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BACKGROUND: U.S. hemodialysis patients with systemic lupus erythematosus (SLE) and end-stage renal disease (ESRD) are less likely than other ESRD patients to have a permanent vascular access (fistula or graft) in place at the dialysis start. We examined whether vascular access outcomes after dialysis start differed for SLE vs. other ESRD patients. METHODS: Among U.S. patients initiating hemodialysis in 2010 with only a catheter (n = 40,911; 384 with SLE) and using a permanent access on first dialysis (n = 13,073; 48 with SLE), we examined the association of SLE status with time to first placement of a permanent access (among catheter-only patients) and to loss of access patency (among patients using a permanent access on first dialysis), both censored 1 year after dialysis start, using multivariable Cox proportional hazards models. RESULTS: Among catheter-only patients, 46.1 % vs. 54.5 % of those with SLE-ESRD vs. other ESRD had a permanent access placed within 1 year after dialysis start. However, with adjustment, there was no association of 1-year placement with SLE status [HR = 1.00 (95 % CI, 0.86-1.17)]. SLE-ESRD vs. other ESRD patients starting dialysis with a permanent access were less likely to experience a 1-year loss of patency (43.8 % vs. 55.0 %), but this association was not statistically significant after adjustment [HR = 0.88 (0.57-1.37)]. CONCLUSION: These results suggest that SLE-ESRD patients starting dialysis with a catheter are not more likely to have a permanent access placed in the first year of dialysis, despite an observed lack of association of SLE status with subsequent loss of vascular access patency among those starting dialysis with a permanent access.

OBJECTIVE: To estimate and identify factors associated with the incidence of all-cause end-stage renal disease (ESRD) among newly diagnosed systemic lupus erythematosus (SLE) patients. METHODS: Data from a national registry of treated ESRD were linked to data from a lupus registry of SLE patients who were newly diagnosed and living in Atlanta, Georgia, 2002-2004 (median followup 7.8 years). Cumulative incidence and incidence rates (ESRD treatment initiations per 1,000 patient-years) were calculated, and age- and race-adjusted Poisson models were used to calculate incidence rate ratios (IRRs). RESULTS: Among 344 newly diagnosed SLE patients, 29 initiated ESRD treatment over 2,603.8 years of followup. Incidence rates were 13.8 (95% confidence interval [95% CI] 9.4-20.3) among black patients and 3.3 (95% CI 0.8-13.0) among white patients, per 1,000 patient-years; corresponding 5-year cumulative incidence was 6.4% and 2.5% among black and white patients, respectively. Lupus nephritis documented prior to 2005, which occurred in 80% of those who progressed to ESRD, was the strongest risk factor for incident ESRD (IRR 6.7 [95% CI 2.7-16.8]; incidence rate 27.6 per 1,000 patient-years). Results suggested that patients who were black versus white (IRR 3.9 [95% CI 0.9-16.4]) or

OBJECTIVE: Whether using provider-attributed end-stage renal disease (ESRD) cause of systemic lupus erythematosus (SLE) in national surveillance data captures the entire population of patients with SLE and ESRD remains uncertain. Our goal was to examine attributed cause of ESRD in US surveillance data among patients with SLE who have developed ESRD. METHODS: Data from a national registry of treated ESRD (United States Renal Data System (USRDS)) were linked to the population-based Georgia Lupus Registry (GLR). The provider-attributed cause of ESRD was extracted from the USRDS for each validated patient with SLE in the GLR (diagnosed through 2004) who initiated treatment for ESRD through 2012. The percentage of these patients with SLE whose ESRD was subsequently attributed to SLE in the USRDS was calculated, overall and by patient characteristics. RESULTS: Among 251 patients with SLE who progressed to ESRD, 78.9% had SLE as their attributed cause of ESRD. Of the remaining 53 patients, 43.4%, 18.9% and 15.6% had ESRD attributed to hypertension, diabetes mellitus type II and non-SLE-related glomerulonephritis, respectively. Attribution of ESRD to SLE was higher among patients aged ≤30 (87.9-93.9%) vs >30 (52.6%; p

Abstract Background Cancer incidence and mortality in sub-Saharan Africa are increasing and do account for significant premature death. The expertise of health care providers is critical to downstaging cancer at diagnosis and improving survival in low- and middle-income countries. We set out to determine the training needs of health care providers for a comprehensive oncology services package in selected hospitals in Uganda, in order to inform capacity development intervention to improve cancer outcomes in the East African region. Methods This was a cross-sectional survey using the WHO Hennessey-Hicks questionnaire to identify the training needs of health workers involved in cancer care, across 22 hospitals in Uganda. Data were captured in real time using the Open Data Kit platform from which the data was exported to Stata version 15 for analysis using the Wilcoxon signed-rank test and Somers-Delta. Results There were 199 respondent health professionals who were predominately female (146/199, 73.37%), with an average age of 38.97 years. There were 158/199 (79.40%) nurses, 24/199 (12.06%) medical doctors and 17/199 (8.54%) allied health professionals. Overall, the research and audit domain had the highest ranking for all the health workers (Somers-D = 0.60). The respondent’s level of education had a significant effect on the observed ranking (P value = 0.03). Most of the continuing medical education (CME) topics suggested by the participants were in the clinical task-related category. Conclusion The “research and audit” domain was identified as the priority area for training interventions to improve oncology services in Uganda. There are opportunities for addressing the identified training needs with an expanded cancer CME programme content, peer support networks and tailored training for the individual health care provider.

Introduction: The Allocation System Changes for Equity in Kidney Transplantation (ASCENT) trial was a cluster-randomized pragmatic, effectiveness-implementation study designed to test whether a multicomponent educational intervention targeting leadership, clinic staff, and patients in dialysis facilities improved knowledge and awareness of the 2014 Kidney Allocation System (KAS) change. Methods: Participants included 690 dialysis facility medical directors, nephrologists, social workers, and other staff within 655 US dialysis facilities, with 51% (n = 334) in the intervention group and 49% (n = 321) in the control group. Intervention activities included a webinar targeting medical directors and facility staff, an approximately 10-minute educational video targeting dialysis staff, an approximately 10-minute educational video targeting patients, and a facility-specific audit and feedback report of transplant performance. The control group received a standard United Network for Organ Sharing brochure. Provider knowledge was a secondary outcome of the ASCENT trial and the primary outcome of this study; knowledge was assessed as a cumulative score on a 5-point Likert scale (higher score = greater knowledge). Intention-to-treat analysis was used. Results: At baseline, nonintervention providers had a higher mean knowledge score (mean ± SD, 2.45 ± 1.43) than intervention providers (mean ± SD, 2.31 ± 1.46). After 3 months, the average knowledge score was slightly higher in the intervention (mean ± SD, 3.14 ± 1.28) versus nonintervention providers (mean ± SD, 3.07 ± 1.24), and the estimated mean difference in knowledge scores between the groups at follow-up minus the mean difference at baseline was 0.25 (95% confidence interval [CI], 0.11–0.48; P = 0.039). The effect size (0.41) was low to moderate. Conclusion: Dialysis facility provider education could help extend the impact of a national policy change in organ allocation.

Introduction: Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)–sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes. Methods: APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. Results: The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. Conclusion: This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation. Keywords: African Americans, APOL1, chronic kidney disease, graft failure, kidney transplantation, outcomes

BACKGROUND: In the US, African Americans (AAs) are four times more likely to develop end stage renal disease (ESRD) but half as likely to receive a kidney transplant as whites. Patient interest in kidney transplantation is a fundamental step in the kidney transplant referral process. Our aim was to determine the factors associated with the willingness to receive a kidney transplant among chronic kidney disease (CKD) patients in a predominantly minority population. METHODS: CKD patients from an outpatient nephrology clinic at a safety-net hospital (n = 213) participated in a cross-sectional survey from April to June, 2013 to examine the factors associated with willingness to receive a kidney transplant among a predominantly minority population. The study questionnaire was developed from previously published literature. Multivariable logistic regression analysis was used to determine factors associated with willingness to undergo a kidney transplant. RESULTS: Respondents were primarily AAs (91.0%), mostly female (57.6%) and middle aged (51.6%). Overall, 53.9% of participants were willing to undergo a kidney transplant. Willingness to undergo a kidney transplant was associated with a positive perception towards living kidney donation (OR 7.31, 95% CI: 1.31-40.88), willingness to attend a class about kidney transplant (OR = 7.15, CI: 1.76-29.05), perception that a kidney transplant will improve quality of life compared to dialysis (OR = 5.40, 95% CI: 1.97-14.81), and obtaining information on kidney transplant from other sources vs. participants physician (OR =3.30, 95% CI: 1.13-9.67), when compared with their reference groups. CONCLUSION: It is essential that the quality of life benefits of kidney transplantation be known to individuals with CKD to increase their willingness to undergo kidney transplantation. Availability of multiple sources of information and classes on kidney transplantation may also contribute to willingness to undergo kidney transplantation, especially among AAs.

OBJECTIVE: Providers recommend waiting to transplant patients with end-stage renal disease (ESRD) secondary to lupus nephritis (LN), to allow for quiescence of systemic lupus erythematosus (SLE)-related immune activity. However, these recommendations are not standardized, and we sought to examine whether duration of time to transplant was associated with risk of graft failure in US LN-ESRD patients. METHODS: Using national ESRD surveillance data (United States Renal Data System), we identified 4,743 US patients with LN-ESRD who received a first transplant on or after January 1, 2000 (followup through September 30, 2011). The association of wait time (time from ESRD start to transplant) with graft failure was assessed with Cox proportional hazards models, with splines of the exposure to allow for nonlinearity of the association and with adjustment for potential confounding by demographic, clinical, and transplant factors. RESULTS: White LN-ESRD patients who were transplanted later (versus at 36 months: adjusted HR 1.98, 95% CI 1.31-2.99). However, no such association was seen among African American recipients (3-12 months: adjusted HR 1.07, 95% CI 0.79-1.45; 12-24 months: adjusted HR 1.01, 95% CI 0.64-1.60; 24-36 months: adjusted HR 0.78, 95% CI 0.51-1.18; and >36 months: adjusted HR 0.74, 95% CI 0.48-1.13). CONCLUSION: While future studies are needed to examine the potential confounding effect of clinically recognized SLE activity on the observed associations, these results suggest that longer wait times to transplant may be associated with equivalent or worse, not better, graft outcomes among LN-ESRD patients.

BACKGROUND: Patients with end-stage renal disease (ESRD) due to lupus nephritis (LN-ESRD) may be followed by multiple providers (nephrologists and rheumatologists) and have greater opportunities to receive recommended ESRD-related care. We aimed to examine whether LN-ESRD patients have better quality of ESRD care compared to other ESRD patients. METHODS: Among incident patients (7/05-9/11) with ESRD due to LN (n = 6,594) vs. other causes (n = 617,758), identified using a national surveillance cohort (United States Renal Data System), we determined the association between attributed cause of ESRD and quality-of-care measures (pre-ESRD nephrology care, placement on the deceased donor kidney transplant waitlist, and placement of permanent vascular access). Multivariable logistic and Cox proportional hazards models were used to estimate adjusted odds ratios (ORs) and hazard ratios (HRs). RESULTS: LN-ESRD patients were more likely than other ESRD patients to receive pre-ESRD care (71% vs. 66%; OR = 1.68, 95% CI 1.57-1.78) and be placed on the transplant waitlist in the first year (206 vs. 86 per 1000 patient-years; HR = 1.42, 95% CI 1.34-1.52). However, only 24% had a permanent vascular access (fistula or graft) in place at dialysis start (vs. 36%; OR = 0.63, 95% CI 0.59-0.67). CONCLUSIONS: LN-ESRD patients are more likely to receive pre-ESRD care and have better access to transplant, but are less likely to have a permanent vascular access for dialysis, than other ESRD patients. Further studies are warranted to examine barriers to permanent vascular access placement, as well as morbidity and mortality associated with temporary access, in patients with LN-ESRD.

OBJECTIVE: To describe end-stage renal disease (ESRD) quality of care (receipt of pre-ESRD nephrology care, access to kidney transplantation, and placement of permanent vascular access for dialysis) in US patients with ESRD due to lupus nephritis (LN-ESRD) and to examine whether quality measures differ by patient sociodemographic characteristics or US region. METHODS: National surveillance data on patients in the US in whom treatment for LN-ESRD was initiated between July 2005 and September 2011 (n = 6,594) were analyzed. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were determined for each quality measure, according to sociodemographic factors and US region. RESULTS: Overall, 71% of the patients received nephrology care prior to ESRD. Black and Hispanic patients were less likely than white patients to receive pre-ESRD care (OR 0.73 [95% CI 0.63-0.85] and OR 0.73 [95% CI 0.60-0.88], respectively) and to be placed on the kidney transplant waitlist within the first year after the start of ESRD (HR 0.78 [95% CI 0.68-0.91] and HR 0.82 [95% CI 0.68-0.98], respectively). Those with Medicaid (HR 0.51 [95% CI 0.44-0.58]) or no insurance (HR 0.36 [95% CI 0.29-0.44]) were less likely than those with private insurance to be placed on the waitlist. Only 24% had a permanent vascular access, and placement was even less likely among the uninsured (OR 0.62 [95% CI 0.49-0.79]). ESRD quality-of-care measures varied 2-3-fold across regions of the US, with patients in the Northeast and Northwest generally having higher probabilities of adequate care. CONCLUSION: LN-ESRD patients have suboptimal ESRD care, particularly with regard to placement of dialysis vascular access. Minority race/ethnicity and lack of private insurance are associated with inadequate ESRD care. Further studies are warranted to examine multilevel barriers to, and develop targeted interventions to improve delivery of, care among patients with LN-ESRD.

White students and teachers who are exposed to information about how oppression works seem to recognize that there is a problem and want to do something to ameliorate the situation. They show up for meetings of diversity clubs, attend conferences and workshops, and will speak to others about their growing understanding of how privilege/ racism works. Yet, for all of this commitment, the system is not really changing. White students who feel that the diversity programs are exclusive or too time consuming are simply ignorant to the fact that racism affects them, albeit in different ways, just as it affects people of color. White privilege is described as a means of insulation that allows a White person to express awareness, but that also keeps the White person from really having to do anything with that awareness. This article asks the question "What exactly is white privilege, and what is the cost of racism to Whites in America? It goes on to present a discussion about a white affinity group, modeled after Tim Wise's group called AWARE (Association for White Anti-Racist Education) for White students interested in becoming actively anti-racist. AWARE is both a student and staff White affinity group that is dedicated to developing positive anti-racist racial identities. The group does that by engaging in cross-cultural dialogues with other affinity groups, such as the Young Men of Color and the Young Woman of Color. Ultimately, putting together a group of White students to explore their racial identity development and anti-racism is an arduous task. This is by no means a simple task; it takes time, dedication, and patience, but this should not be surprising. After all, dismantling a system of racism/White privilege is not exactly an easy endeavor.

BACKGROUND: The Southeastern United States has the lowest kidney transplant rates in the nation, and racial disparities in kidney transplant access are concentrated in this region. The Southeastern Kidney Transplant Coalition (SEKTC) of Georgia, North Carolina, and South Carolina is an academic and community partnership that was formed with the mission to improve access to kidney transplantation and reduce disparities among African American (AA) end stage renal disease (ESRD) patients in the Southeastern United States. METHODS/DESIGN: We describe the community-based participatory research (CBPR) process utilized in planning the Reducing Disparities In Access to kidNey Transplantation (RaDIANT) Community Study, a trial developed by the SEKTC to reduce health disparities in access to kidney transplantation among AA ESRD patients in Georgia, the state with the lowest kidney transplant rates in the nation. The SEKTC Coalition conducted a needs assessment of the ESRD population in the Southeast and used results to develop a multicomponent, dialysis facility-randomized, quality improvement intervention to improve transplant access among dialysis facilities in GA. A total of 134 dialysis facilities are randomized to receive either: (1) standard of care or usual transplant education, or (2) the multicomponent intervention consisting of transplant education and engagement activities targeting dialysis facility leadership, staff, and patients within dialysis facilities. The primary outcome is change in facility-level referral for kidney transplantation from baseline to 12 months; the secondary outcome is reduction in racial disparity in transplant referral. DISCUSSION: The RaDIANT Community Study aims to improve equity in access to kidney transplantation for ESRD patients in the Southeast. TRIAL REGISTRATION: Clinicaltrials.gov number NCT02092727.

BACKGROUND: Improving access to optimal healthcare may depend on the attributes of neighborhoods where patients receive healthcare services. We investigated whether the characteristics of dialysis facility neighborhoods--where most patients with end-stage renal disease are treated--were associated with facility-level kidney transplantation. METHODS: We examined the association between census tract (neighborhood)-level sociodemographic factors and facility-level kidney transplantation rate in 3,983 U.S. dialysis facilities where kidney transplantation rates were high. Number of kidney transplants and total person-years contributed at the facility level in 2007-2010 were obtained from the Dialysis Facility Report and linked to the census tract data on sociodemographic characteristics from the American Community Survey 2006-2010 by dialysis facility location. We used multivariable Poisson models with generalized estimating equations to estimate the link between the neighborhood characteristics and transplant incidence. RESULTS: Dialysis facilities in the United States were located in neighborhoods with substantially greater proportions of black and poor residents, relative to the national average. Most facility neighborhood characteristics were associated with transplant, with incidence rate ratios (95% CI) for standardized increments (in percentage) of neighborhood exposures of: living in poverty, 0.88 (0.84-0.92), black race, 0.83 (0.78-0.89); high school graduates, 1.22 (1.17-1.26); and unemployed, 0.90 (0.85-0.95). CONCLUSION: Dialysis facility neighborhood characteristics may be modestly associated with facility rates of kidney transplantation. The success of dialysis facility interventions to improve access to kidney transplantation may partially depend on reducing neighborhood-level barriers.

Background: LMB-100 is a mesothelin (MSLN)-targeting recombinant immunotoxin (iTox) carrying a Pseudomonas exotoxin A payload that has shown promise against solid tumors, however, efficacy is limited by the development of neutralizing anti-drug antibodies (ADAs). Tofacitinib is an oral Janus Kinase (JAK) inhibitor that prevented ADA formation against iTox in preclinical studies. Methods: A phase 1 trial testing LMB-100 and tofacitinib in patients with MSLNexpressing cancers (pancreatic adenocarcinoma, n=13; cholangiocarcinoma, n=1; appendiceal carcinoma, n=1; cystadenocarcinoma, n=1) was performed to assess safety and to determine if tofacitinib impacted ADA formation. Participants were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 µg/kg) while oral tofacitinib was administered for the first 10 days of the cycle (10 mg BID). Peripheral blood was collected for analysis of ADA levels, serum cytokines and circulating immune subsets. Results: The study was closed early due to occurrence of drug-induced pericarditis in 2 patients. Pericarditis with the combination was not reproducible in a transgenic murine model containing human MSLN. Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred. No radiologic decreases in tumor volume were observed. Discussion: Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings. [ABSTRACT FROM AUTHOR]

Introduction: There are pervasive racial disparities in access to living donor kidney transplantation, which for most patients with end-stage renal disease (ESRD) represents the optimal treatment. We previously developed a theory-driven, culturally sensitive intervention for African American (AA) patients with kidney disease called Living ACTS (About Choices in Transplantation and Sharing) as a DVD and booklet, and found this intervention was effective in increasing living donor transplant knowledge. However, it is unknown whether modifying this intervention for a Web-based environment is effective at increasing access to living donor transplantation. Methods: We describe the Web-based Living ACTS study, a multicenter, randomized controlled study designed to test the effectiveness of a revised Living ACTS intervention in 4 transplant centers in the southeastern United States. The intervention consists of a Web site with 5 modules: Introduction, Benefits and Risks, The Kidney Transplant Process, Identifying a Potential Kidney Donor, and ACT Now (which encourages communication with friends and family about transplantation). Results: This study will enroll approximately 800 patients from the 4 transplant centers. The primary outcome is the percentage of patients with at least 1 inquiry from a potential living donor among patients who receive Living ACTS as compared with those who receive a control Web site. Conclusion: The results from this study are expected to demonstrate the effectiveness of an intervention designed to increase access to living donor transplantation among AA individuals. If successful, the Web-based intervention could be disseminated across the >250 transplant centers in the United States to improve equity in living donor kidney transplantation. Keywords: education, intervention, kidney transplant

Abstract Background D2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma. Methods To study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test. Results D2C7-IT effectively killed CT-2A-dmEGFRvIII (IC50 = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC50 = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival (P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge. Conclusions These data support the development of D2C7-IT and immune checkpoint blockade combinations for patients with malignant glioma.

The diphthamide modification of translation elongation factor 2 is highly conserved in eukaryotes and archaebacteria. Nevertheless, cells lacking diphthamide can carry out protein synthesis and are viable. We have analyzed the phenotypes of diphthamide deficient cells and found that diphthamide deficiency reduces selenocysteine incorporation into selenoproteins. Additional phenotypes resulting from diphthamide deficiency include altered tRNA-synthetase and selenoprotein transcript levels, hypersensitivity to oxidative stress and increased selenite tolerance. Diphthamide-eEF2 occupies the aminoacyl-tRNA translocation site at which UGA either stalls translation or decodes selenocysteine. Its position is in close proximity and mutually exclusive to the ribosomal binding site of release/recycling factor ABCE1, which harbors a redox-sensitive Fe-S cluster and, like diphthamide, is present in eukaryotes and archaea but not in eubacteria. Involvement of diphthamide in UGA-SECIS decoding may explain deregulated selenoprotein expression and as a consequence oxidative stress, NFkB activation and selenite tolerance in diphthamide deficient cells. Keywords: Eukaryotic translation elongation factor 2, Selenocysteine, Oxidative stress, Diphtheria toxin

The WHO END TB strategy requires ≥90% case detection to combat tuberculosis (TB). Increased TB case detection requires a more sensitive and specific screening tool. Currently, the symptoms recommended for screening TB have been found to be suboptimal since up to 44% of individuals with TB are asymptomatic. The chest X-ray (CXR) as a screening tool for pulmonary TB was evaluated in this study, as well as its incremental yield in TB diagnosis using a cross-sectional study involving secondary analysis of data of 4512 consented/assented participants ≥15 years who participated in the Uganda National TB prevalence survey between 2014 and 2015. Participants with a cough ≥2 weeks, fever, weight loss, and night sweats screened positive for TB using the symptoms screening method, while participants with a TB defining abnormality on CXR screened positive for TB by the CXR screening method. The Löwenstein-Jensen (LJ) culture was used as a gold standard for TB diagnosis. The CXR had 93% sensitivity and 65% specificity compared to LJ culture results, while symptoms had 76% sensitivity and 31% specificity. The screening algorithm involving the CXR in addition to symptoms led to a 38% increment in the yield of diagnosed tuberculosis. The number needed to screen using the CXR and symptoms screening algorithm was 32 compared to 45 when the symptoms are used alone. Therefore, the CXR in combination with symptoms is a good TB screening tool and increases the yield of diagnosed TB.

Screening, Brief Intervention, and Referral to Treatment (SBIRT) is an evidence-based protocol that addresses both moderate-risk and high-risk substance use problems for individuals. In an urban college's master's and bachelor's social work programs with 218 students, SBIRT training was introduced into core course curricula, with many students subsequently using SBIRT in their field placements. Evaluation of the initiative demonstrated increases in the students' knowledge and favorable attitudes regarding working with substance using clients. Students' ratings of the usefulness and effectiveness of SBIRT were high. In response to studies indicating the lack of preparedness of graduating social work students to work with substance users, this study demonstrated the effectiveness of SBIRT training to educate students to work with this population.

Background. The current surge of coronavirus 2019 (COVID-19) cases in certain parts of the country has burdened the healthcare system, limiting access to tertiary centers for many. As a result, COVID-19-positive Solid Organ Transplant (SOT) recipients are increasingly being managed by local healthcare providers. It is crucial for community providers to understand disease severity and know if COVID-19-impacted SOT recipients have a different clinical course compared with COVID-19-negative SOT recipients with a similar presentation. Methods. We conducted a retrospective analysis on SOT recipients suspected to have COVID-19 infection tested during March 14, 2020–April 30, 2020. Patients were followed from time of testing to May 31, 2020. Results. One hundred sixty SOT recipients underwent testing: 22 COVID-19 positive and 138 COVID-19 negative. COVID-19-positive patients were more likely to have rapid progression of symptoms (median 3 vs 6 d, P = 0.002), greater hospitalizations (78% vs 64%, P < 0.017), and need for intensive care unit care (45% vs 17%, P < 0.001) Severe COVID-19 infection was not observed in patients on Belatacept for immunosuppression (30% vs 87%,P = 0.001). COVID- 19 positive patients in the intensive care unit were more likely to have multifocal opacities on radiological imaging in comparison to those admitted to the medical floor (90% vs 11%). Survival probability was similar in both cohorts. Conclusion. COVID-19-infected SOT recipients have a propensity for rapid clinical decompensation. Local providers need to be work closely with transplant centers to appropriately triage and manage COVID-19 SOT recipients in the community.

Immunotoxins are cytolytic fusion proteins developed for cancer therapy, composed of an antibody fragment that binds to a cancer cell and a protein toxin fragment that kills the cell. Pseudomonas exotoxin A (PE) is a potent toxin that is used for the killing moiety in many immunotoxins. Moxetumomab Pasudotox (Lumoxiti) contains an anti-CD22 Fv and a 38 kDa portion of PE. Lumoxiti was discovered in the Laboratory of Molecular Biology at the U.S. National Cancer Institute and co-developed with Medimmune/AstraZeneca to treat hairy cell leukemia. In 2018 Lumoxiti was approved by the US Food and Drug Administration for the treatment of drug-resistant Hairy Cell Leukemia. Due to the bacterial origin of the killing moiety, immunotoxins containing PE are highly immunogenic in patients with normal immune systems, but less immunogenic in patients with hematologic malignancies, whose immune systems are often compromised. LMB-100 is a de-immunized variant of the toxin with a humanized antibody that targets mesothelin and a PE toxin that was rationally designed for diminished reactivity with antibodies and B cell receptors. It is now being evaluated in clinical trials for the treatment of mesothelioma and pancreatic cancer and is showing somewhat diminished immunogenicity compared to its un modified parental counterpart. Here we review the immunogenicity of the original and de-immunized PE immunotoxins in mice and patients, the development of anti-drug antibodies (ADAs), their impact on drug availability and their effect on clinical efficacy. Efforts to mitigate the immunogenicity of immunotoxins and its impact on immunogenicity will be described including rational design to identify, remove, or suppress B cell or T cell epitopes, and combination of immunotoxins with immune modulating drugs.

Abstract Background The Reducing Disparities in Access to kidNey Transplantation Community Study (RaDIANT) was an End-Stage Renal Disease (ESRD) Network 6-developed, dialysis facility-level randomized trial testing the effectiveness of a 1-year multicomponent education and quality improvement intervention in increasing referral for kidney transplant evaluation among selected Georgia dialysis facilities. Methods To assess implementation of the RaDIANT intervention, we conducted a process evaluation at the conclusion of the intervention period (January–December 2014). We administered a 20-item survey to the staff involved with transplant education in 67 dialysis facilities randomized to participate in intervention activities. Survey items assessed facility participation in the intervention (fidelity and reach), helpfulness and willingness to continue intervention activities (sustainability), suggestions for improving intervention components (sustainability), and factors that may have influenced participation and study outcomes (context). We defined high fidelity to the intervention as completing 11 or more activities, and high participation in an activity as having at least 75% participation across intervention facilities. Results Staff from 65 of the 67 dialysis facilities completed the questionnaire, and more than half (50.8%) reported high adherence (fidelity) to RaDIANT intervention requirements. Nearly two-thirds (63.1%) of facilities reported that RaDIANT intervention activities were helpful or very helpful, with 90.8% of facilities willing to continue at least one intervention component beyond the study period. Intervention components with high participation emphasized staff and patient-level education, including in-service staff orientations, patient and family education programs, and patient educational materials. Suggested improvements for intervention activities emphasized addressing financial barriers to transplantation, with financial education materials perceived as most helpful among RaDIANT educational materials. Variation in facility-level fidelity of the RADIANT intervention did not significantly influence the mean difference in proportion of patients referred pre- (2013) and post-intervention (2014). Conclusions We found high fidelity to the RaDIANT multicomponent intervention at the majority of intervention facilities, with sustainability of select intervention components at intervention facilities and feasibility for dissemination across ESRD Networks. Future modification of the intervention should emphasize financial education regarding kidney transplantation and amend intervention components that facilities perceive as time-intensive or non-sustainable. Trial registration Clinicaltrials.gov number NCT02092727 . Registered 13 Mar 2014 (retrospectively registered).

Abstract Background Racial/ethnic, gender, and age disparities in access to renal transplantation among end-stage renal disease (ESRD) patients have been well documented, but few studies have explored health care staff attitudes towards these inequalities. Staff perceptions can influence patient care and outcomes, and identifying staff perceptions on disparities could aid in the development of potential interventions to address these health inequities. The objective of this study was to investigate dialysis staff (n = 509), primarily social workers and nurse managers, perceptions of renal transplant disparities in the Southeastern United States. Methods This is a mixed methods study that uses both deductive and inductive qualitative analysis of a dialysis staff survey conducted in 2012 using three open-ended questions that asked staff to discuss their perceptions of factors that may contribute to transplant disparities among African American, female, and elderly patients. Results Study results suggested that the majority of staff (n = 255, 28%) perceived patients’ low socioeconomic status as the primary theme related to why renal transplant disparities exist between African Americans and non-Hispanic whites. Staff cited patient perception of old age as a primary contributor (n = 188, 23%) to the disparity between young and elderly patients. The dialysis staff responses on gender transplant disparities suggested that staff were unaware of differences due to limited experience and observation (n = 76, 14.7%) of gender disparities. Conclusions These findings suggest that dialysis facilities should educate staff on existing renal transplantation disparities, particularly gender disparities, and collaboratively work with transplant facilities to develop strategies to actively address modifiable patient barriers for transplant.