Psychosocial Evaluation of Living Kidney Donors: A Survey of Current Practices in the United States.

BACKGROUND: Best practices in psychosocial evaluation and care of living donor candidates and donors are not well established. METHODS: We surveyed 195 living kidney donor (LKD) transplant centers in United States from October 2021 to April 2022 querying (1) composition of psychosocial teams, (2) evaluation processes including clinical tools and domains assessed, (3) selection criteria, and (4) psychosocial follow-up post-donation. RESULTS: We received 161 responses from 104 programs, representing 53% of active LKD programs and 67% of LKD transplant volume in 2019. Most respondents (63%) were social workers/independent living donor advocates. Over 90% of respondents indicated donor candidates with known mental health or substance use disorders were initially evaluated by the psychosocial team. Validated psychometric or transplant-specific tools were rarely utilized but domains assessed were consistent. Active suicidality, self-harm, and psychosis were considered absolute contraindications in >90% of programs. Active depression was absolute contraindication in 50% of programs; active anxiety disorder was excluded 27%. Conditions not contraindicated to donation include those in remission: anxiety (56%), depression (53%), and posttraumatic stress disorder (41%). There was acceptance of donor candidates using alcohol, tobacco, or cannabis recreationally, but not if pattern met criteria for active use disorder. Seventy-one percent of programs conducted post-donation psychosocial assessment and use local resources to support donors. CONCLUSIONS: There was variation in acceptance of donor candidates with mental health or substance use disorders. Although most programs conducted psychosocial screening post-donation, support is not standardized and unclear if adequate. Future studies are needed for consensus building among transplant centers to form guidelines for donor evaluation, acceptance, and support.

Clinical Data Do Not Reliably Predict Duodenal Histology at Follow-up in Celiac Disease: A 13 Center Correlative Study.

Validated nonbiopsy methods to assure duodenal mucosal healing in celiac disease are lacking, yet ongoing mucosal injury is associated with anemia, osteoporosis, and lymphoma. Most providers utilize clinical data as surrogates of mucosal status to avoid additional esophagogastroduodenoscopy. The reliability of such surrogates to predict mucosal recovery has been incompletely evaluated. The aim of this study was to rigorously assess patterns of histologic mucosal recovery at follow-up in celiac disease and to correlate findings with clinical data. Gastrointestinal pathologists from 13 centers evaluated initial and follow-up duodenal biopsies from 181 celiac disease patients. Marsh scores and intraepithelial lymphocytes (IELs)/100 enterocytes were assessed blindly. Histology at follow-up was correlated with symptoms, immunoglobulin A anti-tissue transglutaminase titers and gluten-free diet adherence. Fifty-six/181 (31%) patients had persistent villous blunting and 46/181 (25%) patients had just persistently elevated IELs at follow-up, with only 79/181 (44%) patients having complete histologic remission. IEL normalization (82/181; 45%) lagged villous recovery (125/181;69%). In a minority of patients, villous blunting was limited to proximal duodenal biopsies. No correlation was found between Marsh scores and symptoms, normalization of immunoglobulin A anti-tissue transglutaminase serology, or diet adherence. Children showed greater recovery of Marsh score ( P <0.001) and IELs ( P <0.01) than adults. Persistent mucosal injury is common in celiac disease, with discordant villous/IEL normalization. Pathologist awareness of expected findings in celiac disease follow-up biopsies, including their frequent lack of correlation with clinical data, is important for patient management, and has implications for eligibility criteria for therapeutics currently in development.

Facilitation and Preferred Models for Delivering Substance Use Disorder Treatment in HIV Clinics: Results From a Multisite Randomized Trial.

BACKGROUND: Integrated addiction treatment in HIV clinics is associated with improved outcomes, yet it is offered inconsistently and with variable models of care. We sought to evaluate the impact of Implementation Facilitation ("Facilitation") on clinician and staff preference for provision of addiction treatment in HIV clinics with on-site resources (all trained or designated on-site specialist) versus outside resources (outside specialist or refer out). METHODS: From July 2017 to July 2020, surveys assessed clinician and staff preferences for addiction treatment models during control (ie, baseline), intervention, evaluation, and maintenance phases in 4 HIV clinics in the Northeast United States. RESULTS: During the control phase, among 76 respondents (response rate, 58%), the proportions who preferred treatment with on-site resources for opioid use disorder (OUD), alcohol use disorder (AUD), and tobacco use disorder (TUD) were 63%, 55%, and 63%, respectively. Compared with control, there were no significant differences in preferred model during the intervention and evaluation phases except for AUD where there was an increased preference for treatment with on-site resources in the intervention versus control phase. Compared with control, during the maintenance phase, a higher proportion of clinicians and staff preferred providing addiction treatment with on-site resources versus outside resources: OUD, 75% (odds ratio [OR; 95% confidence interval {CI}], 1.79 [1.06-3.03]); AUD, 73% (OR [95% CI], 2.23 [1.36-3.65]), and TUD, 76% (OR [95% CI], 1.88 [1.11-3.18]). CONCLUSIONS: The findings from this study lend support for "Facilitation" as a strategy to enhance clinician and staff preference for integrated addiction treatment in HIV clinics with on-site resources.

Human Immunodeficiency Virus Is Associated With Poor Overall Survival Among Patients With Head and Neck Cancer.

BACKGROUND: Head and neck squamous cell cancer (HNSCC) occurs at higher rates among persons with HIV (PWH). This study compares the impact of sociodemographic and clinicopathologic characteristics on outcomes among PWH-HNSCC compared with HNSCC patients without HIV. METHODS: Patient data from HNSCC individuals were collected at a single academic hospital center between 2002 and 2018. Forty-eight patients with HIV (HIV-HNSCC) and 2894 HNSCC patients without HIV were included. Multivariate analysis determined predictors of survival using Cox proportional hazards regression model. HIV-positive and -negative tumors were analyzed by quantitative immunofluorescence for expression of CD4, CD8, CD20 and PD-L1. RESULTS: HIV-HNSCC patients had a lower median overall survival than HNSCC patients without HIV (34 [18-84] vs 94 [86-103] months; P < .001). In multivariate analysis that included age, sex, race/ethnicity, stage, site, tobacco use, time to treatment initiation, and insurance status, HIV was an independent predictor of poorer survival, with a hazard ratio of 1.98 (95% CI: 1.32-2.97; P < .001). PWH with human papillomavirus (HPV)-positive oropharyngeal tumors also had worse prognosis than HPV-positive oropharyngeal tumors in the population without HIV (P < .001). The tumor microenvironment among HIV-HNSCC patients revealed lower intratumoral CD8 infiltration among HIV+ HPV+ tumors compared with HIV- HPV+ tumors (P = .04). CONCLUSIONS: HIV-HNSCC patients had worse prognosis than the non-HIV population, with HIV being an independent predictor of poor clinical outcomes when accounting for important sociodemographic and clinicopathologic factors. Our findings highlight differences in tumor biology that require further detailed characterization in large cohorts and increased inclusion of PWH in immunotherapy trials.

Effect of Implementation Facilitation to Promote Adoption of Medications for Addiction Treatment in US HIV Clinics: A Randomized Clinical Trial.

Importance: Medications for addiction treatment (MAT) are inconsistently offered in HIV clinics. Objective: To evaluate the impact of implementation facilitation (hereafter referred to as "facilitation"), a multicomponent implementation strategy, on increasing provision of MAT for opioid use disorder (MOUD), alcohol use disorder (MAUD), and tobacco use disorder (MTUD). Design, Setting, and Participants: Conducted from July 26, 2016, through July 25, 2020, the Working with HIV Clinics to adopt Addiction Treatment using Implementation Facilitation (WHAT-IF?) study used an unblinded, stepped wedge design to sequentially assign each of 4 HIV clinics in the northeastern US to cross over from control (ie, baseline practices) to facilitation (ie, intervention) and then evaluation and maintenance periods every 6 months. Participants were adult patients with opioid, alcohol, or tobacco use disorder. Data analysis was performed from August 2020 to September 2022. Interventions: Multicomponent facilitation. Main Outcomes and Measures: Outcomes, assessed using electronic health record data, were provision of MAT among patients with opioid, alcohol, or tobacco use disorder during the evaluation (primary outcome) and maintenance periods compared with the control period. Results: Among 3647 patients, the mean (SD) age was 49 (12) years, 1814 (50%) were Black, 781 (22%) were Hispanic, and 1407 (39%) were female; 121 (3%) had opioid use disorder, 126 (3%) had alcohol use disorder, and 420 (12%) had tobacco use disorder. Compared with the control period, there was no increase in provision of MOUD with facilitation during the evaluation period (243 patients [27%; 95% CI, 22%-32%] vs 135 patients [28%; 95% CI, 22%-35%]; P = .59) or maintenance period (198 patients [29%; 95% CI, 22%-36%]; P = .48). The change in provision of MAUD from the control period to the evaluation period was not statistically significant (251 patients [8%; 95% CI, 5%-12%] vs 112 patients [13%; 95% CI, 8%-21%]; P = .11); however, the difference increased and became significant during the maintenance period (180 patients [17%; 95% CI, 12%-24%]; P = .009). There were significant increases in provision of MTUD with facilitation during both the evaluation (810 patients [33%; 95% CI, 30%-36%] vs 471 patients [40%; 95% CI, 36%-45%]; P = .005) and maintenance (643 patients [38%; 95% CI, 34%-41%]; P = .047) periods. Conclusions and Relevance: In this randomized clinical trial, facilitation led to increased provision of MTUD, delayed improvements in MAUD, and no improvements in MOUD in HIV clinics. Enhanced strategies, potentially including clinic and patient incentives, especially for MOUD, may be needed to further increase provision of MAT in HIV clinics. Trial Registration: ClinicalTrials.gov Identifier: NCT02907944.

Widening volume and persistent outcome disparity in valve operations: New York statewide analysis, 2005-2016.

OBJECTIVES: Volume concentration of complex noncardiac operations to high-volume centers has been observed, but whether this is also occurring in cardiac surgery is unknown. We examined the relationship between volume concentration and mortality rates for valve surgery and coronary artery bypass grafting (CABG) between 2005 and 2016 in New York State. METHODS: We analyzed publicly available, hospital-level case volume and risk-adjusted mortality rates (RAMRs) from 2005 to 2016 for isolated CABG and isolated or concomitant valve operations performed in New York. We identified hospitals in the top- and bottom-volume quartiles for each procedure type and compared changes in percent market share and outcomes. Bivariate and univariate longitudinal analysis was used to evaluate the statistical significance of the temporal trend. RESULTS: Among 36 centers, percent market share of the top-volume quartile increased for valve cases from 54.4% to 59.4%, whereas CABG share increased from 41.4% to 44.3%. No significant changes were noted in market share for the bottom quartile. The top-volume quartile demonstrated significant trends in improving outcomes over the study period for both valve procedures (RAMR: -0.261%/year, P < .001) and CABG (RAMR: -0.071%/year, P = .018). No significant trends were noted in the bottom quartile for either procedure. CONCLUSIONS: In New York, over the last decade, highest-volume hospitals increased their market share for valve operations while maintaining lower mortality rates than lowest-volume hospitals. Valve volume is regionalizing in the setting of a persistent outcome gap between the highest- and lowest-volume hospitals, suggesting that volume-based referrals for specialized cardiac procedures may improve surgical mortality.

Incidence and associated risk factors for invasive fungal infections and other serious infections in patients on ibrutinib.

BACKGROUND: Ibrutinib is a small molecule tyrosine kinase inhibitor that blocks the activity of B cells and other immune effectors and is used in a variety of hematologic malignancies. There have been numerous reports of increased frequency of serious infections including invasive fungal infections (IFI) in patients on ibrutinib. METHODS: Demographic and clinical features of all patients receiving ibrutinib at a single tertiary care center were collected from electronic medical records. Univariate and multivariate statistical analyses were performed to find out the factors associated with infection. RESULTS: A total of 244 patients received ibrutinib for hematologic malignancies, of which 44 (18.0%) experienced ≥ 1 serious infection including 5 (2.0%) with IFI (1 pulmonary cryptococcosis, 4 pulmonary aspergillosis), 39 (16.0%) with bacterial infections and 8 (3.3%) with viral infections. Ten patients (4.1%) experienced multiple infections or co-infections while on ibrutinib and 10 (4.1%) expired or were transferred to hospice as a result of infection. In multivariate analysis risk factors that were less common in uninfected versus infected patients included advanced age (73 years vs. 77 years), Eastern Cooperative Oncologic Grade (ECOG) performance score ≥ 2 (6.5% vs. 31.8%) and concurrent use of steroids (4.5% vs. 20.5%) or other cytotoxic agents (0% vs. 4.6%). CONCLUSIONS: There was a high rate of serious infection but relatively few IFI in patients receiving ibrutinib. Most patients who developed serious infections while on ibrutinib had additional predisposing risk factors including concurrent use of steroids or other cytotoxic agents, advanced age and frailty.

Identifying enhancement-based staging markers on baseline MRI in patients with colorectal cancer liver metastases undergoing intra-arterial tumor therapy.

OBJECTIVES: To determine if three-dimensional whole liver and baseline tumor enhancement features on MRI can serve as staging biomarkers and help predict survival of patients with colorectal cancer liver metastases (CRCLM) more accurately than one-dimensional and non-enhancement-based features. METHODS: This retrospective study included 88 patients with CRCLM, treated with transarterial chemoembolization or Y90 transarterial radioembolization between 2001 and 2014. Semi-automated segmentations of up to three dominant lesions were performed on pre-treatment MRI to calculate total tumor volume (TTV) and total liver volumes (TLV). Quantitative 3D analysis was performed to calculate enhancing tumor volume (ETV), enhancing tumor burden (ETB, calculated as ETV/TLV), enhancing liver volume (ELV), and enhancing liver burden (ELB, calculated as ELV/TLV). Overall and enhancing tumor diameters were also measured. A modified Kaplan-Meier method was used to determine appropriate cutoff values for each metric. The predictive value of each parameter was assessed by Kaplan-Meier survival curves and univariable and multivariable cox proportional hazard models. RESULTS: All methods except whole liver (ELB, ELV) and one-dimensional/non-enhancement-based methods were independent predictors of survival. Multivariable analysis showed a HR of 2.1 (95% CI 1.3-3.4, p = 0.004) for enhancing tumor diameter, HR 1.7 (95% CI 1.1-2.8, p = 0.04) for TTV, HR 2.3 (95% CI 1.4-3.9, p < 0.001) for ETV, and HR 2.4 (95% CI 1.4-4.0, p = 0.001) for ETB. CONCLUSIONS: Tumor enhancement of CRCLM on baseline MRI is strongly associated with patient survival after intra-arterial therapy, suggesting that enhancing tumor volume and enhancing tumor burden are better prognostic indicators than non-enhancement-based and one-dimensional-based markers. KEY POINTS: • Tumor enhancement of colorectal cancer liver metastases on MRI prior to treatment with intra-arterial therapies is strongly associated with patient survival. • Three-dimensional, enhancement-based imaging biomarkers such as enhancing tumor volume and enhancing tumor burden may serve as the basis of a novel prognostic staging system for patients with liver-dominant colorectal cancer metastases.

"Randomized trial of physical activity on quality of life and lung cancer biomarkers in patients with advanced stage lung cancer: a pilot study".

BACKGROUND: Lung cancer survivors need more options to improve quality of life (QoL). It is unclear to what extent patients with advanced stage disease are willing to participate in home-based physical activity (PA) and if these interventions improve QoL. The goal of our study was to determine interest in participating in our 3-month home-based walking regimen in patients with advanced stage lung cancer. We used a randomized design to evaluate for potential benefit in PA and patient-reported outcomes. METHODS: We performed an open-label, 1:1 randomized trial in 40 patients with stage III/IV non-small cell lung cancer (NSCLC) evaluating enrollment rate, PA, QoL, dyspnea, depression, and biomarkers. Compared to usual care (UC), the intervention group (IG) received an accelerometer, in-person teaching session, and gain-framed text messages for 12 weeks. RESULTS: We enrolled 56% (40/71) of eligible patients. Participants were on average 65 years and enrolled 1.9 years from diagnosis. Most patients were women (75%), and receiving treatment (85%) for stage IV (73%) adenocarcinoma (83%). A minority of patients were employed part-time or full time (38%). Both groups reported low baseline PA (IG mean 37 (Standard deviation (SD) 46) vs UC 59 (SD 56) minutes/week; p = 0.25). The IG increased PA more than UC (mean change IG + 123 (SD 212) vs UC + 35 (SD 103) minutes/week; p = 0.051)). Step count in the IG was not statistically different between baseline (4707 step/day), week 6 (5605; p = 0.16), and week 12 (4606 steps/day; p = 0.87). The intervention improved EORTC role functioning domain (17 points; p = 0.022) with borderline improvement in dyspnea (- 13 points; p = 0.051) compared to UC. In patients with two blood samples (25%), we observed a significant increase in soluble PD-1 (219.8 (SD 54.5) pg/mL; p < 0.001). CONCLUSIONS: Our pilot trial using a 3-month, home-based, mobile health intervention enrolled over half of eligible patients with stage III and IV NSCLC. The intervention increased PA, and may improve several aspects of QoL. We also identified potential biomarker changes relevant to lung cancer biology. Future research should use a larger sample to examine the effect of exercise on cancer biomarkers, which may mediate the association between PA and QoL. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov ( NCT03352245 ).

Readiness to Provide Medications for Addiction Treatment in HIV Clinics: A Multisite Mixed-Methods Formative Evaluation.

BACKGROUND: We sought to characterize readiness, barriers to, and facilitators of providing medications for addiction treatment (MAT) in HIV clinics. SETTING: Four HIV clinics in the northeastern United States. METHODS: Mixed-methods formative evaluation conducted June 2017-February 2019. Surveys assessed readiness [visual analog scale, less ready (0-<7) vs. more ready (≥7-10)]; evidence and context ratings for MAT provision; and preferred addiction treatment model. A subset (n = 37) participated in focus groups. RESULTS: Among 71 survey respondents (48% prescribers), the proportion more ready to provide addiction treatment medications varied across substances [tobacco (76%), opioid (61%), and alcohol (49%) treatment medications (P values < 0.05)]. Evidence subscale scores were higher for those more ready to provide tobacco [median (interquartile range) = 4.0 (4.0, 5.0) vs. 4.0 (3.0, 4.0), P = 0.008] treatment medications, but not significantly different for opioid [5.0 (4.0, 5.0) vs. 4.0 (4.0, 5.0), P = 0.11] and alcohol [4.0 (3.0, 5.0) vs. 4.0 (3.0, 4.0), P = 0.42] treatment medications. Median context subscale scores ranged from 3.3 to 4.0 and generally did not vary by readiness status (P values > 0.05). Most favored integrating MAT into HIV care but preferred models differed across substances. Barriers to MAT included identification of treatment-eligible patients, variable experiences with MAT and perceived medication complexity, perceived need for robust behavioral services, and inconsistent availability of on-site specialists. Facilitators included knowledge of adverse health consequences of opioid and tobacco use, local champions, focus on quality improvement, and multidisciplinary teamwork. CONCLUSIONS: Efforts to implement MAT in HIV clinics should address both gaps in perspectives regarding the evidence for MAT and contextual factors and may require substance-specific models.

Decreased Overall Survival in HIV-associated Non-small-cell Lung Cancer.

INTRODUCTION: This study aimed to compare demographics, disease characteristics, and outcomes of patients with HIV-infection with non-small-cell lung cancer (NSCLC) with the general NSCLC population. PATIENTS AND METHODS: A retrospective cohort study was used to compare the HIV-infected and -uninfected groups. Medical records of all patients who were HIV-positive diagnosed with NSCLC between 2000 and 2016 at Yale New Haven Hospital (New Haven, CT) were reviewed and compared with the general Yale NSCLC population regarding demographics, NSCLC characteristics, treatment, and survival. Log-rank tests and Kaplan-Meier curves were used to analyze survival differences. Unadjusted and adjusted Cox proportional hazard models were used to assess predictors of survival. RESULTS: Thirty-five patients with HIV-NSCLC and 5187 general patients with NSCLC were identified. The median age at cancer diagnosis was 54 years (interquartile range [IQR], 49-59 years) for patients with HIV-NSCLC versus 68 years (IQR, 61-76 years) for patients with NSCLC (P < .001). Both groups had high rates of tobacco use. At the time of NSCLC diagnosis, 80% of patients with HIV-NSCLC were on antiretroviral therapy, 60% had an HIV-1 RNA < 400 copies/mL, and their median CD4 was 407 cells/µL (IQR, 218-592 cells/µL). Histology, cancer stage, and first-line cancer treatment regimens were not significantly different between groups. The overall median survival was 12.4 months (95% confidence interval [CI], 7.2-20.4 months) for patients with HIV-NSCLC versus 22.8 months (95% CI, 21.2-24.1 months) for general patients with NSCLC. Patients with HIV-NSCLC had decreased survival at 2 years (P = .028) and 3 years (P = .014) compared with general patients with NSCLC. HIV status was an independent risk factor for poorer outcomes when controlling for other factors (hazard ratio, 1.8; 95% CI, 1.24-2.62). CONCLUSION: Despite similar histology, stage, and treatment between groups, patients with HIV had worse outcomes for NSCLC.

Predicting Infiltrative Hepatocellular Carcinoma Patient Outcome Post-TACE: MR Bias Field Correction Effect on 3D-quantitative Image Analysis.

Background and Aims: To investigate the impact of MR bias field correction on response determination and survival prediction using volumetric tumor enhancement analysis in patients with infiltrative hepatocellular carcinoma, after transcatheter arterial chemoembolization (TACE). Methods: This study included 101 patients treated with conventional or drug-eluting beads TACE between the years of 2001 and 2013. Semi-automated 3D quantification software was used to segment and calculate the enhancing tumor volume (ETV) of the liver with and without bias-field correction on multi-phasic contrast-enhanced MRI before and 1-month after initial TACE. ETV (expressed as cm3) at baseline imaging and the relative change in ETV (as % change, ETV%) before and after TACE were used to predict response and survival, respectively. Statistical survival analyses included Kaplan-Meier curve generation and Cox proportional hazards modeling. Q statistics were calculated and used to identify the best cut-off value for ETV to separate responders and non-responders (ETV cm3). The difference in survival was evaluated between responders and non-responders using Kaplan-Meier and Cox models. Results: MR bias field correction correlated with improved response calculation from baseline MR as well as survival after TACE; using a 415 cm3 cut-off for ETV at baseline (hazard ratio: 2.00, 95% confidence interval: 1.23-3.26, p=0.01) resulted in significantly improved response prediction (median survival in patients with baseline ETV <415 cm3: 19.66 months vs. ≥415 cm3: 9.21 months, p<0.001, log-rank test). A ≥41% relative decrease in ETV (hazard ratio: 0.58, 95%confidence interval: 0.37-0.93, p=0.02) was significant in predicting survival (ETV ≥41%: 19.20 months vs. ETV <41%: 8.71 months, p=0.008, log-rank test). Without MR bias field correction, response from baseline ETV could be predicted but survival after TACE could not. Conclusions: MR bias field correction improves both response assessment and accuracy of survival prediction using whole liver tumor enhancement analysis from baseline MR after initial TACE in patients with infiltrative hepatocellular carcinoma.

Adoption of Immune Checkpoint Inhibitors and Patterns of Care at the End of Life.

PURPOSE: As immune checkpoint inhibitors (ICIs) have transformed the care of patients with cancer, it is unclear whether treatment at the end of life (EOL) has changed. Because aggressive therapy at the EOL is associated with increased costs and patient distress, we explored the association between the Food and Drug Administration (FDA) approvals of ICIs and treatment patterns at the EOL. METHODS: We conducted a retrospective, observational study using patient-level data from a nationwide electronic health record-derived database. Patients had advanced melanoma, non-small-cell lung cancer (NSCLC; cancer types with an ICI indication), or microsatellite stable (MSS) colon cancer (a cancer type without an ICI indication) and died between 2013 and 2017. We calculated annual proportions of decedents who received systemic cancer therapy in the final 30 days of life, using logistic regression to model the association between the post-ICI FDA approval time and use of systemic therapy at the EOL, adjusting for patient characteristics. We assessed the use of chemotherapy or targeted/biologic therapies at the EOL, before and after FDA approval of ICIs using Pearson chi-square test. RESULTS: There was an increase in use of EOL systemic cancer therapy in the post-ICI approval period for both melanoma (33.9% to 43.2%; P < .001) and NSCLC (37.4% to 40.3%; P < .001), with no significant change in use of systemic therapy in MSS colon cancer. After FDA approval of ICIs, patients with NSCLC and melanoma had a decrease in the use of chemotherapy, with a concomitant increase in use of ICIs at the EOL. CONCLUSION: The adoption of ICIs was associated with a substantive increase in the use of systemic therapy at the EOL in melanoma and a smaller yet significant increase in NSCLC.

Podocyte histone deacetylase activity regulates murine and human glomerular diseases.

We identified 2 genes, histone deacetylase 1 (HDAC1) and HDAC2, contributing to the pathogenesis of proteinuric kidney diseases, the leading cause of end-stage kidney disease. mRNA expression profiling from proteinuric mouse glomeruli was linked to Connectivity Map databases, identifying HDAC1 and HDAC2 with the differentially expressed gene set reversible by HDAC inhibitors. In numerous progressive glomerular disease models, treatment with valproic acid (a class I HDAC inhibitor) or SAHA (a pan-HDAC inhibitor) mitigated the degree of proteinuria and glomerulosclerosis, leading to a striking increase in survival. Podocyte HDAC1 and HDAC2 activities were increased in mice podocytopathy models, and podocyte-associated Hdac1 and Hdac2 genetic ablation improved proteinuria and glomerulosclerosis. Podocyte early growth response 1 (EGR1) was increased in proteinuric patients and mice in an HDAC1- and HDAC2-dependent manner. Loss of EGR1 in mice reduced proteinuria and glomerulosclerosis. Longitudinal analysis of the multicenter Veterans Aging Cohort Study demonstrated a 30% reduction in mean annual loss of estimated glomerular filtration rate, and this effect was more pronounced in proteinuric patients receiving valproic acid. These results strongly suggest that inhibition of HDAC1 and HDAC2 activities may suppress the progression of human proteinuric kidney diseases through the regulation of EGR1.

HLA, Non-HLA Antibodies, and Eplet Mismatches in Pediatric Liver Transplantation: Observations From a Small, Single-Center Cohort.

OBJECTIVES: To identify the risk of developing acute rejection, allograft fibrosis, and antibody-mediated rejection, a retrospective review of pediatric patients who underwent liver transplant between July 31, 1998 and February 29, 2016 and had donor-specific antibodies measured at time of liver biopsy was undertaken. MATERIALS AND METHODS: HLAMatchmaker Software (http://www.hlamatchmaker.net) was used to define epitope mismatches between donors and recipients and to predict de novo donor-specific antibody risk. Epitope mismatches were evaluated for their immunogenicity. RESULTS: In our group of 42 recipients, 20 (48%) had donor-specific antibodies. Having an antibody against HLA-DQB1*02 was associated with acute rejection (66.6% vs 36%; P = .024). We found that DQ epitope mismatch load was greater in recipients with class II donor-specific antibodies (9.7 vs 3.6; P = .001). HLA-DQ (7.4 vs 3.6; P = .04) and HLA-DR (8.8 vs 3.8; P = .04) epitope mismatch loads were higher in recipients with DQ + DR donor-specific antibodies. A high portal fibrosis score was associated with higher mismatch load at the DQ locus (P = .005) and DQ + DR loci (P = .03). Having > 5 or > 6 epitope mismatch loads at the DQ locus identified a threshold above which development of DQ donor-specific antibodies would occur (area under the curve = 0.878). Mismatches for eplet 4Q, 45GE, 52PQ, and 52PL, thought to be immunodominant epitopes, were observed for several recipients. CONCLUSIONS: Knowledge of epitope mismatches between recipients and donors may aid transplant physicians in devising immunosuppression strategies.

Body Image in Liver Transplantation Recipients.

Body image (BI) concerns have been reported to play a significant role in the psychological adaptation after organ transplantation. There is a paucity of data about BI beliefs in liver transplant recipients. We report the results of a cross-sectional study of 177 liver transplant recipients for whom we assessed BI, anxiety, depression, and quality of life (QOL) using validated instruments. Our results indicate that higher BI concerns correlated with higher levels of anxiety and depression. BI concerns were more elevated in females, younger patients, and patients with a lower income. Patients with chronic liver disease had more BI concerns than patients who received liver transplantation for acute liver failure. Specific BI concerns also correlated independently with QOL scores. We conclude that BI concerns are significant in liver transplant recipients and should be evaluated by clinicians involved in the mental health care of this population.

Establishing and Validating an Ichthyosis Severity Index.

We designed and validated a Visual Index for Ichthyosis Severity for scale and erythema that provides (1) written descriptions of the features characteristic of each level of severity, (2) visual standards for four body sites, and (3) two distinct standards to account for different types of scale. We tested the Visual Index for Ichthyosis Severity for reliability and reproducibility using two different settings: one that utilized scoring of 60 test photographs by 10 dermatologists, and one with in-person evaluations on 85 subjects by 12 dermatologists at the Foundation for Ichthyosis and Related Skin Types conference. The validation process revealed high reliability and reproducibility for both scale and erythema. The interrater and intrarater intraclass correlation coefficients for scale were consistently near or greater than 0.7 in both settings. By contrast, the interrater reliability for erythema was higher during in-person validation compared with validation on test photographs. Our analysis indicates that the Visual Index for Ichthyosis Severity performs better in person than with photographs, an important consideration in the design of clinical trials. Power analysis predicts that a 1-point difference on this 5-step scale would be detectable with 12 subjects in each of two defined groups. This index provides a tool for clinical phenotyping and assessment of therapeutic response for many disorders of keratinization.

Clinical and Serologic Responses After a Two-dose Series of High-dose Influenza Vaccine in Plasma Cell Disorders: A Prospective, Single-arm Trial.

BACKGROUND: Patients with multiple myeloma (MM) and other plasma cell disorders are highly susceptible to influenza infections, which are major causes of morbidity in this population, despite the routine administration of a seasonal influenza vaccination. Existing data are limited by small and retrospective studies, which suggest poor seroprotection rates of < 20% after standard influenza vaccination in patients with MM. PATIENTS AND METHODS: Patients with plasma cell dyscrasia (n = 51) were treated with a 2-dose series of high-dose inactivated trivalent influenza vaccine during the 2014 to 2015 influenza season. Laboratory-confirmed influenza infections were identified through seasonal surveillance, sera were collected for influenza hemagglutination antibody inhibition (HAI) titer assays, and logistic regression models were used to identify the clinical correlates to the HAI serologic responses. RESULTS: Influenza vaccine was well tolerated, without any vaccine-related grade ≥ 2 adverse events. Only 3 patients (6%) experienced laboratory-confirmed influenza. The rates of HAI seroprotection against all 3 vaccine strains (A/California/7/2009 [H1N1] pdm09-like virus; A/Texas/50/2012 [H3N2]-like virus; and a B/Massachusetts/2/2012-like virus) increased from 4% at baseline to 49% and 65% after 1 and 2 doses, respectively. The risk factors associated with a lower likelihood of HAI serologic response included plasma cell disorder requiring therapy, less than a partial response found on disease response assessment, and active conventional chemotherapy. Alternatively, active therapy with an immunomodulatory drug alone or with a proteasome inhibitor was associated with a greater likelihood of an HAI serologic response. CONCLUSION: These data have demonstrated that, in contrast to the historically poor results with standard influenza vaccination, this novel high-dose booster vaccination strategy leads to high rates of seroprotection. Randomized controlled studies are needed to compare this novel strategy to the standard vaccination strategy.

Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients.

INTRODUCTION: Colorectal cancer (CRC) diagnosed before age 30 years is a fatal disease whose biology remains poorly understood. To understand its pathogenesis, we compared molecular and clinical data in surgically treated early-age onset and adult onset patients. MATERIALS AND METHODS: Clinical data and tumor tissue were collected retrospectively for 94 patients with early-age onset CRC (age ≤30 years) and compared to 275 adult CRC patients (age ≥50 years). Tumor morphology, microsatellite instability (MSI) and stability (MSS), KRAS and BRAF mutations, and mismatch repair (MMR) expression (MSH2, MLH1, MSH6, PMS2) were assessed. RESULTS: Early-age CRC was distinguished from adult CRC by advanced stage presentation (P<0.001), frequent high grade cancers (P<0.001), and poor prognosis (P<0.001). MSI was associated with favorable survival and MMR loss in both groups. Compared to adults, MSI in early-onset CRC was more prevalent (P<0.01), not tightly linked to MLH1/PMS2 loss, and never associated with BRAFV600E mutations (P<0.01). MSS/BRAFV600E genotype had poor prognosis and was more prevalent in early-age CRC (9% vs. 3%). DISCUSSION: Specific genetic subtypes are found at different frequencies in early-age onset and adult onset CRC. Complete absence of the indolent MSI/BRAFV600E genotype and enrichment in the unfavorable MSS/BRAFV600E genotype help explain the poor prognosis of early onset CRC.

Effects of proinflammatory cytokines on the claudin-19 rich tight junctions of human retinal pigment epithelium.

PURPOSE: Chronic, subclinical inflammation contributes to the pathogenesis of several ocular diseases, including age-related macular degeneration. Proinflammatory cytokines affect tight junctions in epithelia that lack claudin-19, but in the retinal pigment epithelium claudin-19 predominates. We examined the effects of cytokines on the tight junctions of human fetal RPE (hfRPE). METHODS: hfRPE was incubated with interleukin 1-beta (IL-1ß), interferon-gamma (IFNγ), or tumor necrosis factor-alpha (TNFα), alone or in combination. Permeability and selectivity of the tight junctions were assessed using nonionic tracers and electrophysiology. Claudins, occludin, and ZO-1 were examined using PCR, immunoblotting, and confocal immunofluorescence microscopy. RESULTS: Only TNFα consistently reduced transepithelial electrical resistance (TER) >80%. A serum-free medium revealed two effects of TNFα: (1) decreased TER was observed only when TNFα was added to the apical side of the monolayer, and (2) expression of TNFα receptors and inhibitors of apoptosis were induced from either side of the monolayer. In untreated cultures, tight junctions were slightly cation selective, and this was affected minimally by TNFα. The results were unexplained by effects on claudin-2, claudin-3, claudin-19, occludin, and ZO-1, but changes in the morphology of the junctions and actin cytoskeleton may have a role. CONCLUSIONS: Claudin-19-rich tight junctions have low permeability for ionic and nonionic solutes, and are slightly cation-selective. Claudin-19 is not a direct target of TNFα. TNFα may protect RPE from apoptosis, but makes the monolayer leaky when it is presented to the apical side of the monolayer. Unlike other epithelia, IFNγ failed to augment the effect of TNFα on tight junctions.