Risk factors for renal dysfunction after isolated intestinal transplantation.

INTRODUCTION: Kidney dysfunction is a known complication of intestinal transplantation; however, the rate of development and risk factors for chronic kidney disease (CKD) remain poorly defined. METHODS: This was a single-center retrospective review of isolated adult intestinal allograft recipients from 2011 to 2019. Patients who died or experienced graft loss within 1-year or had a prior transplant were excluded. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation at 0-, 6- and 12-months post-transplant, and multivariable linear regression was performed to identify variables associated with adjusted eGFR at 1-year. Independent variables included age, ethnicity, BMI, history of diabetes/hypertension, vasopressor use, TPN and stoma days, urinary or bloodstream infections, intravenous contrast exposure, rejection, concomitant immunosuppression, and time above the therapeutic range of tacrolimus. Variables with a p < .1 in univariate analysis were considered for multivariable modeling. RESULTS: Thirty-three patients were included with a mean age of 43.9 ± 13.0. A mean 42.3% decline in eGFR was observed at 1-year post-transplant, with 15.2% of patients developing new stage 4/5 CKD. Factors associated with a greater decline in adjusted eGFR in the univariate model included increasing age, decreased BMI, stoma days, and vasopressor use. In the adjusted multivariable model patient age (ß = -.77, p < .01) and stoma days (ß = -.06, p < .01) remained significant. Tacrolimus and sirolimus exposure were not associated with decline in eGFR at 1 year. CONCLUSIONS: Renal dysfunction is common following intestinal transplantation. The need for stoma creation should be carefully considered, and reversal should be performed when feasible for renal protection.

Utility of nifedipine use for Doppler ultrasound early after liver transplantation to predict short-term complications and long-term outcomes.

PURPOSE: To evaluate the response to nifedipine administration measured by changes in hepatic arterial (HA) flow on post-operative Doppler ultrasound (US) to predict short-term complications and long-term outcomes in liver transplant (LT) patients. METHODS: Patients who underwent LT with post-operative Doppler US within 3 days between 1 January 2005 and 31 December 2015 were included in this retrospective single center study. The patients who received and did not receive nifedipine during the Doppler US comprised the study and control groups, respectively. A positive response to nifedipine was defined as the detection of HA flow when none was present initially or a reduction in HA resistive index (RI) ≥ 0.1 after nifedipine administration. The rates of re-transplantation, re-operation, percutaneous intervention (PCI), and overall survival (OS) were recorded. Cox proportional hazards regression was used to evaluate the association of clinic-demographic variables and Doppler findings with the outcome measures. RESULTS: 444 LT patients (305 M/139F, mean age 51.7 ± 17.4 years, mean interval between LT-Doppler US 1.12 ± 0.9 days) are presented. 220 patients comprised the nifedipine study group [n = 157/220 (71.4%) responder, n = 63/220 (28.6%) nonresponder] and 224 patients comprised the control group. There was no difference in re-transplantation or PCI rates between the groups (all p-values ≥ 0.2 and ≥ 0.08, respectively). The responder group had a lower rate of re-operation vs. the control group (15.9% vs. 24.1%, p = 0.03) and nonresponder group (15.9% vs. 31.8%, p = 0.004). 1-year and 2-year OS were similar between the groups (all p-values > 0.37). CONCLUSION: Short-term complication rates and long-term outcomes for patients with liver transplant who responded to nifedipine administration on Doppler US are similar to those who did not require nifedipine administration. A lack of response to nifedipine was associated with a higher re-operation rate.

Geography Influences Susceptibility to SARS-CoV-2 Serological Response in Patients With Inflammatory Bowel Disease: Multinational Analysis From the ICARUS-IBD Consortium.

BACKGROUND: Beyond systematic reviews and meta-analyses, there have been no direct studies of serological response to COVID-19 in patients with inflammatory bowel disease (IBD) across continents. In particular, there has been limited data from Asia, with no data reported from India. The ICARUS-IBD (International study of COVID-19 Antibody Response Under Sustained immunosuppression in IBD) consortium assessed serological response to SARS-CoV-2 in patients with IBD in North America, Europe, and Asia. METHODS: The ICARUS-IBD study is a multicenter observational cohort study spanning sites in 7 countries. We report seroprevalence data from 2303 patients with IBD before COVID-19 vaccination between May 2020 and November 2021. SARS-CoV-2 anti-spike and anti-nucleocapsid antibodies were analyzed. RESULTS: The highest and lowest SARS-CoV-2 anti-spike seropositivity rates were found in Asia (81.2% in Chandigarh and 57.9% in Delhi, India; and 0% in Hong Kong). By multivariable analysis, country (India: odds ratio [OR], 18.01; 95% confidence interval [CI], 12.03-26.95; P < .0001; United Kingdom: OR, 2.43; 95% CI, 1.58-3.72; P < .0001; United States: OR, 2.21; 95% CI, 1.27-3.85; P = .005), male sex (OR, 1.46; 95% CI, 1.07-1.99; P = .016), and diabetes (OR, 2.37; 95% CI, 1.04-5.46; P = .039) conferred higher seropositivity rates. Biological therapies associated with lower seroprevalence (OR, 0.22; 95% CI, 0.15-0.33; P < .0001). Multiple linear regression showed associations between anti-spike and anti-nucleocapsid titers with medications (P < .0001) but not with country (P = .3841). CONCLUSIONS: While the effects of medications on anti-SARS-CoV-2 antibody titers in patients with IBD were consistent across sites, geographical location conferred the highest risk of susceptibility to serologically detectable SARS-CoV-2 infection. Over half of IBD patients in India were seropositive prior to vaccination. These insights can help to inform shielding advice, therapeutic choices, and vaccine strategies in IBD patients for COVID-19 and future viral challenges.

In this multinational study of SARS-CoV-2 seroprevalence prior to vaccination, including the first data from India, where over half of patients seroconverted, geographical location conferred the highest risk of susceptibility to serologically detectable infection.

Sociodemographic Factors Associated with Do-Not-Resuscitate Order Utilization in the Surgical Intensive Care Unit: An Observational Study.

The use of a do-not-resuscitate (DNR) order is a powerful tool in outlining end-of-life care. This study explores sociodemographic factors associated with selection of a DNR order and assigning a healthcare proxy in the Surgical Intensive Care Unit (SICU). A retrospective chart review of 312 patients who expired in the SICU over a 7-year period was conducted. We analyzed the association of sociodemographic factors to selection of a DNR order and assignment of a healthcare proxy. Year of admission, age, religion, and proxy were independently associated with selection of DNR. In particular, the relative chance of a DNR selection in 2019 compared to 2012 was 3.538 (95% CL = 2.001-6.255, P < .01). There are significant sociodemographic factors that influence DNR utilization, highlighting the need to consider the social and religious backgrounds when engaging patients and their families in end-of-life care. Future studies will need to be conducted on whether these sociodemographic factors influence surviving patients as this study's findings can only be applied to those who have expired.

Lessons learned from a social worker's approach to advance care planning discussions with Chinese-immigrant oncology outpatients.

PURPOSE: To examine Chinese-immigrant cancer patients' openness to advance care planning (ACP) in an outpatient oncology setting. DESIGN: Retrospective review of social work assessment data. SAMPLE: 150 Chinese-immigrant patient charts were reviewed (55% Cantonese, 45% Mandarin). METHODS: Data were summarized descriptively and with logistic regression analyses. FINDINGS: Sixteen percent of patients had completed ACP prior to meeting with the oncology social worker (OSW). Twenty percent of patients agreed to complete a health care proxy (HCP) after receiving culturally-tailored education in their language of origin from the OSW, while 75% remained open to ongoing consideration of ACP and HCP completion. CONCLUSIONS: This study illuminates how Chinese immigrants engage in ACP discussions in an oncology setting. IMPLICATIONS FOR PSYCHOSOCIAL PROVIDER: OSWs can play an integral role in advocating, educating, and intervening with this population and can assist the interdisciplinary team in understanding the importance of the cultural differences, even if the OSW's primary language differs from that of a patient's.

Placement of Simultaneous Inferior Vena Cava Filter During Emergent Open Pulmonary Thromboembolectomy.

BACKGROUND: This study retrospectively reviewed results of simultaneous (SIM) inferior vena cava (IVC) filter and separate (SEP) IVC filter placement with open pulmonary thromboembolectomy (PTE) in pulmonary embolism and its clinical outcomes. MATERIALS AND METHODS: From November 2006 to May 2014, 23 patients (14 females and 9 males; median age 58 years; range, 21-88 years) underwent emergent PTE for submassive (12) or massive (11) pulmonary embolism (PE). All had a preoperative computed tomography (CT) scan and echocardiography consistent with right ventricular (RV) strain. Mean cardiopulmonary bypass times and temperatures; chest tube outputs; length of stay; perioperative complications; and survival were compared between groups. RESULTS: There were 13 patients in the SIM group and 10 in the SEP group. PE consisted of 14 acute (60.9%) and nine acute on chronic (39.1%). There were seven deaths (30.4%). Median follow up was 44 days (range, 2-2204 days). Follow up was 81% complete in surviving patients. Actuarial survival at one and three years was 83% for the SIM group and 43% for the SEP group, respectively. There were no differences in cardiopulmonary bypass (CPB) times and temperatures, chest tube outputs, or length of stay between groups. Using multivariable logistic regression, we found SIM was associated with increased survival (p=0.09). Further analysis showed patients >55 years in the SEP group were at significantly higher risk of death (hazard ratio [HR]=7.1:1; 95% confidence interval [CI]: 1.55, 32.5, p=0.011). CONCLUSION: IVC filter placement can be performed simultaneously and safely at PTE. Age >55 years and PTE with IVC filter placed separately were at significantly higher risk of death. A larger cohort is needed to evaluate efficacy of simultaneous IVC filter placement and PTE.

Inhibition of HIPK2 Alleviates Thoracic Aortic Disease in Mice With Progressively Severe Marfan Syndrome.

Objective: Despite considerable research, the goal of finding nonsurgical remedies against thoracic aortic aneurysm and acute aortic dissection remains elusive. We sought to identify a novel aortic PK (protein kinase) that can be pharmacologically targeted to mitigate aneurysmal disease in a well-established mouse model of early-onset progressively severe Marfan syndrome (MFS). Approach and Results: Computational analyses of transcriptomic data derived from the ascending aorta of MFS mice predicted a probable association between thoracic aortic aneurysm and acute aortic dissection development and the multifunctional, stress-activated HIPK2 (homeodomain-interacting protein kinase 2). Consistent with this prediction, Hipk2 gene inactivation significantly extended the survival of MFS mice by slowing aneurysm growth and delaying transmural rupture. HIPK2 also ranked among the top predicted PKs in computational analyses of DEGs (differentially expressed genes) in the dilated aorta of 3 MFS patients, which strengthened the clinical relevance of the experimental finding. Additional in silico analyses of the human and mouse data sets identified the TGF (transforming growth factor)-ß/Smad3 signaling pathway as a potential target of HIPK2 in the MFS aorta. Chronic treatment of MFS mice with an allosteric inhibitor of HIPK2-mediated stimulation of Smad3 signaling validated this prediction by mitigating thoracic aortic aneurysm and acute aortic dissection pathology and partially improving aortic material stiffness. Conclusions: HIPK2 is a previously unrecognized determinant of aneurysmal disease and an attractive new target for antithoracic aortic aneurysm and acute aortic dissection multidrug therapy.

Tacrolimus time-in-therapeutic range is associated with freedom from acute rejection and graft failure following intestinal transplantation.

BACKGROUND: Trough-adjusted tacrolimus is commonly prescribed following intestinal transplantation to prevent allograft rejection. Despite established practice, there remains limited direct evidence linking tacrolimus levels with improved clinical outcomes. METHODS: This was a single-center review of all adult non-liver containing intestinal allograft recipients from 2011 to 2018. Patients received lymphocyte depleting induction and maintenance immunosuppression consisting of tacrolimus and a corticosteroid taper. Tacrolimus time-in-therapeutic range (TAC-TTR) was calculated for all patients from the date of transplant until 1-year post-transplant using Rosendaal's method. Cox-Proportional hazards modeling was utilized to assess freedom from acute rejection and graft failure stratified by TAC-TTR quartile. RESULTS: 47 patients were included in the review. Mean TAC-TTR for the cohort was 30.2% ± 11.4. Fifteen episodes of acute rejection were observed, 8 of which were severe. Patients in the highest TAC-TTR quartile >36% had a lower incidence of acute rejection and graft failure relative to patients with a TAC-TTR <20%. Cox-Proportional hazards modeling found a 10% decrease in TAC-TTR was associated with an increased hazard for acute rejection (2.03), severe acute rejection (2.19), and graft loss (3.33). CONCLUSION: The results of this study suggest that decreasing TAC-TTR is a risk factor for both acute rejection as well as intestinal allograft failure.

Hydroxylation of N-acetylneuraminic Acid Influences the in vivo Tropism of N-linked Sialic Acid-Binding Adeno-Associated Viruses AAV1, AAV5, and AAV6.

Adeno-associated virus (AAV) vectors are promising candidates for gene therapy. However, a number of recent preclinical large animal studies failed to translate into the clinic. This illustrates the formidable challenge of choosing the animal models that promise the best chance of a successful translation into the clinic. Several of the most common AAV serotypes use sialic acid (SIA) as their primary receptor. However, in contrast to most mammals, humans lack the enzyme CMAH, which hydroxylates cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac) into cytidine monophosphate-N-glycolylneuraminic acid (CMP-Neu5Gc). As a result, human glycans only contain Neu5Ac and not Neu5Gc. Here, we investigate the tropism of AAV1, 5, 6 and 9 in wild-type C57BL/6J (WT) and CMAH knock-out (CMAH-/-) mice. All N-linked SIA-binding serotypes (AAV1, 5 and 6) showed significantly lower transduction of the heart in CMAH-/- when compared to WT mice (5-5.8-fold) and, strikingly, skeletal muscle transduction by AAV5 was almost 30-fold higher in CMAH-/- compared to WT mice. Importantly, the AAV tropism or distribution of expression among different organs was also affected. For AAV1, AAV5 and AAV6, expression in the heart compared to the liver was 4.6-8-fold higher in WT than in CMAH-/- mice, and for AAV5 the expression in the heart compared to the skeletal muscle was 57.3-fold higher in WT than in CMAH-/- mice. These data thus strongly suggest that the relative abundance of Neu5Ac and Neu5Gc plays a role in AAV tropism, and that results obtained in commonly used animal models might not translate into the clinic.

Surveillance of high-risk individuals for pancreatic cancer with EUS and MRI: A meta-analysis.

BACKGROUND/OBJECTIVES: Consensus guidelines recommend surveillance of high-risk individuals (HRIs) for pancreatic cancer (PC) using endoscopic ultrasonography (EUS) and/or magnetic resonance imaging (MRI). This study aims to assess the yield of PC surveillance programs of HRIs and compare the detection of high-grade dysplasia or T1N0M0 adenocarcinoma by EUS and MRI. METHODS: The MEDLINE and Embase (Ovid) databases were searched for prospective studies published up to April 11, 2019 using EUS and/or MRI to screen HRIs for PC. Baseline detection of focal pancreatic abnormalities, cystic lesions, solid lesions, high-grade dysplasia or T1N0M0 adenocarcinoma, and all pancreatic adenocarcinoma were recorded. Weighted pooled proportions of outcomes detected were compared between EUS and MRI using random effects modeling. RESULTS: A total of 1097 studies were reviewed and 24 were included, representing 2112 HRIs who underwent imaging. The weighted pooled proportion of focal pancreatic abnormalities detected by baseline EUS (0.34, 95% CI 0.30-0.37) was significantly higher (p = 0.006) than by MRI (0.31, 95% CI 0.28-0.33). There were no significant differences between EUS and MRI in detection of other outcomes. The overall weighted pooled proportion of patients with high-grade dysplasia or T1N0M0 adenocarcinoma detected at baseline (regardless of imaging modality) was 0.0090 (95% CI 0.0022-0.016), corresponding to a number-needed-to-screen (NNS) of 111 patients to detect one high-grade dysplasia or T1N0M0 adenocarcinoma. CONCLUSIONS: Surveillance programs are successful in detecting high-risk precursor lesions. No differences between EUS and MRI were noted in the detection of high-grade dysplasia or T1N0M0 adenocarcinoma, supporting the use of either imaging modality.

Psychometric Study of the Social Responsiveness Scale in Phelan-McDermid Syndrome.

The Social Responsiveness Scale-2 (SRS-2) is a quantitative measure used to characterize symptoms of autism spectrum disorder (ASD). However, research suggests that SRS-2 scores are significantly influenced by language ability and intellectual disability (ID). Efforts to refine the SRS-2 by Sturm, Kuhfeld, Kasari, and Mccracken [Journal of Child Psychology and Psychiatry, 58(9), 1053-1061] yielded a shortened form, yet its psychometric properties in populations with severe ID remain unknown. This study aims to examine the psychometric properties of the SRS-2 in Phelan-McDermid syndrome (PMS), a genetic condition associated with ASD and ID, thereby guiding score interpretation in this population and future development of targeted scales. Analyses, including Item Response Theory (IRT), were conducted on a sample of individuals with PMS (n = 91) recruited at six sites nationally. Psychometric properties evaluated include measures of reliability (internal consistency, test-retest reliability) and validity (structural, construct, content). While both SRS-2 forms are reliable, the shortened SRS-2 shows superior validity to the full SRS-2 for measuring ASD symptoms in PMS. On IRT analysis, the shortened SRS-2 shows excellent discrimination and precisely evaluates respondents across a wide range of ASD symptomatology but interpretation is limited by uncertain content validity and small sample size. The shortened SRS-2 shows some promise for use in PMS, but future refinements and additions are needed to develop items that are tailored to identify ASD in children with severe ID and specifically PMS. LAY SUMMARY: This study determined that a shortened form of the Social Responsiveness Scale, Second Edition (SRS-2) shows both promise and limitations for the characterization of autism symptomatology in individuals with Phelan-McDermid syndrome (PMS), a population characterized by intellectual disability (ID). Caution should be used when interpreting SRS-2 scores in individuals with ID and future research should modify existing items and develop new items to improve the SRS-2's ability to accurately characterize autism symptomatology in PMS. Autism Res 2020, 13: 1383-1396. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

A visual analog scale for patient-reported voice outcomes: The VAS voice.

OBJECTIVES: Although patient-reported outcome measures (PROMs) can be useful for assessing quality of life, they can be complex and cognitively burdensome. In this study, we prospectively evaluated a simple patient-reported voice assessment measure on a visual analog scale (VAS voice) and compared it with the Voice Handicap Index (VHI-10). STUDY DESIGN: Prospective survey. METHODS: An abbreviated voice measure was designed by a team of otolaryngologists, speech pathologists, and patients that consisted of four VAS questions related to (a) a global question of voice disturbance, (b) physical function of voice, (c) functional issues, and (d) emotional handicap. All English-speaking patients presenting to an academic laryngology clinic for a voice complaint were included. Internal consistency and validity were assessed with comparison to the VHI-10. RESULTS: A total of 209 patients were enrolled. Ninety-two percent of patients reported understanding the survey. The four-item VAS survey was highly correlated with VHI-10 score (Pearson correlation .81, P < .0001), and the Cronbach's alpha between all four VAS questions was .94. Age, gender, and diagnosis were not associated with either the global VAS or VHI-10 tool. CONCLUSION: Reducing the complexity of instruments assessing voice-related quality of life is feasible, and the VAS voice correlated with existing measures. Simplified assessments may offer advantages compared to more cumbersome PROMs. LEVEL OF EVIDENCE: 2c.

Utilization of peritoneal dialysis in the United States: Reasons for underutilization, specifically in New York State and the boroughs of New York City.

Peritoneal dialysis (PD) is currently underutilized in the United States (US), even within resource-rich neighborhoods. We analyzed data from US Renal Data Service to determine PD utilization within the US, New York State (NYS), selected boroughs within New York City (NYC), and Boston, Massachusetts. We then compared the odds of selecting PD with hemodialysis (HD) and analyzed how diabetes mellitus status, age >65 years, gender, and race influenced PD utilization between 2010 and 2016. We then compared a high-volume PD center (HVC) with a low-volume PD center (LVC). The odds of starting PD vs HD were as follows: Brooklyn 0.30 (0.25-0.36; <0.0001), Bronx 0.56 (0.47-0.67; <0.0001), Queens 0.66 (0.54-0.80; <0.0001), and Manhattan 0.61 (0.52-0.71; <0.0001). In 2016, the odds of starting PD compared with the rest of the US were as follows: Brooklyn 0.14 (0.08-0.22; <0.0001), Bronx 0.39 (0.27-0.56; <0.0001), Queens 0.32 (0.23-0.45; <0.0001), Manhattan 0.54 (0.36-0.79; 0.002), and Boston 0.89 (0.58-1.4; 0.624). Analysis of influencing factors showed that only age >65 significantly (<0.0001) influenced PD modality selection in Brooklyn and Boston. Differences between HVC and LVC in terms of modality transition, peritonitis rate, or provider:patient ratio were not statistically significant. Factors that influence PD utilization in urban neighborhoods are discussed and remediation measures are proposed.

Conversion to belatacept within 1-year of renal transplantation in a diverse cohort including patients with donor-specific antibodies.

Early conversion from a calcineurin inhibitor to belatacept has the potential to improve long-term renal allograft function; however, there remains limited experience with this strategy among African Americans and patients with preformed donor-specific antibodies (DSA). To examine these subgroups, we performed a single-center review of kidney transplant recipients converted to belatacept within 1-year of transplant between 01/2011 and 10/2017. All patients received lymphocyte-depleting induction with maintenance tacrolimus and mycophenolate +/- corticosteroids. Patients were switched to belatacept for clinical indication and followed from date of conversion until allograft failure or study conclusion. The primary endpoint at 1-year was a composite of allograft loss, biopsy proven rejection, de novo DSA formation, proteinuria, and declining renal function. Thirty-two patients were included in the review. The majority were African American, and 28.1% had DSA at transplant. Patient and allograft survival at 1-year was 96.9% and 93.8%, respectively, and estimated glomerular filtration rate improved from 41.9 to 58.4 mL/min. No African Americans or patients with pretreatment DSA developed rejection or allograft failure within 1-year. The only clinical variable correlated with suboptimal allograft function was baseline weight ≥80 kg (OR = 6.2; 95% CI, 1.2-32.3). Early conversion to belatacept appears safe for select patients with DSA and African Americans receiving lymphocyte-depleting induction.

Safety of direct-acting oral anticoagulants relative to warfarin in a matched cohort of liver transplant recipients.

Despite increasingly widespread utilization of direct-acting oral anticoagulants (DOACs), there remains limited experience with the use of these agents following liver transplantation. We performed a single-center, retrospective review of liver transplant recipients prescribed DOACs or warfarin between January 2014 and January 2018. Patients receiving DOACs were matched with warfarin-treated controls based on discrete clinical parameters and followed from the time of anticoagulant prescription, until treatment discontinuation or study conclusion. The primary endpoint for this review was the incidence of clinically relevant major or non-major bleeding among the treatment groups. Twenty-seven patients prescribed DOACs were identified for inclusion in the review, of which 20 could be matched with suitable warfarin controls. At the conclusion of the study, warfarin-treated patients had a significantly higher incidence of clinically relevant bleeding (45% vs 15%; P = .01). No statistically significant differences were found in the rate of new or recurrent thrombotic events. Multivariable logistic regression demonstrated that warfarin treatment was associated with a significantly higher odds of a bleeding event compared to treatment with a DOAC (OR = 6.9; 95% CI, 1.1-44.6). DOAC use appears relatively safe compared with warfarin in select liver transplant recipients. Patient-specific factors still bear consideration when selecting between the various anticoagulant options.

Outer Retinal Thickness and Fundus Autofluorescence in Geographic Atrophy.

PURPOSE: Most studies of fundus autofluorescence (FAF) in geographic atrophy (GA) have been nonquantitative, with inadequate registration of image modalities. Furthermore, as pointed out in the recent Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT, it is unclear whether decreased FAF would be correlated exclusively with a single category of OCT-defined atrophy. We sought to determine how FAF intensity in eyes with GA correlates with structural changes of the outer retina and choroid as seen on co-registered spectral domain OCT (SD-OCT) images. DESIGN: Retrospective cross-sectional. PARTICIPANTS: Twenty eyes of 11 patients with GA secondary to non-neovascular age-related macular degeneration (AMD). METHODS: Spectral domain OCT and FAF images for each eye were co-registered using MATLAB (MathWorks Inc, Natick, MA). On B-scans, the choroid, retinal pigment epithelium (RPE), photoreceptor (PR) layer, and outer nuclear layer (ONL) were segmented. Regions of interest (ROIs) including all atrophic and border regions were selected manually on the FAF scans. Regions of interest were subdivided into quartiles of FAF level to correlate with retinal thickness measurements taken along the B-scans. Mean choroid, RPE, PR, and ONL thicknesses were compared across quartiles using an analysis of variance factorial design testing for interaction effects, adjusted for repeated measures (on both eyes) with a within-subjects factor. RESULTS: Seventeen eyes of 10 patients were selected for analysis. The mean choroidal thicknesses were not significantly different across FAF quartiles, but the overall differences in mean RPE, PR layer, and ONL thicknesses across quartiles were statistically significant (analysis of variance, P < 0.001, P < 0.001, and P = 0.015, respectively). Post hoc analysis demonstrated significant differences in thickness among quartiles 1, 2, and 3 for the RPE and PR layers (Tukey, P < 0.01 in each case). The FAF quartiles within GA did not correlate exclusively with single categories of Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration-defined atrophy. CONCLUSIONS: Not only RPE but also PR layer thickness on SD-OCT varies significantly with FAF levels in GA. This suggests that although the RPE cells are losing thickness and function, evidenced by decreased FAF from fluorophores, delicate PR cells also succumb early in the disease process. These relationships should be pursued as a possibly better-detailed mechanism in GA.

Targeting thrombogenicity and inflammation in chronic HIV infection.

Persons with HIV infection (PWH) have increased risk for cardiovascular disease (CVD), but the underlying mechanisms remain unclear. Coronary thrombosis is known to provoke myocardial infarctions, but whether PWH have elevated thrombotic propensity is unknown. We compared thrombogenicity of PWH on antiretroviral therapy versus matched controls using the Badimon chamber. Measures of inflammation, platelet reactivity, and innate immune activation were simultaneously performed. Enrolled PWH were then randomized to placebo, aspirin (81 mg), or clopidogrel (75 mg) for 24 weeks to assess treatment effects on study parameters. Thrombogenicity was significantly higher in PWH and correlated strongly with plasma levels of D-dimer, soluble TNF receptors 1 and 2, and circulating classical and nonclassical monocytes in PWH. Clopidogrel significantly reduced thrombogenicity and sCD14. Our data suggest that higher thrombogenicity, interacting with inflammatory and immune activation markers, contributes to the increased CVD risk observed in PWH. Clopidogrel exhibits an anti-inflammatory activity in addition to its antithrombotic effect in PWH.

Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms.

Marfan syndrome (MFS) is associated with mutations in fibrillin-1 that predispose afflicted individuals to progressive thoracic aortic aneurysm (TAA) leading to dissection and rupture of the vessel wall. Here we combined computational and experimental approaches to identify and test FDA-approved drugs that may slow or even halt aneurysm progression. Computational analyses of transcriptomic data derived from the aortas of MFS patients and MFS mice (Fbn1mgR/mgR mice) predicted that subcellular pathways associated with reduced muscle contractility are key TAA determinants that could be targeted with the GABAB receptor agonist baclofen. Systemic administration of baclofen to Fbn1mgR/mgR mice validated our computational prediction by mitigating arterial disease progression at the cellular and physiological levels. Interestingly, baclofen improved muscle contraction-related subcellular pathways by upregulating a different set of genes than those downregulated in the aorta of vehicle-treated Fbn1mgR/mgR mice. Distinct transcriptomic profiles were also associated with drug-treated MFS and wild-type mice. Thus, systems pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.

Impact of a Child Life and Music Therapy Procedural Support Intervention on Parental Perception of Their Child's Distress During Intravenous Placement.

OBJECTIVES: Child life specialists and music therapists have a unique and integral role in providing psychosocial care to pediatric patients and families. These professionals are trained to provide clinical interventions that support coping and adjustment and reduce the risk of psychological trauma related to hospital visits and health care encounters. The researchers devised a multimodal approach using a combined child life and music therapy intervention to address procedure-related distress in patients receiving intravenous (IV) placement in the pediatric emergency department. The aim of this study was to investigate the efficacy of this collaborative intervention by evaluating parental perception of their child's distress. METHODS: This study was a prospective analysis investigating the impact of a child life and music therapy intervention on children aged 4 to 11 years old receiving an IV placement in the pediatric emergency department. Efficacy was evaluated by comparing scores between a 4-question pretest and subsequent 4-question posttest that asked the child's parent to evaluate how they anticipated their child would respond to the procedure, and then to evaluate how they perceived their child to have responded after the procedure. Qualitative data were collected in the form of open-ended comments, which were accommodated at the end of the posttest. Data were analyzed by the Cochran-Mantel-Haenszel method for testing repeated ordinal responses and the PROC GENMOD procedure in the SAS system software. RESULTS: A total of 41 participants were enrolled in this study. Results of the statistical analysis revealed significant differences between all pre- and posttest scores (P < 0.05), and significant likelihood that the patient would improve relative to the 4 questions, as a result of the child life and music therapy intervention. CONCLUSIONS: Improvement was demonstrated across all 4 questions, suggesting that the child life and music therapy intervention supported healthy, adaptive coping and helped to minimize distress experienced by patients during IV placement. These results underscore the importance and potential clinical impact of child life psychological preparation and psychotherapy-based music therapy interventions in reducing distress in pediatric patients during common medical procedures.