Reprogramming Chromosome Ends by Functional Histone Acetylation.

Cancers harness embryonic programs to evade aging and promote survival. Normally, sequences at chromosome ends called telomeres shorten with cell division, serving as a countdown clock to limit cell replication. Therefore, a crucial aspect of cancerous transformation is avoiding replicative aging by activation of telomere repair programs. Mouse embryonic stem cells (mESCs) activate a transient expression of the gene Zscan4, which correlates with chromatin de-condensation and telomere extension. Head and neck squamous cell carcinoma (HNSCC) cancers reactivate ZSCAN4, which in turn regulates the phenotype of cancer stem cells (CSCs). Our study reveals a new role for human ZSCAN4 in facilitating functional histone H3 acetylation at telomere chromatin. Next-generation sequencing indicates ZSCAN4 enrichment at telomere chromatin. These changes correlate with ZSCAN4-induced histone H3 acetylation and telomere elongation, while CRISPR/Cas9 knockout of ZSCAN4 leads to reduced H3 acetylation and telomere shortening. Our study elucidates the intricate involvement of ZSCAN4 and its significant contribution to telomere chromatin remodeling. These findings suggest that ZSCAN4 induction serves as a novel link between 'stemness' and telomere maintenance. Targeting ZSCAN4 may offer new therapeutic approaches to effectively limit or enhance the replicative lifespan of stem cells and cancer cells.

The Brain Gene Registry: a data snapshot.

Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource's (ClinGen's) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen's BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders.

A Case of Persistent Junctional Reciprocating Tachycardia Coincident With Cor Triatriatum Sinister.

Persistent junctional reciprocating tachycardia is a rare form of refractory atrioventricular reentrant tachycardia that accounts for <1% of supraventricular tachycardia in pediatrics. The accessory pathways are generally isolated with few reported underlying structural heart defects. We present a case of a five-month-old male with refractory tachyarrhythmia found to have cor triatriatum sinister, which to our knowledge, is the first reported case of these two rare anomalies coexisting.

A pilot study to assess blood-brain barrier permeability in long COVID.

The etiology of brain fog associated with long COVID is not clear. Based on some preliminary work, disruption of the blood-brain barrier has been hypothesized, but has not been tested in patients with long COVID. In this case-control pilot study, we evaluated blood-brain barrier permeability in patients with long COVID and subjective memory loss or brain fog. We used 99 m Technetium diethylenetriaminepentaacetic acid single-photon emission computed tomography (SPECT) to measure blood-brain barrier permeability and a telephone assessment (T-cog) to measure cognitive function. The blood-brain barrier permeability was quantified via SPECT standard uptake value (SUV). We assessed the blood-brain barrier permeability in 14 long COVID patients and 10 control participants without subjective cognitive impairment or brain fog. Participants in the two groups were similar in age. The long COVID group had more comorbidities compared to the control group. There was no difference in the SUVs in the long COVID (0.22 ± 0.12) vs the control (0.17 ± 0.04) group. There was no difference in the T-cog results in the two groups either. We found no evidence of a difference in blood-brain permeability in patients with long COVID when compared to controls without a known history of COVID-19 infection. Larger studies are needed to confirm these findings.

Immunologic predictors of vaccine responsiveness in patients with lymphoma and CLL.

Patients with B-cell lymphomas have altered cellular components of vaccine responses due to malignancy and therapy, and the optimal timing of vaccination relative to therapy remains unknown. SARS-CoV-2 vaccines created an opportunity for new insights in vaccine timing because patients were challenged with a novel antigen across multiple phases of treatment. We studied serologic mRNA vaccine response in retrospective and prospective cohorts with lymphoma and CLL, paired with clinical and research immune parameters. Reduced serologic response was observed more frequently during active therapies, but non-response was also common within observation and post-treatment groups. Total IgA and IgM correlated with successful vaccine response. In individuals treated with CART-19, non-response was associated with reduced B and T follicular helper cells. Predictors of vaccine response varied by disease and therapeutic group, and therefore further studies of immune health during and after cancer therapies are needed to allow individualized vaccine timing.

Pf bacteriophages hinder sputum antibiotic diffusion via electrostatic binding.

Despite great progress in the field, chronic Pseudomonas aeruginosa (Pa) infections remain a major cause of morbidity and mortality in patients with cystic fibrosis, necessitating treatment with inhaled antibiotics. Pf phage is a filamentous bacteriophage produced by Pa that has been reported to act as a structural element in Pa biofilms. Pf presence has been associated with resistance to antibiotics and poor outcomes in cystic fibrosis, though the underlying mechanisms are unclear. Here, we have investigated how Pf phages and sputum biopolymers impede antibiotic diffusion using human sputum samples and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf phages and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf phages in sputum reduce the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf phages and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronic Pa infections and may offer potential strategies for novel therapeutic approaches.

Role of Surgical and Medical Management of Chronic Thromboembolic Pulmonary Hypertension: A Systematic Review.

Chronic thromboembolic pulmonary hypertension (CTEPH) is underdiagnosed and has recently surfaced as one of the leading triggers of severe pulmonary hypertension. This disease process is described by structural changes of pulmonary arteries such as fibrous stenosis, complete obliteration, or the presence of a resistant intraluminal thrombus, resulting in increased pulmonary resistance and eventually progressing to right-sided heart failure. Hence, this study aims to describe the current treatments for CTEPH and their efficacy in hemodynamic improvement and prevention of recurring thromboembolic episodes in patients. This systematic review promptly follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. On February 13, 2022, our team searched through the following databases: PubMed, ProQuest, and ScienceDirect. The following keywords were used across all databases: CTEPH AND Pulmonary Endarterectomy (PEA), CTEPH AND Balloon Pulmonary Angioplasty (BPA), and CTEPH AND Medical Therapy OR Anticoagulation therapy. Twenty-nine thousand eighty-nine articles on current management techniques (PEA, Balloon angioplasty, anticoagulants) were selected, analyzed, and reviewed with each other. We found 19 articles concerning PEA, 15 concerning BPA, and six regarding anticoagulants. Most papers showed high success rates and promising evidence of PEA and anticoagulants as a post-operative regimen. BPA was the least preferred but is still reputable in patients unfit for invasive techniques. CTEPH is a condition presenting with either fibrous stenosis, complete obliteration of the artery, or a clogged thrombus. Recent studies have shown three techniques that physicians have used to treat CTEPH: balloon-pulmonary angioplasty, PEA, and medical management with anticoagulants. PEA followed by anticoagulants is preferred to balloon pulmonary angioplasties. CTEPH is an ongoing topic in research; as it continues to be researched, we hope to see more management techniques available.

Design of a pragmatic randomized implementation effectiveness trial testing a health system wide hypertension program for older adults.

Hypertension control remains poor. Multiple barriers at the level of patients, providers, and health systems interfere with implementation of hypertension guidelines and effective lowering of BP. Some strategies such as self-measured blood pressure (SMBP) and remote management by pharmacists are safe and effectively lower BP but have not been effectively implemented. In this study, we combine such evidence-based strategies to build a remote hypertension program and test its effectiveness and implementation in large health systems. This randomized, controlled, pragmatic type I hybrid implementation effectiveness trial will examine the virtual collaborative care clinic (vCCC), a hypertension program that integrates automated patient identification, SMBP, remote BP monitoring by trained health system pharmacists, and frequent patient-provider communication. We will randomize 1000 patients with uncontrolled hypertension from two large health systems in a 1:1 ratio to either vCCC or control (usual care with education) groups for a 2-year intervention. Outcome measures including BP measurements, cognitive function, and a symptom checklist will be completed during study visits. Other outcome measures of cardiovascular events, mortality, and health care utilization will be assessed using Medicare data. For the primary outcome of proportion achieving BP control (defined as systolic BP < 130 mmHg) in the two groups, we will use a generalized linear mixed model analysis. Implementation outcomes include acceptability and feasibility of the program. This study will guide implementation of a hypertension program within large health systems to effectively lower BP.

Multimodal dataset using OCTA and fundus images for the study of diabetic retinopathy.

This article presents a Multimodal database consisting of 222 images of 76 people wherein 111 are OCTA images and 111 are color fundus images taken at the Natasha Eye Care and Research Institute of Pune Maharashtra, India. Nonmydriatic fundus images were acquired using a confocal SLO widefield fundus imaging Eidon machine. Nonmydriatic OCTA images were acquired using the Optovue Avanti Edition machine Initially, the clinical approach described in this article was used to obtain the retinal images. Following that, the dataset was categorized by two experienced eye specialists. To identify instances of Non-Proliferative Diabetic Retinopathy (NPDR) with their various stages, medical professionals and scholars can use this data. Research scholars and ophthalmologists can utilize the data created to develop the initial stages of automated identification techniques for diabetic retinopathy (DR).

Changes in Cognitive Function After Kidney Transplantation: A Longitudinal Cohort Study.

RATIONALE & OBJECTIVE: Kidney disease negatively affects cognition. We assessed the effect of kidney transplantation (KT) on different cognitive domains. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We examined pre- versus post-KT cognition in patients waitlisted for KT at an academic center. PREDICTORS: Transplant status. We measured cognitive function before KT (n=101), 3 months after KT (n=78), and 1 year after KT (n = 83). OUTCOMES: Our primary outcome was change in cognitive function before versus after KT. We used standard neuropsychological tests to assess global cognition (Mini-Mental State Exam [MMSE]), episodic/declarative memory (Logical Memory), psychomotor speed/visuospatial function (Digit Symbol Substitution Test [DSST], Trail Making Test [TMT] A), working memory/attention (Digit Span), executive function (TMT B), and semantic memory/verbal fluency/language (Category Fluency). ANALYTICAL APPROACH: Using linear mixed model analysis, we evaluated the changes in neuropsychological test scores adjusted for age, sex, race, education, and number of assessments. RESULTS: Before KT, Logical Memory I and II, DSST, MMSE, Category Fluency (animal naming), and Digit Span backward scores were low compared with normative values from the National Alzheimer's Coordinating Center data. Logical Memory I and II scores improved after KT (pre- vs post-KT, estimated group difference [d]=3.3, P<0.001 for Logical Memory I; d=4.27, P<0.001 for Logical Memory II), such that post-KT scores were similar to normative values (post-KT vs normative values, d = -0.37, P=0.06 for Logical Memory I; d = -0.89, P=0.08 for Logical Memory II). Category Fluency (animal naming; d=2.4, P<0.001) and DSST (d=3.12, P=0.01) scores also improved with KT, but post-KT DSST scores remained lower than normative values (post-KT vs normative values, d = -5.17, P<0.001). MMSE, Digit Span, and TMT A and B scores did not change after KT. LIMITATIONS: Single-center study. CONCLUSIONS: Episodic and verbal declarative memory normalize after KT. Semantic memory, verbal fluency, language, psychomotor speed, and visuospatial function show partial improvement. Cognitive impairment in kidney disease is therefore at least partly reversible with KT. PLAIN-LANGUAGE SUMMARY: Cognitive impairment in kidney disease affects self-esteem, vocational abilities, quality of life, health care costs, and mortality. It is not clear whether kidney transplantation (KT) improves cognition and whether the improvement is uniform across cognitive domains. The distinction between reversible and irreversible cognitive impairment has important implications in the clinical care of patients before and after KT. We assessed cognition before KT and 3 months and 12 months after KT and discovered that episodic and verbal declarative memory normalized with KT. Semantic memory, verbal fluency, language, psychomotor speed, and visuospatial function also improved with KT but did not reach normal levels. Cognitive impairment in kidney disease is therefore at least partly reversible.

DeepFreeze 3D-biofabrication for Bioengineering and Storage of Stem Cells in Thick and Large-Scale Human Tissue Analogs.

3D bioprinting holds great promise for meeting the increasing need for transplantable tissues and organs. However, slow printing, interlayer mixing, and the extended exposure of cells to non-physiological conditions in thick structures still hinder clinical applications. Here the DeepFreeze-3D (DF-3D) procedure and bioink for creating multilayered human-scale tissue mimetics is presented for the first time. The bioink is tailored to support stem cell viability, throughout the rapid freeform DF-3D biofabrication process. While the printer nozzle is warmed to room temperature, each layer solidifies at contact with the stage (-80 °C), or the subsequent layers, ensuring precise separation. After thawing, the encapsulated stem cells remain viable without interlayer mixing or delamination. The composed cell-laden constructs can be cryogenically stored and thawed when needed. Moreover, it is shown that under inductive conditions the stem cells differentiate into bone-like cells and grow for months after thawing, to form large tissue-mimetics in the scale of centimeters. This is important, as this approach allows the generation and storage of tissue mimetics in the size and thickness of human tissues. Therefore, DF-3D biofabrication opens new avenues for generating off-the-shelf human tissue analogs. It further holds the potential for regenerative treatments and for studying tissue pathologies caused by disease, tumor, or trauma.

Developing machine learning models to predict primary graft dysfunction after lung transplantation.

Primary graft dysfunction (PGD) is the leading cause of morbidity and mortality in the first 30 days after lung transplantation. Risk factors for the development of PGD include donor and recipient characteristics, but how multiple variables interact to impact the development of PGD and how clinicians should consider these in making decisions about donor acceptance remain unclear. This was a single-center retrospective cohort study to develop and evaluate machine learning pipelines to predict the development of PGD grade 3 within the first 72 hours of transplantation using donor and recipient variables that are known at the time of donor offer acceptance. Among 576 bilateral lung recipients, 173 (30%) developed PGD grade 3. The cohort underwent a 75% to 25% train-test split, and lasso regression was used to identify 11 variables for model development. A K-nearest neighbor's model showing the best calibration and performance with relatively small confidence intervals was selected as the final predictive model with an area under the receiver operating characteristics curve of 0.65. Machine learning models can predict the risk for development of PGD grade 3 based on data available at the time of donor offer acceptance. This may improve donor-recipient matching and donor utilization in the future.

Persistent Patent Vertical Vein After Repair of Total Anomalous Pulmonary Venous Connection (TAPVR): A Rare Cause of Hypoxemia Post-Fontan Procedure.

Vertical vein (VV) ligation during total anomalous pulmonary venous return (TAPVR) repair is controversial. While some surgeons prefer ligation of the VV to prevent adverse sequelae of shunting across it and to promote flow through the newly created anastomosis, others leave it to serve as a "pop off valve" to the left heart structures, which are believed to be hypoplastic and noncompliant, presumably contributing to a more favorable post-operative outcome. We report two patients post-Fontan procedure, who underwent cardiac catheterization to explore the etiology of hypoxia and were found to have a persistent VV responsible for right to left shunting. Both patients underwent closure of the VV with improvement in the cyanosis and clinical course. These cases provide evidence supporting surgical ligation of the VV at the time of TAPVR repair, especially in patients with single ventricle.

Toxic posterior segment syndrome with retinal vasculitis likely caused by intraocular cotton fiber after vitreoretinal surgery - a case report.

BACKGROUND: Intraocular inflammation is common after anterior or posterior segment surgery. They typically manifest either as non-infectious inflammation of the anterior or posterior segment, known as toxic anterior or posterior segment syndrome (TPSS), or as sterile or infective endophthalmitis. In this report, we describe a rare case of TPSS following vitreoretinal surgery, presenting as hemorrhagic retinal vasculitis. CASE PRESENTATION: A 58-year-old male diagnosed with a left eye acute rhegmatogenous retinal detachment underwent an uneventful primary pars plana vitrectomy with silicone oil endotamponade on the same day of presentation. At presentation, there were no signs of intraocular inflammation, and his visual acuity in the affected eye was 20/200. RESULTS: The retina was well-attached with silicone oil in place on the first post-operative day. Along the inferior retinal periphery, a hemorrhagic occlusive vasculitis was observed. Clinical examination revealed retained intraocular cotton fiber along the inferotemporal quadrant over the retinal surface. In addition to the standard post-operative medications, a course of systemic steroids (40 mg per day of Prednisolone tablets) was started. At the end of the first post-operative week, clinical signs of hemorrhagic retinal vasculitis were beginning to resolve, and by the end of the fourth post-operative week, they had completely resolved. CONCLUSION: This report describes an unusual diagnosis of TPSS after vitreoretinal surgery, most likely due to the presence of an intraocular cotton fiber. This excessive inflammation of the posterior segment usually responds to a course of topical and systemic steroids.

Impact of preexisting coronary artery and peripheral artery disease on outcomes in diabetic patients after kidney transplant.

BACKGROUND: Atherosclerotic cardiovascular disease is highly prevalent in patients with end-stage kidney disease (ESKD). Kidney transplant (KT) improves patient survival and cardiovascular outcomes. The impact of preexisting coronary artery disease (CAD) and peripheral artery disease (PAD) on posttransplant outcomes remains unclear. METHODS: This is a retrospective study utilizing the United States Renal Data System. Adult diabetic dialysis patients who underwent first KT between 2006 and 2017 were included. The study population was divided into four cohorts based on presence of CAD/PAD: (1) polyvascular disease (CAD + PAD); (2) CAD without PAD; (3) PAD without CAD; (4) no CAD or PAD (reference cohort). The primary outcome was 3-year all-cause mortality. Secondary outcomes were incidence of posttransplant myocardial infarction (MI), cerebrovascular accidents (CVA), and graft failure. RESULTS: The study population included 19,329 patients with 64.4% men, mean age 55.4 years, and median dialysis duration of 2.8 years. Atherosclerotic cardiovascular disease was present in 28% of patients. The median follow up was 3 years. All-cause mortality and incidence of posttransplant MI were higher with CAD and highest in patients with polyvascular disease. The cohort with polyvascular disease had twofold higher all-cause mortality (16.7%, adjusted hazard ratio (aHR) 1.5, p < 0.0001) and a fourfold higher incidence of MI (12.7%, aHR 3.3, p < 0.0001) compared to the reference cohort (8.0% and 3.1%, respectively). There was a higher incidence of posttransplant CVA in the cohort with PAD (3.4%, aHR 1.5, p = 0.01) compared to the reference cohort (2.0%). The cohorts had no difference in graft failure rates. CONCLUSIONS: Preexisting CAD and/or PAD result in worse posttransplant survival and cardiovascular outcomes in patients with diabetes mellitus and ESKD without a reduction in graft survival.

Beyond mathematics, statistics, and programming: data science, machine learning, and artificial intelligence competencies and curricula for clinicians, informaticians, science journalists, and researchers.

Data science, machine learning and artificial intelligence applications impact clinicians, informaticians, science journalists, and researchers. Most biomedical data science training focuses on learning a programming language in addition to higher mathematics and advanced statistics. This approach is appropriate for graduate students but greatly reduces the number of individuals in healthcare who can be involved in data science. To serve these four stakeholder audiences, we describe several curricular strategies focusing on solving real problems of interest to these audiences. Relevant competencies for these audiences include using intuitive programming tools that facilitate data exploration with minimal programming background, creating data models, evaluating results of data analyses, and assessing data science research reports, among others. Offering the curricula described here more broadly could broaden the stakeholder groups knowledgeable about and engaged in data science.

Cidofovir in Severe Hypoxemic Adenoviral Pneumonia.

The authors present a 16-mo-old boy with flu like symptoms, not responding to supportive management and progressed to severe hypoxemic pneumonia. Adenovirus was detected in the nasopharyngeal aspirate. He showed rapid improvement after intravenous cidofovir administration.

Association Between Socioeconomic Factors, Race, and Use of a Specialty Memory Clinic.

BACKGROUND AND OBJECTIVES: The capacity of specialty memory clinics in the United States is very limited. If lower socioeconomic status or minoritized racial group is associated with reduced use of memory clinics, this could exacerbate health care disparities, especially if more effective treatments of Alzheimer disease become available. We aimed to understand how use of a memory clinic is associated with neighborhood-level measures of socioeconomic factors and the intersectionality of race. METHODS: We conducted an observational cross-sectional study using electronic health record data to compare the neighborhood advantage of patients seen at the Washington University Memory Diagnostic Center with the catchment area using a geographical information system. Furthermore, we compared the severity of dementia at the initial visit between patients who self-identified as Black or White. We used a multinomial logistic regression model to assess the Clinical Dementia Rating at the initial visit and t tests to compare neighborhood characteristics, including Area Deprivation Index, with those of the catchment area. RESULTS: A total of 4,824 patients seen at the memory clinic between 2008 and 2018 were included in this study (mean age 72.7 [SD 11.0] years, 2,712 [56%] female, 543 [11%] Black). Most of the memory clinic patients lived in more advantaged neighborhoods within the overall catchment area. The percentage of patients self-identifying as Black (11%) was lower than the average percentage of Black individuals by census tract in the catchment area (16%) (p < 0.001). Black patients lived in less advantaged neighborhoods, and Black patients were more likely than White patients to have moderate or severe dementia at their initial visit (odds ratio 1.59, 95% CI 1.11-2.25). DISCUSSION: This study demonstrates that patients living in less affluent neighborhoods were less likely to be seen in one large memory clinic. Black patients were under-represented in the clinic, and Black patients had more severe dementia at their initial visit. These findings suggest that patients with a lower socioeconomic status and who identify as Black are less likely to be seen in memory clinics, which are likely to be a major point of access for any new Alzheimer disease treatments that may become available.