Anatomical and Three-Dimensional Study of the Female Feline Abdominal and Pelvic Vascular System Using Dissections, Computed Tomography Angiography and Magnetic Resonance Angiography.

This study describes the anatomical characteristics of the abdominal and pelvic vascular system of two healthy mature female cats via three-dimensional contrast enhanced computed tomography angiography, non-contrast enhanced magnetic resonance angiography and three-dimensional printing. Volume-rendering computed tomography angiography images were acquired from the ventral aspect using RadiAnt, Amira and OsiriX MD Dicom three-dimensional formats, and three-dimensional printing was obtained and compared with the corresponding computed tomography angiography images. Non-contrast enhanced magnetic resonance angiography was made using the time-of-flight imaging in ventral, oblique and lateral views. In addition, three cadavers with colored latex injection were dissected to facilitate the identification of the vascular structures. Three-dimensional computed tomography angiography showed the main vascular structures, whereas with the time-of-flight blood appeared with a high signal intensity compared with associated abdominal and pelvic tissues. Three-dimensional computed tomography angiography images and time-of-flight sequences provided adequate anatomical details of the main arteries and veins that could be used for future feline anatomical and clinical vascular studies of the abdomen and pelvis.

Proceedings of the inaugural Dark Genome Symposium: November 2022.

In November 2022 the first Dark Genome Symposium was held in Boston, USA. The meeting was hosted by Rome Therapeutics and Enara Bio, two biotechnology companies working on translating our growing understanding of this vast genetic landscape into therapies for human disease. The spirit and ambition of the meeting was one of shared knowledge, looking to strengthen the network of researchers engaged in the field. The meeting opened with a welcome from Rosana Kapeller and Kevin Pojasek followed by a first session of field defining talks from key academics in the space. A series of panels, bringing together academia and industry views, were then convened covering a wide range of pertinent topics. Finally, Richard Young and David Ting gave their views on the future direction and promise for patient impact inherent in the growing understanding of the Dark Genome.

Cardiopulmonary physiological effects of diuretic therapy in preterm infants with chronic pulmonary hypertension.

OBJECTIVE: Using targeted neonatal echocardiography (TNE) to examine cardiopulmonary physiological impact of diuretics in preterm infants with chronic pulmonary hypertension (cPH). STUDY DESIGN: Retrospective study comparing TNE indices pre- and ≤2 weeks (post) of initiating diuretic therapy in infants born <32 weeks gestational age with cPH. RESULTS: Twenty-seven neonates with mean gestational age, birthweight and interval between pre-post diuretic TNE of 27.0 ± 2.8 weeks, 859 ± 294 grams, and 7.8 ± 3.0 days respectively were studied. Diuretics was associated with improvement in pulmonary vascular resistance [pulmonary artery acceleration time (PAAT); 34.27(9.76) vs. 40.24(11.10)ms, p = 0.01), right ventricular (RV) ejection time:PAAT ratio [5.92(1.66) vs. 4.83(1.14), p < 0.01)], RV fractional area change [41.6(9.8) vs. 46.4(6.5%), p = 0.03)] and left ventricular myocardial performance index [0.55(0.09) vs. 0.41(0.23), p < 0.01)]. Post-treatment, frequency of bidirectional/right-to-left inter-atrial shunts decreased significantly (24% vs. 4%, p = 0.05). CONCLUSION: Primary diuretic treatment in neonates with cPH may result in improvement in PVR, RV and LV function and compliance.

A Neural Network Approach to Reducing the Costs of Parameter-Setting in the Production of Polyethylene Oxide Nanofibers.

Nanofibers, which are formed by the electrospinning process, are used in a variety of applications. For this purpose, a specific diameter suited for each application is required, which is achieved by varying a set of parameters. This parameter adjustment process is empirical and works by trial and error, causing high input costs and wasting time and financial resources. In this work, an artificial neural network model is presented to predict the diameter of polyethylene nanofibers, based on the adjustment of 15 parameters. The model was trained from 105 records from data obtained from the literature and was then validated with nine nanofibers that were obtained and measured in the laboratory. The average error between the actual results was 2.29%. This result differs from those taken in an evaluation of the dataset. Therefore, the importance of increasing the dataset and the validation using independent data is highlighted.

Creation of Three-Dimensional Anatomical Vascular and Biliary Models for the Study of the Feline Liver (Felis silvestris catus L.): A Comparative CT, Volume Rendering (Vr), Cast and 3D Printing Study.

In this study, six adult feline cadavers were examined using CTA, 3D printing, and casts injected with epoxy. The aorta, the portal vein, and the gallbladder of 3 feline cadavers were separately injected with a 50% mixture of colored vulcanized latex and hydrated barium sulfate as contrast medium to analyze by CT the arterial, venous and biliary systems. The other three cadavers were injected with a mixture of epoxy resin in the aorta, gallbladder and hepatic veins, separately. After the corrosion and washing process, hepatic vascular and biliary casts were obtained. The images obtained by CT showed the vascular and biliary system using a soft tissue window. For the identification of vascular and biliary structures, the 3D prints together with the 3D reconstructions were analyzed, and the results were compared with the casts obtained with epoxy resin. Each of the arterial, venous and biliary branches associated with each of the liver lobes were identified with the help of the printings. In conclusion, the creation of 3D prototypes of nonpathological feline hepatic parenchyma can be used in the veterinary clinic as a basis for the detection of pathological problems in addition to obtaining future pathological hepatic 3D models.

Targeted neonatal echocardiography and lung ultrasound in preterm infants with chronic lung disease with and without pulmonary hypertension, screened using a standardized algorithm.

Introduction: Increased recognition of the development of chronic pulmonary hypertension (cPH) in preterm infants with chronic lung disease (CLD) has prompted enhanced monitoring for the identification of different phenotypes. Methods: All newborns consulted for oxygen/respiratory support dependency (CLD assessment) from January 2018 to December 2021 were included. TnECHO and LUS screening for cPH-CLD were performed at 36 weeks postmenstrual age. Cases of cPH related to increased pulmonary blood flow (cPH-IPBF) were referred to Pediatric Cardiology. The objective of the study was to identify all cases of cPH (cPH-CLD/IPBF) in the CLD patients screened and to compare outcomes. Following a standardized algorithm, cPH-CLD patients were treated with diuretics; ultrasounds taken before and after treatment were analyzed. Results: Seventy-two patients with CLD were screened. Twenty-two (30%) had cPH-CLD, and nine (12%) had cPH-IPBF. cPH infants underwent more days of mechanical ventilation, were more likely to have retinopathy of prematurity, and showed increased mortality. The LUS pattern observed in the 72 CLD patients consisted of a thickened pleural line and a B-line interstitial heterogeneous pattern; 29% of patients were found to have lung consolidations. After diuretic therapy, step-down in respiratory support occurred in 59% of neonates with cPH-CLD. A decrease in respiratory rate (RR), right ventricular output (RVO), markers of pulmonary vascular resistance (PVR), and B-line pattern was observed. In tissue Doppler imaging, biventricular diastolic function was found to be modified after diuretics. Conclusions: CLD infants with cPH showed increased morbidity and mortality. In cPH-CLD patients, a decrease in RR and step-down in respiratory support was observed after diuretic treatment. Follow-up ultrasound showed a decrease in RVO, markers of PVR, and B-lines.

A Modified Sonographic Algorithm for Image Acquisition in Life-Threatening Emergencies in the Critically Ill Newborn.

The use of routine point-of-care ultrasound (POCUS) is increasing in neonatal intensive care units (NICUs), with several centers advocating for 24 h equipment availability. In 2018, the sonographic algorithm for life-threatening emergencies (SAFE) protocol was published, which allows the assessment of neonates with sudden decompensation to identify abnormal contractility, tamponade, pneumothorax, and pleural effusion. In the study unit (with a consulting neonatal hemodynamics and POCUS service), the algorithm was adapted by including consolidated core steps to support at-risk newborns, aiding clinicians in managing cardiac arrest, and adding views to verify correct intubation. This paper presents a protocol that can be applied in the NICU and the delivery room (DR) in relation to three scenarios: cardiac arrest, hemodynamic deterioration, or respiratory decompensation. This protocol can be performed with a state-of-the-art ultrasound machine or an affordable handheld device; the image acquisition protocol is carefully detailed. This method was designed to be learned as a general competence to obtain the timely diagnosis of life-threatening scenarios; the method aims to save time but does not represent a substitute for comprehensive and standardized hemodynamic and radiological analyses by a multidisciplinary team, which might not universally be on call but needs to be involved in the process. From January 2019 to July 2022, in our center, 1,045 hemodynamic consultation/POCUS consults were performed with 25 patients requiring the modified SAFE protocol (2.3%), and a total of 19 procedures were performed. In five cases, trained fellows on call resolved life-threatening situations. Clinical examples are provided that show the importance of including this technique in the care of critical newborns.

The role of non-additive gene action on gene expression variation in plant domestication.

BACKGROUND: Plant domestication is a remarkable example of rapid phenotypic transformation of polygenic traits, such as organ size. Evidence from a handful of study cases suggests this transformation is due to gene regulatory changes that result in non-additive phenotypes. Employing data from published genetic crosses, we estimated the role of non-additive gene action in the modulation of transcriptional landscapes in three domesticated plants: maize, sunflower, and chili pepper. Using A. thaliana, we assessed the correlation between gene regulatory network (GRN) connectivity properties, transcript abundance variation, and gene action. Finally, we investigated the propagation of non-additive gene action in GRNs. RESULTS: We compared crosses between domesticated plants and their wild relatives to a set of control crosses that included a pair of subspecies evolving under natural selection and a set of inbred lines evolving under domestication. We found abundance differences on a higher portion of transcripts in crosses between domesticated-wild plants relative to the control crosses. These transcripts showed non-additive gene action more often in crosses of domesticated-wild plants than in our control crosses. This pattern was strong for genes associated with cell cycle and cell fate determination, which control organ size. We found weak but significant negative correlations between the number of targets of trans-acting genes (Out-degree) and both the magnitude of transcript abundance difference a well as the absolute degree of dominance. Likewise, we found that the number of regulators that control a gene's expression (In-degree) is weakly but negatively correlated with the magnitude of transcript abundance differences. We observed that dominant-recessive gene action is highly propagable through GRNs. Finally, we found that transgressive gene action is driven by trans-acting regulators showing additive gene action. CONCLUSIONS: Our study highlights the role of non-additive gene action on modulating domestication-related traits, such as organ size via regulatory divergence. We propose that GRNs are shaped by regulatory changes at genes with modest connectivity, which reduces the effects of antagonistic pleiotropy. Finally, we provide empirical evidence of the propagation of non-additive gene action in GRNs, which suggests a transcriptional epistatic model for the control of polygenic traits, such as organ size.

Historical view of medical Spanish instruction in a medical school at the US-Mexico border region.

With a growing speaking Spanish population in the USA, it is necessary to help meet their healthcare needs. The Paul L. Foster School of Medicine is located in El Paso at the US-Mexico border. The medical Spanish curriculum is required for all medical students and begins on their first day of medical school, with conversational Spanish and medical Spanish through the preclerkship years. One of the key elements to the success of this course is the use of instructors with expertise in language instruction with an emphasis on task-based instruction. In addition to language instruction, this course also emphasizes instruction and experience in the culture of the US-Mexico border region. While taught medical Spanish, students are also prompted to understand when their skills are not adequate for the situation, in which case they need to enlist a skilled translator. Students report that, on a daily basis, they productively use what they learned in this preclerkship curriculum.

Lung Ultrasound Characteristics in Neonates With Positive Real Time Polymerase Chain Reaction for SARS-CoV-2 on a Tertiary Level Referral Hospital in Mexico City.

Introduction: Acute respiratory syndrome secondary to SARS-CoV-2 virus infection has been declared a pandemic since December 2019. On neonates, severe presentations are infrequent but possible. Lung ultrasound (LUS) has been shown to be useful in diagnosing lung involvement and following up patients, giving more information, and reducing exposure compared to traditional examination. Methods: LUS was performed after the diagnosis of SARS-CoV-2 infection with respiratory Real Time Polymerase Chain Reaction RT-PCR with portable equipment protected with a silicone sleeve. If hemodynamic or cardiology consultation was necessary, a prepared complete ultrasound machine was used. Ten regions were explored (anterior superior and inferior, lateral, and posterior superior and inferior, right and left), and a semiquantitative score (LUSS) was calculated. Disease severity was determined with a pediatric modified score. Results: Thirty-eight patients with positive RT-PCR were admitted, 32 (81%) of which underwent LUS. Included patients had heterogenous diagnosis and gestational ages as expected on a referral neonatal intensive care unit (NICU) (median, ICR: 36, 30-38). LUS abnormalities found were B-line interstitial pattern 90%, irregular/interrupted/thick pleural line 88%, compact B-lines 65%, small consolidations (≤5 mm) 34%, and extensive consolidations (≥5 mm) 37%. Consolidations showed posterior predominance (70%). LUSS showed a median difference between levels of disease severity and ventilatory support (Kruskal-Wallis, p = 0.001) and decreased with patient improvement (Wilcoxon signed-rank test p = 0.005). There was a positive correlation between LUSS and FiO2 needed (Spearman r = 0.72, p = 0.01). The most common recommendation to the attending team was pronation (41%) and increase in positive end expiratory pressure (34%). Five patients with comorbidities died. A significant rank difference of LUSS and FiO2 needed between survivors and non-survivors was found (Mann-Whitney U-test, p = 0.005). Conclusion: LUS patterns found were like the ones described in other series (neonatal and pediatrics). Eighty-eight percent of the studies were performed with handheld affordable equipment. While there is no specific pattern, it varies according to gestational age and baseline diagnosis LUS, which were shown to be useful in assessing lung involvement that correlated with the degree of disease severity and respiratory support.

Pathophysiology of Perinatal Asphyxia in Humans and Animal Models.

Perinatal asphyxia is caused by lack of oxygen delivery (hypoxia) to end organs due to an hypoxemic or ischemic insult occurring in temporal proximity to labor (peripartum) or delivery (intrapartum). Hypoxic-ischemic encephalopathy is the clinical manifestation of hypoxic injury to the brain and is usually graded as mild, moderate, or severe. The search for useful biomarkers to precisely predict the severity of lesions in perinatal asphyxia and hypoxic-ischemic encephalopathy (HIE) is a field of increasing interest. As pathophysiology is not fully comprehended, the gold standard for treatment remains an active area of research. Hypothermia has proven to be an effective neuroprotective strategy and has been implemented in clinical routine. Current studies are exploring various add-on therapies, including erythropoietin, xenon, topiramate, melatonin, and stem cells. This review aims to perform an updated integration of the pathophysiological processes after perinatal asphyxia in humans and animal models to allow us to answer some questions and provide an interim update on progress in this field.

Direct targeting of amplified gene loci for proapoptotic anticancer therapy.

Gene amplification drives oncogenesis in a broad spectrum of cancers. A number of drugs have been developed to inhibit the protein products of amplified driver genes, but their clinical efficacy is often hampered by drug resistance. Here, we introduce a therapeutic strategy for targeting cancer-associated gene amplifications by activating the DNA damage response with triplex-forming oligonucleotides (TFOs), which drive the induction of apoptosis in tumors, whereas cells without amplifications process lower levels of DNA damage. Focusing on cancers driven by HER2 amplification, we find that TFOs targeting HER2 induce copy number-dependent DNA double-strand breaks (DSBs) and activate p53-independent apoptosis in HER2-positive cancer cells and human tumor xenografts via a mechanism that is independent of HER2 cellular function. This strategy has demonstrated in vivo efficacy comparable to that of current precision medicines and provided a feasible alternative to combat drug resistance in HER2-positive breast and ovarian cancer models. These findings offer a general strategy for targeting tumors with amplified genomic loci.

Impact of fetal endoscopic tracheal occlusion in fetuses with congenital diaphragmatic hernia and moderate lung hypoplasia.

OBJECTIVE: To assess the effect of Fetal Endoscopic Tracheal Occlusion (FETO) on neonatal survival in fetuses with left congenital diaphragmatic hernia (CDH) and moderate lung hypoplasia. STUDY DESIGN: CDH fetuses with moderate pulmonary hypoplasia (observed/expected lung area to head ratio between 26% and 35%, or between 36% and 45% with liver herniation) were prospectively recruited. Included patients were matched to a control group who were ineligible for FETO. Primary outcomes were survival at 28 days, at discharge, and at 6 months of age, respectively. RESULTS: 58 cases were recruited, 29 treated with FETO and 29 matched controls. Median gestational age (GA) at balloon placement and removal were 29.6 and 33.6 weeks, respectively. FETO group showed significantly lower GA at delivery (35.2 vs. 37.1 weeks, respectively, p < 0.01), higher survival at 28 days (51.7 vs. 24.1%, respectively, p = 0.03), at discharge (48.3 vs. 24.1%, respectively, p = 0.06), and at six months of age (41.4 vs. 24.1%, respectively, p = 0.16), and significantly lower length of ventilatory support (17.8 vs. 32.3 days, p = 0.01) and NICU stay (34.2 vs. 58.3 days, p = <0.01) compared to controls. CONCLUSION: FETO was associated with a non-significant increase in survival and significantly lower neonatal respiratory morbidity among CDH fetuses with moderate lung hypoplasia.

Vulnerability of IDH1-Mutant Cancers to Histone Deacetylase Inhibition via Orthogonal Suppression of DNA Repair.

Exploitation of DNA repair defects has enabled major advances in treating specific cancers. Recent work discovered that the oncometabolite 2-hydroxyglutarate (2-HG), produced by neomorphic isocitrate dehydrogenase 1/2 (IDH1/2) mutations, confers a homology-directed repair (HDR) defect through 2-HG-induced histone hypermethylation masking HDR signaling. Here, we report that IDH1-mutant cancer cells are profoundly sensitive to the histone deacetylase inhibitor (HDACi) vorinostat, by further suppressing the residual HDR in 2-HG-producing cells. Vorinostat downregulates repair factors BRCA1 and RAD51 via disrupted E2F-factor regulation, causing increased DNA double-strand breaks, reduced DNA repair factor foci, and functional HDR deficiency even beyond 2-HG's effects. This results in greater cell death of IDH1-mutant cells and confers synergy with radiation and PARPi, both against cells in culture and patient-derived tumor xenografts. Our work identifies HDACi's utility against IDH1-mutant cancers, and presents IDH1/2 mutations as potential biomarkers to guide trials testing HDACi in gliomas and other malignancies. IMPLICATIONS: IDH1-mutant cells show profound vulnerability to HDACi treatment, alone and with PARPi and radiation, via HDR suppression, presenting IDH1/2 mutations as biomarkers for HDACi use in gliomas and other malignancies.

Caffeine: cardiorespiratory effects and tissue protection in animal models.

The aim of this review is to analyze the cardiorespiratory and tissue-protective effects of caffeine in animal models. Peer-reviewed literature published between 1975 and 2021 was retrieved from CAB Abstracts, PubMed, ISI Web of Knowledge, and Scopus. Extracted data were analyzed to address the mechanism of action of caffeine on cardiorespiratory parameters (heart rate and rhythm), vasopressor effects, and some indices of respiratory function; we close this review by discussing the current debate on the research carried out on the effects of caffeine on tissue protection. Adenosine acts through specific receptors and is a negative inotropic and chronotropic agent. Blockage of its cardiac receptors can cause tachycardia (with arrhythmogenic potential) due to the intense activity of ß1 receptors. In terms of tissue protection, caffeine inhibits hyperoxia-induced pulmonary inflammation by decreasing proinflammatory cytokine expression in animal models. The protection that caffeine provides to tissues is not limited to the CNS, as studies have demonstrated that it generates attenuation of inflammatory effects in pulmonary tissue. It inhibits the effects of some pro-inflammatory cytokines and prevents functional and structural changes.

Multicentre prospective observational study exploring the predictive value of functional echocardiographic indices for early identification of preterm neonates at risk of developing chronic pulmonary hypertension secondary to chronic neonatal lung disease.

INTRODUCTION: Although chronic pulmonary hypertension (cPH) secondary to chronic neonatal lung disease is associated with increased mortality and respiratory and neurodevelopmental morbidities, late diagnosis (typically ≥36 weeks postmenstrual age, PMA) and the use of qualitative echocardiographic diagnostic criterion (flat interventricular septum in systole) remain significant limitations in clinical care. Our objective in this study is to evaluate the utility of relevant quantitative echocardiographic indices to identify cPH in preterm neonates, early in postnatal course and to develop a diagnostic test based on the best combination of markers. METHODS AND ANALYSIS: In this ongoing international prospective multicentre observational diagnostic accuracy study, we aim to recruit 350 neonates born <27 weeks PMA and/or birth weight <1000 g and perform echocardiograms in the third week of age and at 32 weeks PMA (early diagnostic assessments, EDA) in addition to the standard diagnostic assessment (SDA) for cPH at 36 weeks PMA. Predefined echocardiographic markers under investigation will be measured at each EDA and examined to create a scoring system to identify neonates who subsequently meet the primary outcome of cPH/death at SDA. Diagnostic test characteristics will be defined for each EDA. Pulmonary artery acceleration time and tricuspid annular plane systolic excursion are the primary markers of interest. ETHICS AND DISSEMINATION: Ethics approval has been received by the Mount Sinai Hospital Research Ethics Board (REB) (#16-0111-E), Sunnybrook Health Sciences Centre REB (#228-2016), NHS Health Research Authority (IRAS 266498), University of Iowa Human Subjects Office/Institutional Review Board (201903736), Rotunda Hospital Research and Ethics Committee (REC-2019-008), and UBC Children's and Women's REB (H19-02738), and is under review at Boston Children's Hospital Institutional Review Board. Study results will be disseminated to participating families in lay format, presented to the scientific community at paediatric and critical care conferences and published in relevant peer-reviewed journals. TRAIL REGISTRATION NUMBER: NCT04402645.

Can topical epinephrine application to the papilla prevent pancreatitis after endoscopic retrograde cholangiopancreatography? Results from a double blind, multicentre, placebo controlled, randomised clinical trial.

BACKGROUND AND STUDY AIMS: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is a complication associated with important morbidity, occasional mortality and high costs. Preventive strategies are suboptimal as PEP continues to affect 4% to 9% of patients. Spraying epinephrine on the papilla may decrease oedema and prevent PEP. This study aimed to compare rectal indomethacin plus epinephrine (EI) versus rectal indomethacin plus sterile water (WI) for the prevention of PEP. PATIENTS AND METHODS: This multicentre randomised controlled trial included patients aged >18 years with an indication for ERCP and naive major papilla. All patients received 100 mg of rectal indomethacin and 10 mL of sterile water or a 1:10 000 epinephrine dilution. Patients were asked about PEP symptoms via telephone 24 hours and 7 days after the procedure. The trial was stopped half way through after a new publication reported an increased incidence of PEP among patients receiving epinephrine. RESULTS: Of the 3602 patients deemed eligible, 3054 were excluded after screening. The remaining 548 patients were randomised to EI group (n=275) or WI group (n=273). The EI and WI groups had similar baseline characteristics. Patients in the EI group had a similar incidence of PEP to those in the WI group (3.6% (10/275) vs 5.12% (14/273), p=0.41). Pancreatic duct guidewire insertion was identified as a risk factor for PEP (OR 4.38, 95% CI (1.44 to 13.29), p=0.009). CONCLUSION: Spraying epinephrine on the papilla was no more effective than rectal indomethacin alone for the prevention of PEP. TRIAL REGISTRATION NUMBER: This study was registered with ClinicalTrials.gov (NCT02959112).