Sitravatinib combined with PD-1 blockade enhances cytotoxic T-cell infiltration by M2 to M1 tumor macrophage repolarization in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a leading cause of cancer-related mortality. Sitravatinib is a novel multi-gene tyrosine kinase inhibitor (TKI) that targets tumor-associated macrophage (TAM) receptors, VEGF, PDGF and c-Kit. Currently, sitravatinib is actively being studied in clinical trials across solid tumors and other TKIs have shown efficacy in combination with immune checkpoint inhibitors (ICI) in cancer models. In this study, we investigated the anti-tumor activity of sitravatinib alone and in combination with PD-1 blockade in an EAC rat model. Treatment response was evaluated by mortality, pre- and post-treatment MRI, gene expression, immunofluorescence and immunohistochemistry. Our results demonstrated adequate safety and significant tumor shrinkage in animals treated with sitravatinib, and more profoundly, sitravatinib and PD-1 inhibitor, AUNP-12 (P < 0.01). Suppression of TAM receptors resulted in increased gene expression of pro-inflammatory cytokines and decreased expression of anti-inflammatory cytokines, enhanced infiltration of CD8+ T cells, and M2 to M1 macrophage phenotype repolarization in the tumor microenvironment of treated animals (P < 0.01). Moreover, endpoint immunohistochemistry staining corroborated the anti-tumor activity by downregulation of Ki67 and upregulation of Caspase-3 in the treated animals. Additionally, pretreatment gene expression of TAM receptors and PD-L1 were significantly higher in major responders compared with the non-responders, in animals that received sitravatinib and AUNP-12 (P < 0.02), confirming that TAM suppression enhances the efficacy of PD-1 blockade. In conclusion, this study proposes a promising immunomodulatory strategy using a multi-gene TKI to overcome developed resistance to an ICI in EAC, establishing rationale for future clinical development.

Targeting interleukin-6 as a treatment approach for peritoneal carcinomatosis.

Peritoneal carcinomatosis (PC) is a complex manifestation of abdominal cancers, with a poor prognosis and limited treatment options. Recent work identifying high concentrations of the cytokine interleukin-6 (IL-6) and its soluble receptor (sIL-6-Rα) in the peritoneal cavity of patients with PC has highlighted this pathway as an emerging potential therapeutic target. This review article provides a comprehensive overview of the current understanding of the potential role of IL-6 in the development and progression of PC. We discuss mechansims by which the IL-6 pathway may contribute to peritoneal tumor dissemination, mesothelial adhesion and invasion, stromal invasion and proliferation, and immune response modulation. Finally, we review the prospects for targeting the IL-6 pathway in the treatment of PC, focusing on common sites of origin, including ovarian, gastric, pancreatic, colorectal and appendiceal cancer, and mesothelioma.

Characterizing the Immune Environment in Peritoneal Carcinomatosis: Insights for Novel Immunotherapy Strategies.

BACKGROUND OR PURPOSE: Carcinomatosis, a distinct pattern of metastatic cancer in the peritoneal cavity, poses challenges for treatment and has limited therapeutic options. Understanding the immune environment of peritoneal surface malignancies is crucial for developing effective immunotherapeutic approaches. This study characterizes soluble immune mediators in the peritoneal fluid of patients with and without carcinomatosis to identify targets for novel treatment strategies. PATIENTS AND METHODS: Serum and peritoneal fluid samples were collected from surgical patients, and a multianalyte analysis was performed using the Luminex platform. Patient characteristics, tumor sites, and sample collection details were recorded. Soluble immune mediator levels were measured and compared between peritoneal fluid and serum samples and among clinical subgroups. Statistical analysis was conducted to assess differences in analyte concentrations and correlations between samples. RESULTS: There were 39 patients included in the study, with varying surgical indications. Significant differences were observed in soluble immune mediator levels between peritoneal fluid and serum, with peritoneal fluid exhibiting lower concentrations. Carcinomatosis was associated with elevated levels of proinflammatory mediators, including IL-6 and IL-8, while adaptive immune response markers were low in peritoneal fluid. CONCLUSIONS: The peritoneal immune microenvironment in carcinomatosis favors innate immunity, presenting a challenging environment for effective antitumor response. High levels of proinflammatory mediators suggest potential targets for intervention, such as the IL-6 axis, FGF2, IL-8, and CCL2; these could be explored as potential mitigators of malignant ascites and enhance anti-tumor immune responses. These findings provide valuable insights for developing immunotherapy strategies and improving outcomes in patients with peritoneal carcinomatosis.

Transition of care in CHD: a single-centre experience: an enigma remains.

Transition of care refers to the continuity of health care during the movement from one healthcare setting to another as care needs change during a chronic illness. We sought to describe social, demographic, and clinical factors related to successful transition in a tertiary urban care facility in patients with CHD. Patients were identified utilising the electronic medical record. Inclusion criteria were patients with CHDs aged ≥15 years seen in the paediatric cardiology clinic between 2013 and 2014. Deceased patients were excluded. Clinical and demographic variables were collected. Patient charts were reviewed in 2015-2021 to determine if included patients were a) still in paediatric cardiology care, b) transitioned to adult cardiology/adult CHD, or were c) lost to follow-up. A total of 322 patients, 53% male (N:172), 46% female (N:149) were included. Majority had moderately complex lesions (N:132, 41%). Most patients had public insurance (N:172, 53%), followed by private insurance (N:67, 21%), while 15% of patients (N:47) were uninsured. Only 49% (N = 159) had successful transition, while 22% (N = 70) continued in care with paediatric cardiology, and 29% (N = 93) were lost to follow-up. Severity of CHD (p = 0.0002), having healthcare insurance (p < .0001), presence of a defibrillator (p = 0.0028), and frequency of paediatric cardiology visits (p = 0.0005) were significantly associated with successful transition. Most patients lost to follow-up (N:42,62%) were either uninsured or had public insurance. Lack of successful transition is multifactorial, and further efforts are needed to improve the process in patients with CHD.

Design of a multi-institutional neurocognitive discovery study in adult congenital heart disease (MINDS-ACHD).

BACKGROUND: Neurocognitive dysfunction (NCD) is a common comorbidity among children with congenital heart disease (CHD). However, it is unclear how underlying CHD and its sequelae combine with genetics and acquired cardiovascular and neurological disease to impact NCD and outcomes across the lifespan in adults with CHD. METHODS: The Multi-Institutional Neurocognitive Discovery Study in Adults with Congenital Heart Disease (MINDS-ACHD) is a partnership between the Pediatric Heart Network (PHN) and the Adult Alliance for Research in Congenital Cardiology (AARCC) that examines objective and subjective neurocognitive function and genetics in young ACHD. This multicenter cross-sectional pilot study is enrolling 500 young adults between 18 and 30 years with moderate or severe complexity CHD at 14 centers in North America. Enrollment includes 4 groups (125 participants each): (1) d-looped Transposition of the Great Arteries (d-TGA); (2) Tetralogy of Fallot (TOF); (3) single ventricle (SV) physiology; and (4) "other moderately or severely complex CHD." Participants complete the standardized tests from the NIH Toolbox Cognitive Battery, the NeuroQoL, the Hospital Anxiety and Depression Scale, and the PROMIS Global QoL measure. Clinical and demographic variables are collected by interview and medical record review, and an optional biospecimen is collected for genetic analysis. Due to the COVID-19 pandemic, participation may be done remotely. Tests are reviewed by a Neurocognitive Core Laboratory. CONCLUSIONS: MINDS-ACHD is the largest study to date characterizing NCD in young adults with moderate or severely complex CHD in North America. Its results will provide valuable data to inform screening and management strategies for NCD in ACHD and improve lifelong care.

Impact of Obesity on Ventriculo-Arterial Interaction in Patients After Coarctation of Aorta repair.

Survival of patients after repair of coarctation of Aorta (CoA) has improved significantly over the decades, but patients have decreased life expectancy as compared to the general population. This has been attributed to increased hypertension, cerebrovascular disease, and coronary artery disease. There has also been an increasing concern of overweight and obesity in patients with adult congenital heart disease. While there have been studies looking at the impact of long-term hypertension on myocardial performance and outcomes in this population, this study aims to assess the impact of obesity in these patients on their myocardial performance. Ventriculo-arterial coupling is used as a measure of myocardial performance which reflects the interaction between cardiac contractility and arterial elastance. Patients after CoA repair are known to have hypertension affecting the arterial elastance. Obesity affects cardiac contractility as well. This study demonstrated that in a group of young patients after CoA repair, body mass index (BMI) has a relationship with left ventricular (LV) contractility and myocardial performance. This relationship was independent of blood pressure. BMI itself was not seen to affect the determinants of diastolic function in this study, suggesting that LV contractility may be affected before one can notice a change in the diastolic function secondary to BMI.

Challenges in Accurate Diagnosis of HCC in FALD: A Case Series.

Patients with single ventricle cardiac disease palliated with Fontan procedures inevitably develop Fontan-Associated Liver Disease (FALD), which poses a significant risk for hepatocellular carcinoma (HCC). Standard imaging criteria for the diagnosis of cirrhosis are not reliable due to parenchymal heterogeneity of FALD. We present 6 cases to demonstrate our center's experience and the challenges in diagnosing HCC within this patient population.

CSF-1R inhibitor, pexidartinib, sensitizes esophageal adenocarcinoma to PD-1 immune checkpoint blockade in a rat model.

Esophageal adenocarcinoma (EAC) is a leading cause of cancer deaths. Pexidartinib, a multi-gene tyrosine kinase inhibitor, through targeting colony-stimulating factor 1 (CSF-1) receptor (CSF-1R), down modulates macrophage-mediated pro-survival tumor signaling. Previously, CSF-1R inhibitors have successfully shown to enhance antitumor activity of PD-1/PD-L1 inhibitors by suppressing tumor immune evasion, in solid tumors. In this study, we investigated the antitumor activity of pexidartinib alone or in combination with blockade of PD-1 in a de novo EAC rat model. Here, we showed limited toxicity with significant tumor shrinkage in pexidartinib treated animals compared to controls, single agent and in combination with a PD-1 inhibitor, AUNP-12. Suppression of CSF-1/CSF-1R axis resulted in enhanced infiltration of CD3 + CD8 + T cells with reduced M2 macrophage polarization, in the tumor microenvironment (TME). Endpoint tissue gene expression in pexidartinib treated animals demonstrated upregulation of BAX, Cas3, TNFα, IFNγ and IL6 and downregulation of Ki67, IL13, IL10, TGFß and Arg1 (P < 0.05). Additionally, among the pexidartinib treated animals responders compared to nonresponders demonstrated a significant upregulation of pretreatment CSF-1 gene, confirming that tumor-associated macrophage suppression directly translates to clinical benefit. Moreover, a posttreatment serum cytokine assay exhibited similar systemic trends as the gene expression in the TME, depicting increases in proinflammatory cytokines and decreases in anti-inflammatory cytokines. In conclusion, our study established a promising combinatorial strategy using a CSF-1R inhibitor to overcome resistance to PD-1/PD-L1 axis blockade in an EAC model, providing the rationale for future clinical strategies.

A microRNA-based liquid biopsy signature for the early detection of esophageal squamous cell carcinoma: a retrospective, prospective and multicenter study.

BACKGROUND: Currently, there is no clinically relevant non-invasive biomarker for early detection of esophageal squamous cell carcinoma (ESCC). Herein, we established and evaluated a circulating microRNA (miRNA)-based signature for the early detection of ESCC using a systematic genome-wide miRNA expression profiling analysis. METHODS: We performed miRNA candidate discovery using three ESCC tissue miRNA datasets (n = 108, 238, and 216) and the candidate miRNAs were confirmed in tissue specimens (n = 64) by qRT-PCR. Using a serum training cohort (n = 408), we conducted multivariate logistic regression analysis to develop an ESCC circulating miRNA signature and the signature was subsequently validated in two independent retrospective and two prospective cohorts. RESULTS: We identified eighteen initial miRNA candidates from three miRNA expression datasets (n = 108, 238, and 216) and subsequently validated their expression in ESCC tissues. We thereafter confirmed the overexpression of 8 miRNAs (miR-103, miR-106b, miR-151, miR-17, miR-181a, miR-21, miR-25, and miR-93) in serum specimens. Using a serum training cohort, we developed a circulating miRNA signature (AUC:0.83 [95%CI:0.79-0.87]) and the diagnostic performance of the miRNA signature was confirmed in two independent validation cohorts (n = 126, AUC:0.80 [95%CI:0.69-0.91]; and n = 165, AUC:0.89 [95%CI:0.83-0.94]). Finally, we demonstrated the diagnostic performance of the 8-miRNA signature in two prospective cohorts (n = 185, AUC:0.92, [95%CI:0.87-0.96]); and (n = 188, AUC:0.93, [95%CI:0.88-0.97]). Importantly, the 8-miRNA signature was superior to current clinical serological markers in discriminating early stage ESCC patients from healthy controls (p < 0.001). CONCLUSIONS: We have developed a novel and robust circulating miRNA-based signature for early detection of ESCC, which was successfully validated in multiple retrospective and prospective multinational, multicenter cohorts.

A blood-based circulating microbial metagenomic panel for early diagnosis and prognosis of oesophageal adenocarcinoma.

BACKGROUND: Emerging evidence indicates the potential clinical significance of specific microbial signatures as diagnostic and prognostic biomarkers, in multiple cancers. However, to date, no studies have systematically interrogated circulating metagenome profiling in oesophageal adenocarcinoma (EAC) patients, particularly as novel non-invasive, early detection, surveillance and prognostic classifiers. METHODS: Metagenome sequencing was performed on 81 serum specimens collected across EAC spectrum, with sequencing reads classified using Bracken and MetaPhlAn3. Followed by the Linear Discriminant Analysis effect size (LEfSe) method to identify microbial profiles between groups. Logistic regression and Kaplan-Meier analyses were used to build classifiers. RESULTS: A significant loss of alpha and beta diversity was identified in serum specimens from EAC patients. We observed a shift in microbial taxa between each group-at the phylum, genus, and species level-with Lactobacillus sakei as the most prominent species in gastroesophageal reflux (GERD) vs other patient groups. Interestingly, LEfSe analysis identified a complete loss of Lactobacillus (L. Sakei and L. Curvatus), Collinsella stercoris and Bacteroides stercoris but conversely a significant increase in Escherichia coli in patients with EAC. Finally, we developed a metagenome panel that discriminated EAC from GERD patients with an AUC value of 0.89 (95% CI: 0.78-0.95; P < 0.001) and this panel in conjunction with the TNM stage was a robust predictor of overall survival (≥24 months; AUC = 0.84 (95% CI: 0.66-0.92; P = 0.006)). CONCLUSION: This study firstly describes unique blood-based microbial profiles in patients across EAC carcinogenesis, that are further utilised to establish a novel circulating diagnostic and prognostic metagenomic signature for EAC. TRANSLATIONAL RELEVANCE: Accumulating data indicates the clinical relevance of specific microbial signatures as diagnostic and prognostic biomarkers, in multiple cancers. However, to date, no studies have systematically interrogated circulating metagenome profiling in patients with oesophageal adenocarcinoma (EAC). Herein, we performed metagenome sequencing in serum specimens from EAC patients 81 collected across EAC spectrum and observed a significant loss of alpha and beta diversity, with a shift in microbial taxa between each group-at the phylum, genus, and species level-with Lactobacillus sakei as the most prominent species in gastroesophageal reflux (GERD) vs other patient groups. Interestingly, LEfSe analysis identified a complete loss of Lactobacillus (L. Sakei and L. Curvatus), Collinsella stercoris and Bacteroides stercoris but conversely a significant increase in Escherichia coli in patients with EAC. Finally, we developed a metagenome panel that discriminated EAC from GERD patients with an AUC value of 0.89 and this panel, in conjunction with the TNM stage, was a robust predictor of overall survival. This study for the first time describes unique blood-based microbial profiles in patients across EAC carcinogenesis, that are further utilised to establish a novel circulating diagnostic and prognostic metagenomic signature for EAC.

Use of Adhesive Tape to Facilitate Optimal Mask Positioning and Use in the Emergency Department: A Randomized Controlled Trial.

STUDY HYPOTHESIS: We hypothesize that placing a piece of surgical tape at the bridge of the nose over the mask will improve proper mask use among emergency department patients by creating a physical deterrent to mask removal. METHODS: This study was an open-label single-center randomized controlled trial of a simple intervention to improve mask use performed at Eskenazi Hospital between April 2020 and October 2020. We permitted participants to either use their own mask or the surgical/cloth mask that we provided. We then randomized the participants to either the control group (no tape over the mask/nose) or to the intervention group (tape placed over the face mask at the bridge of the nose). The primary outcome of this study was the frequency at which participants correctly wore their masks upon reevaluation at 60 minutes. A subgroup analysis based on the mask type compared adherence in those with a hospital-provided mask versus in those with a patient-supplied mask. RESULTS: We enrolled 123 participants in this trial. At 60 minutes, 100% of the intervention group participants were correctly wearing their masks versus 69% of control participants (absolute risk reduction, 31%; 95% CI, 19% to 43%; number needed to treat=3.2 patients). Subjects who were observed wearing their masks incorrectly exhibited some combination of either their mask removed or their nose and/or mouth exposed. Hospital-provided masks were not more likely to be worn correctly (odds ratio, 3.4; 95% CI, 0.9 to 12.3). CONCLUSION: Applying a piece of tape to a mask on the bridge of the nose affords a simple, low-cost, and low-risk solution that resulted in 100% of patients wearing their masks correctly at a 60-minute reevaluation.

Protonation and orientation: a computational approach to cocaine diffusion through a model membrane.

We study the diffusion of cocaine through a DMPC lipid bilayer as an example of a protonable, amphiphilic molecule passing a biological membrane. Using classical molecular dynamics simulations, the free energy surfaces are computed applying the umbrella sampling technique for the protonated and the neutral molecule. For the combined surface, we numerically solve the diffusion equation at constant flow and for time-dependent concentrations. We find a potential of mean force dominated by a barrier of 3.5 kcal mol-1 within the membrane, and a pH-dependent entry and exit barrier of 2.0 kcal mol-1 and 4.1 kcal mol-1, respectively. This behaviour can be rationalized chemically by the amphiphilic nature of the molecule and the change of its protonation state while passing the membrane. Diffusion through the barriers is 3.5 times slower than along the membrane, and the typical time scale of passage amounts to 0.1 ms. We discuss biochemical and medical implications of our findings, and comment on the mechanism of the drug passing the blood-brain barrier.

Bicuspid Aortic Valves: an Up-to-Date Review on Genetics, Natural History, and Management.

PURPOSE OF REVIEW: Bicuspid aortic valve (BAV) is the most common congenital cardiac abnormality. It has a wide spectrum of clinical manifestations including aortic regurgitation (AR), aortic stenosis, and an associated aortopathy with a small but increased risk of aortic dissection. This review describes current knowledge of BAV, from anatomy and genetics to a discussion of multifaceted strategies utilized in the management of this unique patient population. This review will also highlight critical knowledge gaps in areas of basic and clinical research to enhance further understanding of this clinical entity. RECENT FINDINGS: The current knowledge regarding pathophysiologic mechanisms, screening, and surveillance guidelines for BAV and the associated aortopathy is discussed. We also discuss current management techniques for aortic valve repair versus replacement, indications for aortic surgery (root or ascending aorta), and the emergence of the Ross procedure as a viable management option not only in children, but also in adolescents and adults. The varied clinical phenotype of the BAV, resulting in its specific complex hemodynamic interactions, renders it an entity which is separate and distinct from the tricuspid aortic valve pathologies. While various aortic histopathologic and protein alterations in BAV patients have been described, it remains unclear if these changes are causal or the result of hemodynamic alterations imposed by sheer stress on the intrinsically dysfunctional BAV. Medical management for patients with BAV with AS, AI, or dilated aortic roots/ascending aortas remains challenging and needs further investigation. More than 50% of patients with BAV will undergo AVR during their lifetime, and more than 25% of patients with BAV undergo aortic surgery performed for dilation of the aortic root or ascending aorta, often concurrently with AVR. The search for the ultimate genetic or epigenetic cause of the different bicuspid phenotypes will ultimately be facilitated by the next-generation sequencing tools that allow for study of large populations at low cost. Improvements in diagnostic and stratification criteria to accurately risk assess BAV patients are critical to this process.

Optical Monitoring of Breathing Patterns and Tissue Oxygenation: A Potential Application in COVID-19 Screening and Monitoring.

The worldwide outbreak of the novel Coronavirus (COVID-19) has highlighted the need for a screening and monitoring system for infectious respiratory diseases in the acute and chronic phase. The purpose of this study was to examine the feasibility of using a wearable near-infrared spectroscopy (NIRS) sensor to collect respiratory signals and distinguish between normal and simulated pathological breathing. Twenty-one healthy adults participated in an experiment that examined five separate breathing conditions. Respiratory signals were collected with a continuous-wave NIRS sensor (PortaLite, Artinis Medical Systems) affixed over the sternal manubrium. Following a three-minute baseline, participants began five minutes of imposed difficult breathing using a respiratory trainer. After a five minute recovery period, participants began five minutes of imposed rapid and shallow breathing. The study concluded with five additional minutes of regular breathing. NIRS signals were analyzed using a machine learning model to distinguish between normal and simulated pathological breathing. Three features: breathing interval, breathing depth, and O2Hb signal amplitude were extracted from the NIRS data and, when used together, resulted in a weighted average accuracy of 0.87. This study demonstrated that a wearable NIRS sensor can monitor respiratory patterns continuously and non-invasively and we identified three respiratory features that can distinguish between normal and simulated pathological breathing.

Fontan-Associated Liver Disease: Screening, Management, and Transplant Considerations.

Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An estimated global population of 70 000 patients have undergone the Fontan procedure and are alive today, most of whom are <25 years of age. Several unexpected consequences of the Fontan circulation include Fontan-associated liver disease. Surveillance biopsies have demonstrated that virtually 100% of these patients develop clinically silent fibrosis by adolescence. As they mature, there are increasing reports of combined heart-liver transplantation resulting from advanced liver disease, including bridging fibrosis, cirrhosis, and hepatocellular carcinoma, in this population. In the absence of a transplantation option, these young patients face a poor quality of life and overall survival. Acknowledging that there are no consensus guidelines for diagnosing and monitoring Fontan-associated liver disease or when to consider heart transplantation versus combined heart-liver transplantation in these patients, a multidisciplinary working group reviewed the literature surrounding Fontan-associated liver disease, with a specific focus on considerations for transplantation.

Access to cardiac surgery centers for cardiac and non-cardiac hospitalizations in adolescents and adults with congenital heart defects- a descriptive case series study.

BACKGROUND: Individuals with congenital heart defects (CHDs) are recommended to receive all inpatient cardiac and noncardiac care at facilities that can offer specialized care. We describe geographic accessibility to such centers in New York State and determine several factors associated with receiving care there. METHODS: We used inpatient hospitalization data from the Statewide Planning and Research Cooperative System (SPARCS) in New York State 2008-2013. In the absence of specific adult CHD care center designations during our study period, we identified pediatric/adult and adult-only cardiac surgery centers through the Cardiac Surgery Reporting System to estimate age-based specialized care. We calculated one-way drive and public transit time (in minutes) from residential address to centers using R gmapsdistance package and the Google Maps Distance Application Programming Interface (API). We calculated prevalence ratios using modified Poisson regression with model-based standard errors, fit with generalized estimating equations clustered at the hospital level and subclustered at the individual level. RESULTS: Individuals with CHDs were more likely to seek care at pediatric/adult or adult-only cardiac surgery centers if they had severe CHDs, private health insurance, higher severity of illness at encounter, a surgical procedure, cardiac encounter, and shorter drive time. These findings can be used to increase care receipt (especially for noncardiac care) at pediatric/adult or adult-only cardiac surgery centers, identify areas with limited access, and reduce disparities in access to specialized care among this high-risk population.

Measurement of outflow resistance imposed by magnetic sphincter augmentation: defining normal values and clinical implication.

INTRODUCTION: No manometric criteria have been defined to select patients for magnetic sphincter augmentation (MSA). The first step to establish such criteria is to measure the outflow resistance at esophagogastric junction (EGJ) imposed by MSA. This resistance needs to be overcome by the esophageal contraction in order for the esophagus to empty and to avoid postoperative dysphagia. This study was designed to measure the outflow resistance caused by MSA in patients free of postoperative dysphagia. METHODS: Records of the patients who underwent MSA in our institution were reviewed. A group of MSA patients with excellent functional outcome, who were free of clinically significant postoperative dysphagia, were selected. These patients then underwent high-resolution impedance manometry (HRIM) at a target date of 1 year after surgery. The outflow resistance was measured by the esophageal intrabolus pressure (iBP) recorded 2 cm proximal to the lower esophageal sphincter (LES). RESULTS: The study population consisted of 43 patients. HRIM was performed at mean of 20.4 (10.4) months after surgery. The mean (SD) amplitude of the iBP was 13.5 (4.3) before surgery and increased to 19.1 (5.6) after MSA (p < 0.0001). Patients with a smaller size LINX device (≤ 14 beads) had a similar iBP when compared to those with a larger device (> 15 beads) [19.7 (4.5) vs. 18.4 (5.9), p = 0.35]. There was a significant correlation between the iBP and % incomplete bolus clearance [Spearman R: 0.44 (95% CI 0.15-0.66), p = 0.0032]. The 95th percentile value for iBP after MSA was 30.4 mmHg. CONCLUSION: The EGJ outflow resistance measured by iBP is increased after MSA. The upper limit of normal for iBP is 30 mmHg in this cohort of patients who were free of dysphagia after MSA. This degree of resistance needs to be overcome by distal esophageal contraction and will likely be requisite to prevent persistent postoperative dysphagia.

Visual Function in Eyes with Intermediate AMD with and without Retinal Pigment Abnormalities.

SIGNIFICANCE: In intermediate AMD, a simple, clinically feasible vision test of sensitivity to radial deformation is significantly more impaired in eyes with hyperpigmentation than in eyes with large drusen but normal retinal pigmentation, consistent with the former's increased risk of progression to advanced AMD. This ongoing longitudinal study will determine whether this vision measure is predictive of progression to advanced AMD. PURPOSE: This study aimed to determine whether simple, clinically feasible psychophysical measures distinguish between two levels of intermediate AMD that differ in their risk of progression to advanced AMD: eyes with large macular drusen and retinal pigment abnormalities versus eyes with large macular drusen without pigment abnormalities. Abnormal pigmentation in the presence of large drusen is associated with a higher risk of development of advanced AMD. METHODS: Each eye of 39 individuals with the same form of intermediate AMD in both eyes was tested monocularly on a battery of vision tests. The measures (photopic optotype contrast sensitivity, discrimination of desaturated colors, and sensitivity to radial deformation [shape discrimination hyperacuity]) were compared for both dominant and nondominant eyes. ANOVA with eye (dominant or nondominant) as a within-subject factor and retinal status (pigmentary abnormalities present or absent from the macula) as a between-subject factor was used to determine statistical significance. RESULTS: Sensitivity to radial deformation was significantly reduced in eyes with large drusen and pigment changes compared with eyes with large drusen and normal retinal pigmentation (-0.40 ± 0.04 vs. -0.61 ± 0.02, respectively; F = 13.31, P = .001). CONCLUSIONS: In the presence of large macular drusen, performance on a shape discrimination task is related to the presence versus absence of abnormal retinal pigmentation, being poorer in the higher-risk group, supportive of the measure's potential to predict progression to advanced AMD.

Medical Therapy for Systemic Right Ventricles: A Systematic Review (Part 1) for the 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

Patients with systemic morphological right ventricles (RVs), including congenitally corrected transposition of the great arteries and dextro-transposition of the great arteries with a Mustard or Senning atrial baffle repair, have a high likelihood of developing systemic ventricular dysfunction. Unfortunately, there are a limited number of clinical studies on the efficacy of medical therapy for systemic RV dysfunction. We performed a systematic review and meta-analysis to assess the effect of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), beta blockers, and aldosterone antagonists in adults with systemic RVs. The inclusion criteria included age ≥18 years, systemic RVs, and at least 3 months of treatment with ACE inhibitor, ARB, beta blocker, or aldosterone antagonist. The outcomes included RV end-diastolic and end-systolic dimensions, RV ejection fraction, functional class, and exercise capacity. EMBASE, PubMed, and Cochrane databases were searched. The selected data were pooled and analyzed with the DerSimonian-Laird random-effects meta-analysis model. Between-study heterogeneity was assessed with Cochran's Q test. A Bayesian meta-analysis model was also used in the event that heterogeneity was low. Bias assessment was performed with the Newcastle-Ottawa Scale and Cochrane Risk of Bias Tool, and statistical risk of bias was assessed with Begg and Mazumdar's test and Egger's test. Six studies met the inclusion criteria, contributing a total of 187 patients; treatment with beta blocker was the intervention that could not be analyzed because of the small number of patients and diversity of outcomes reported. After at least 3 months of treatment with ACE inhibitors, ARBs, or aldosterone antagonists, there was no statistically significant change in mean ejection fraction, ventricular dimensions, or peak ventilatory equivalent of oxygen. The methodological quality of the majority of included studies was low, mainly because of a lack of a randomized and controlled design, small sample size, and incomplete follow-up. In conclusion, pooled results across the limited available studies did not provide conclusive evidence with regard to a beneficial effect of medical therapy in adults with systemic RV dysfunction. Randomized controlled trials or comparative-effectiveness studies that are sufficiently powered to demonstrate effect are needed to elucidate the efficacy of ACE inhibitors, ARBs, beta blockers, and aldosterone antagonists in patients with systemic RVs.

Cardiovascular Risk Reduction in High-Risk Pediatric Patients: A Scientific Statement From the American Heart Association.

This scientific statement presents considerations for clinical management regarding the assessment and risk reduction of select pediatric populations at high risk for premature cardiovascular disease, including acquired arteriosclerosis or atherosclerosis. For each topic, the evidence for accelerated acquired coronary artery disease and stroke in childhood and adolescence and the evidence for benefit of interventions in youth will be reviewed. Children and adolescents may be at higher risk for cardiovascular disease because of significant atherosclerotic or arteriosclerotic risk factors, high-risk conditions that promote atherosclerosis, or coronary artery or other cardiac or vascular abnormalities that make the individual more vulnerable to the adverse effects of traditional cardiovascular risk factors. Existing scientific statements and guidelines will be referenced when applicable, and suggestions for risk identification and reduction specific to each setting will be described. This statement is directed toward pediatric cardiologists, primary care providers, and subspecialists who provide clinical care for these young patients. The focus will be on management and justification for management, minimizing information on pathophysiology and epidemiology.