Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction.

Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin, and independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina. Deletion of Hdac3 in cardiac progenitor cells releases genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes; in contrast, restricting Hdac3 to the nuclear periphery rescues myogenesis in progenitors otherwise lacking Hdac3. Our results suggest that availability of genomic regions for activation by lineage-specific factors is regulated in part through dynamic chromatin-nuclear lamina interactions and that competence of a progenitor cell to respond to differentiation signals may depend upon coordinated movement of responding gene loci away from the nuclear periphery.

Introduction of transcatheter edge-to-edge repair in patients with congenital heart disease at a children's hospital.

BACKGROUND: Atrioventricular valve regurgitation (AVVR) is a devastating complication in children and young adults with congenital heart disease (CHD), particularly in patients with single ventricle physiology. Transcatheter edge-to-edge repair (TEER) is a rapidly expanding, minimally invasive option for the treatment of AVVR in adults that avoids the morbidity and mortality associated with open heart surgery. However, application of TEER in in CHD and in children is quite novel. We describe the development of a peri-procedural protocol including image-derived pre-intervention simulation, with successful application to four patients. AIMS: To describe the initial experience using the MitraClip system for TEER of dysfunctional systemic atrioventricular valves in patients with congential heart disease within a pediatric hospital. METHODS: A standardized screening and planning process was developed using cardiac magnetic resonance imaging, three dimensional echocardiography and both virtual and physical simulation. Procedures were performed using the MitraClip G4 system and patients were clinically followed post-intervention. RESULTS: A series of four CHD patients with at least severe AVVR were screened for suitability for TEER with the MitraClip system: three patients had single ventricle physiology and Fontan palliation, and one had repair of a common atrioventricular canal defect. Each patient had at least severe systemic AVVR and was considered at prohibitively high risk for surgical repair. Each patient underwent a standardized preprocedural screening protocol and image-derived modeling followed by the TEER procedure with successful clip placement at the intended location in all cases. CONCLUSIONS: The early results of our protocolized efforts to introduce TEER repair of severe AV valve regurgitation with MitraClip into the CHD population within our institution are encouraging. Further investigations of the use of TEER in this challenging population are warranted.

Risk Factors for Acute Ischemic Stroke Caused by Anterior Large Vessel Occlusion.

Background and Purpose- Accurate prediction of acute ischemic stroke (AIS) caused by anterior large vessel occlusion (LVO) that is amendable to mechanical thrombectomy remains a challenge. We developed and validated a prediction model for anterior circulation LVO stroke using past medical history elements present on admission and neurological examination. Methods- We retrospectively reviewed AIS patients admitted between 2009 and 2017 to 3 hospitals within a large healthcare system in the United States. Patients with occlusions of the internal carotid artery or M1 or M2 segments of the middle cerebral artery were randomly split into 2/3 derivation and 1/3 validation cohorts for development of an anterior circulation LVO prediction model and score that was further curtailed for potential use in the prehospital setting. Results- A total of 1654 AIS were reviewed, including 248 (15%) with proximal anterior circulation LVO AIS. In the derivation cohort, National Institutes of Health Stroke Scale score at the time of cerebrovascular imaging, current smoking status, type 2 diabetes mellitus, extracranial carotid, and intracranial atherosclerotic stenosis was significantly associated with anterior circulation LVO stroke. The prehospital score was curtailed to National Institutes of Health Stroke Scale score, current smoking status, and type 2 diabetes mellitus. The areas under the curve for the prediction model, prehospital score, and National Institutes of Health Stroke Scale score alone were 0.796, 0.757, and 0.725 for the derivation cohort and 0.770, 0.689, and 0.665 for the validation cohort, respectively. The Youden index J was 0.46 for a score of >6 with 84.7% sensitivity and 62.0% specificity for the prediction model. Conclusions- Previously reported LVO stroke prediction scores focus solely on elements of the neurological examination. In addition to stroke severity, smoking, diabetes mellitus, extracranial carotid, and intracranial atherosclerotic stenosis were associated with anterior circulation LVO AIS. Although atherosclerotic stenosis may not be known until imaging is obtained, smoking and diabetes mellitus history can be readily obtained in the field and represent important elements of the prehospital score supplementing National Institutes of Health Stroke Scale score.

Proteins Encoded by the gerP Operon Are Localized to the Inner Coat in Bacillus cereus Spores and Are Dependent on GerPA and SafA for Assembly.

The germination of Bacillus spores is triggered by certain amino acids and sugar molecules which permeate the outermost layers of the spore to interact with receptor complexes that reside in the inner membrane. Previous studies have shown that mutations in the hexacistronic gerP locus reduce the rate of spore germination, with experimental evidence indicating that the defect stems from reduced permeability of the spore coat to germinant molecules. Here, we use the ellipsoid localization microscopy technique to reveal that all six Bacillus cereus GerP proteins share proximity with cortex-lytic enzymes within the inner coat. We also reveal that the GerPA protein alone can localize in the absence of all other GerP proteins and that it has an essential role for the localization of all other GerP proteins within the spore. Its essential role is also demonstrated to be dependent on SafA, but not CotE, for localization, which is consistent with an inner coat location. GerP-null spores are shown also to have reduced permeability to fluorescently labeled dextran molecules compared to wild-type spores. Overall, the results support the hypothesis that the GerP proteins have a structural role within the spore associated with coat permeability.IMPORTANCE The bacterial spore coat comprises a multilayered proteinaceous structure that influences the distribution, survival, and germination properties of spores in the environment. The results from the current study are significant since they increase our understanding of coat assembly and architecture while adding detail to existing models of germination. We demonstrate also that the ellipsoid localization microscopy (ELM) image analysis technique can be used as a novel tool to provide direct quantitative measurements of spore coat permeability. Progress in all of these areas should ultimately facilitate improved methods of spore control in a range of industrial, health care, and environmental sectors.

Comparative analysis of contextual bias around the translation initiation sites in plant genomes.

Nucleotide distribution around translation initiation site (TIS) is thought to play an important role in determining translation efficiency. Kozak in vertebrates and later Joshi et al. in plants identified context sequence having a key role in translation efficiency, but a great variation regarding this context sequence has been observed among different taxa. The present study aims to refine the context sequence around initiation codon in plants and addresses the sampling error problem by using complete genomes of 7 monocots and 7 dicots separately. Besides positions -3 and +4, significant conservation at -2 and +5 positions was also found and nucleotide bias at the latter two positions was shown to directly influence translation efficiency in the taxon studied. About 1.8% (monocots) and 2.4% (dicots) of the total sequences fit the context sequence from positions -3 to +5, which might be indicative of lower number of housekeeping genes in the transcriptome. A three base periodicity was observed in 5' UTR and CDS of monocots and only in CDS of dicots as confirmed against random occurrence and annotation errors. Deterministic enrichment of GCNAUGGC in monocots, AANAUGGC in dicots and GCNAUGGC in plants around TIS was also established (where AUG denotes the start codon), which can serve as an arbiter of putative TIS with efficient translation in plants.

Semaphorin 3d and semaphorin 3e direct endothelial motility through distinct molecular signaling pathways.

Class 3 semaphorins were initially described as axonal growth cone guidance molecules that signal through plexin and neuropilin coreceptors and since then have been established to be regulators of vascular development. Semaphorin 3e (Sema3e) has been shown previously to repel endothelial cells and is the only class 3 semaphorin known to be capable of signaling via a plexin receptor without a neuropilin coreceptor. Sema3e signals through plexin D1 (Plxnd1) to regulate vascular patterning by modulating the cytoskeleton and focal adhesion structures. We showed recently that semaphorin 3d (Sema3d) mediates endothelial cell repulsion and pulmonary vein patterning during embryogenesis. Here we show that Sema3d and Sema3e affect human umbilical vein endothelial cells similarly but through distinct molecular signaling pathways. Time-lapse imaging studies show that both Sema3d and Sema3e can inhibit cell motility and migration, and tube formation assays indicate that both can impede tubulogenesis. Endothelial cells incubated with either Sema3d or Sema3e demonstrate a loss of actin stress fibers and focal adhesions. However, the addition of neuropilin 1 (Nrp1)-blocking antibody or siRNA knockdown of Nrp1 inhibits Sema3d-mediated, but not Sema3e-mediated, cytoskeletal reorganization, and siRNA knockdown of Nrp1 abrogates Sema3d-mediated, but not Sema3e-mediated, inhibition of tubulogenesis. On the other hand, endothelial cells deficient in Plxnd1 are resistant to endothelial repulsion mediated by Sema3e but not Sema3d. Unlike Sema3e, Sema3d incubation results in phosphorylation of Akt in human umbilical vein endothelial cells, and inhibition of the PI3K/Akt pathway blocks the endothelial guidance and cytoskeletal reorganization functions of Sema3d but not Sema3e.

Murine craniofacial development requires Hdac3-mediated repression of Msx gene expression.

Craniofacial development is characterized by reciprocal interactions between neural crest cells and neighboring cell populations of ectodermal, endodermal and mesodermal origin. Various genetic pathways play critical roles in coordinating the development of cranial structures by modulating the growth, survival and differentiation of neural crest cells. However, the regulation of these pathways, particularly at the epigenomic level, remains poorly understood. Using murine genetics, we show that neural crest cells exhibit a requirement for the class I histone deacetylase Hdac3 during craniofacial development. Mice in which Hdac3 has been conditionally deleted in neural crest demonstrate fully penetrant craniofacial abnormalities, including microcephaly, cleft secondary palate and dental hypoplasia. Consistent with these abnormalities, we observe dysregulation of cell cycle genes and increased apoptosis in neural crest structures in mutant embryos. Known regulators of cell cycle progression and apoptosis in neural crest, including Msx1, Msx2 and Bmp4, are upregulated in Hdac3-deficient cranial mesenchyme. These results suggest that Hdac3 serves as a critical regulator of craniofacial morphogenesis, in part by repressing core apoptotic pathways in cranial neural crest cells.

Pulmonary Artery Wedge Pressure Can Underestimate Direct Pulmonary Vein Pressure in Pediatric Pulmonary Vein Stenosis.

Background: Pulmonary artery wedge pressure (PAWP) can underestimate directly measured pulmonary vein pressure (PVP) as demonstrated in animal studies and human case reports. This concept has not been validated in a larger cohort of pediatric patients with pulmonary vein stenosis (PVS). Methods: Pediatric patients who underwent cardiac catheterization for PVS at a single center from January 1, 2018, to March 31, 2023, were retrospectively reviewed. Mismatch between the PAWP and directly measured PVP or LA pressure was defined as >3 mm Hg. Preintervention angiography was reviewed and percent stenosis calculated. Results: Twenty-six patients met inclusion criteria; 51 lower pulmonary veins (34 left, 17 right) from 42 catheterizations were evaluated. Significant PVS (≥30% stenosis) was seen in 38/51 (75%) veins, and 9/51 (18%) veins had no angiographic narrowing (0% stenosis). PAWP-PVP mismatch occurred in 37/51 (73%) veins with a median difference of 8 mm Hg (IQR, 6-12). Of these, PAWP was equal to LA pressure in 26 instances, all of which had significant PVS (median % stenosis 54 [IQR, 45-60]). Six of the cases with PAWP-PVP mismatch, PVS (range, 41%-70% stenosis), and no PAWP-LA mismatch reported both a proximal and distal segmental PAWP. In all 6 instances, there was no distal PAWP-PVP mismatch (median difference 1 mm Hg [range, 0-3]). Conclusions: In this single-center study of pediatric patients with PVS, PAWP significantly underestimated directly measured PVP in lower pulmonary veins. Balloon wedge or end hole catheter position in a distal lobar segment may more accurately estimate the PVP.

Clinical impact of multidetector row computed tomography before bronchial artery embolization in patients with hemoptysis: a prospective study.

PURPOSE: To evaluate prospectively the role and impact of multidetector row computed tomography (MDCT) before bronchial artery embolization (BAE) in patients with hemoptysis. METHODS: MDCT of the thorax was performed in 27 patients (21 men, 6 women; age range, 22-70 years; mean, 39 years) with hemoptysis who were referred for BAE. Transverse, multiplanar reconstruction, and 3-dimensional reconstruction (maximum intensity projection and volume rendered) images were analysed to identify the abnormal hypertrophied bronchial and nonbronchial systemic arteries causing hemoptysis, their origin and course were noted. Digital subtraction angiography was performed with the knowledge of findings of MDCT. Selective arteriogram of abnormal bronchial as well as nonbronchial arteries was performed. Embolization was attempted in 25 of these patients (92.6%) by using polyvinyl alcohol particles (350-500 µm), Gelfoam or Embospheres (400-700 µm). Follow-up was done for a mean period of 20.5 months. RESULTS: Based on MDCT, 2 of 27 patients were found unsuitable for BAE. On computed tomography, 38 arteries (27 bronchial and 11 nonbronchial systemic arteries) were identified as abnormal hypertrophied vessels. On angiography, 34 of these arteries (25 bronchial and 9 nonbronchial systemic arteries) were found to be responsible for hemoptysis. Three of these arteries could not be evaluated during angiography, and 1 artery that was identified as abnormal on computed tomography was found normal on angiography. All 25 bronchial and 9 nonbronchial systemic arteries that cause hemoptysis were detected at MDCT. Embolization was successful in 23 of 25 patients. CONCLUSION: MDCT enables detection and depiction of all bronchial and nonbronchial systemic arteries causing hemoptysis.

Contemporary Plural Deliberations and Perspectives in Revision Middle Ear Surgery. Causes, Outcomes and Lessons Learned.

The indications for revision middle ear surgery are inter-linked to the objectives of surgery and needs of the patient. Revision middle ear surgery is often challengingly arduous not only for the patient but for the surgeon as well. This study concentrates on the causes of failures of primary ear surgery, indications, techniques, outcomes and lessons learned in revision ear surgery. This retrospectivedescriptive study included 22 cases (12.29%) of revision surgery,with a follow up of at least one year, out of total 179 cases of middle ear surgeries performed over a period of 5 years.These revision cases included tympanoplasty, cortical mastoidectomy and modified radical mastoidectomy alongwith ossiculoplasty and scutumplasty, wherever required. Hearing improvement, closure of perforation, and prevention of recrudescence were the main outcome parameters. The overall morphologic success of revision surgery in our series was 90.90%.There was one graft failure, one attic retraction and the main complication observed was post-operative worsening of hearing.Mean postoperative pure-tone average air -bone gap (ABG) was 20.86 ± 11.29 dB compared with preoperative ABG of 29.64 ± 10.63 dB and the difference was statistically significant ( p < 0.05) with p value 0.0112 on paired t-test. Detailed knowledge and anticipation of the cause of failure is a must in preventing another failure in revision ear surgeries. Hearing preservation must be considered in a pragmatic perspective and accordingly surgical indications must complement the realistic and reasonable expectations of the patients.

Coil Embolization of a Ruptured Mycotic Coronary Artery Aneurysm in a Pediatric Patient.

Mycotic coronary artery aneurysms are rare but have a high risk of mortality. Traditional management is surgical, but percutaneous intervention can be performed in patients with high surgical risk. In this report, we describe a case of mycotic coronary aneurysm in a pediatric patient successfully managed with percutaneous coil embolization. (Level of Difficulty: Advanced.).

Association between missed appointments and hospitalization for child physical abuse.

Missed cases of child physical abuse (CPA) persist despite known risk factors. Prior studies have not evaluated missed medical appointments as a risk factor for CPA. The objective of this study was to determine if an association exists between missed appointments and hospitalization for CPA. We conducted a 20-year, single health system, retrospective chart review of hospitalized patients ≤36 months of age meeting International Classification of Diseases (ICD) 9/10 criteria for CPA with ≥1 scheduled appointment in our system prior to their admission. Cases were categorized as definite CPA, high likelihood, or no concern for CPA/unable to be determined. Cases identified as definite or high likelihood of CPA were matched (5:1) with controls based on age, distance to primary care provider's (PCP's) office, sex, prior hospitalization, and race. Missed appointments were compared between cases (n = 146) and controls (n = 730). A significant difference was identified between cases and controls (26 % vs 9 %, p < 0.001) for the median proportion of missed appointments. After adjusting for matched and significant covariates, there was a 3 % increase in a patient's odds of admission for CPA for every 1 % increase in missed appointments. We found an association between missed appointments and future admission for CPA. This finding has potential to assist clinicians with CPA risk stratification and future child abuse research. Limitations include single healthcare system, ICD criteria determined by research team, and narrow definition of definite CPA.

Validation of the Surprise Question and the Development of a Multivariable Model.

CONTEXT: The Surprise Question (SQ) (would you be surprised if this patient died within a year?) is a prognostic variable explored in chronic illnesses. Validation is limited to sensitivity, specificity, and predictive values. OBJECTIVES: Our objective is to validate the SQ in cancer patients and develop a predictive model with additional variables. METHODS: A prospective cohort study of adult (age>18) cancer patients seen between October 1, 2019, through March 31, 2021, undergoing systemic therapies had the SQ completed by oncologists prior to each change in systemic therapy. The primary outcome was survival for one year. Secondary outcomes were predictions of survival at three, six, and nine months. Patients were grouped into negative SQ (not surprised) and positive SQ (surprised). Sensitivity, specificity, predictive values, and likelihood ratios (LR) were calculated for the SQ. Additional prognostic variables were age, gender, cancer stage, line of therapy, Charleson Comorbid Index (CCI), palliative care consultation (prior to, after the SQ, or not at all), and healthcare utilization (outpatient, inpatient, and emergency department (ED). Logistic regression and receiver operating characteristics (ROC) were used for discrimination and modeling. Akaike information criterion (AIC) was used to compare the model fit as each predictor. RESULTS: 1366 patients had 1 SQ; 784 died within a year. The SQ predicted survival at one year (P = 0.008), with a positive LR of 1.459 (95%CI 1.316-1.602) and a c-statistic of 0.565 (95%CI 0.530-0.600). Additional variables increased the c-statistic to 0.648 (95% CI 0.608-0.686). The total model best predicted survival at three months, c-statistic of 0.663 (95% CI 0.616-0.706). However, the total model c-statistic remained <0.70. CONCLUSIONS: The SQ, as a single factor, poorly predicts survival and should not be used to alter therapies. Adding additional objective variables improved prognostication, but further refinement and external validation are needed.

Performance Characteristics of a Rule-Based Electronic Health Record Algorithm to Identify Patients with Gross and Microscopic Hematuria.

BACKGROUND: Two million patients per year are referred to urologists for hematuria, or blood in the urine. The American Urological Association recently adopted a risk-stratified hematuria evaluation guideline to limit multi-phase computed tomography to individuals at highest risk of occult malignancy. OBJECTIVES: To understand population-level hematuria evaluations, we developed an algorithm to accurately identify hematuria cases from electronic health records (EHRs). METHODS: We used International Classification of Diseases (ICD)-9/ICD-10 diagnosis codes, urine color, and urine microscopy values to identify hematuria cases and to differentiate between gross and microscopic hematuria. Using an iterative process, we refined the ICD-9 algorithm on a gold standard, chart-reviewed cohort of 3,094 hematuria cases, and the ICD-10 algorithm on a 300 patient cohort. We applied the algorithm to Geisinger patients ≥35 years (n = 539,516) and determined performance by conducting chart review (n = 500). RESULTS: After applying the hematuria algorithm, we identified 51,500 hematuria cases and 488,016 clean controls. Of the hematuria cases, 11,435 were categorized as gross, 26,658 as microscopic, 12,562 as indeterminate, and 845 were uncategorized. The positive predictive value (PPV) of identifying hematuria cases using the algorithm was 100% and the negative predictive value (NPV) was 99%. The gross hematuria algorithm had a PPV of 100% and NPV of 99%. The microscopic hematuria algorithm had lower PPV of 78% and NPV of 100%. CONCLUSION: We developed an algorithm utilizing diagnosis codes and urine laboratory values to accurately identify hematuria and categorize as gross or microscopic in EHRs. Applying the algorithm will help researchers to understand patterns of care for this common condition.

Incidence and Prevalence of Cough in a Rural Health System: A 20-Year Study.

OBJECTIVE: Understanding the cough population is critical to addressing clinical needs and gaps in best practice. We sought to characterize and stratify cough patients with the hypothesis that there are opportunities to improve access to care in our health system and characterize the population. METHODS: Following institutional review board exempt status, a retrospective electronic record review was performed on all patients coded with ICD-9 786.2 or ICD-10 is R05 from January 1, 2001 through December 31, 2020 at our health system. Inclusion criteria were one or more visits for cough. The subgroup with more than one visit in each of 2 years was classified as multiple encounters. Patients were characterized by sex, age at first cough encounter, number of cough encounters, smoking status, and insurance status. Results were stratified by year, calculating frequencies, and percentages. RESULTS: There were 302,284 unique patients diagnosed with cough, among 1,764,387 patients seen in our health system, representing an average incidence of 3.0% (2.7%-3.7%) and prevalence of 4.9% (3.1%-5.6%). New single encounter cough patients totaled 179,963, and new multiple encounter cough patients totaled 122,321. Of the 39,828,073 total encounters, there were 469,802 for new or existing cough (1.17%-1.73% annually). The age at initial presentation demonstrated 36.5% seen <10 years old, with an even distribution over the remaining decades of life. The majority were seen for cough once, but 23.8% of group two patients had two or more visits for cough in a year. CONCLUSION: We demonstrate a lower-than-expected incidence and prevalence of cough in our health population, suggesting challenges with access to care when compared to 10% prevalence and 3% of encounters previously documented in the literature. The study also provides a platform to explore the importance of pediatric cough, as well as population health and the longitudinal journey of cough patients in underserved areas. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1191-1196, 2023.

3-Dimensional Modeling Guided Transcatheter Repair of Dehisced Pulmonary Venous Baffle With Gore ASD Device.

A 38-year-old woman with sinus venosus atrial septal defect and partial anomalous return of the right upper pulmonary vein underwent a Warden procedure but experienced a large residual defect after patch dehiscence. Image-derived 3D modeling informed novel device closure with a Gore Cardioform atrial septal occluder. (Level of Difficulty: Advanced.).

Radiation Therapy in the Last Month of Life: Association With Aggressive Care at the End of Life.

CONTEXT: Half of the patients with cancer who undergo radiation therapy do so with palliative intent. OBJECTIVES: To determine the proportion of undergoing radiation in the last month of life, patient characteristics, cancer course, the type and duration of radiation, whether palliative care was involved, and the of radiation with aggressive cancer care metrics. METHODS: One thousand seven hundred twenty-seven patients who died of cancer between January 1, 2018, and December 31, 2019, were included. Demographics, cancer stage, palliative care referral, advance directives, use of home health care, radiation timing, and survival were collected. Type of radiation, course, and intent were reviewed. Chi-square analysis was utilized for categorical variables, and Kruskal-Wallis tests for continuous variables. A stepwise selection was used to build a Cox proportional hazard model. RESULTS: Two hundred thirty-three patients underwent radiation in the last month of life. Younger patients underwent radiation 67.3 years (SD 11.52) versus 69.2 years (SD 11.96). 42.6% had radiation within two weeks of death. The average fraction number was 5.5. Individuals undergoing radiation were more likely to start chemotherapy within the last 30 days of life, continue chemotherapy within two weeks of death, be admitted to the ICU, and have two or more hospitalizations or emergency room visits. Survival measured from the date of diagnosis was shorter for those undergoing radiation, 122 days (IQR 58-462) versus 474 days (IQR 225-1150). Palliative care consultations occurred later in those undergoing radiation therapy. CONCLUSION: Radiation therapy in the last month of life occurs in younger patients with rapidly progressive cancer, who are subject to more aggressive cancer care, and have late palliative care consults.

Decreased cell adhesion promotes angiogenesis in a Pyk2-dependent manner.

Angiogenesis is regulated by both soluble growth factors and cellular interactions with the extracellular matrix (ECM). While cell adhesion via integrins has been shown to be required for angiogenesis, the effects of quantitative changes in cell adhesion and spreading against the ECM remain less clear. Here, we show that angiogenic sprouting in natural and engineered three-dimensional matrices exhibited a biphasic response, with peak sprouting when adhesion to the matrix was limited to intermediate levels. Examining changes in global gene expression to determine a genetic basis for this response, we demonstrate a vascular endothelial growth factor (VEGF)-induced upregulation of genes associated with vascular invasion and remodeling when cell adhesion was limited, whereas cells on highly adhesive surfaces upregulated genes associated with proliferation. To explore a mechanistic basis for this effect, we turned to focal adhesion kinase (FAK), a central player in adhesion signaling previously implicated in angiogenesis, and its homologue, proline-rich tyrosine kinase 2 (Pyk2). While FAK signaling had some impact, our results suggested that Pyk2 can regulate both gene expression and endothelial sprouting through its enhanced activation by VEGF in limited adhesion contexts. We also demonstrate decreased sprouting of tissue explants from Pyk2-null mice as compared to wild type mice as further confirmation of the role of Pyk2 in angiogenic sprouting. These results suggest a surprising finding that limited cell adhesion can enhance endothelial responsiveness to VEGF and demonstrate a novel role for Pyk2 in the adhesive regulation of angiogenesis.

Improved COVID-19 detection with chest x-ray images using deep learning.

The novel coronavirus disease, which originated in Wuhan, developed into a severe public health problem worldwide. Immense stress in the society and health department was advanced due to the multiplying numbers of COVID carriers and deaths. This stress can be lowered by performing a high-speed diagnosis for the disease, which can be a crucial stride for opposing the deadly virus. A good large amount of time is consumed in the diagnosis. Some applications that use medical images like X-Rays or CT-Scans can pace up the time used in diagnosis. Hence, this paper aims to create a computer-aided-design system that will use the chest X-Ray as input and further classify it into one of the three classes, namely COVID-19, viral Pneumonia, and healthy. Since the COVID-19 positive chest X-Rays dataset was low, we have exploited four pre-trained deep neural networks (DNNs) to find the best for this system. The dataset consisted of 2905 images with 219 COVID-19 cases, 1341 healthy cases, and 1345 viral pneumonia cases. Out of these images, the models were evaluated on 30 images of each class for the testing, while the rest of them were used for training. It is observed that AlexNet attained an accuracy of 97.6% with an average precision, recall, and F1 score of 0.98, 0.97, and 0.98, respectively.

Applying computable phenotypes within a common data model to identify heart failure patients for an implantable cardiac device registry.

BACKGROUND: Use of existing data in electronic health records (EHRs) could be used more extensively to better leverage real world data for clinical studies, but only if standard, reliable processes are developed. Numerous computable phenotypes have been validated against manual chart review, and common data models (CDMs) exist to aid implementation of such phenotypes across platforms and sites. Our objective was to measure consistency between data that had previously been manually collected for an implantable cardiac device registry and CDM-based phenotypes for the condition of heart failure (HF). METHODS: Patients enrolled in an implantable cardiac device registry at two hospitals from 2013 to 2018 contributed to this analysis wherein registry data were compared to PCORnet CDM-formatted EHR data. Seven different phenotype algorithms were used to search for the presence of HF and compare the results with the registry. Sensitivity, specificity, predictive value and congruence were calculated for each phenotype. RESULTS: In the registry, 176 of 319 (55%) patients had history of HF, compared with different phenotypes estimating between 96 (30%) and 188 (59%). The least-restrictive phenotypes (any diagnosis) had high sensitivity and specificity (90%/80%), but more restrictive phenotypes had higher specificity (e.g., code present in problem list, 94%). Differences were observed using time-based criteria (e.g., days between visit diagnoses) and between participating hospitals. CONCLUSIONS: Consistency between manually-collected registry data and CDM-based phenotypes for history of HF was high overall, but use of different phenotypes impacted sensitivity and specificity, and results may differ depending on the medical condition of interest.