Future Screening Research Articles

Effect of Th2 cytokines on ceramide subclasses based on a model of reconstructed human epidermis.

Atopic dermatitis (AD) is associated with chronic inflammation and an altered skin barrier. Lipids of the stratum corneum of AD patients are known to differ substantially in composition from those of healthy subjects. A reconstructed human epidermis (RHE) model has been developed in vitro in order to mimic the characteristics of AD. In this study, using this model, we compared lipid profile modifications between control RHE and RHE treated with Th2 cytokines in order to mimic AD. We focused particularly on the lipid profile of the ceramide subclasses: non-hydroxy sphingosine (NS) and esterified ω-hydroxy sphingosine (EOS), which have been reported to be clearly modified in atopic skin. RHE lipids were extracted and analysed using high-performance liquid chromatography coupled to high-resolution mass spectrometry. The following lipid profile changes were observed in Th2-cytokine-treated RHE: (i) an increase in ceramide NS composed of an unsaturated fatty acid chain; (ii) an increase in saturated ceramide NS with small total carbon content (≤40 carbon atoms), whereas NS with a higher total carbon content (≥42 carbon atoms) was decreased; and (iii) a decrease in ceramide EOS. These results are in accordance with reported lipid profiles of human atopic skin in vivo. Moreover, the in vitro model represents a useful tool to better understand the pathogenesis of AD which may be used for future screening of new effective treatments.

Clinical and genetic characteristics of patients with TRG 0 and TRG III in esophageal squamous cell carcinoma after neoadjuvant therapy

Neoadjuvant therapy (NAT) is an important treatment for patients with resectable locally advanced esophageal squamous cell carcinoma (ESCC), but neoadjuvant resistance affects the overall treatment outcome. Therefore, it is particularly important to accurately screen the population for NAT and explore the mechanism of resistance. Usually, different chemotherapy regimens cause different drug resistance mechanisms. Prior to combining immunotherapy with chemotherapy, extensive research has been conducted on previous drug resistance mechanisms. Currently, the mainstream NAT for ESCC involves chemotherapy combined with immunotherapy. We have witnessed the remarkable effect of this combination therapy; however, there are still a considerable number of patients whose tumor tissues show no change or even progress after NAT, and their drug resistance mechanisms remain unclear. Hence, we aim to identify relevant evidence that can distinguish and predict the effectiveness of NAT from a clinical perspective in order to provide a clinical basis for future screening of suitable populations for NAT and discovery of drug resistance mechanisms. This study is based in China's high incidence area of esophageal cancer, where enrolled patients all receive the current mainstream NAT regimen resulting in more reliable outcomes.

The Development and Reliability of an Updated Dance-Specific Star Excursion Balance Test Protocol.

Background: While the previous research has made crucial developments in a dance-specific version of the SEBT, current modifications to the SEBT have not conclusively produced a valid dance-specific dynamic balance test. Purpose: The aim of this paper was to utilize the most practical dance-specific variations from previous research and incorporate them into a reliable test to be considered for future screenings for dancers. Methods: Twenty-one female dancers voluntarily took part in the research (age: 20.86 ± 3.68 years). This protocol consists of 3 stages, each increasing in difficulty; stage one: dsSEBT Average Tempo, stage two: dsSEBT Block, and stage three: a combination of stage 1 and stage 2, the dsSEBT Average Tempo on Block. Reach distance (% of limb length), error scores, and average time to complete each stage were recorded. A stage completion criteria was developed to move from one stage to the next wherein certain reach distance and error score standards needed to be met. Results: Between previous research using the same participants and the current study, each reach direction exhibits a statistically significant correlation (P < .05) with good to excellent ICC values ranging from .750 to .918, suggesting that test-retest reliability is high. Overall, 90.48% of participants succeeded in passing stage one, 19.05% of total participants passed stage two, and only 4.76% of the 21 participants passed all 3 stages with statistically significant differences detected for reach distance and incomplete trials between stages (P < .05). Conclusion: This data suggests that the test is challenging enough to show dancers weaknesses and push the limits of their balance capabilities. With a clear increase in difficulty from stage to stage, the test adds layers of demanding tasks designed to test the dancer proprioceptively.

Exploring Active Case Detection Approaches for Leprosy Diagnosis in Varied Endemic Settings: A Comprehensive Scoping Review.

(1) Background: The global burden of leprosy is not shared equally; with the majority of cases being diagnosed in Brazil, India, and Indonesia. Understanding the methods of active case detection (ACD) used in high and low endemic regions is vital for the development of future screening programs. (2) Methods: A systematic search of three databases, PubMed, Embase and Web of Science, was conducted for English language papers, published since the year 2000, which discussed the use of active case detection methods for leprosy screening. The paper utilised the Integrated Screening Action Model (I-SAM) as a tool for the analysis of these methods. (3) Results: 23 papers were identified from 11 different countries. The papers identified 6 different methods of active case detection: Household contact/social contact identification; door-to-door case detection; screening questionnaire distribution; rapid village surveys; school-based screening; and prison-based screening. 15 were located in high endemic regions and 8 of these were located in low endemic regions. (4) Conclusions: For selecting the appropriate methods of active case finding, the leprosy endemicity must be taken into consideration. The findings contribute to policy decision making allowing for more successful future leprosy case detection programs to be designed, ultimately reducing the global burden of the disease, and achieving the WHO's aim of zero leprosy.

Using the consolidated framework for implementation research to identify church leaders’ perspectives on contextual determinants of community-based colorectal cancer screening for Black Kentuckians

BackgroundBlack Kentuckians experience more deleterious colorectal cancer (CRC) outcomes than their White counterparts, a disparity that could be reduced by increased screening in Black communities. Previous research has shown that Black Kentuckians may not be equitably informed of different CRC screening options by health care providers, making community-based screening a potentially effective option among this disparate population. We used the Consolidated Framework for Implementation Research (CFIR) to identify church leaders’ perspectives of contextual factors that might influence community-based screening and explore the feasibility of using church-based screening outreach.MethodsSix participants were selected, based on leadership roles and interest in CRC screening, from five established Louisville-area church partners that had previously participated in community health initiatives. Data were collected, both virtually and in-person, in Summer 2021 using semi-structured interview guides developed with guidance from the CFIR Guide that focused on domains most relevant to community-based interventions. Data were transcribed verbatim, coded by two independent researchers, and member checked for accuracy.ResultsData were aligned primarily with six CFIR constructs: key stakeholders, champions, opinion leaders, tension for change, compatibility, and culture. Participants noted a strong tension for change in their community due to perceptions of inadequacy with clinical approaches to CRC screening. Additionally, they stressed the importance of identifying individuals both within the church who could champion CRC screening and help implement program activities, as well as those outside the church who could collaborate with other local organizations to increase participant reach. Finally, participants agreed that faith-based CRC screening aligned with church culture and would also likely be compatible with overall community values.ConclusionsOverall, our church partners strongly endorsed the need for, and importance of, community-based CRC screening. Given a history of successful implementation of health promotion programs within our partner churches, it is highly likely that a CRC screening intervention would also be effective. Findings from this study will be used to identify implementation strategies that might positively impact a future faith-based CRC screening intervention, as well as CFIR constructs that are most positively associated with CRC screening completion.

May Measurement Month 2021: an analysis of blood pressure screening campaign results from India.

Raised blood pressure (BP) is the leading preventable risk factor for cardiovascular diseases that makes a major impact on early mortality and morbidity. Recognizing hypertension in the community, educating people about routine BP monitoring, and improving medication compliance are all important steps in detecting, controlling, and managing hypertension. During the course of 5 months, members of the Indian Society of Hypertension organized unique medical indoor and outdoor camps at 100 screening locations around India for the May Measurement Month (MMM) 2021 study. At every location, BP was measured three times, and a questionnaire was completed. Participants known to have hypertension before the study whether taking or not taking treatment were not included (not a normal pre-requisite for exclusion in MMM). The analysis included 15 045 participants in total. After calculating the average of the second and third BP measurements, 16.4% of participants were found to have hypertension based on ≥140/90 mmHg thresholds (2461 out of 15 045). 14.0% of females and 16.4% of males had hypertension. 16.4% of participants had undiagnosed hypertension and were not receiving treatment. The MMM screening campaign has the potential for identifying large numbers of people with undiagnosed hypertension and raising awareness of the importance of raised BP among the general public, medical professionals, policymakers, the government, and the media. Future BP screening campaigns should be larger in scope and involve follow-ups with past participants.

Information needs persist after genetic counseling and testing for BRCA1/2 and Lynch Syndrome.

Research has shown that cancer genetic risk is often not well understood by patients undergoing genetic testing and counseling. We describe the barriers to understanding genetic risk and the needs of high-risk persons and cancer survivors who have undergone genetic testing. Using data from an internet survey of adults living in the USA who responded 'yes' to having ever had a genetic test to determine cancer risk (N = 696), we conducted bivariate analyses and multivariable logistic regression models to evaluate associations between demographic, clinical, and communication-related variables by our key outcome of having vs. not having enough information about genetics and cancer to speak with family. Percentages for yes and no responses to queries about unmet informational needs were calculated. Patient satisfaction with counseling and percentage disclosure of genetic risk status to family were also calculated. We found that a lack of resources provided by provider to inform family members and a lack of materials provided along with genetic test results were strongly associated with not having enough information about genetics and cancer (OR 4.54 95% CI 2.40-8.59 and OR 2.19 95% CI 1.16-4.14 respectively). Among participants undergoing genetic counseling, almost half reported needing more information on what genetic risk means for them and their family and how genetic testing results might impact future screening. High levels of satisfaction with genetic counseling may not give a full picture of the patient-provider interaction and may miss potential unmet needs of the patient. Accessible resources and ongoing opportunities for updating family history information could reinforce knowledge about genetic risk.

Estimating sojourn time and sensitivity of screening for ovarian cancer using a Bayesian framework.

Ovarian cancer is among the leading causes of gynecologic cancer-related death. Past ovarian cancer screening trials using combination of cancer antigen 125 testing and transvaginal ultrasound failed to yield statistically significant mortality reduction. Estimates of ovarian cancer sojourn time-that is, the period from when the cancer is first screen detectable until clinical detection-may inform future screening programs. We modeled ovarian cancer progression as a continuous time Markov chain and estimated screening modality-specific sojourn time and sensitivity using a Bayesian approach. Model inputs were derived from the screening arms (multimodal and ultrasound) of the UK Collaborative Trial of Ovarian Cancer Screening and the Prostate, Lung, Colorectal and Ovarian cancer screening trials. We assessed the quality of our estimates by using the posterior predictive P value. We derived histology-specific sojourn times by adjusting the overall sojourn time based on the corresponding histology-specific survival from the Surveillance, Epidemiology, and End Results Program. The overall ovarian cancer sojourn time was 2.1 years (posterior predictive P value = .469) in the Prostate, Lung, Colorectal and Ovarian studies, with 65.7% screening sensitivity. The sojourn time was 2.0 years (posterior predictive P value = .532) in the United Kingdom Collaborative Trial of Ovarian Cancer Screening's multimodal screening arm and 2.4 years (posterior predictive P value = .640) in the ultrasound screening arm, with sensitivities of 93.2% and 64.5%, respectively. Stage-specific screening sensitivities in the Prostate, Lung, Colorectal and Ovarian studies were 39.1% and 82.9% for early-stage and advanced-stage disease, respectively. The histology-specific sojourn times ranged from 0.8 to 1.8 years for type II ovarian cancer and 2.9 to 6.6 years for type I ovarian cancer. Annual screening is not effective for all ovarian cancer subtypes. Screening sensitivity for early-stage ovarian cancers is not sufficient for substantial mortality reduction.

A novel high-throughput qPCR chip for solving co-infections in RAS farmed rainbow trout

Recirculating aquaculture systems (RAS) have become more attractive due to reduced water consumption and effluent discharge. However, intensification of production increases the risk of introducing pathogens at farming sites. The emergence of uncultivable pathogens and RAS pathobiome diversity shifts the traditional disease paradigm from “one pathogen, one disease” to complex multiple-pathogen disease cases. Piscine orthoreovirus genotype 3 (PRV-3) is an excellent example, as it is capable of inducing anemia and heart pathology resembling heart and skeletal muscle inflammation under experimental conditions, and is associated with increased mortality in association with other pathogens in the field. The aim of this study was to develop a method for detection of multiple pathogens and putative pathogens, as co-infections are common in aquaculture. To do this, in the pilot study, we mapped the pathobiome of RAS-farmed rainbow trout (Oncorhynchus mykiss) (commercial RAS, farm A) using both standard diagnostic methods and metabarcording (16S rRNA) to investigate the gill microbiome. During this study, we observed infections with multiple pathogens, and detected two putative gill pathogens Candidatus Branchiomonas cysticola and Candidatus Piscichlamydia salmonis, both of which have been linked with complex gill disease in Atlantic salmon (Salmo salar). Based on the pilot study, we developed and tested a high throughput qPCR (HT-qPCR) chip targeting 22 viral and bacterial pathogens and putative pathogens, followed by a surveillance of a fish cohort in a commercial RAS farm during production (farm B). Co-infection with PRV-3 and Ca. B. cysticola combined with stress inducing management practices may explain the severe disease outbreak observed (37% mortality). The time course study sets the base for a future screening scheme for disease prediction and addresses limitations of the method when testing environmental DNA/RNA.

Peptide Coated Polycaprolactone-Benzalkonium Chloride Nanocapsules for Targeted Drug Delivery to the Pancreatic β-Cell.

Targeting of current therapies to treat or prevent loss of pancreatic islet β-cells in Type 1 Diabetes (T1D) may provide improved efficacy and reduce off target effects. Current efforts to target the β-cell are limited by a lack of β-cell specific targets and the inability to test multiple targeting moieties with the same delivery vehicle. Here we fabricate a novel tailorable polycaprolactone nanocapsule (NC) where multiple different targeting peptides can be interchangeably attached for β-cell specific delivery. Incorporation of a cationic surfactant in the NC shell allows for the attachment of Exendin-4 and an antibody for ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) for β-cell specific targeting. The average NC size ranges from 250-300nm with a polydispersity index under 0.2. The NCs are non-toxic, stable in media culture, and can be lyophilized and reconstituted. NCs coated with targeting peptide were taken up by human cadaveric islet β-cells and human stem cell-derived β-like cells (sBC) in vitro with a high level of specificity. Furthermore, NCs successfully delivered both hydrophobic and hydrophilic cargo to human β-cells. Finally, Exendin-4 coated NCs were stable and targeted the mouse pancreatic islet β-cell in vivo . Our unique NC design allows for the interchangeable coating of targeting peptides for future screening of targets with improved cell specificity. The ability to target and deliver thera-peutics to human pancreatic β-cells opens avenues for improved therapies and treatments to help the delay onset, prevent, or reverse T1D.

A metabolic atlas of blood cells in young and aged mice identifies uridine as a metabolite to rejuvenate aged hematopoietic stem cells.

Aging of hematopoietic stem cells (HSCs) is accompanied by impaired self-renewal ability, myeloid skewing, immunodeficiencies and increased susceptibility to malignancies. Although previous studies highlighted the pivotal roles of individual metabolites in hematopoiesis, comprehensive and high-resolution metabolomic profiles of different hematopoietic cells across ages are still lacking. In this study, we created a metabolome atlas of different blood cells across ages in mice. We reveal here that purine, pyrimidine and retinol metabolism are enriched in young hematopoietic stem and progenitor cells (HSPCs), whereas glutamate and sphingolipid metabolism are concentrated in aged HSPCs. Through metabolic screening, we identified uridine as a potential regulator to rejuvenate aged HSPCs. Mechanistically, uridine treatment upregulates the FoxO signaling pathway and enhances self-renewal while suppressing inflammation in aged HSCs. Finally, we constructed an open-source platform for public easy access and metabolomic analysis in blood cells. Collectively, we provide a resource for metabolic studies in hematopoiesis that can contribute to future anti-aging metabolite screening.

Selective metallization of polymer based on nanoscale tungsten oxide laser activators for advanced electronics

In recent years, laser-induced selective metallization (LISM) has been widely used to fabricate complex metal patterns and circuits due to its superior precision. Laser sensitizers known as laser-activated for electroless copper plating (ECP) are a significant premise in LISM. Herein, we confirmed that tungsten oxides (WO2.72, WO2.92, and WO3) exhibited excellent LISM activity due to oxygen vacancies (OVs) in their lattice. Moreover, non-stoichiometric tungsten (WO2.72, WO2.92) presented higher activity due to a higher concentration of OVs than the stoichiometric form of WO3, indicating the importance of OVs to the activity of laser sensitizers in LISM. Moreover, a higher OVs concentration in the laser sensitizer resulted in a higher LISM activity. This finding points out the direction for future laser sensitizer screening, synthesis, and development. After 30 min ECP, the square resistance of the prepared copper layer on ABS/WO2.72, ABS/WO2.92, and ABS/WO3 are 0.014, 0.035, and 0.176 Ω/sq, respectively. The nanoscale tungsten oxides with excellent LISM activity enabled the rapid fabrication of metal patterns and circuits in various scenarios, which expands the research field and application prospect of LISM technology. We demonstrate the advantages of LISM with tungsten oxides in fabricating advanced electronics. A strategy for replacing hand-wound windings in electromagnetic generators with 2D on-chip planar inductor arrays from LISM was proposed. The generated current reached a high level of 193 mA, and can be directly connected to wireless sensor networks to supply power. This work is the first research ever reporting laser sensitizers of tungsten oxides and introducing LISM technology into self-powered electronics.

Estimating the Effects of Cancer Screening in Clinical Practice Settings: The Role of Selective Uptake and Suboptimal Adherence along the Cancer Screening Continuum.

Randomized controlled trials (RCT) are the gold standard in determining efficacy of cancer screening tests. Yet, systematic differences between RCT and the general populations eligible for screening raise concerns about the generalizability and relevance of RCT findings to guide the development and dissemination of cancer screening programs. Observational studies from clinical practice settings have documented selective uptake in screening-i.e., variation across subgroups regarding who is screened and not screened-as well as suboptimal adherence to screening recommendations, including follow-up of positive findings with subsequent imaging studies and diagnostic invasive procedures. When the effectiveness of a screening intervention varies across subgroups, and there is selective uptake and suboptimal adherence to screening in clinical practice relative to that in the RCT, the effects of screening reported in RCTs are not expected to generalize to clinical practice settings. Understanding the impacts of selective uptake and suboptimal adherence on estimates of the effectiveness of cancer screening in clinical practice will generate evidence that can be used to inform future screening recommendations and enhance shared decision-making tools.

Discordant Prenatal Cell-Free DNA Screening vs. Diagnostic Results of Sex Chromosome Aneuploidies: Implications for Newborn Screening and Genetic Counseling.

Sex chromosome aneuploidies (SCAs) collectively occur in 1 in 500 livebirths, and diagnoses in the neonatal period are increasing with advancements in prenatal and early genetic testing. Inevitably, SCA will be identified on either routine prenatal or newborn screening in the near future. Tetrasomy SCAs are rare, manifesting more significant phenotypes compared to trisomies. Prenatal cell-free DNA (cfDNA) screening has been demonstrated to have relatively poor positive predictive values (PPV) in SCAs, directing genetic counseling discussions towards false-positive likelihood rather than thoroughly addressing all possible outcomes and phenotypes, respectively. The eXtraordinarY Babies study is a natural history study of children prenatally identified with SCAs, and it developed a longitudinal data resource and common data elements with the Newborn Screening Translational Research Network (NBSTRN). A review of cfDNA and diagnostic reports from participants identified a higher than anticipated rate of discordance. The aims of this project are to (1) compare our findings to outcomes from a regional clinical cytogenetic laboratory and (2) describe discordant outcomes from both samples. Twenty-one (10%), and seven (8.3%) cases were found to be discordant between cfDNA (result or indication reported to lab) and diagnosis for the Babies Study and regional laboratory, respectively. Discordant results represented six distinct discordance categories when comparing cfDNA to diagnostic results, with the largest groups being Trisomy cfDNA vs. Tetrasomy diagnosis (66.7% of discordance in eXtraordinarY Babies study) and Mosaicism (57.1% in regional laboratory). Traditional genetic counseling for SCA-related cfDNA results is inadequate given a high degree of discordance that jeopardizes the accuracy of the information discussed and informed decision making following prenatal genetic counseling.

Experiences of Self-Sampling and Future Screening Preferences in Non-Attenders Who Returned an HPV Vaginal Self-Sample in the YouScreen Study: Findings From a Cross-Sectional Questionnaire.

We assessed experiences of human papillomavirus (HPV) vaginal self-sampling and future screening preferences in an ethnically and socio-economically diverse group of women overdue for cervical screening. A postal questionnaire was embedded in the YouScreen self-sampling trial in England: 32.5% (2712/8338) of kit completers returned the survey. Kit non-completers were encouraged to return a questionnaire, but no responses were received. Participants were ethnically diverse (40.3% came from ethnic minority backgrounds), and 59.1% came from the two most deprived quintiles. Differences in confidence in kit completion, trust in the test results and intention to attend a follow-up test if HPV-positive were evaluated using Pearson's χ2 analyses. Binary logistic regression models explored predictors of a future screening choice and preferences for urine versus vaginal self-sampling. Most kit-completers reported high confidence in self-sampling (82.6%) and high trust in the results (79.9%), but experiences varied by ethnicity and screening status. Most free-text comments were positive but some reported difficulties using the device, pain or discomfort. Most women would opt for self-sampling in the future (71.3% vs. 10.4% for a clinician-taken test) and it was more often preferred by ethnic minority groups, overdue screeners and never attenders. Urine self-tests were preferred to vaginal tests (41.9% vs. 15.4%), especially among women from Asian, Black or Other Ethnic backgrounds. Kit-completers were confident, found the test easy to complete, and trusted the self-sample results. However, experiences varied by ethnic group and some women highlighted difficulties with the kit. Most women would prefer self-sampling in the future, but it was not a universal preference, so offering a choice will be important. We did not have direct patient and public involvement and engagement (PPIE) in the questionnaire design. However, patients and public representatives did input into the design of the YouScreen trial and reviewed the wider study materials (e.g. participant information sheet). This questionnaire study was embedded in the YouScreen trial. The protocol for the YouScreen trial is available at https://www.isrctn.com/ISRCTN12759467. The National Institute for Health Research 43 Clinical Research Network (NIHR CRN) Central Portfolio Management System (CPMS) ID is 4441934.

Utilizing nutrient type compounds as anti-bacterial compounds: arginine and cysteine inhibit Salmonella survival in egg white.

Because of growing levels of antibiotic resistance, new methods to combat bacteria are needed. We hypothesized that because bacteria evolved to survive in specific environments, the addition of compounds, including nutrient type compounds, to an environment, might result in a modification of that environment that will disrupt bacterial growth or in maladaptive bacterial behavior, i.e., gene expression. As a proof of concept, we focused on the egg white environment and the pathogen Salmonella. Despite egg white's antibacterial nature, Salmonella is able to survive and grow in egg white, and this ability of Salmonella leads to infection of chicks and humans. Here, the 20L-amino-acids were screened for their ability to affect the growth of Salmonella in egg white. L-arginine and L-cysteine were found to reduce growth in egg white in physiologically relevant concentrations. To determine the mechanism behind L-arginine inhibition TnSeq was utilized. TnSeq identified many Salmonella genes required for survival in egg white including genes required for iron import, biotin synthesis, stress responses, cell integrity, and DNA repair. However, a comparison of Salmonella in egg white with and without L-arginine identified only a few differences in the frequency of transposon insertions, including the possible contribution of perturbations in the cell envelope to the inhibition mechanism. Finally, both D-arginine and D-cysteine were found to inhibit Salmonella in egg white. This implied that the effect of arginine and cysteine in egg white is chemical rather than biological, likely on the egg white environment or on the bacterial outer membrane. To conclude, these results show that this approach of addition of compounds, including nutrient type compounds, to an environment can be used to limit bacterial growth. Importantly, these compounds have no inherent anti-bacterial properties, are used as nutrients by animals and bacteria, and only become anti-bacterial in a specific environmental context. Future research screening for the effects of compounds in relevant environments might uncover new ways to reduce pathogen levels in the poultry industry and beyond.

Characterization of peripheral artery disease and associations with traditional risk factors, mobility, and biomarkers in the project baseline health study

There is a dearth of research on immunophenotyping in peripheral artery disease (PAD). This study aimed to describe the baseline characteristics, immunophenotypic profile, and quality of life (QoL) of participants with PAD in the Project Baseline Health Study (PBHS). The PBHS study is a prospective, multicenter, longitudinal cohort study that collected clinical, molecular, and biometric data from participants recruited between 2017 and 2018. In this analysis, baseline demographic, clinical, mobility, QoL, and flow cytometry data were stratified by the presence of PAD (ankle brachial index [ABI] ≤0.90). Of 2,209 participants, 58 (2.6%) had lower-extremity PAD, and only 2 (3.4%) had pre-existing PAD diagnosed prior to enrollment. Comorbid smoking (29.3% vs 14%, P < .001), hypertension (54% vs 30%, P < .001), diabetes (25% vs 14%, P = .031), and at least moderate coronary calcifications (Agatston score >100: 32% vs 17%, P = .01) were significantly higher in participants with PAD than in those with normal ABIs, as were high-sensitivity C-reactive protein levels (5.86 vs 2.83, P < .001). After adjusting for demographic and risk factors, participants with PAD had significantly fewer circulating CD56-high natural killer cells, IgM+ memory B cells, and CD10/CD27 double-positive B cells (P < .05 for all). This study reinforces existing evidence that a large proportion of PAD without claudication may be underdiagnosed, particularly in female and Black or African American participants. We describe a novel immunophenotypic profile of participants with PAD that could represent a potential future screening or diagnostic tool to facilitate earlier diagnosis of PAD. NCT03154346, https://clinicaltrials.gov/ct2/show/NCT03154346.

Microbial signatures and continuum in endometrial cancer and benign patients

BackgroundEndometrial cancer is a multifactorial disease with inflammatory, metabolic and potentially microbial cues involved in disease pathogenesis. The endometrial cancer microbiome has been poorly characterised so far and studies have often overestimated bacterial biomass due to lack of integration of appropriate contamination controls. There is also a scarcity of evidence on the functionality of microbial microenvironments in endometrial cancer. This work addresses that knowledge gap by interrogating the genuine, contamination-free microbial signatures in the female genital tract and rectum of women with endometrial cancer and the mechanistic role of microbiome on carcinogenic processes.ResultsHere we sampled different regions of the reproductive tract (vagina, cervix, endometrium, fallopian tubes and ovaries) and rectum of 61 patients (37 endometrial cancer; 24 benign controls). We performed 16S rRNA gene sequencing of the V1–V2 hypervariable regions and qPCR of the 16S rRNA gene to qualitatively and quantitatively assess microbial communities and used 3D benign and endometrial cancer organoids to evaluate the effect of microbial products of L. crispatus, which was found depleted in endometrial cancer patients following primary analysis, on endometrial cell proliferation and inflammation. We found that the upper genital tract of a subset of women with and without endometrial cancer harbour microbiota quantitatively and compositionally distinguishable from background contaminants. Endometrial cancer was associated with reduced cervicovaginal and rectal bacterial load together with depletion of Lactobacillus species relative abundance, including L. crispatus, increased bacterial diversity and enrichment of Porphyromonas, Prevotella, Peptoniphilus and Anaerococcus in the lower genital tract and endometrium. Treatment of benign and malignant endometrial organoids with L. crispatus conditioned media exerted an anti-proliferative effect at high concentrations but had minimal impact on cytokine and chemokine profiles.ConclusionsOur findings provide evidence that the upper female reproductive tract of some women contains detectable levels of bacteria, the composition of which is associated with endometrial cancer. Whether this is a cause or consequence of cancer pathophysiology and what is the functional significance of this finding remain to be elucidated to guide future screening tools and microbiome-based therapeutics.7srhokZSHNZrvrGZNmjDS4Video

Prevalence of Candida auris Among High-Risk Patients at a Comprehensive Cancer Center

Background: Candida auris (C. auris) is a multidrug-resistant fungus that is increasingly implicated in outbreaks in healthcare facilities worldwide. The Centers for Disease Control and Prevention (CDC) and the Texas Department of State Health Services recommend healthcare facilities screen patients who are considered high-risk for C. auris, including patients with an overnight stay in a healthcare facility outside the United States (U.S.) in the previous year, or recently stayed in a rehabilitation (rehab) facility, long-term acute care (LTAC), or skilled nursing facility (SNF). Screening patients for C. auris colonization allows for early implementation of infection control measures, preventing transmission to healthcare workers and other patients. According to the CDC, most cases of C. auris result from local spread within and among healthcare facilities in the same city or state. In Texas, 160 clinical cases have been reported during the past 12 months. At present, the necessity of screening high-risk patients at our center for C. auris is not known. We aimed to determine the prevalence of C. auris colonization among our patient population. Method: During a 4-week period, we performed targeted screening of patients meeting the CDC’s high-risk definition for C. auris. Admitted patients were screened by an Infection Preventionist (IP) using the electronic health record to identify patients who were either international or admitted from a rehab or care facility. A composite swab of bilateral axilla and groin creases was collected using an eSwab™ (Becton Dickinson) and sent to a reference lab (Mayo Clinic Laboratories) for polymerase chain reaction (PCR)-based detection of C. auris. Additionally, we reviewed historic cases of C. auris diagnosed at our institution to better define our at-risk patients. Results: Between July 14 – August 8, 2023, we consecutively screened 25 high-risk patients, including 18 (72%) international and 7 (28%) patients from rehabs, LTAC, or SNF. None were positive for C. auris. Since 2019, we identified six patients with C. auris positive cultures, including five clinical cases and one colonization case. Five patients were international and one was local with no history of international travel or stay in a care facility. Interestingly, all six were known to be colonized with extended-spectrum beta-lactamase (ESBL) E. coli. Conclusion: We have a very low prevalence of C. auris among CDC-defined high-risk patients. A review of historic C. auris cases indicated an association with colonization by other multidrug-resistant organisms, specifically ESBL E. coli, which will inform future screening protocols at our institution.Disclosure: Roy Chemaly: Contracted Research paid for my institution: Merck, Karius, AiCuris, Ansun Pharmaceuticals, Takeda, Genentech, Oxford Immunotec, and Eurofins-Viracor; Honorarium/Ad Board/Consultant: ADMA Biologics, Janssen, Merck/MSD, Partner Therapeutics, Takeda, Shinogi, AiCuris, Roche/Genentech, Astellas, Tether, Oxford Immunotec, Karius, Moderna, and Ansun Pharmaceuticals; Stock Options: Xenex

Creation of an Isogenic Human iPSC-Based RGC Model of Dominant Optic Atrophy Harboring the Pathogenic Variant c.1861C>T (p.Gln621Ter) in the OPA1 Gene.

Autosomal dominant optic atrophy (ADOA) is a rare progressive disease mainly caused by mutations in OPA1, a nuclear gene encoding for a mitochondrial protein that plays an essential role in mitochondrial dynamics, cell survival, oxidative phosphorylation, and mtDNA maintenance. ADOA is characterized by the degeneration of retinal ganglion cells (RGCs). This causes visual loss, which can lead to legal blindness in many cases. Nowadays, there is no effective treatment for ADOA. In this article, we have established an isogenic human RGC model for ADOA using iPSC technology and the genome editing tool CRISPR/Cas9 from a previously generated iPSC line of an ADOA plus patient harboring the pathogenic variant NM_015560.3: c.1861C>T (p.Gln621Ter) in heterozygosis in OPA1. To this end, a protocol based on supplementing the iPSC culture media with several small molecules and defined factors trying to mimic embryonic development has been employed. Subsequently, the created model was validated, confirming the presence of a defect of intergenomic communication, impaired mitochondrial respiration, and an increase in apoptosis and ROS generation. Finally, we propose the analysis of OPA1 expression by qPCR as an easy read-out method to carry out future drug screening studies using the created RGC model. In summary, this model provides a useful platform for further investigation of the underlying pathophysiological mechanisms of ADOA plus and for testing compounds with potential pharmacological action.