Search

Objective To apply the International Ovarian Tumor Analysis (IOTA) Simple Rules (SR), IOTA Simple Rules Risk assessment (SRR), IOTA Assessment of Different NEoplasias in the adneXa (ADNEX) model, and the Ovarian-Adnexal Reporting and Data System (O-RADS) in the same cohort of patients and to compare their performance in the preoperative discrimination between benign and malignant adnexal lesions. Methods This is a single-center diagnostic accuracy study performed between March 2018 and February 2021, which includes 150 women with adnexal lesions. The lesions were classified prospectively using the ADNEX model; whereas, SR, SRR assessment, and O-RADS were applied retrospectively. Surgery with histology was performed within 6 months of the ultrasound exam. Sensitivity and specificity were determined for each testing modality. Results Of the 150 women, 110 (73.3%) had a benign ovarian tumor and 40 (26.7%) had a malignant tumor. The mean risk of malignancy generated by the ADNEX model without CA 125 was significantly higher in malignant lesions versus benign lesions, 63.3% vs 11.8%, respectively. The area under the receiver operating characteristic curve (AUC) of the ADNEX model for differentiating between benign and malignant adnexal masses at the time of ultrasound examination was 0.937. The mean risk of malignancy generated by SRR assessment was also significantly higher in malignant lesions than in benign lesions, 74.1% and vs 15.9%, respectively. The AUC of SRR assessment differentiating between benign and malignant adnexal masses at the time of ultrasound examination was 0.941. For purposes of comparison among ADNEX, SRR assessment, and O-RADS, the malignancy risk threshold was set at >10%. This cut-off differentiates O-RADS low-risk categories (3 or lower) from intermediate to high-risk categories (4 and 5). At a threshold malignancy risk of >10%, the sensitivity and specificity of the ADNEX model were 97.5% (95%CI, 85.3%-99.9%) and 63.6% (95%CI, 53.9%-72.4%), respectively; while, the sensitivity and specificity of the SRR model were 100% (95%CI, 89.1%-100%) and 51.8% (95%CI, 42.1%-61.4%), respectively. In the 113 cases for which the SR could be applied, sensitivity was 100% (95% CI, 81.5%-100%) and specificity 95.6% (95% CI, 88.5%-98.6%). If the designation of the 37 inconclusive cases is changed to "malignant," sensitivity remains at 100% but the specificity is reduced to 79.1% (95%CI, 70.1%-86.0%). The 150 cases fell into the following O-RADS categories: 17 lesions (11.3%) in category 2, 34 lesions (22.7%) in category 3, 66 (44.0%) lesions in category 4, and 33 (22.0%) in category 5. There were no histologically proven malignant lesions in either category 2 or 3. There were 14 malignant lesions in category 4 and 26 in category 5. The sensitivity and specificity of O-RADS using >10% threshold were 100% (95%CI, 89.1%-100.0%) and 46.4% (95%CI, 36.9%-56.1%), respectively. Conclusions When IOTA terms and techniques are used, the performance of IOTA models in a North American patient population is in line with published IOTA literature. The IOTA SR, SRR assessment, and ADNEX model and O-RADS have similar sensitivity in the preoperative discrimination of malignant and benign pelvic tumors; however, the IOTA models have higher specificity. This article is protected by copyright. All rights reserved.

The types of immune cells that populate the trachea after ILTV vaccination and infection have not been assessed. The objective of this study was to quantify CD4+, CD8α+, CD8β+, TCRγδ+, and MRC1LB+ cells that infiltrate the trachea after vaccination with chicken embryo origin (CEO), tissue culture origin (TCO), and recombinant herpesvirus of turkey-laryngotracheitis (rHVT-LT) vaccines, and after challenge of vaccinated and non-vaccinated chickens with a virulent ILTV strain. Eye-drop vaccination with CEO, or TCO, or in ovo vaccination with rHVT-LT did not alter the number of CD4+, CD8α+, CD8β+, TCRγδ+, and MRC1LB+ cells in the trachea. After challenge, the CEO vaccinated group of chickens showed swift clearance of the challenge virus, the mucosa epithelium of the trachea remained intact, and a limited number of CD4+, CD8α+, and CD8β+ cells were detected in the upper trachea mucosa. The TCO and rHVT-LT vaccinated groups of chickens showed narrow viral clearance with moderate disruption of the trachea epithelial integrity, and a significant increase in CD4+, CD8α+, CD8β+, and TCRγδ+ cells infiltrated the upper trachea mucosa. Non-vaccinated challenged chickens showed high levels of viral replication, the epithelial organization of the upper trachea mucosa was heavily disrupted, and the predominant infiltrates were CD4+, TCRγδ+, and MRC1LB+ cells. Hence, the very robust protection provided by CEO vaccination was characterized by minimal immune cell infiltration to the trachea mucosa. In contrast, partial protection induced by the TCO and rHVT-LT vaccines requires a prolonged period of T cell expansion to overcome the established infection in the trachea mucosa.

OBJECTIVES To determine survival outcomes following enucleation for uveal melanoma. To compare these outcomes with the 8th edition AJCC classification and determine the influence of cytogenetics, using Fluorescent in situ Hybridisation (FISH), on survival. To determine whether failure to gain sufficient sample for cytogenetics using Fine Needle Aspiration Biopsy (FNAB) correlates with survival. SUBJECTS/METHODS All patients undergoing primary enucleation for uveal melanoma at Moorfields Eye Hospital between 2012 and 2015 were included. Clinical, pathological, cytological and survival data were analysed for all patients. RESULTS In total, 155 subjects were included. Mean age at enucleation was 65.9 years (SD 14.13). 88 (56.8%) patients died at a mean of three (SD 1.9) years following enucleation. Of these, 52 (33.5%) died from metastatic melanoma, 16 (10.3%) from other causes and 20 (12.9%) causes of death were unknown. Cumulative incidence analysis demonstrated AJCC grade, chromosome 8q gain and monosomy three all predict metastatic mortality. The greatest 5-year mortality rate (62%, SD10.1%) was in those with both chromosome abnormalities and AJCC stage III (Stage IV patients excluded due to low numbers). Largest basal diameter and chromosome status, both independently (p = 0.02 and p

Background: Prior studies have demonstrated that patients with low left atrial pressure (LAP) undergoing transcatheter mitral valve repair (TMVr) have a high incidence of chronic lung disease, and ...

Patients with patent foramen ovale can manifest in a variety of ways. These presentations and their resolution are discussed in this article.

Objectives Papua New Guinea (PNG) has among the highest rates of sexually transmitted infections (STIs) globally and is committed to reducing their incidence. The Syphilis Interventions Towards Elimination (SITE) model was used to explore the expected impact and cost of alternative syphilis intervention scale-up scenarios. Methods SITE is a dynamical model of syphilis transmission among adults 15–49 years. Individuals are divided into nine groups based on sexual behaviour and into six stages of infection. The model was calibrated to PNG using data from routine surveillance, bio-behavioural surveys, research studies and program records. Inputs included syphilis prevalence, risk behaviours, intervention coverage and service delivery unit costs. Scenarios compared different interventions (clinical treatment, contact tracing, syphilis screening, and condom promotion) for incidence and cost per infection averted over 2021–2030. Results Increasing treatment coverage of symptomatic primary/secondary-stage syphilis cases from 25 to 35% in 2020 to 60% from 2023 onwards reduced estimated incidence over 2021–2030 by 55%, compared to a scenario assuming constant coverage at 2019–2020 levels. The introduction of contact tracing in 2020, assuming 0.4 contacts per symptomatic person treated, reduced incidence over 2021–2030 by 10%. Increasing screening coverage by 20–30 percentage points from the 2019–2020 level reduced incidence over 2021–2030 by 3–16% depending on the target population. Scaling-up clinical, symptom-driven treatment and contact tracing had the lowest cost per infection averted, followed by condom promotion and periodic screening of female sex workers and men who have sex with men. Conclusions PNG could considerably reduce its syphilis burden by scaling-up clinical treatment and contact tracing alongside targeted behavioural risk reduction interventions. SITE is a useful tool countries can apply to inform national STI programming and resource allocation.

This study evaluates the relationship between substance use and impairment and current suicidal thoughts or behaviors in adolescent patients screened in a pediatric emergency department (ED).Data were collected between June 2013 and February 2018 from adolescent patients who presented to a single, urban, pediatric ED. Adolescents completed a computerized, self-administered assessment that evaluates depression, suicide, posttraumatic stress, violence, traumatic exposure, bullying, and substance use. Assessments are administered as standard care to all ED patients aged 14 to 18 years. We used binary logistic regression to estimate the odds of reporting current suicidal thoughts or behaviors associated with patient demographics (ie, age, sex, and race), substance use in the past month, and substance-related impairment.A total of 11,623 adolescent patients (65.4% female and 52.9% African American) completed the assessment. Participants were, on average, 15.7 years old (SD = 1.27). Younger age (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.74-0.84) and substance use impairment (OR, 0.44; 95% CI, 0.33-0.58) decreased the odds of reporting current suicidal thoughts or behaviors, whereas male sex (OR, 1.51; 95% CI, 1.28-1.79) and those with past-month substance use (OR, 1.85; 95% CI, 1.51-2.26) increased the odds.Recent substance use and male sex are associated with a higher likelihood of adolescents reporting current suicidal thoughts or behaviors during an ED visit. Standardized screening during pediatric ED visits may allow for more efficient evaluation of patients in higher-risk groups.

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.

OBJECTIVE To investigate the impact of residual β-cell function on continuous glucose monitoring (CGM) outcomes following acute exercise in people with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS Thirty participants with T1D for ≥3 years were recruited. First, participants wore a blinded CGM unit for 7 days of free-living data capture. Second, a 3-h mixed-meal test assessed stimulated C-peptide and glucagon. Peak C-peptide was used to allocate participants into undetectable (Cpepund 200 pmol/L) C-peptide groups. Finally, participants completed 45 min of incline treadmill walking at 60% VO2peak followed by a further 48-h CGM capture. RESULTS CGM parameters were comparable across groups during the free-living observation week. In the 12- and 24-h postexercise periods (12 h and 24 h), the Cpephigh group had a significantly greater amount of time spent with glucose 3.9–10 mmol/L (12 h, 73.5 ± 27.6%; 24 h, 76.3 ± 19.2%) compared with Cpeplow (12 h, 43.6 ± 26.1%, P = 0.027; 24 h, 52.3 ± 25.0%, P = 0.067) or Cpepund (12 h, 40.6 ± 17.0%, P = 0.010; 24 h, 51.3 ± 22.3%, P = 0.041). Time spent in hyperglycemia (12 h and 24 h glucose >10 and >13.9 mmol/L, P < 0.05) and glycemic variability (12 h and 24 h SD, P < 0.01) were significantly lower in the Cpephigh group compared with Cpepund and Cpeplow. Change in CGM outcomes from pre-exercise to 24-h postexercise was divergent: Cpepund and Cpeplow experienced worsening (glucose 3.9–10 mmol/L: −9.1% and −16.2%, respectively), with Cpephigh experiencing improvement (+12.1%) (P = 0.017). CONCLUSIONS Residual β-cell function may partially explain the interindividual variation in the acute glycemic benefits of exercise in individuals with T1D. Quantifying C-peptide could aid in providing personalized and targeted support for exercising patients.

Background In recognition of the potential of data to drive care and the need for early identification of patients with sepsis, HCA Healthcare developed an automated sepsis detection algorithm—SPOT (Sepsis Prediction and Optimization of Therapy). The algorithm was deployed at scale and served as a mechanism to reduce the time to detection and improve sepsis mortality in 173 hospitals across the United States. Methods The SPOT algorithm was designed as a rules-based detection of defined criteria that would interpret available electronic and basic laboratory data in near real time. Working from an organizational recognition of the need to construct a national clinical data warehouse to allow for the aggregation and analysis of data streams, HCA Healthcare designed and deployed SPOT and delivered the alert from the algorithm to the bedside to initiate existing clinical workflows for patients with sepsis. Results SPOT improved the timeliness of sepsis detection by providing alerts when signals of sepsis become available, triggering initiation of sepsis screens. This gave an advantage of about six hours over the legacy practice of sepsis screening at shift change. When deployed alongside existing sepsis improvement initiatives, SPOT was associated with an acceleration of improvement in mortality—particularly in the not-present-on-admission (NPOA) septic shock population, the patients at greatest risk for mortality. This population had seen little improvement with prior initiatives, but mortality improved 3.9 percentage points from 2018 to 2019. When accounting for seasonal variation, there was a decline in mortality rate following the deployment of SPOT, as compared to the year prior, of 9.9% for NPOA severe sepsis and 5.1% for NPOA septic shock. Conclusion Development of the SPOT algorithm for the detection of sepsis from data available in the electronic health record resulted in more timely recognition, faster initiation of treatment, and improved survival for patients.

Central nervous system ischemic injury features neuronal dysfunction, inflammation and breakdown of vascular integrity. Here we show that activation of endothelial caspase-9 after hypoxia-ischemia is a critical event in subsequent dysfunction of the blood-retina barrier, using a panel of interrelated ophthalmic in vivo imaging measures in a mouse model of retinal vein occlusion (RVO). Rapid nonapoptotic activation of caspase-9 and its downstream effector caspase-7 in endothelial cells promotes capillary ischemia and retinal neurodegeneration. Topical eye-drop delivery of a highly selective caspase-9 inhibitor provides morphological and functional retinal protection. Inducible endothelial-specific caspase-9 deletion phenocopies this protection, with attenuated retinal edema, reduced inflammation and preserved neuroretinal morphology and function following RVO. These results reveal a non-apoptotic function of endothelial caspase-9 which regulates blood-retina barrier integrity and neuronal survival, and identify caspase-9 as a therapeutic target in neurovascular disease., Retinal vein occlusion can cause blindness, and features neuronal dysfunction, inflammation and breakdown of vascular integrity. Here the authors report a non-apoptotic role of endothelial caspase-9 in regulating blood-retina barrier integrity and neuronal survival, which can be therapeutically targeted in a mouse model of retinal vein occlusion.

ObjectiveA subset of patients at the time of transcatheter mitral valve repair (TMVR) will have normal left atrial pressure (LAP) (MethodsA single-centre retrospective cohort of consecutive patients who underwent transcatheter edge-to-edge mitral valve clip and continuous LAP monitoring between 5/1/2014 and 5/1/2018 was analysed. One-year mortality was compared by Kaplan–Meier survival curves. Multivariable analysis was performed to identify predictors of normal LAP and 1 year mortality.ResultsOf the 204 patients undergoing TMVR, 65% were men and the mean age was 81. Of these patients, 31 (15%) had normal LAP (mean LAP 10.5 mm Hg, mean V wave 16.5 mm Hg) and 173 had elevated LAP (mean LAP 19 mm Hg, mean V wave 32.5 mm Hg). The prevalence of severe MR was not different between groups, although the normal LAP group had significantly lower effective regurgitant orifice area and regurgitant volume. Other notable baseline characteristics including prior cardiac surgery, atrial fibrillation, hypertension, diabetes, congestive heart failure, body mass index, mechanism of MR and ejection fraction were similar between groups. However, there was an increased prevalence of chronic lung disease (CLD) (45.2% vs 17.3%, pConclusionNormal LAP at the time of TMVR is associated with a higher incidence of CLD which independently predicts increased 1-year mortality. In patients with CLD and apparently severe MR, measurement of LAP may help identify those with lower likelihood of benefit from TMVR.

Human immunodeficiency virus (HIV) testing is a cornerstone in preventing HIV infections and accessing treatment for HIV. However, HIV testing remains low among men in the Democratic Republic of Congo (DRC). The purpose of this study was to assess the correlates of HIV testing among men in the DRC. Data from the 2014 DRC Demographic Health Survey were analyzed to assess the relationships between HIV testing and the correlates of HIV testing among 7830 men aged 15-59 years. Although more than half (4763 or 63.7%) knew of an HIV testing site, only one-sixth (1187 or 16.6%) reported ever being tested for HIV. The multivariate logistic regression indicated that men aged between 25 and 34 years were more likely to have tested for HIV than those aged between 15 and 24 years (aOR = 1.70; 95% CI: [1.23-2.34]). In addition, men with college experience were 5.47 more likely to have tested for HIV than men with no formal education (aOR = 5.47; 95% CI: [2.53-11.84]). The results highlight the need for a national HIV testing awareness and uptake campaign for Congolese men to increase HIV testing among this group and prevent HIV infections.

Purpose To study the use of iris-claw Artisan intraocular lenses (IOLs) in patients with uveitis. Setting Moorfields Eye Hospital, London, England. Design Retrospective case series. Methods Data on all patients with anterior uveitis, intermediate uveitis, and panuveitis who had anterior-fixated Artisan IOL insertion between January 2014 and July 2019 at Moorfields Eye Hospital were assessed. Patients who had less than 2 months of follow-up were excluded from the analysis. Results The study comprised 11 patients. The mean age of the 7 women and 4 men was 61 years ± 14 (SD). The mean follow-up was 1.7 years. After Artisan IOL insertion, the corrected distance visual acuity (CDVA) improved significantly from 20/200 to 20/50 (P = .02). No patients had a significant flare-up of their uveitis after the surgery, and there were no intraocular pressure-related events. One patient developed cystoid macular edema, which responded to treatment. Conclusion This case series showed the efficacy and safety of Artisan-style IOLs in patients with a history of uveitis. After the Artisan IOL insertions, these patients experienced a significant improvement in CDVA with minimal side effects.

ObjectiveClinical guidelines recommend weight loss to manage non-alcoholic fatty liver disease (NAFLD). However, the majority of patients find weight loss a significant challenge. We identified factors associated with engagement and adherence to a low-energy diet (LED) as a treatment option for NAFLD.Design23 patients with NAFLD enrolled in a LED (~800 kcal/day) were individually interviewed. Transcripts were thematically analysed.Results14/23 patients achieved ≥10% weight loss, 18/23 achieved ≥7% weight loss and 19/23 achieved ≥5% weight loss. Six themes were generated from the data. A desire to achieve rapid weight loss to improve liver health and prevent disease progression was the most salient facilitator to engagement. Early and significant weight loss, accountability to clinicians and regular appointments with personalised feedback were facilitators to engagement and adherence. The desire to receive positive reinforcement from a consultant was a frequently reported facilitator to adherence. Practical and emotional support from friends and family members was critically important outside of the clinical setting. Irregular working patterns preventing attendance at appointments was a barrier to adherence and completion of the intervention.ConclusionsEngagement and adherence to a LED in patients with NAFLD were encouraged by early and rapid weight loss, personalised feedback and positive reinforcement in the clinical setting combined with ongoing support from friends and family members. Findings support those identified in patients who completed a LED to achieve type 2 diabetes remission and highlight the importance of behaviour change support during the early stages of a LED to promote adherence.

Background: Tricuspid edge to edge repair (TEER) is a novel treatment for severe tricuspid regurgitation and is highly dependent on intraprocedural image quality. To date, transesophageal echocardiography (TEE) has been the primary imaging modality used to guide TEER. The role of intracardiac echocardiography (ICE) has not been assessed. The objective of this study was to describe the use and role of 2-dimensional ICE in the early experience of TEER. Methods: Consecutive patients undergoing TEER (with or without concomitant mitral repair) with off-label use of MitraClip (Abbott, Santa Clara, CA) were included in the study. Utilization of 2-dimensional ICE in comparison with TEE imaging were collected in each procedure through retrospective review of the procedural reports and images. Results: Of 42 TEER cases, ICE was used in 15 (36%) and concomitant mitral repair was performed in 37 (86%). ICE was increasingly used over time for TEER. ICE was able to visualize the tricuspid leaflets with high resolution and provided superior leaflet visualization to TEE in 40% of cases where it was used. Patients treated with ICE guidance tended to have a greater baseline severity of tricuspid regurgitation compared with patients treated with TEE guidance alone (8/15 [53%] massive or greater tricuspid regurgitation versus 6/27 [22%]; P =0.09). Degree of tricuspid regurgitation reduction was similar with TEE alone versus ICE plus TEE guidance (1.9±1.0 versus 2.1±1.1 grade reduction, P =0.28). Conclusions: ICE was increasingly used in the early experience of TEER over time. ICE facilitates leaflet visualization for grasping and is a useful adjunct to TEE during TEER.

Background The predictors and clinical significance of increased Doppler-derived mean diastolic gradient (MG) following transcatheter edge-to-edge mitral valve repair (MVTEER) remain controversial. Objective We sought to examine baseline correlates of Doppler-derived increased MG post-MVTEER and its impact on intermediate-term outcomes. Methods Patients undergoing MVTEER were analyzed retrospectively. Post-MVTEER increased MG was defined as >5 mmHg or aborted clip implantation due to increased MG intraprocedurally. Baseline MG and 3D-guided mitral valve area (MVA) by planimetry were retrospectively available in 233 and 109 patients. Results 243 patients were included; 62 (26%) had MG > 5 mmHg post-MVTEER or aborted clip insertion, including 7 (11%) that had aborted clip implantation. Mortality occurred in 63 (26%) during a median follow up of 516 days (IQR 211, 1021). Increased post-MVTEER MG occurred more frequently in females (44% vs. 16%, p Conclusions Smaller baseline MVA and increased baseline MG are associated with increased MG post-MVTEER and patients with a Doppler-derived post-MVTEER MG >5 mmHg suffered excess subsequent mortality. In high risk patients considered for MVTEER, identification of those at risk of iatrogenic mitral stenosis with MVTEER is important as they may be optimally treated with alternate surgical or transcatheter therapies.

Exercise mobilizes angiogenic cells, which stimulate vascular repair. However, limited research suggests exercise-induced increase of endothelial progenitor cell (EPCs) is completely lacking in type 1 diabetes (T1D). Clarification, along with investigating how T1D influences exercise-induced increases of other angiogenic cells (hematopoietic progenitor cells; HPCs) and cell surface expression of chemokine receptor 4 (CXCR4) and 7 (CXCR7), is needed. Thirty T1D patients and 30 matched non-diabetes controls completed 45 min of incline walking. Circulating HPCs (CD34+, CD34+CD45dim) and EPCs (CD34+VEGFR2+, CD34+CD45dimVEGFR2+), and subsequent expression of CXCR4 and CXCR7, were enumerated by flow cytometry at rest and post-exercise. Counts of HPCs, EPCs and expression of CXCR4 and CXCR7 were significantly lower at rest in the T1D group. In both groups, exercise increased circulating angiogenic cells. However, increases was largely attenuated in the T1D group, up to 55% lower, with CD34+ (331 ± 437 Δcells/mL vs. 734 ± 876 Δcells/mL p = 0.048), CD34+VEGFR2+ (171 ± 342 Δcells/mL vs. 303 ± 267 Δcells/mL, p = 0.006) and CD34+VEGFR2+CXCR4+ (126 ± 242 Δcells/mL vs. 218 ± 217 Δcells/mL, p = 0.040) significantly lower. Exercise-induced increases of angiogenic cells is possible in T1D patients, albeit attenuated compared to controls. Decreased mobilization likely results in reduced migration to, and repair of, vascular damage, potentially limiting the cardiovascular benefits of exercise.Trial registration: ISRCTN63739203.

PurposeElevated postprandial glycaemia [PPG] increases the risk of cardiometabolic complications in insulin-resistant, centrally obese individuals. Therefore, strategies that improve PPG are of importance for this population. Consuming large doses of whey protein [WP] before meals reduces PPG by delaying gastric emptying and stimulating the secretion of the incretin peptides, glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide 1 [GLP-1]. It is unclear if these effects are observed after smaller amounts of WP and what impact central adiposity has on these gastrointestinal processes.MethodsIn a randomised-crossover design, 12 lean and 12 centrally obese adult males performed two 240 min mixed-meal tests, ~5–10 d apart. After an overnight fast, participants consumed a novel, ready-to-drink WP shot (15 g) or volume-matched water (100 ml; PLA) 10 min before a mixed-nutrient meal. Gastric emptying was estimated by oral acetaminophen absorbance. Interval blood samples were collected to measure glucose, insulin, GIP, GLP-1, and acetaminophen.ResultsWP reduced PPG area under the curve [AUC0–60] by 13 and 18.2% in the centrally obese and lean cohorts, respectively (both p ACTIVE/TOTAL ratio comparative to PLA (p = 0.004), indicative of reduced GLP-1 degradation. Conversely, no treatment effects for GLP-1ACTIVE/TOTAL were seen in obese subjects.ConclusionPre-meal ingestion of a novel, ready-to-drink WP shot containing just 15 g of dietary protein reduced PPG in lean and centrally obese males. However, an attenuated GLP-1 response to mealtime WP and increased incretin degradation might impact the efficacy of nutritional strategies utilising the actions of GLP-1 to regulate PPG in centrally obese populations. Whether these defects are caused by an individual’s insulin resistance, their obese state, or other obesity-related ailments needs further investigation.Clinical Trial RegistrationISRCTN.com, identifier [ISRCTN95281775]. https://www.isrctn.com/.

Objective Although several treatments have been shown to be effective in treatment of youth suicidal thoughts and behaviors (STBs), there is a pressing need to account for the substantial variation in adolescents’ response to and outcomes from these treatments. Method Secondary analyses of data from a 16-week randomized trial of Attachment-Based Family Therapy (ABFT) and Family-Enhanced NonDirective Supportive Therapy (FE-NST) identified distinct classes of adolescents’ treatment response. Established risk factors for STBs, along with treatment condition and sociodemographic variables, were then tested as predictors of class membership. Results Three patterns of adolescents’ treatment response and outcome were identified: a) nonresponders (15.8%), b) good responders (57.5%), and c) partial responders (26.7%). After controlling for initial symptom severity, nonresponders were more likely to have higher levels of nonsuicidal self-injury and pessimism and were more likely to meet diagnostic criteria for major depressive disorder (MDD) than good or partial responders. Partial responders were more likely than good responders to meet criteria for MDD and to have higher perceived burdensomeness. Conclusion Although most adolescents showed significant symptom reductions with both treatments, adolescents with higher pretreatment levels of pessimism, MDD, nonsuicidal self-injury, and perceived burdensomeness were less likely to show an optimal pattern of treatment benefit. The findings point to heterogeneity in treatment response that may require adapting treatments for adolescents with these pretreatment profiles. Clinical trial registration information Attachment-Based Family Therapy for Suicidal Adolescents; http://clinicaltrials.gov ; NCT01537419 .

Eating disorders are a serious, life-threating condition impacting adolescents and young adults. Providers in primary care settings have an important role in identifying disordered eating (DE) symptoms. Unfortunately, symptoms go undetected in 50% of patients in medical settings. Using the behavioral health screen, this study identified DE risk profiles in a sample of 3620 female adolescents and young adults (ages 14–24), presenting in primary care. A latent class analysis with twenty psychosocial factors identified three DE risk groups. The group at highest risk for DE was characterized by endorsement of internalizing symptoms and a history of trauma. The next risk group consisted of those with externalizing symptoms, particularly substance use. The group at lowest risk for DE reported more time spent with friends compared to their peers. Primary care providers and psychiatric teams can benefit from knowing the psychosocial risk patterns affiliated with DE, and using brief, comprehensive screening tools to identify these symptoms. Published (Publication status)

To review our experience with balloon testing prior to atrial septal defect (ASD) closure in adults with left ventricular (LV) diastolic dysfunction.ASD closure in patients with LV diastolic dysfunction may precipitate LV failure. Temporary ASD occlusion has been used in this scenario but data are limited.Retrospective review of 27 patients age ≥ 50 years undergoing temporary ASD balloon occlusion between 2000 and 2018 for suspected LV diastolic dysfunction or elevated LV end-diastolic pressure (LVEDP).Median age was 72 years (IQR 66.7; 75.2). Atrial fibrillation was seen in 58% of patients, hypertension in 58%, and coronary artery disease in 26%; 52% were females. Median ASD size was 13 mm (10; 18) and Qp/Qs 1.8 (1.6; 2.2). Median LVEDP was 14 mmHg (12; 22); pulmonary artery wedge pressure (PAWP) 12 mmHg (9; 16.5) and left atrial pressure (LAP) 13.5 mmHg (8; 16.3). After a median of 5 min (3; 10) of balloon occlusion, patients with baseline LVEDP ≥15 mmHg had more significant increases in LVEDP (9 [6; 12] vs. 2 mmHg [0.5; 5]; p = 0.03) and LAP/PAWP (10.5 [8.3; 16.3] vs. 1.5 mmHg [-1.5; 3]; p = 0.0003) than those with baseline LVEDP15 mmHg. None of those with a baseline LVEDP15 mmHg had a LAP/PAWP15 mmHg during balloon testing compared to 92% of patients with a baseline LVEDP ≥15 mmHg.LVEDP might be used to predict LAP post-ASD closure. Comorbidities typically associated with LV diastolic dysfunction are common in these patients and should be considered in their management.

Pyrin is an inflammasome sensor that promotes caspase-1–mediated pyroptotic cell death and maturation of proinflammatory cytokines IL-1β and IL-18. Familial Mediterranean fever (FMF), an autoinflammatory disorder, is associated with mutations in the gene encoding pyrin (MEFV). FMF-knockin (FMF-KI) mice that express chimeric pyrin protein with FMF mutation (Mefv(V726A/V726A)) exhibit an autoinflammatory disorder mediated by autoactivation of the pyrin inflammasome. Increase in the levels of TNF are observed in FMF-KI mice, and many features of FMF overlap with the autoinflammatory disorder associated with TNF receptor signaling. In this study, we assessed the contribution of TNF signaling to pyrin inflammasome activation and its consequent role in distinct FMF pathologies. TNF signaling promoted the expression of pyrin in response to multiple stimuli and was required for inflammasome activation in response to canonical pyrin stimuli and in myeloid cells from FMF-KI mice. TNF signaling promoted systemic wasting, anemia, and neutrophilia in the FMF-KI mice. Further, TNF-induced pathology was induced specifically through the TNFR1 receptor, while TNFR2-mediated signaling was distinctly protective in colitis and ankle joint inflammation. Overall, our data show that TNF is a critical modulator of pyrin expression, inflammasome activation, and pyrin-inflammasomopathy. Further, specific blockade of TNFR1 or activation of TNFR2 could provide substantial protection against FMF pathologies.

Aims: Percutaneous mitral balloon valvotomy PMBV is an acceptable alternative to Mitral valve surgery for patients with mitral stenosis. The purpose of this study was to explore the immediate results of PMBV with respect to echocardiographic changes, outcomes, and complications, using a meta-analysis approach. Methods: MEDLINE, and EMBASE databases were searched (01/2012 to 10/2018) for original research articles regarding the efficacy and safety of PMBV. Two reviewers independently screened references for inclusion and abstracted data including article details and echocardiographic parameters before and 24–72 h after PMBV, follow-up duration, and acute complications. Disagreements were resolved by third adjudicator. Quality of all included studies was evaluated using the Newcastle-Ottawa Scale NOS. Results: 44/990 references met the inclusion criteria representing 6537 patients. Our findings suggest that PMBV leads to a significant increase in MVA (MD = 0.81 cm2; 0.76–0.87, p

SummaryBy mirroring their function as tissue repair organizers in normal tissues, immune cells regulate tumor growth. To understand the different facets of immune-tumor collaboration through genetics, spatial transcriptomics, and immunological manipulation with non-invasive, longitudinal imaging, we generated a penetrant double oncogene-driven autochthonous model of neuroblastoma. Using spatial transcriptomic analysis, we co-localized CD4+and myeloid populations within the tumor parenchyma, while CD8+T cells and B cells were peripherally dispersed. Depletion of CD4+T cells or CCR2+macrophages, but not B cells, CD8+, or NK cells, prevented tumor formation. Tumor CD4+T cells displayed unconventional phenotypes, were clonotypically diverse, and antigen-independent. Within the myeloid fraction, tumor growth required myeloid cells expressing Arginase-1. Overall, our results suggest that arginine-metabolizing myeloid cells conspire with pathogenic CD4+T cells to create permissive conditions for tumor formation, and therefore suggest that these pro-tumorigenic pathways can be disabled by targeting myeloid amino acid metabolism.

Mitral valve regurgitation (MR) is the most common valvular regurgitant abnormality, increasing in prevalence with age and affecting approximately 4 million people in the United States alone. Percutaneous edge-to-edge transcatheter mitral valve repair (TMVR) (also known as the MitraClip® system) provides a durable alternative in severe (≥ 3+ MR) MR and was approved by the Food and Drug Administration (FDA) in October 2013 for prohibitive-risk patients with primary MR. Recently published results of the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial demonstrated the benefit of this technology in secondary MR in terms of lower hospitalization rates and all-cause mortality within 24 months of follow-up. This chapter will review the indications, pre-procedural imaging and planning, procedural details, troubleshooting, and post-procedural follow-up for MitraClip®.

Adult cardiac structural heart interventions performed in the 1980s included aortic and mitral balloon valvuloplasty, atrial septostomy, and early attempts at atrial septal defect closure. The first aortic balloon valvuloplasty with performed in 1986 by Cribier. Later that year this procedure was performed at Mayo Clinic. Mayo’s contribution to the knowledge base included delineation of the mechanism of gradient reduction by demonstrating fracture of calcific deposits in a detailed pathology-based study. Additionally, there were developments in Doppler methodology used to determine aortic stenosis severity, and these methods were refined in studies involving a close collaboration between the echocardiographic laboratory and the cardiac catheterization laboratory. Follow-up echo Doppler studies demonstrated the transient nature of the benefit of aortic balloon valvuloplasty, with occurrence of restenosis within 3–6 months. The first mitral balloon valvuloplasty at Mayo Clinic was performed in 1987. Unlike aortic balloon valvuloplasty, the mitral dilation procedure was shown to give more lasting results in most patients. The role of commissural calcification as a negative factor for valvuloplasty success was well defined in a Mayo study. Echocardiographic monitoring during the procedure became an important and well-established method of assessing both successful results and avoidance of complications. Balloon atrial septostomy had been performed in pediatric patients for several years, but rarely in adult patients. The observation that patients with primary pulmonary hypertension survived longer if there was an atrial septal communication gave rise to the concept of therapeutic atrial septostomy in this patient population. There was initial enthusiasm and utilization of this procedure, but it gradually became less important with the advent of more powerful pulmonary vasodilator drugs. Early devices for atrial septal defect closure were available in the late 1980s, and cases were performed at Mayo Clinic under the guidance of the pediatric cardiologists. Better devices were available in the next decade and became more widely utilized.

Secundum atrial septal defects presenting in adult patients can often be closed percutaneously. Most present with a murmur, abnormal second heart sound, or an echocardiogram showing right ventricular enlargement. Hemodynamic catheterization is usually unnecessary unless there are complicating features such as pulmonary hypertension or valvular regurgitation. Approved devices in the United States include the Amplatzer Septal Occluder, Amplatzer Cribriform Occluder, the Gore Cardioform Septal Occluder, and the Gore Cardioform ASD Occluder. The procedure is performed with echocardiographic guidance—either transesophageal echo or intracardiac echo. The latter is preferred for patient comfort. A transfemoral venous approach allows easy passage of the catheter, guidewire, and closure device into the left atrium, and subsequently deployment across the atrial septum. Closure of the patent foramen ovale (PFO) may be considered in patients with cryptogenic stroke. A thorough search for common stroke causes, including atrial fibrillation, is mandatory. Techniques for device closure are similar to those for atrial septal defect. Approved devices in the United States include the Amplatzer PFO Occluder and the Gore Cardioform Septal Occluder. PFO closure is also indicated for individuals with orthodeoxia due to atrial shunting. An emerging indication includes selected patients with right heart pacemaker/defibrillator leads, lead-associated thrombus, and atrial right-to-left shunting. Atrial septostomy utilizing atrial septal puncture and balloon dilation of the atrial septum is occasionally useful for palliation of low cardiac output in patients with severe pulmonary hypertension or palliation of left atrial hypertension in individuals with stiff left atrial syndrome or heart failure with preserved ejection fraction. Consultation with a pulmonary hypertension specialist or heart failure specialist is desirable in these circumstances.

Immune cells regulate tumor growth by mirroring their function as tissue repair organizers in normal tissues. To understand the different facets of immune–tumor collaboration through genetics, spatial transcriptomics, and immunologic manipulation with noninvasive, longitudinal imaging, we generated a penetrant double oncogene–driven autochthonous model of neuroblastoma. Spatial transcriptomic analysis showed that CD4+ and myeloid populations colocalized within the tumor parenchyma, while CD8+ T cells and B cells were peripherally dispersed. Depletion of CD4+ T cells or CCR2+ macrophages, but not B cells, CD8+ T cells, or natural killer (NK) cells, prevented tumor formation. Tumor CD4+ T cells displayed unconventional phenotypes and were clonotypically diverse and antigen independent. Within the myeloid fraction, tumor growth required myeloid cells expressing arginase-1. Overall, these results demonstrate how arginine-metabolizing myeloid cells conspire with pathogenic CD4+ T cells to create permissive conditions for tumor formation, suggesting that these protumorigenic pathways could be disabled by targeting myeloid arginine metabolism. Significance: A new model of human neuroblastoma provides ways to track tumor formation and expansion in living animals, allowing identification of CD4+ T-cell and macrophage functions required for oncogenesis.

Background Iatrogenic mitral stenosis is a known limitation of transcatheter edge-to-edge mitral valve repair (TMVr), but determinants of increased postprocedural mean diastolic gradient (MG) are not well defined. The aim of this study was to determine correlates of increased post-TMVr MG or aborted clip implantation due to increased MG. Methods Procedural three-dimensional transesophageal echocardiographic (TEE) data sets of 112 patients who underwent TMVr were retrospectively analyzed. Three-dimensional TEE mitral valve area (MVA) planimetry and mitral annular calcification (MAC) were quantified using multiplanar reconstruction. When MAC extension into the mitral leaflets was present, MAC with leaflet calcification (MAC-LC) length was recorded as the maximum distance from the mitral annulus to the most distal leaflet calcification. Increased MG after TMVr, measured on intraprocedural TEE imaging, was defined as ≥5 mm Hg or aborted clip implantation due to increased MG. Results Baseline MVA was 5.9 ± 1.7 cm2, baseline MG was 2.1 ± 1.2 mm Hg, and MAC-LC length was 4.0 ± 4.5 mm. Thirty-two patients (29%) had increased post-TMVr MG. Risk for increased post-TMVr MG was 86%, 28%, and 14% in patients with baseline MVA 6.0 cm2, respectively (P 6.0 cm2, the risk for increased post-TMVr MG was similar in the presence or absence of baseline MG ≥ 4 mm Hg or MAC-LC ≥ 6 mm (P > .05 for both). Conclusions Patients with baseline three-dimensional TEE MVA

Aims: Endothelial and Hematopoietic Progenitor Cells (EPCs and HPCs) promote vascular health through secreting proangiogenic factors and replacing damaged cells. Exercise has been shown to be a mobiliser of these rare cells in healthy individuals, however, the response in chronic diseases such as type 1 diabetes (T1D) is unclear. We compared EPC and HPC counts at rest and after acute exercise in people with and without T1D. Methods: Thirty T1D participants (38±12 years, HbA1c 58.5±9.3 mmol/mol-1, diabetes duration 20±13 years) and 30 age, sex, BMI and fitness matched non diabetes controls were recruited. After a maximal exercise test, participants attended a second visit to complete 45mins of walking at 60%VO2peak. Blood samples were taken at rest, immediately and 1 hour post exercise. Circulating levels of two HPCs and five EPC phenotypes were enumerated by flow cytometry. Data (mean±SD) were analysed by mixed model ANOVA and t-test with significance accepted at p≤0.05. Results: The T1D group had significantly lower rest count of HPCs and EPCs, ranging from 21 to 41% lower across all samples compared to the control. Exercise mobilized all cell phenotypes in both groups, with significant increases from rest to post exercise, while HPCs and CD34+CD31+ EPCs remained elevated 1hr post exercise. However, the change (Δ) in HPCs and EPCs from rest to post exercise was greater in the control versus T1D group, with higher CD34+CD45dim HPCs (p=0.03, Δ 48±65 vs. 24±33 cells/ml), as well as CD34+CD31+ (p=0.04, Δ 23±19 vs. 15±25 cells/ml) and CD34+VEGFR2+ EPCs (p=0.02, Δ 24 ±24 vs. 15±31 cells/ml). Conclusion: People with T1D have reduced numbers of HPCs and EPCs at rest and also display a blunted exercise induced increase in these rare blood vessel protecting cells. Further research is needed to understand the clinical significance of an attenuated exercise mobilization of these EPCs and HPCs phenotypes in predicting future cardiovascular complications in T1D. Disclosure G.S. Taylor: None. K. Smith: None. J. Scragg: None. A. Bashir: None. A. Flatt: None. E.J. Stevenson: None. J.A. Shaw: Advisory Panel; Self; Medtronic. Speaker’s Bureau; Self; Novo Nordisk A/S. M.D. Ross: None. D.J. West: None. Funding Diabetes Research & Wellness Foundation (to D.J.W.)

Aims: β-cells can function for years after diagnosis in people with type 1 diabetes (T1D). It is unknown how C-peptide secretion impacts upon rare blood vessel protecting Endothelial and Hematopoietic Progenitor Cells (EPCs and HPCs), particularly in response to cardiovascular stress, such as exercise. We compared EPC and HPC counts at rest and after acute exercise in clinically diagnosed people with T1D with undetectable and high C-peptide. Methods: After quantification of stimulated C-peptide, 11 participants with undetectable C-peptide (Cpepund 200 pmol/L) were recruited, with no differences in age, fitness or HbA1c, while the Cpephigh group had shorter diabetes duration (27±13 vs. 11±3 years, p=0.01). After a maximal exercise test, participants attended a third visit to complete 45mins of walking at 60%VO2peak. Blood samples were taken at rest, immediately and 1 hour post exercise. Two HPC and five EPC phenotypes were enumerated by flow cytometry. Data (mean±SD) were analysed by two-way ANOVA and t-test with significance accepted at p≤0.05. Results: The Cpephigh group displayed higher rest values of HPCs than the Cpepund group, and increased rest to post exercise mobilization (p Conclusion: People with T1D who maintained a high residual β-cell function had increased counts of HPCs and EPCs, and sustained a >5 fold exercise mobilization of EPCs compared to people with no C-peptide. Future research needs to understand if these differences are due to clinical characteristics or the potential direct impact of C-peptide upon vasculature. Disclosure K. Smith: None. J. Scragg: None. A. Bashir: None. A. Flatt: None. E.J. Stevenson: None. T.J. McDonald: None. R.A. Oram: None. J.A. Shaw: Advisory Panel; Self; Medtronic. Speaker’s Bureau; Self; Novo Nordisk A/S. M.D. Ross: None. D.J. West: None. Funding Diabetes Research & Wellness Foundation (to D.J.W.)

Background: The consumption of large (∼50g) doses of whey protein [WP] before meals (i.e., preload) has been shown to improve postprandial glycemic [PPG] excursions in people with type 2 diabetes [T2D]. Yet, studies to date have not accounted for treatment palatability, the energy associated with large WP doses, or the burden allied with preload preparation, limiting its ecological translation. Herein, we examined the PPG responses to a mixed-meal tolerance test [MMTT] following prior consumption of a low dose of WP from a novel, pre-made shot in people with T2D. Methods: Nine adults with T2D (8M/1F; HbA1c 57.6±10.1 mmol∙mol) attended the laboratory on two occasions, ∼14d apart. After an overnight fast, subjects randomly consumed a bespoke, ready-to-drink WP (15g) or placebo [PLA] shot (100ml) 10min prior to a 4hr MMTT (387kcal; 58% CHO). At 4hr, a further shot was consumed 10min before an ad libitum lunch. Subjective appetite and preload palatability were assessed by visual analog scales. Interstitial glucose was measured throughout. Data (mean±SD) were analyzed by a two-way repeated measures ANOVA. Results: Compared to PLA, WP attenuated early [0-60min] (-48.9±35.9%; p=0.01) and total [0-240min] PPG area under the curve (-22.7±17.5%; p0.05) and ad libitum energy intake were similar between trials (p=0.48). Both preloads were rated highly palatable. Conclusion: Consuming a small, bespoke WP shot lowers post-meal hyperglycemia in people with T2D without affecting satiety and satiation. We highlight the potential for small, contemporary WP beverages that encompass both glycemic benefit but also patient taste and convenience, which may have lasting clinical value beyond formal research studies. Disclosure K. Smith: None. G.S. Taylor: None. K.A. Bowden Davies: None. L.H. Brunsgaard: None. E. Jensen: Employee; Self; Arla Foods Ingredients. M. Walker: None. E.J. Stevenson: None. D.J. West: None. Funding Arla Foods Ingredients Group P/S

Transmissible viral proventriculitis (TVP) is a disease of chickens, mostly in broilers of 2-8 wk of age. Chicken proventricular necrosis virus (CPNV), a birnavirus, is the etiologic agent. Characteristic gross lesions are enlargement, atony, and pallor of the proventriculus. Cases diagnosed in California between 2000 and 2018 (n = 477), originating from 93 different farms representing all major companies in the region, were analyzed. Frequency of cases varied widely between years, with no recognizable seasonality. The flocks were between 6 and 61 days of age; the average age was 34.0 days, and the median age was 35 days. In 166 cases, between 6.3% and 100% of the submitted birds had gross lesions in the proventriculus. The most common findings were enlarged or dilated proventriculi, thickened walls, and pale or mottled serosal appearance. Histopathologically, inflammation of the glands was the most frequent finding. Other lesions included necrosis, hyperplasia, or both conditions of the glandular epithelium; dilated glands; and occasionally fibrin deposition, fibrosis, and hemorrhages. Twenty-three proventriculi from six cases were tested by immunohistochemistry for the presence of CPNV antigen; 21 stained positive. In 209 cases, birds also had lesions in the bursa fabricii attributed to infectious bursal disease, but with no significant difference in the mean percentage of birds with gross lesions in the proventriculus between cases with or without lesions in the bursa fabricii. The results show that TVP is a common disease of broiler flocks in California and confirms that CPNV is the likely causative agent.

OBJECTIVES We sought to determine hemodynamic effects of aortic paravalvular leak (PVL) and predictors of clinical outcomes after aortic PVL closure. BACKGROUND The significance of hemodynamic alterations in PVL and relation to severity, procedural success of percutaneous closure and clinical outcomes have not been defined. METHODS Patients undergoing percutaneous PVL closure between July 21, 2004 and September 10, 2018 were included. PVL severity was assessed by echocardiography and aortic angiography. Hemodynamics were assessed by intra-arterial pressure tracings before and after PVL closure. The primary outcome was a composite of mortality, redo aortic valve replacement (AVR) and redo PVL closure. RESULTS One hundred and seventeen patients (mean age 70.3 ± 14.9 years, 79% surgical and 21% transcatheter prostheses) underwent PVL closure with 94% technical success. PVL was moderate or greater in 106 (91%) at baseline and 11 (11%) post-procedure. Diastolic BP for those with moderate or greater PVL was lower than for those with less PVL (50.3 ± 11.7 vs. 56.5 ± 12.4 mmHg, p

Mice with mutant ATG16L develop spontaneous, severe Alzheimer’s-like disease with age, despite normal autophagy., Noncanonical functions of autophagy proteins have been implicated in neurodegenerative conditions, including Alzheimer’s disease (AD). The WD domain of the autophagy protein Atg16L is dispensable for canonical autophagy but required for its noncanonical functions. Two-year-old mice lacking this domain presented with robust β-amyloid (Aβ) pathology, tau hyperphosphorylation, reactive microgliosis, pervasive neurodegeneration, and severe behavioral and memory deficiencies, consistent with human disease. Mechanistically, we found this WD domain was required for the recycling of Aβ receptors in primary microglia. Pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in this novel AD model. Therefore, loss of the Atg16L WD domain drives spontaneous AD in mice, and inhibition of neuroinflammation is a potential therapeutic approach for treating neurodegeneration and memory loss. A decline in expression of ATG16L in the brains of human patients with AD suggests the possibility that a similar mechanism may contribute in human disease.

Background/AimsTo analyse the complications and outcomes of vitrectomy surgery for endophthalmitis.MethodsThis was a retrospective case series. All cases that underwent 23-gauge vitrectomy surgery for endophthalmitis at a tertiary centre between 1 February 2013 and 1 February 2018 were included. Main outcome measures were as follows: visual acuity (VA) at final visit and post-vitrectomy complications.Results33 patients were included in the study with 20 men and 13 women, average age 63 years. Main post-surgical causes for endophthalmitis included phacoemulsification (n=9), trabeculectomy (n=5), intravitreal injection (n=5), corneal graft (n=4), vitreoretinal surgery (n=3) and endogenous endophthalmitis (n=6). Average follow-up was 18 months (SD 14). 21/33 (64%) patients had baseline perception of light VA. Analysis of exogenous endophthalmitis cases only demonstrated: mean LogMAR VA improved significantly from 2.68 to 1.66 (p=0.001). At final follow-up, 12% had VA of 6/12 or better, and 28% had VA of 6/36 or better. Vitrectomy within 7 days resulted in improved final VA outcomes (1.49 vs 2.16 LogMAR, p=0.032). Complications included retinal detachment (24.2%), macular hole (3%), hypotony (6%), suprachoroidal haemorrhage (3%) and enucleation/evisceration (6%).ConclusionVitrectomy for endophthalmitis leads to VA gains in some cases. Surgical outcomes may be improved with early vitrectomy performed within 7 days of the initial event for exogenous endophthalmitis. Patients should be advised of the potential risk of severe complications with/and without surgery.

Background Transcatheter edge-to-edge mitral valve repair (TMVR; MitraClip, Abbott Vascular) is clinically approved for treatment of severe, symptomatic mitral regurgitation (MR) in high or prohibitive surgical risk patients. Iatrogenic mitral stenosis is a known complication of TMVR, but determinants of increased post-procedure mean diastolic gradient are not well defined. Purpose We aimed to investigate the determinants of increased mitral mean diastolic gradient after TMVR. Methods We retrospectively reviewed 59 patients. 2D and 3D TEE data sets acquired before and immediately after procedure were analyzed. 4D Cardio-View and 4D MV-Assessment (TomTec, Germany) were used for the analysis of the 3D volume data set. Quantitative mitral valve analysis was done at the end of systole. Increased mitral mean diastolic gradient after TMVR was correlated with pre-procedure 2D and 3D echocardiographic data. Results 34 patients had primary MR, 25 patients had mixed/secondary MR. Baseline mean mitral diastolic gradient was 2.0 ± 0.9mmHg and increased to 3.9 ± 1.8mmHg post-TMVR and the mean 3D planimetric mitral valve area decreased from 5.3 ± 1.5cm2 to 2.6 ± 1.0cm2. Implantation of multiple clips was performed less frequently in patients with smaller baseline mitral valve area; 8% vs 47% in the lowest quartile vs all others (p = 0.006). 12(20%) of patients had a mean diastolic gradient >5mmHg post-TMVR and 15(25%) of patients had a post-TMVR mitral valve area 5mmHg (p = 0.08). Patient characteristics according to post-TMVR mean diastolic gradient are shown in the Table. Post-TMVR mean diastolic gradient >5mmHg was more common in patients with increased pre-procedure mean diastolic gradient(p = 0.006), post-TMVR mitral valve area 5mmHg(p = 0.04). Conclusions Elevated post-TMVR mean diastolic gradient is multifactorial and related to mitral stenosis, but residual mitral regurgitation also appears to be an important contributor to increased gradients in some patients. Larger cohorts are likely needed to assess the concurrent impact of mitral annular calcification, leaflet calcification, and other variables on post-TMVR mean gradient. Abstract P1798 Figure. 2D and 3D Echocardiographic Parameters

HIV status disclosure among people living with HIV/AIDS has been shown to have a number of both personal and public health benefits, but rates of HIV status disclosure remain low in many African countries, including the Democratic Republic of the Congo (DRC). This systematic review uses the Disclosure Process Model to examine the factors involved in serostatus disclosure and nondisclosure to various persons in the lives of people living with HIV/AIDS (PLWHA) in the DRC, as well as the specific outcomes of their disclosure or nondisclosure. MEDLINE/PubMed, Embase, Web of Science, Global Health, and PsycINFO were searched and research studies were included if: (i) the study discussed disclosure of HIV status; (ii) the study population included HIV-infected people in DRC; and (iii) the study was published in English. Fourteen articles met the inclusion criteria and were included in the study. Factors contributing to nondisclosure were generally associated with high stigma of HIV in adults and concern for emotional wellbeing when disclosing to HIV positive minors. Factors contributing to disclosure among adults were increased social support and religion. In disclosing to HIV positive minors, increasing age and health benefits were identified as approach goals that supported disclosure. The findings highlight the importance of understanding the avoidance and approach goals involved in HIV status disclosure among populations living in the DRC. Interventions and future research directed at increasing HIV disclosure among Congolese PLWHA should move beyond individual-level to consider multilevel factors including circumstantial social behaviors.

OBJECTIVES: To present the visual acuity (VA) results and complication rates following Artisan intraocular lens (IOL) insertion in vitrectomised eyes. METHODS: Outcome data were collected for all vitrectomised patients who had undergone Artisan IOL insertion between January 2014 and May 2019 at Moorfields Eye Hospital. All those with follow-up greater than 2 months were included in the analysis. RESULTS: Sixty-nine eyes from 61 patients were included. Average follow up was 2 years. Fifty-five (80%) eyes had at least one ocular comorbidity prior to Artisan IOL insertion. At final follow up 46 (67%) eyes had best-corrected VA better than 6/12. Sixty-three eyes (91%) either gained or maintained VA. Mean post-operative spherical equivalent was −0.2D. Two (3%) lenses became de-enclavated requiring further surgery. Two (3%) eyes developed acute post-operative cystoid macular oedema. Two (3%) required additional topical IOP-lowering therapy to their pre-operative glaucoma regimen. One eye had mild corneal oedema, which persisted for 1 year following surgery and subsequently resolved. CONCLUSIONS: Artisan IOL insertion is a safe and effective option for the surgical correction of aphakia in vitrectomised eyes lacking capsular support. Refractive results comparable to posterior chamber IOL placement can be achieved with these lenses.

In patients with unexplained cardiomyopathy, electroanatomical mapping can identify abnormal tissue to target during electrophysiology-guided endomyocardial biopsy (EP-guided EMB). The objective of this study is to determine whether catheter ablation performed in the same setting as EP-guided EMB increases procedural risk. Sixty-seven patients (mean age 54.4 ± 13.8, 57% male) undergoing EP-guided EMB were included. Radiofrequency catheter ablation was performed in 17 patients (25%) for ventricular arrhythmias and in 2 (3%) for typical atrial flutter. Femoral arterial access was obtained in 90% ablation patients and 40% biopsy-only patients; vascular access complications were more common in the ablation group than in the EMB-only group (p = 0.02). There were no significant differences in rate of tricuspid regurgitation, thromboembolism, or pericardial effusion, whether procedural anticoagulation was used. In conclusion, catheter ablation and procedural anticoagulation can be combined with EP-guided EMB with an increased risk of vascular access complications, but no significant increase in intracardiac complications.

Members of the SCY1-like (SCYL) family of protein kinases are evolutionarily conserved and ubiquitously expressed proteins characterized by an N-terminal pseudokinase domain, centrally located Huntingtin, elongation factor 3, protein phosphatase 2A, yeast kinase TOR1 repeats, and an overall disorganized C-terminal segment. In mammals, three family members encoded by genesScyl1,Scyl2, andScyl3have been described. Studies have pointed to a role for SCYL1 and SCYL2 in regulating neuronal function and viability in mice and humans, but little is known about the biological function of SCYL3. Here, we show that the biochemical and cell biological properties of SCYL3 are similar to those of SCYL1 and both proteins work in conjunction to maintain motor neuron viability. Specifically, although lack ofScyl3in mice has no apparent effect on embryogenesis and postnatal life, it accelerates the onset of the motor neuron disorder caused byScyl1deficiency. Growth abnormalities, motor dysfunction, hindlimb paralysis, muscle wasting, neurogenic atrophy, motor neuron degeneration, and loss of large-caliber axons in peripheral nerves occurred at an earlier age inScyl1/Scyl3double-deficient mice than inScyl1-deficient mice. Disease onset also correlated with the mislocalization of TDP-43 in spinal motor neurons, suggesting that SCYL1 and SCYL3 regulate TDP-43 proteostasis. Together, our results demonstrate an overlapping role for SCYL1 and SCYL3in vivoand highlight the importance the SCYL family of proteins in regulating neuronal function and survival. Only male mice were used in this study.SIGNIFICANCE STATEMENTSCYL1 and SCYL2, members of the SCY1-like family of pseudokinases, have well established roles in neuronal function. Herein, we uncover the role of SCYL3 in maintaining motor neuron viability. Although targeted disruption ofScyl3in mice had little or no effect on embryonic development and postnatal life, it accelerated disease onset associated with the loss ofScyl1, a novel motor neuron disease gene in humans.Scyl1andScyl3double-deficient mice had neuronal defects characteristic of amyotrophic lateral sclerosis, including TDP-43 pathology, at an earlier age than didScyl1-deficient mice. Thus, we show that SCYL1 and SCYL3 play overlapping roles in maintaining motor neuronal viabilityin vivoand confirm that SCYL family members are critical regulators of neuronal function and survival.

Coronary embolism is the underlying cause of 3% of acute coronary syndromes but is often not considered in the differential of acute coronary syndromes. It should be suspected in the case of high thrombus burden despite a relatively normal underlying vessel or recurrent coronary thrombus. Coronary embolism may be direct (from the aortic valve or left atrial appendage), paroxysmal (from the venous circulation through a patent foramen ovale), or iatrogenic (following cardiac intervention). Investigations include transesophageal echocardiography to assess the left atrial appendage and atrial septum and continuous electrocardiographic monitoring to assess for paroxysmal atrial fibrillation. The authors review the historic and contemporary published data about this important cause of acute coronary syndromes. The authors propose an investigation and management strategy for work-up and anticoagulation strategy for patients with suspected coronary embolism.

Donor-derived malignancy, particularly melanoma, is a rare but known complication of organ transplantation. Here we describe a case of metastatic melanoma in a deceased-donor kidney transplant recipient. After diagnosis, the patient was successfully treated with cessation of immunosuppression, explantation of the renal allograft, and novel melanoma therapies, including the mutation-targeted agents dabrafenib and trametinib and the immune checkpoint inhibitor nivolumab. These 2 new classes of melanoma therapy have revolutionized the course of metastatic melanoma, altering it from one of nearly certain mortality to one of potential cure. This case reviews the mechanisms of action of these therapies and reports our experience with them in the rare setting of donor-derived melanoma in a dialysis-dependent patient.

Objectives The aim of this study was to demonstrate the physiologic effects of percutaneous mitral paravalvular leak (PVL) closure through pre- and post-closure left and right heart catheterization. Background Mitral PVL represents a significant source of morbidity and mortality following mitral valve repair and replacement. Although percutaneous PVL closure is an effective treatment with improvements in symptoms and mortality, data regarding the acute hemodynamic effects of such closure are lacking. Methods Consecutive patients with clinically significant heart failure and/or hemolysis attributed to mitral PVL underwent percutaneous mitral PVL closure with pre- and post-procedural right and left heart catheterization. Hemodynamic measurements of cardiovascular function obtained in this manner were compared and stratified according to pre- and post-procedural echocardiographic severity of PVL. Results Twenty-four patients (age 68 ± 9.4 years, 75% male) underwent percutaneous mitral PVL closure. Significant improvements were found in left atrial pressure (LAP) (mean LAP lowered from 21 ± 4 to 19 ± 3 mm Hg, P = 0.005), pulmonary artery pressure (PAP) (mean PAP lowered from 36 ± 11 to 33 ± 9, P = 0.04), and cardiac index (increased from 2.8 ± 0.8 to 3.0 ± 0.7 L/min/m2, P = 0.01). Left atrial v-wave reduction of 20% was associated with ≤ mild residual PVL by transesophageal echocardiography (P = 0.09). Conclusions Percutaneous mitral PVL closure is associated with significant reductions in LAP and PAP and an increase in cardiac index. These hemodynamic effects underlie the clinical benefits of PVL closure and may be a useful tool for intraprocedural guidance. © 2017 Wiley Periodicals, Inc.

Marek's disease virus (MDV) is a herpesvirus that induces lymphoma and immunosuppression in chickens. MDV-induced immunosuppression (MDV-IS) is complex and can be divided into two phases: early-MDV-IS associated with cytolytic infection in the lymphoid organs in chickens lacking maternal antibodies against MDV (MAbs) and late-MDV-IS that appears later in the pathogenesis and occurs even in chickens bearing MAbs. We have recently developed a model to reproduce late-MDV-IS under laboratory conditions. This model evaluates late-MDV-IS indirectly by assessing the effect of MDV infection on the efficacy of infectious laryngotracheitis (ILT) vaccines against challenge with ILT virus. In the present study, we have used this model to investigate the role of two factors (MDV pathotype and host sex) on the development of late-MDV-IS. Five MDV strains representing three different pathotypes: virulent (vMDV; 617A, GA), very virulent (vvMDV; Md5), and very virulent plus (vv+MDV; 648A, 686), were evaluated. Only vv+ strains were able to induce late-MDV-IS. An immunosuppression rank (IS-rank) was established based on the ability of MDV to reduce the efficacy of chicken embryo origin vaccine (values go from 0 to 100, with 100 being the highest immunosuppressive ability). The IS-rank of the evaluated MDV strains ranged from 5.97 (GA) to 20.8 (617A) in the vMDV strains, 5.97 to 16.24 in the vvMDV strain Md5, and 39.08 to 68.2 in the vv+ strains 648A and 686. In this study both male and female chickens were equally susceptible to MDV-IS by vv+MDV 686. Our findings suggest that late-MDV-IS is a unique feature of vv+ strains.