Benzofurans as Acetylcholinesterase Inhibitors for Treating Alzheimer's Disease: Synthesis, in†vitro Testing, and in†silico Analysis.

Alzheimer's disease (AD) is a neurodegenerative disorder and the leading cause of dementia worldwide. It is characterized by a progressive decline in cholinergic neurotransmission. During the development of AD, acetylcholinesterase (AChE) binds to ß-amyloid peptides to form amyloid fibrils, which aggregate into plaque deposits. Meanwhile, tau proteins are hyperphosphorylated, forming neurofibrillary tangles (NFTs) that aggregate into inclusions. These complexes are cytotoxic for the brain, causing impairment of memory, attention, and cognition. AChE inhibitors are the main treatment for AD, but their effect is only palliative. This study aimed to design and synthesize novel benzofuran derivatives and evaluate their inhibition of AChE in vitro and in silico. Results: The seven synthesized benzofuran derivatives inhibited AChE in vitro. Benzofurans hydroxy ester 4, amino ester 5, and amido ester (±)-7 had the lowest inhibition constant (Ki) values and displayed good affinity for EeAChE in molecular docking. Six derivatives showed competitive inhibition, while the best compound (5: Ki=36.53 µM) exhibited uncompetitive inhibition. The amino, hydroxyl, amide, and ester groups of the ligands favored interaction with the enzyme by hydrogen bonds. Conclusion: Three benzofurans were promising AChE inhibitors with excellent Ki values. In future research on their their application to AD, 5 will be considered as the base structure.

The ecto-enzyme CD38 modulates CD4 T cell immunometabolic responses and participates in HIV pathogenesis.

Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4 T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after TCR-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular NAD and NMN concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the OCR/ECAR ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ectoCD38 catalytic activity in memory CD4 T cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous pro-inflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morpho-functionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4 T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.

Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy.

BACKGROUND: Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille's heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking. METHODS: The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action. RESULTS: We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration. CONCLUSIONS: Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.

Eliminating Algorithmic Racial Bias in Clinical Decision Support Algorithms: Use Cases from the Veterans Health Administration.

The Veterans Health Administration uses equity- and evidence-based principles to examine, correct, and eliminate use of potentially biased clinical equations and predictive models. We discuss the processes, successes, challenges, and next steps in four examples. We detail elimination of the race modifier for estimated kidney function and discuss steps to achieve more equitable pulmonary function testing measurement. We detail the use of equity lenses in two predictive clinical modeling tools: Stratification Tool for Opioid Risk Mitigation (STORM) and Care Assessment Need (CAN) predictive models. We conclude with consideration of ways to advance racial health equity in clinical decision support algorithms.

Timing Matters: Effects of Early and Late Estrogen Replacement Therapy on Glucose Metabolism and Vascular Reactivity in Ovariectomized Aged Wistar Rats.

Cardiovascular disease incidence increases after menopause due to the loss of estrogen cardioprotective effects. However, there are conflicting data regarding the timing of estrogen therapy (ERT) and its effect on vascular dysfunction associated with impaired glucose metabolism. The aim of this work was to evaluate the effect of early and late ERT on blood glucose/insulin balance and vascular reactivity in aged ovariectomized Wistar rats. Eighteen-month-old female Wistar rats were randomized as follows: (1) sham, (2) 10-week postovariectomy (10 w), (3) 10 w postovariectomy+early estradiol therapy (10 w-early E2), (4) 20-week postovariectomy (20 w), and (5) 20-week postovariectomy+late estradiol therapy (20 w-late E2). Early E2 was administered 3 days after ovariectomy and late therapy after 10 weeks, in both groups. 17ß-Estradiol (E2) was administered daily for 10 weeks (5 µg/kg/day). Concentration-response curves to angiotensin II, KCl, and acetylcholine (ACh) were performed. Heart rate (HR), diastolic and systolic blood pressure (DBP and SBP), glucose, insulin, HOMA-IR, and nitric oxide (NO) levels were determined. Higher glucose levels were found in all groups compared to the sham group, except the 20 w-late E2 group. Insulin was increased in all ovariectomized groups compared to sham. The HOMA-IR index showed insulin resistance in all ovariectomized groups, except for the 10 w-early E2 group. The 10 w-early E2 group increased NO levels vs. the 10 w group. After 10 w postovariectomy, the vascular response to KCl and Ach increases, despite early E2 administration. Early and late E2 treatment decreased vascular reactivity to Ang II. At 20-week postovariectomy, DBP increased, even with E2 administration, while SBP and HR remained unchanged. The effects of E2 therapy on blood glucose/insulin balance and vascular reactivity depend on the timing of therapy. Early ERT may provide some protective effects on insulin resistance and vascular function, whereas late ERT may not have the same benefits.

The NYCKidSeq randomized controlled trial: Impact of GUÍA digitally enhanced genetic results disclosure in diverse families.

Digital solutions are needed to support rapid increases in the application of genetic/genomic tests (GTs) in diverse clinical settings and patient populations. We developed GUÍA, a bilingual digital application that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial enrolled diverse children with neurologic, cardiac, and immunologic conditions who underwent GTs. The trial evaluated GUÍA's impact on understanding the GT results by randomizing families to results disclosure genetic counseling with GUÍA (intervention) or standard of care (SOC). Parents/legal guardians (participants) completed surveys at baseline, post-results disclosure, and 6 months later. Survey measures assessed the primary study outcomes of participants' perceived understanding of and confidence in explaining their child's GT results and the secondary outcome of objective understanding. The analysis included 551 diverse participants, 270 in the GUÍA arm and 281 in SOC. Participants in the GUÍA arm had significantly higher perceived understanding post-results (OR = 2.8, CI[1.004, 7.617], p = 0.049) and maintained higher objective understanding over time (OR = 1.1, CI[1.004, 1.127], p = 0.038) compared to SOC. There was no impact on perceived confidence. Hispanic/Latino(a) individuals in the GUÍA arm maintained higher perceived understanding (OR = 3.9, CI[1.603, 9.254], p = 0.003), confidence (OR = 2.7, CI[1.021, 7.277], p = 0.046), and objective understanding (OR = 1.1, CI[1.009, 1.212], p = 0.032) compared to SOC. This trial demonstrates that GUÍA positively impacts understanding of GT results in diverse parents of children with suspected genetic conditions and builds a case for utilizing GUÍA to deliver complex results. Continued development and evaluation of digital applications in diverse populations are critical for equitably scaling GT offerings in specialty clinics.

Robotic Surgery: A Comprehensive Review of the Literature and Current Trends.

Robotic surgery (RS) is an evolution of minimally invasive surgery that combines medical science, robotics, and engineering. The first robots approved by the Food and Drug Administration (FDA) were the Da Vinci Surgical System and the ZEUS Robotic Surgical System, which have been improving over time. Through the decades, the equipment applied to RS had undergone a wide transformation as a response to the development of new techniques and facilities for the assembly and implementation of the own. RS has revolutionized the field of urology, enabling surgeons to perform complex procedures with greater precision and accuracy, and many other surgical specialties such as gynecology, general surgery, otolaryngology, cardiothoracic surgery, and neurosurgery. Several benefits, such as a better approach to the surgical site, a three-dimensional image that improves depth perception, and smaller scars, enhance range of motion, allowing the surgeon to conduct more complicated surgical operations, and reduced postoperative complications have made robotic-assisted surgery an increasingly popular approach. However, some points like the cost of surgical procedures, equipment-instrument, and maintenance are important aspects to consider. Machine learning will likely have a role to play in surgical training shortly through "automated performance metrics," where algorithms observe and "learn" individual surgeons' techniques, assess performance, and anticipate surgical outcomes with the potential to individualize surgical training and aid decision-making in real time.

Molecular dynamics modelling of the interaction of a synthetic zinc-finger miniprotein with DNA.

We report the modelling of the DNA complex of an artificial miniprotein composed of two zinc finger modules and an AT-hook linking peptide. The computational study provides for the first time a structural view of these types of complexes, dissecting interactions that are key to modulate their stability. The relevance of these interactions was validated experimentally. These results confirm the potential of this type of computational approach for studying peptide-DNA complexes and suggest that they could be very useful for the rational design of non-natural, DNA binding miniproteins.

Lower Urinary Tract Obstruction in Newborns.

Lower urinary tract obstruction (LUTO) is a rare birth defect with a prevalence between 1 in 5,000 and 1 in 25,000 pregnancies. LUTO is one of the most common causes of congenital abnormalities of the renal tract. Several genetic conditions have been associated with LUTO. Most common causes of LUTO are posterior urethral valves and urethral atresia. Despite available prenatal and postnatal treatments, LUTO is a significant cause of morbidity and mortality in newborns causing significant end stage renal disease and pulmonary hypoplasia.

The NYCKidSeq randomized controlled trial: Impact of GUÍA digitally enhanced genetic counseling in racially and ethnically diverse families.

Background: Digital solutions are needed to support rapid increases in the application of genetic and genomic tests (GT) in diverse clinical settings and patient populations. We developed GUÍA, a bi-lingual web-based platform that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial evaluated GUÍA's impact on understanding of GT results. Methods: NYCKidSeq enrolled diverse children with neurologic, cardiac, and immunologic conditions who underwent GT. Families were randomized to genetic counseling with GUÍA (intervention) or standard of care (SOC) genetic counseling for results disclosure. Parents/legal guardians (participants) completed surveys at baseline, post-results disclosure, and 6-months later. Survey measures assessed the primary study outcomes of perceived understanding of and confidence in explaining their child's GT results and the secondary outcome of objective understanding. We used regression models to evaluate the association between the intervention and the study outcomes. Results: The analysis included 551 participants, 270 in the GUÍA arm and 281 in SOC. Participants' mean age was 41.1 years and 88.6% were mothers. Most participants were Hispanic/Latino(a) (46.3%), White/European American (24.5%), or Black/African American (15.8%). Participants in the GUÍA arm had significantly higher perceived understanding post-results (OR=2.8, CI[1.004,7.617], P=0.049) and maintained higher objective understanding over time (OR=1.1, CI[1.004, 1.127], P=0.038) compared to those in the SOC arm. There was no impact on perceived confidence. Hispanic/Latino(a) individuals in the GUÍA arm maintained higher perceived understanding (OR=3.9, CI[1.6, 9.3], P=0.003), confidence (OR=2.7, CI[1.021, 7.277], P=0.046), and objective understanding (OR=1.1, CI[1.009, 1.212], P=0.032) compared to SOC . Conclusions: This trial demonstrates that GUÍA positively impacts understanding of GT results in diverse parents of children with suspected genetic conditions. These findings build a case for utilizing GUÍA to deliver complex and often ambiguous genetic results. Continued development and evaluation of digital applications in diverse populations are critical for equitably scaling GT offerings in specialty clinics. Trial Registration: Clinicaltrials.gov identifier NCT03738098.

Identification of Driver Epistatic Gene Pairs Combining Germline and Somatic Mutations in Cancer.

Cancer arises from the complex interplay of various factors. Traditionally, the identification of driver genes focuses primarily on the analysis of somatic mutations. We describe a new method for the detection of driver gene pairs based on an epistasis analysis that considers both germline and somatic variations. Specifically, the identification of significantly mutated gene pairs entails the calculation of a contingency table, wherein one of the co-mutated genes can exhibit a germline variant. By adopting this approach, it is possible to select gene pairs in which the individual genes do not exhibit significant associations with cancer. Finally, a survival analysis is used to select clinically relevant gene pairs. To test the efficacy of the new algorithm, we analyzed the colon adenocarcinoma (COAD) and lung adenocarcinoma (LUAD) samples available at The Cancer Genome Atlas (TCGA). In the analysis of the COAD and LUAD samples, we identify epistatic gene pairs significantly mutated in tumor tissue with respect to normal tissue. We believe that further analysis of the gene pairs detected by our method will unveil new biological insights, enhancing a better description of the cancer mechanism.

Molecular diagnostic yield of genome sequencing versus targeted gene panel testing in racially and ethnically diverse pediatric patients.

PURPOSE: Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions. METHODS: Probands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing. Diagnostic yield was compared using a fully paired study design. RESULTS: A total of 645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses (P < .001). Yield was greater for GS vs TGPs in Hispanic/Latino(a) (17.2% vs 9.5%, P < .001) and White/European American (19.8% vs 7.9%, P < .001) but not in Black/African American (11.5% vs 7.7%, P = .22) population groups by self-report. A higher rate of inconclusive results was seen in the Black/African American (63.8%) vs White/European American (47.6%; P = .01) population group. Most causal copy number variants (17 of 19) and mosaic variants (6 of 8) were detected only by GS. CONCLUSION: GS may yield up to twice as many diagnoses in pediatric patients compared with TGP testing but not yet across all population groups.

Clinical characteristics and comorbidities associated with SARS-CoV-2 breakthrough infection in the University of California Healthcare Systems.

BACKGROUND: To evaluate the degree to which clinical comorbidities or combinations of comorbidities are associated with SARS-CoV-2 breakthrough infection. MATERIALS AND METHODS: A breakthrough infection was defined as a positive test at least 14 days after a full vaccination regimen. Logistic regression was used to calculate aORs, which were adjusted for age, sex, and race information. RESULTS: A total of 110,380 patients from the UC CORDS database were included. After adjustment, stage 5 CKD due to hypertension (aOR: 7.33; 95% CI: 4.86-10.69; p<.001; power=1) displayed higher odds of infection than any other comorbidity. Lung transplantation history (aOR: 4.79; 95% CI: 3.25-6.82; p<.001; power= 1), coronary atherosclerosis (aOR: 2.12; 95% CI: 1.77-2.52; p<.001; power=1), and vitamin D deficiency (aOR: 1.87; 95% CI: 1.69-2.06; p<.001; power=1) were significantly correlated to breakthrough infection. Patients with obesity in addition to essential hypertension (aOR: 1.74; 95% CI: 1.51-2.01; p<.001; power=1) and anemia (aOR: 1.80; 95% CI: 1.47-2.19; p<.001; power=1) were at additional risk of breakthrough infection compared to those with essential hypertension and anemia alone. CONCLUSIONS: Further measures should be taken to prevent breakthrough infection for individuals with these conditions, such as acquiring additional doses of the SARS-CoV-2 vaccine to boost immunity.

Development and validation of a standardized blood culture contamination definition and metric dashboard for a large health care system.

OBJECTIVES: Blood culture contamination is a major problem in health care, with significant impacts on both patient safety and cost. Initiatives to reduce blood culture contamination require a reliable, consistent metric to track the success of interventions. The objective of our project was to establish a standardized definition of blood culture contamination suitable for use in a Veterans Health Administration (VHA) national data query, then to validate this definition and query. A secondary objective was to construct a national VHA data dashboard to display the data from this query that could be used in VHA quality improvement projects aimed at reducing blood culture contamination. METHODS: A VHA microbiology expert work group was formed to generate a standardized definition and oversee the validation studies. The standardized definition was used to generate data for calendar year 2021 using a Structured Query Language data query. Twelve VHA hospital microbiology laboratories compared the data from the query against their own locally derived contamination data and recorded those data in a data collection worksheet that all sites used. Data were collated and presented to the work group. RESULTS: More than 50,000 blood culture accessions were in the validation data set, with more than 1,200 contamination events. The overall blood culture contamination rate for the 12 facilities participating was 2.56% with local definitions and data and 2.43% with the standardized definitions and data query. The main differences noted between the 2 data sets were deemed to be issues in local definitions. The query and definition were then converted into a national data dashboard that all VHA facilities can now access. CONCLUSIONS: A standardized definition for blood culture contamination and a national data query were validated for enterprise-wide VHA use. To our knowledge, this represents the first reported standardized, validated, and automated approach for calculating and tracking blood culture contamination. This tool will be key in quality initiatives aimed at reducing contamination events in VHA.

Molecular diagnostic yield of genome sequencing versus targeted gene panel testing in racially and ethnically diverse pediatric patients.

Purpose: Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions. Methods: Probands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing. Diagnostic yield was compared using a fully paired study design. Results: 645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses ( P < .001). Yield was greater for GS vs . TGPs in Hispanic/Latino(a) (17.2% vs . 9.5%, P < .001) and White/European American (19.8% vs . 7.9%, P < .001), but not in Black/African American (11.5% vs . 7.7%, P = .22) population groups by self-report. A higher rate of inconclusive results was seen in the Black/African American (63.8%) vs . White/European American (47.6%; P = .01) population group. Most causal copy number variants (17 of 19) and mosaic variants (6 of 8) were detected only by GS. Conclusion: GS may yield up to twice as many diagnoses in pediatric patients compared to TGP testing, but not yet across all population groups.

Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage.

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."

The TeleKidSeq pilot study: incorporating telehealth into clinical care of children from diverse backgrounds undergoing whole genome sequencing.

BACKGROUND: The COVID-19 pandemic forced healthcare institutions and many clinical research programs to adopt telehealth modalities in order to mitigate viral spread. With the expanded use of telehealth, there is the potential to increase access to genomic medicine to medically underserved populations, yet little is known about how best to communicate genomic results via telehealth while also ensuring equitable access. NYCKidSeq, a multi-institutional clinical genomics research program in New York City, launched the TeleKidSeq pilot study to assess alternative forms of genomic communication and telehealth service delivery models with families from medically underserved populations. METHODS: We aim to enroll 496 participants between 0 and 21 years old to receive clinical genome sequencing. These individuals have a neurologic, cardiovascular, and/or immunologic disease. Participants will be English- or Spanish-speaking and predominantly from underrepresented groups who receive care in the New York metropolitan area. Prior to enrollment, participants will be randomized to either genetic counseling via videoconferencing with screen-sharing or genetic counseling via videoconferencing without screen-sharing. Using surveys administered at baseline, results disclosure, and 6-months post-results disclosure, we will evaluate the impact of the use of screen-sharing on participant understanding, satisfaction, and uptake of medical recommendations, as well as the psychological and socioeconomic implications of obtaining genome sequencing. Clinical utility, cost, and diagnostic yield of genome sequencing will also be assessed. DISCUSSION: The TeleKidSeq pilot study will contribute to innovations in communicating genomic test results to diverse populations through telehealth technology. In conjunction with NYCKidSeq, this work will inform best practices for the implementation of genomic medicine in diverse, English- and Spanish-speaking populations.

Zirconium-Catalyzed C-H Alumination of Polyolefins, Paraffins, and Methane.

C-H/Et-Al exchange in zirconium-catalyzed reactions of saturated hydrocarbons and AlEt3 affords versatile organoaluminum compounds and ethane. The grafting of commercially available Zr(OtBu)4 on silica/alumina gives monopodal ≡SiO-Zr(OtBu)3 surface pre-catalyst sites that are activated in situ by ligand exchange with AlEt3. The catalytic C-H alumination of dodecane at 150 °C followed by quenching in air affords n-dodecanol as the major product, revealing selectivity for methyl group activation. Shorter hydrocarbon or alcohol products were not detected under these conditions. Catalytic reactions of cyclooctane and AlEt3, however, afford ring-opened products, indicating that C-C bond cleavage occurs readily in methyl group-free reactants. This selectivity for methyl group alumination enables the C-H alumination of polyethylenes, polypropylene, polystyrene, and poly-α-olefin oils without significant chain deconstruction. In addition, the smallest hydrocarbon, methane, undergoes selective mono-alumination under solvent-free catalytic conditions, providing a direct route to Al-Me species.

A repeated cross-sectional study of intestinal parasites in Texas shelter dogs using fecal flotation and saline sedimentation.

Estimates of intestinal parasite prevalence in canine populations have largely been based on use of fecal flotation methods only. Dogs in animal shelters are likely at higher risk of intestinal parasite infection because of their previous exposure history. Our objectives were to estimate the prevalence of intestinal parasites among Texas shelter dogs using centrifugal fecal flotation and saline sedimentation techniques, to identify risk factors for infection, and to compare proportions of positive samples detected via fecal flotation vs. saline sedimentation for the most common parasites. Using a repeated cross-sectional study design, we collected fecal samples from dogs on three visits to each of seven Texas animal shelters between May 2013 and December 2014. Fecal flotation and/or saline sedimentation were used to identify parasites in samples. Fecal samples were collected from 529 dogs. The most frequently detected parasites were Ancylostoma caninum (26.4% via fecal flotation, 20.7% via saline sedimentation) and Trichuris vulpis (12.0% via fecal flotation, 14.1% via saline sedimentation). Risk factors for certain parasites were identified; for example, dogs with abnormal fecal consistency were more likely to be shedding T. vulpis eggs than dogs with normal fecal consistency (OR = 1.8, p = 0.005). The addition of fecal sedimentation not only added to the number of parasite species detected in this study, but it also increased the number of dogs diagnosed with the common intestinal parasites that are primarily detected using fecal flotation methods. Texas shelter dogs carry a high burden of intestinal parasites, including those of zoonotic importance.

Nationwide Genomic Surveillance and Response to COVID-19: The VA SeqFORCE and SeqCURE Consortiums.

Background: The US Department of Veterans Affairs (VA) has dedicated significant resources toward countering the COVID-19 pandemic. Sequencing for Research Clinical and Epidemiology (SeqFORCE) and Sequencing Collaborations United for Research and Epidemiology (SeqCURE) were developed as clinical and research consortiums, respectively, focused on the genetic COVID-19 surveillance. Observations: Through genetic sequencing, VA SeqFORCE and SeqCURE collaborations contributed to the COVID-19 pandemic response and scientific understanding. Future directions for each program include the assessment of the unique impact of COVID-19 on the veteran population, as well as the adaptation of these programs to future infectious disease threats. We foresee the use of these established platforms beyond infectious diseases. Conclusions: VA SeqFORCE and SeqCURE were established as clinical and research programs dedicated to sequencing COVID-19 as part of ongoing clinical and surveillance efforts. In the future, we anticipate that having these programs embedded within the largest integrated health care system in the US will enable the study of pathogens and pandemics beyond COVID-19 and at an unprecedented scale. The investment in these programs will form an integral part of our nation's response to emerging infectious diseases, with future applications to precision medicine and beyond.