo uso en pacientes con litiasis en el Centro Médico Docente La Trinidad año 2023. Métodos: Serealizó un estudio descriptivo retrospectivo, unicéntrico, como una investigación transversal con datos de octubre 2022 a julio del 2023, en el Centro Médico Docente la Trinidad con una población de 31 pacientes distribuidos en sexo masculino y femenino, lo cual se realizó cirugía intrarenal retrograda. Resultados: La media de edad fue de 47 años, mínimo 20, máximo 72, y un promedio de 51. El tamaño promedio de los litos fue de 8,31 mm, máximo 30mm, y el sito más frecuente el riñón 48,39%. La tasa libre de litiasis de 90%. Doble J intraoperatorio se colocó en el 100% de los pacientes. Se presentó una complicación del (3%) y 15 reintervenciones (48%). Conclusiones: El uso de ureterorenoscopio flexible y láser en el tratamiento de la litiasis renal , con diámetros mayores hasta 20 mm logró TLC (tasa libre de cálculos) equiparables con las reportadas en la literatura, con un porcentaje bajo de complicaciones, por lo tanto por ser el primer trabajo en nuestro país recomendamos su uso por los beneficios ofrecidos, menor tasa de complicaciones, infecciones y menos tiempo de hospitalización.

Abstract Embryo development is a dynamic process and critical stages may go unnoticed with the use of traditional morphologic assessments, especially the timing of embryonic divisions and aberrant zygotic cleavage patterns. Bovine embryo development is impaired after oocyte vitrification, but little is known about the underlying morphokinetic behavior. Here, bovine zygotes from fresh (n = 708) and vitrified oocytes (n = 182) were monitored by time-lapse imaging and the timing and nature of early blastomere divisions were modeled to find associations with blastocyst development at day 8. The predictive potential of morphokinetic parameters was analyzed by logistic regression and receiver operating characteristic curve analysis to determine optimal cut-off values. Lag-phase was highly correlated with embryo development. Remarkably, 100% of zygotes that reached the blastocyst stage showed a lag-phase. Fast first cleavage increased the chance of blastocyst development to 30% with a cut-off of 32 h and 22 min. Aberrant zygotic cleavage events, including multipolar division, unequal blastomere sizes, and membrane ruffling resulted in decreased blastocyst development. Multipolar division leads to uneven blastomeres, which was associated with anuclear and multinuclear blastomeres, indicating genome segregation errors. Moreover, we described for the first time morphokinetics of embryos derived from vitrified bovine oocytes. Vitrification severely affected blastocyst development, although lower cryoprotectant concentration in equilibration solutions seems to be less detrimental for embryo yield. Impaired development was linked to slow cleavages, lower lag-phase incidence, and increased early embryonic arrest. Typically, less than 15% of the embryos produced from vitrified oocytes reached more than eight cells. Interestingly, the rate of abnormal first cleavage events was not affected by oocyte vitrification. In conclusion, time to first cleavage, the presence of a lag-phase, and the absence of aberrant zygotic cleavage were the best predictors of bovine blastocyst development for both fresh and vitrified oocytes.

In 2020, Montana, USA, reported a large increase in Colorado tick fever (CTF) cases. To investigate potential causes of the increase, we conducted a case–control study of Montana residents who tested positive or negative for CTF during 2020, assessed healthcare providers’ CTF awareness and testing practices, and reviewed CTF testing methods. Case-patients reported more time recreating outdoors on weekends, and all reported finding a tick on themselves before illness. No consistent changes were identified in provider practices. Previously, only CTF serologic testing was used in Montana. In 2020, because of SARS-CoV-2 testing needs, the state laboratory sent specimens for CTF testing to the Centers for Disease Control and Prevention, where more sensitive molecular methods are used. This change in testing probably increased the number of CTF cases detected. Molecular testing is optimal for CTF diagnosis during acute illness. Tick bite prevention measures should continue to be advised for persons doing outdoor activities.

OBJECTIVES/GOALS: We aimed to conduct an updated genome-wide meta-analysis of keloids in expanded populations, including those most afflicted by keloids. Our overall objective was to improve understanding of keloid development though the identification and further characterization of keloid-associated genes with genetically predicted gene expression (GPGE). METHODS/STUDY POPULATION: We used publicly available summary statistics from several large-scale DNA biobanks, including the UK Biobank, FinnGen, and Biobank Japan. We also leveraged data from the Million Veterans Program and performed genome-wide association studies of keloids in BioVU and eMERGE. For each of these datasets, cases were determined from ICD-9/ICD-10 codes and phecodes. With these data we conducted fixed effects meta-analysis, both across ancestries and stratified by broad ancestry groups. This approach allowed us to consider cumulative evidence for genetic risk factors for keloids and explore potential ancestry-specific components of risk. We used FUMA for functional annotation of results and LDSC to estimate ancestry-specific heritability. We performed GPGE analysis using S-PrediXcan with GTEx v8 tissues. RESULTS/ANTICIPATED RESULTS: We detected 30 (23 novel) genomic risk loci in the cross-ancestry analysis. Major risk loci were broadly consistent between ancestries, with variable effects. Keloid heritability estimates from LDSC were 6%, 21%, and 34% for European, East Asian, and African ancestry, respectively. The top hit (P = 1.7e-77) in the cross-ancestry analysis was at a replicated variant (rs10863683) located downstream of LINC01705. GPGE analysis identified an association between decreased risk of keloids and increased expression of LINC01705 in fibroblasts (P = 3.6e10-20), which are important in wound healing. The top hit in the African-ancestry analysis (P = 5.5e-31) was a novel variant (rs34647667) in a conserved region downstream of ITGA11. ITGA11 encodes a collagen receptor and was previously associated with uterine fibroids. DISCUSSION/SIGNIFICANCE: This work significantly increases the yield of discoveries from keloid genetic association studies, describing both common and ancestry-specific effects. Stark differences in heritability support a potential adaptive origin for keloid disparities. Further work will continue to examine keloids in the broader context of other fibrotic diseases.

Introduction Health information systems represent an opportunity to improve the care provided to people with multimorbidity. There is a pressing need to assess their impact on clinical outcomes to validate this intervention. Our study will determine whether using a digital platform (Multimorbidity Management Health Information System, METHIS) to manage multimorbidity improves health-related quality of life (HR-QoL).Methods and analysis A superiority, cluster randomised trial will be conducted at primary healthcare practices (1:1 allocation ratio). All public practices in the Lisbon and Tagus Valley (LVT) Region, Portugal, not involved in a previous pilot trial, will be eligible. At the participant level, eligible patients will be people with complex multimorbidity, aged 50 years or older, with access to an internet connection and a communication technology device. Participants who cannot sign/read/write and who do not have access to an email account will not be included in the study. The intervention combines a training programme and a customised information system (METHIS). Both are designed to help clinicians adopt a goal-oriented care model approach and to encourage patients and carers to play a more active role in autonomous healthcare. The primary outcome is HR-QoL, measured at 12 months with the physical component scale of the 12-item Short Form questionnaire (SF-12). Secondary outcomes will also be measured at 12 months and include mental health (mental component Scale SF-12, Hospital Anxiety and Depression Scale). We will also assess serious adverse events during the trial, including hospitalisation and emergency services. Finally, at 18 months, we will ask the general practitioners for any potentially missed diagnoses.Ethics and dissemination The Research and Ethics Committee (LVT Region) approved the trial protocol. Clinicians and patients will sign an informed consent. A data management officer will handle all data, and the publication of several scientific papers and presentations at relevant conferences/workshops is envisaged.Trial registration number NCT05593835.

BACKGROUND Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODS In this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTS Plerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSION Plerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATION Clinicaltrials.gov NCT02231879.FUNDING This study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

Introduction Misinformation refers to inadvertent misleading information that the public may be exposed and share without intent to cause harm, and can delay or prevent effective care, affect mental health, lead to misallocation of health resources and/or create or exacerbate public-health crises. There are many strategies to address misinformation, but there is a need to evaluate their effects. Our objective is to synthesise and routinely update evidence to assess the impact of strategies to mitigate health-related misinformation in diverse settings, and populations.Methods and analysis We will search seven databases in May 2023 with planned updates at 6 and 9 months, which will be supplemented with searches for grey literature and reference lists of included studies and contacting experts. Two reviewers will independently screen all search results for studies that evaluate one or more approaches to addressing health-related misinformation. One researcher will conduct data extraction and risk of bias assessments, which will be reviewed by a second reviewer for accuracy. We will include experimental, quasi-experimental and observational studies for any populations, settings and diseases without language or publication restrictions. We will conduct quantitative analysis if meta-analytical pooling is possible. If pooling is not possible, we will synthesise quantitative data according to outcomes and interventions addressed, and present a narrative summary of findings disaggregated by sex and/or gender, irrespective of whether differences were found.Ethics and dissemination There are no individuals or protected health information involved and no safety issues identified. Results will be published through the Global Commission on Evidence and COVID-END websites, in a peer-reviewed journal, as well as through plain-language materials.PROSPERO registration number CRD42023421149.

BackgroundThere is significant heterogeneity in disease progression among hospitalized patients with COVID-19. The pathogenesis of SARS-CoV-2 infection is attributed to a complex interplay between virus and host immune response that in some patients unpredictably and rapidly leads to “hyperinflammation” associated with increased risk of mortality. The early identification of patients at risk of progression to hyperinflammation may help inform timely therapeutic decisions and lead to improved outcomes. ObjectiveThe primary objective of this study was to use machine learning to reproducibly identify specific risk-stratifying clinical phenotypes across hospitalized patients with COVID-19 and compare treatment response characteristics and outcomes. A secondary objective was to derive a predictive phenotype classification model using routinely available early encounter data that may be useful in informing optimal COVID-19 bedside clinical management. MethodsThis was a retrospective analysis of electronic health record data of adult patients (N=4379) who were admitted to a Johns Hopkins Health System hospital for COVID-19 treatment from 2020 to 2021. Phenotypes were identified by clustering 38 routine clinical observations recorded during inpatient care. To examine the reproducibility and validity of the derived phenotypes, patient data were randomly divided into 2 cohorts, and clustering analysis was performed independently for each cohort. A predictive phenotype classifier using the gradient-boosting machine method was derived using routine clinical observations recorded during the first 6 hours following admission. ResultsA total of 2 phenotypes (designated as phenotype 1 and phenotype 2) were identified in patients admitted for COVID-19 in both the training and validation cohorts with similar distributions of features, correlations with biomarkers, treatments, comorbidities, and outcomes. In both the training and validation cohorts, phenotype-2 patients were older; had elevated markers of inflammation; and were at an increased risk of requiring intensive care unit–level care, developing sepsis, and mortality compared with phenotype-1 patients. The gradient-boosting machine phenotype prediction model yielded an area under the curve of 0.89 and a positive predictive value of 0.83. ConclusionsUsing machine learning clustering, we identified and internally validated 2 clinical COVID-19 phenotypes with distinct treatment or response characteristics consistent with similar 2-phenotype models derived from other hospitalized populations with COVID-19, supporting the reliability and generalizability of these findings. COVID-19 phenotypes can be accurately identified using machine learning models based on readily available early encounter clinical data. A phenotype prediction model based on early encounter data may be clinically useful for timely bedside risk stratification and treatment personalization.

Background: The prevalence of prenatal over-the-counter medication use in Canadian women is unknown. Methods: A cross-sectional study of prenatal over-the-counter medication use and safety knowledge was conducted among pregnant and post-partum women attending an academic hospital obstetrics clinic. Results: Seventy-two women participated; 90.3% were Caucasian, 69.4% had a college/university degree, and 61.1% lived in an urban area. Of the 72 women, 87.5% used over-the-counter medications prenatally, first (55.6%), second (65.3%), and third (47.2%) trimesters, with prenatal acetaminophen use most common (72.2%). Women who used over-the-counter medications 1–0onths before conception were more likely to use over-the-counter medications during pregnancy, and 18% of women initiated over-the-counter medications in pregnancy. Women self-reported a medium level of over-the-counter medication safety knowledge (73.6%) and responded that not all over-the-counter medications are safe during pregnancy (95.8%). Conclusion: Despite limited safety profiles of some over-the-counter medications, pre-conception and prenatal over-the-counter medication use was high. Further research on the risk of over-the-counter medications and combinations in pregnancy is needed to help women to make safe choices during pregnancy.

Abstract The placenta is critical to human growth and development and has been implicated in health outcomes. Understanding the mechanisms through which the placenta influences perinatal and later-life outcomes requires further investigation. We evaluated the relationships between birthweight and adult body mass index (BMI) and genetically-predicted gene expression in human placenta. Birthweight genome-wide association summary statistics were obtained from the Early Growth Genetics Consortium (N = 298,142). Adult BMI summary statistics were obtained from the GIANT consortium (N = 681,275). We used S-PrediXcan to evaluate associations between the outcomes and predicted gene expression in placental tissue and, to identify genes where placental expression was exclusively associated with the outcomes, compared to 48 other tissues (GTEx v7). We identified 24 genes where predicted placental expression was significantly associated with birthweight, 15 of which were not associated with birthweight in any other tissue. One of these genes has been previously linked to birthweight. Analyses identified 182 genes where placental expression was associated with adult BMI, 110 were not associated with BMI in any other tissue. Eleven genes that had placental gene expression levels exclusively associated with BMI have been previously associated with BMI. Expression of a single gene, PAX4, was associated with both outcomes exclusively in the placenta. Inter-individual variation of gene expression in placental tissue may contribute to observed variation in birthweight and adult BMI, supporting developmental origins hypothesis.

Ewart et al. assess the performance of a human Liver-Chip for predictive toxicology. They also perform an economic analysis to demonstrate its potential financial value for the pharmaceutical industry.

Abstract Background Identifying pregnancies at risk for preterm birth, one of the leading causes of worldwide infant mortality, has the potential to improve prenatal care. However, we lack broadly applicable methods to accurately predict preterm birth risk. The dense longitudinal information present in electronic health records (EHRs) is enabling scalable and cost-efficient risk modeling of many diseases, but EHR resources have been largely untapped in the study of pregnancy. Methods Here, we apply machine learning to diverse data from EHRs with 35,282 deliveries to predict singleton preterm birth. Results We find that machine learning models based on billing codes alone can predict preterm birth risk at various gestational ages (e.g., ROC-AUC = 0.75, PR-AUC = 0.40 at 28 weeks of gestation) and outperform comparable models trained using known risk factors (e.g., ROC-AUC = 0.65, PR-AUC = 0.25 at 28 weeks). Examining the patterns learned by the model reveals it stratifies deliveries into interpretable groups, including high-risk preterm birth subtypes enriched for distinct comorbidities. Our machine learning approach also predicts preterm birth subtypes (spontaneous vs. indicated), mode of delivery, and recurrent preterm birth. Finally, we demonstrate the portability of our approach by showing that the prediction models maintain their accuracy on a large, independent cohort (5978 deliveries) from a different healthcare system. Conclusions By leveraging rich phenotypic and genetic features derived from EHRs, we suggest that machine learning algorithms have great potential to improve medical care during pregnancy. However, further work is needed before these models can be applied in clinical settings.

Introduction SARS-CoV-2 has been identified as the cause of the disease officially named COVID-19, primarily a respiratory illness. COVID-19 was characterised as a pandemic on 11 March 2020. It has been estimated that approximately 20% of people with COVID-19 require oxygen therapy. Oxygen has been listed on the WHO Model List of Essential Medicines List and Essential Medicines List for Children for almost two decades. The COVID-19 pandemic has highlighted, more than ever, the acute need for scale-up of oxygen therapy. Detailed data on the use of oxygen therapy in low-and-middle income countries at the patient and facility level are needed to target interventions better globally.Methods and analysis We aim to describe the requirements and use of oxygen at the facility and patient level of approximately 4500 patients with COVID-19 in 30 countries. Our objectives are specifically to characterise type and duration of different modalities of oxygen therapy delivered to patients; describe demographics and outcomes of hospitalised patients with COVID-19; and describe facility-level oxygen production and support. Primary analyses will be descriptive in nature. Respiratory support transitions will be described in Sankey plots, and Kaplan-Meier models will be used to estimate probability of each transition. A multistate model will be used to study the course of hospital stay of the study population, evaluating transitions of escalating respiratory support transitions to the absorbing states.Ethics and dissemination WHO Ad Hoc COVID-19 Research Ethics Review Committee (ERC) has approved this global protocol. When this protocol is adopted at specific country sites, national ERCs may make require adjustments in accordance with their respective national research ethics guidelines. Dissemination of this protocol and global findings will be open access through peer-reviewed scientific journals, study website, press and online media.Trial registration number NCT04918875.

Objectives Adolescent childbirth is associated with older adult adverse health outcomes that negatively affect mobility function, but these associations have not been studied globally in large samples of reproductive-age women. This study examines the association between age at first childbirth and mobility disability in national surveys from low-income and middle-income countries, and hypotheses that adolescent childbirth is associated with mobility disability.Design Cross-sectional analysis.Setting Population health surveys from 2013 to 2018 containing mobility disability measures among ever-pregnant women ages 15–49. These included 13 Demographic Health Surveys from Haiti, Pakistan, Uganda, Cambodia, Colombia, South Africa, Timor-Leste, Albania, Gambia, Maldives, Peru, Senegal and Yemen and 1 Maternal Health Survey from Ghana.Participants The sample included 157 988 women ages 15–49 years.Primary outcome measure Adolescent childbirth was defined as 10–19 years of age. Poisson regression models were used to estimate prevalence ratios (PRs) of mobility disability among women who first gave birth during adolescence and in adult life (ages 20–45 years) in each country and across the whole sample. Countries were also analysed according to the use of standard and non-standard mobility disability measures. Covariates included current age, urban/rural residence, education and household wealth.Results Prevalence of adolescent childbirth (17.5%–66.2%) and mobility disability (0.32%–21.45%) varied widely across countries. Adolescent childbirth was significantly (p

Background: Undernutrition is projected to be a major consequence of climate change. Biodiversity could enhance climate change resilience by improving nutritional outcomes and providing healthy food resources during and/or after climate-related events. For Indigenous populations who currently base their diet on local biodiversity, rapid climate changes may affect their ability to produce, access or gather food and consequently impact their nutritional status. There is a knowledge gap regarding whether nutritional status among Indigenous populations is better among those who consume a diet with greater biodiversity than those who have a diet with low biodiversity. Objective: This study aims to investigate the role of food biodiversity (FBD) in nutritional resilience to extreme flooding events of Shawi Amazon Indigenous adults living in Peruvian communities that have experienced extreme floods in the past five years. Methods: This study will use a mixed-method sequential explanatory design. The quantitative component includes a cross-sectional survey to assess the association between food biodiversity (FBD) and the prevalence of anaemia in adults aged 15 to 60 years old (n=365). Anaemia will be evaluated using blood hemoglobin and serum ferritin. FBD will be measured with a food frequency questionnaire and a 24-hour dietary recall. Soil-transmitted helminth infections, malaria, and inflammatory biomarkers will also be evaluated. Qualitative component will include a community-based participatory approach to investigate the role of FBD in the responses to extreme floods. Male (n=14) and female (n=14) participants, previously identified in the quantitative phase with high and low levels of FBD, will be invited to participate in a Photovoice activity and semi-structured interviews. A analytical framework for climate change resilience will be used to integrate the data. Discussion: Findings will be integrated to identify features of diet quality to suggest nutritional interventions that are resilient to changing climatic conditions in the Amazon and respect Indigenous views.

Odontocetes first appeared in the fossil record by the early Oligocene, and their early evolutionary history can provide clues as to how some of their unique adaptations, such as echolocation, evolved. Here, three new specimens from the early to late Oligocene Pysht Formation are described further increasing our understanding of the richness and diversity of early odontocetes, particularly for the North Pacific. Phylogenetic analysis shows that the new specimens are part of a more inclusive, redefined Simocetidae, which now includes Simocetus rayi, Olympicetus sp. 1, Olympicetus avitus, O. thalassodon sp. nov., and a large unnamed taxon (Simocetidae gen. et sp. A), all part of a North Pacific clade that represents one of the earliest diverging groups of odontocetes. Amongst these, Olympicetus thalassodon sp. nov. represents one of the best known simocetids, offering new information on the cranial and dental morphology of early odontocetes. Furthermore, the inclusion of CCNHM 1000, here considered to represent a neonate of Olympicetus sp., as part of the Simocetidae, suggests that members of this group may not have had the capability of ultrasonic hearing, at least during their early ontogenetic stages. Based on the new specimens, the dentition of simocetids is interpreted as being plesiomorphic, with a tooth count more akin to that of basilosaurids and early toothed mysticetes, while other features of the skull and hyoid suggest various forms of prey acquisition, including raptorial or combined feeding in Olympicetus spp., and suction feeding in Simocetus. Finally, body size estimates show that small to moderately large taxa are present in Simocetidae, with the largest taxon represented by Simocetidae gen. et sp. A with an estimated body length of 3 m, which places it as the largest known simocetid, and amongst the largest Oligocene odontocetes. The new specimens described here add to a growing list of Oligocene marine tetrapods from the North Pacific, further promoting faunistic comparisons across other contemporaneous and younger assemblages, that will allow for an improved understanding of the evolution of marine faunas in the region.

Endometriosis is a chronic, complex disease for which there are vast disparities in diagnosis and treatment between sociodemographic groups. Clinical presentation of endometriosis can vary from asymptomatic disease—often identified during (in)fertility consultations—to dysmenorrhea and debilitating pelvic pain. Because of this complexity, delayed diagnosis (mean time to diagnosis is 1.7–3.6 years) and misdiagnosis is common. Early and accurate diagnosis of endometriosis remains a research priority for patient advocates and healthcare providers. Electronic health records (EHRs) have been widely adopted as a data source in biomedical research. However, they remain a largely untapped source of data for endometriosis research. EHRs capture diverse, real-world patient populations and care trajectories and can be used to learn patterns of underlying risk factors for endometriosis which, in turn, can be used to inform screening guidelines to help clinicians efficiently and effectively recognize and diagnose the disease in all patient populations reducing inequities in care. Here, we provide an overview of the advantages and limitations of using EHR data to study endometriosis. We describe the prevalence of endometriosis observed in diverse populations from multiple healthcare institutions, examples of variables that can be extracted from EHRs to enhance the accuracy of endometriosis prediction, and opportunities to leverage longitudinal EHR data to improve our understanding of long-term health consequences for all patients.

Background and Objectives: The development of severe COVID-19 is related to the preexistence of comorbidities and an inadequate nutritional status. The latter is a critical factor for the development of infection and the progression of the disease. Notably, optimal nutrition impacts immune system function, as malnutrition is related to high cytokine levels in the late phase of the disease, correlating with a poor prognosis. In this sense, omega-3 fatty acids (O3FAs) have anti-inflammatory properties that may reduce morbidity and mortality from COVID-19 infection. O3FAs are linked to a better prognosis in COVID-19 patients. Materials and Methods: In this randomized, double-blind clinical trial, we evaluate the administration of O3FAs to unvaccinated Mexican patients for two weeks starting after the first two hours of hospitalization. Results: The findings support the notion that O3FAs (in a dose high enough to satisfy human physiological requirements in a short time, one capsule of 1.4 g O3FAs daily) exert a comprehensive multi-systemic modulatory influence, affecting inflammatory and metabolic pathways. Significant perturbations in biomarkers, including absolute neutrophil count, hematocrit, and platelet indices, underscore the compound’s anti-inflammatory effect. Concurrently, the intervention modulates pivotal metabolic and hepatic parameters, attenuating cardiovascular risk profiles and expediting patient convalescence. These multifarious effects are likely orchestrated through intricate biochemical mechanisms and are subject to individual variations predicated on metabolic factors. Conclusions: The results of this trial support the notion that O3FA supplementation has beneficial effects on COVID-19 patients with moderate presentation by regulating metabolism and limiting inflammation.

Abstract Serological testing for SARS-CoV-2 IgG antibodies is used to assess their presence in blood samples from exposed individuals and provides a measure of the magnitude of immune response to infection. The measurement of neutralizing antibodies (NAbs) in particular provides information about the severity of prior infection and level of protective immunity against re-infection. Much of the work investigating the association between prior infection severity and NAb levels has been conducted among clinical populations, and less is known about this relationship in the general population. Accordingly, we utilize data from a large (n = 790) community-based cohort of unvaccinated, seropositive participants. We analyzed the association between NAb response, measured via surrogate virus neutralization assay, with patterns of symptoms and household exposure. Our results indicate no detectable NAb activity in 63.8% of the seropositive participants (n = 504). Those with detectable NAb levels demonstrated a positive relationship between NAb activity and both self-reported previous symptom severity and household exposure. These findings are significant in light of recent concerns about degree of protective immunity conferred by prior infection or vaccination, and we highlight the value of community-based research for investigating variation in immune response.

Abstract Microglia contain multiple mechanisms that shape the synaptic landscape during postnatal development. Whether the synaptic changes mediated by microglia reflect the developmental refinement of neuronal responses in sensory cortices, however, remains poorly understood. In postnatal life, the development of increased orientation and spatial frequency selectivity of neuronal responses in primary visual cortex (V1) supports the emergence of high visual acuity. Here, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to rapidly and durably deplete microglia in mice during the juvenile period in which increased orientation and spatial frequency selectivity emerge. Excitatory and inhibitory tuning properties were measured simultaneously using multi-photon calcium imaging in layer II/III of mouse V1. We found that microglia depletion generally increased evoked activity which, in turn, reduced orientation selectivity. Surprisingly, microglia were not required for the emergence of high spatial frequency tuned responses. In addition, microglia depletion did not perturb cortical binocularity, suggesting normal depth processing. Together, our finding that orientation and high spatial frequency selectivity in V1 are differentially supported by microglia reveal that microglia are required normal sensory processing, albeit selectively.

Abstract Background To respond to the COVID-19 pandemic, the Substance Abuse and Mental Health Services Administration-funded Technology Transfer Centers had to rapidly adapt to ensure that the behavioral health workforce had continuous access to remote training and technical assistance (TTA). Although the Technology Transfer Centers have historically relied partially upon virtual methods for delivering TTA, the shift to a strictly virtual approach necessitated by COVID-19 restrictions has raised new questions for how to best proceed with services when social distancing guidelines are relaxed. The objective of this exploratory paper was to compare TTA provision in the six-month period prior to (9/1/19 thru 2/28/20) and during (4/1/20 thru 9/30/20) early COVID-19 restrictions to determine the extent to which the shift to virtual service provision impacted the behavioral health and medical workforce. Specifically, we examined participants’ access to TTA, geographic reach of TTA, and workforce perceptions of satisfaction and utility with TTA provision. Method Participant and event-level data were analyzed to compare the following metrics before and during the COVID pandemic: number of events and attendees; participant demographics; zip codes reached; coverage of rural, suburban, and urban areas; and perceptions of satisfaction with and utility of training. Results Findings showed a 40% increase in the number of events delivered (p

Abstract Background and Aims A noninterventional prospective study was performed in Colombia and Peru. The aim was to describe the impact of access to treatment on Patient‐reported outcomes (PRO) in patients with Rheumatoid arthritis (RA) after failure to conventional disease‐modifying antirheumatic drugs (DMARDs) in real‐life conditions. Methods The impact of access to treatment was measured by access barriers, time to supply (TtS) and interruption evaluating their effect in changes of PROs between baseline and 6‐month follow‐up between February 2017 and November 2019. The association of access to care with disease activity, functional status, health‐related quality of life was assessed using bivariate and multivariable analysis. Results are expressed in least mean difference; TtS in mean number of days for delivery of treatment at baseline. Variability measures were standard deviation and standard error. Results One hundred seventy patients were recruited, 70 treated with tofacitinib and 100 with biological DMARDs. Thirty‐nine patients reported access barriers. The mean of TtS was 23 ± 38.83 days. The difference from baseline to 6‐month visit in PROs were affected by access barriers and interruptions. There was not statistically significant difference in the of PRO's score among visits in patients that reported delay of supply of more than 23 days compared to patients with less days of delay. Conclusion This study suggested the access to treatment can affect the response to the treatment at 6 months of follow‐up. There seems to be no effect in the PROs for delay of TtS during the studied period.

The control of ticks through vaccination offers a sustainable alternative to the use of chemicals that cause contamination and the selection of resistant tick strains. However, only a limited number of anti-tick vaccines have reached commercial realization. In this sense, an antigen effective against different tick species is a desirable target for developing such vaccines. A peptide derived from the tick P0 protein (pP0) conjugated to a carrier protein has been demonstrated to be effective against the Rhipicephalus microplus, Rhipicephalus sanguineus, and Amblyomma mixtum tick species. The aim of this work was to assess the efficacy of this peptide when conjugated to the Bm86 protein against Dermacentor nitens and Ixodes ricinus ticks. An RNAi experiment using P0 dsRNA from I. ricinus showed a dramatic reduction in the feeding of injected female ticks on guinea pigs. In the follow-up vaccination experiments, rabbits were immunized with the pP0-Bm86 conjugate and challenged simultaneously with larvae, nymphs, and the adults of I. ricinus ticks. In the same way, horses were immunized with the pP0-Bm86 conjugate and challenged with D. nitens larva. The pP0-Bm86 conjugate showed efficacies of 63% and 55% against I. ricinus and D. nitens ticks, respectively. These results, combined with previous reports of efficacy for this conjugate, show the promising potential for its development as a broad-spectrum anti-tick vaccine.

Acute febrile syndrome is a frequent reason for medical consultations in tropical and subtropical countries where the cause could have an infectious origin. Malaria and dengue are the primary etiologies in Colombia. As such, constant epidemiological surveillance and new diagnostic tools are required to identify the causative agents. A descriptive cross-sectional study was conducted to evaluate the circulation and differential diagnosis of six pathogens in two regions of Colombia. The results obtained via multiplex reverse transcription polymerase chain reaction combined with a microwell hybridization assay (m-RT-PCR-ELISA) were comparable to those obtained using rapid tests conducted at the time of patient enrollment. Of 155 patients evaluated, 25 (16.1%) and 16 (10.3%) were positive for malaria and dengue, respectively; no samples were positive for any of the other infectious agents tested. In most cases, m-RT-PCR-ELISA confirmed the results previously obtained through rapid testing.

An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it is well appreciated that macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive macrophages are classically defined by the expression of the enzyme Arginase 1 (ARG1), which we demonstrated is potently expressed in pancreatic tumor-associated macrophages from both human patients and mouse models. While routinely used as a polarization marker, ARG1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. Genetic inactivation of Arg1 in macrophages, using a dual recombinase genetically engineered mouse model of pancreatic cancer, delayed formation of invasive disease, while increasing CD8+ T cell infiltration. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of macrophages. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit arginase. Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8+ T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting arginine and inhibiting T cell activation.

Introducción: la citología permite examinar células de un tejido de manera mínimamente invasiva, sin embargo, la capacidad de realizar técnicas complementarias como la inmunocitoquímica (ICQ) no está exenta de dificultades. Es el objetivo de nuestro trabajo presentar una metodología que permita la utilización de ICQ automatizada asociada a un análisis automatizado mediante técnica de patología digital. Métodos: se incluyeron 5 sujetos sanos y se obtuvieron muestras de superficie ocular utilizando un citocepillo. La muestra fue procesada de manera automatizada mediante citología en fase líquida. Posteriormente se realizó ICQ automatizada para detectar la positividad nuclear del receptor de vitamina D. Para la evaluación, se utilizaron dos métodos: cuantificación directa bajo microscopio de luz y análisis automatizado usando analizador de imágenes en las diapositivas digitales obtenidas con un Scanner. El porcentaje de positividad encontrado con ambos métodos fueron comparados utilizando la prueba de Kappa. Resultados: todas las muestras presentaron una celularidad adecuada. En todos los casos fue posible realizar ICQ automatizada, más aún, todas las muestras presentaron una calidad óptima. Al comparar ambos métodos (manual versus automatizado) se observó un nivel de acuerdo sustancial (Kappa=0,69). Conclusiones: la metodología presentada en este manuscrito permite la evaluación automatizada de marcadores inmunohistoquímicos de la superficie ocular de manera mínimamente invasiva, siendo similar al conteo manual, pero más objetivo y reproducible. Esta técnica podría ser útil para el estudio proteómico en patologías como la enfermedad por ojo seco.

OBJECTIVES/GOALS: Preeclampsia (PE) is a hypertensive disorder of pregnancy, affecting 5 - 7% of pregnancies worldwide. A major cause of morbidity and mortality, PE is also associated with subsequent adverse health outcomes, including long-term increased risk of cardiovascular disease. The genetics conferring increased risk for PE are incompletely understood. METHODS/STUDY POPULATION: We performed a cross-ancestry, fixed-effects meta-analysis, incorporating both published and unpublished genome-wide association study (GWAS) summary statistics. In addition to publicly available summary statistics from two prior studies, we generated GWAS data from three electronic health record biobanks (BioVU, eMERGE, and PMBB). In total, we utilized data from 359,378 individuals (4,411 cases and 354,967 controls). Leveraging this large-scale biobank data importantly allows for detection of complex factors contributing to the diverse etiology of PE. Cases across cohorts were defined using PE-specific ICD-9/ICD-10 codes and phecodes. Cohorts included pregnant individuals of self-identified non-Hispanic Black, non-Hispanic White, and East Asian ancestry. RESULTS/ANTICIPATED RESULTS: 2 of 20,204,625 loci achieved genome-wide significance (p < 5 × 10–8) when minor allele frequency was limited to common variants (>0.01). The most significant locus was rs138180605 (p = 1.77 × 10–8), located in an intergenic region between FGFR2 and ATE1, both previously associated with breast cancer. The other significant locus was rs137895377 (p = 2.33 × 10–8), located in an intronic region of PLEKHO1. Another 225 loci achieved suggestive significance (p < 1 × 10–5). 203 loci could be mapped to 109 unique genes, some previously associated with related phenotypes such as hypertension. Next steps will focus on functional analyses, including genetically predicted gene expression incorporating placental tissue, followed by construction of a PE polygenic risk score to demonstrate predictive utility of results. DISCUSSION/SIGNIFICANCE: This work has contributed to the limited body of knowledge surrounding maternal genetic susceptibility to PE by identifying several loci warranting further investigation. Further work will expand on these results to improve understanding of genetic factors and clarify clinical risk of disease.

Expression of the transcription factor interferon regulatory factor 4 (IRF4) is required for the development of lung conventional DCs type 2 (cDC2s) that elicit Th2 responses, yet how IRF4 functions in lung cDC2s throughout the acute and memory allergic response is not clear. Here, we used a mouse model that loses IRF4 expression after lung cDC2 development to demonstrate that mice with IRF4-deficient DCs display impaired memory responses to allergen. This defect in the memory response was a direct result of ineffective Th2 induction and impaired recruitment of activated effector T cells to the lung after sensitization. IRF4-deficient DCs demonstrated defects in their migration to the draining lymph node and in T cell priming. Finally, T cells primed by IRF4-competent DCs mediated potent memory responses independently of IRF4-expressing DCs, demonstrating that IRF4-expressing DCs are not necessary during the memory response. Thus, IRF4 controlled a program in mature DCs governing Th2 priming and effector responses, but IRF4-expressing DCs were dispensable during tissue-resident memory T cell–dependent memory responses.

Background Although psoriasis burden and treatment have been well characterized in developed countries, there are scarce in-depth epidemiological studies in Latin American countries. Objectives To describe the sociodemographic and clinical features and the economic burden of psoriasis among children and adult patients from Colombia. Methods This cross-sectional study included patients from dermatology private practice offices, health provider institutions and hospitals in seven Colombian cities. We collected data on disease distribution, weight, height, body mass index, waist-hip ratio, disease severity, therapy, personal history of comorbidities, and direct costs. Multiple logistic regression analyses were conducted to assess the associations between severity scales and sociodemographic and clinical variables. Results Two-hundred-three patients (43.8% women, 56.2% men) with an age range between 7 to 89 years old were included. The main subtype was psoriasis vulgaris and mean age of diagnosis was 37.1 years. The most common comorbidities were obesity, hypertension, psoriatic arthritis, dyslipidemia and diabetes. Women had a significant increased odds of presenting with psoriatic arthritis. Body-mass-index and hypertension were significantly associated with a higher psoriasis severity, whereas being female and non-obese was associated with a lower risk. A third of the patients had a family history of psoriasis and sleeping disorders. Forty-one percent of participants either had no income or had an income below 224 US dollars per month and >20% of their income was spent on their disease. Conclusions This study is supported by robust scientific data and contributes to understanding the burden of psoriasis in Latin America. This study adds well-supported data through an in-depth clinical and economical characterization of Colombian children and adult patients with psoriasis and shows the high impact and burden of the disease on patients and their families.