Citations

Abstract BACKGROUND A major impediment to improving neuro-oncology outcomes is poor clinical trial accrual. METHODS We convened a multi-stakeholder group including Society for Neuro-Oncology, Response Assessment in Neuro-Oncology, patient advocacy groups, clinical trial cooperative groups, and other partners to determine how we can improve trial accrual. RESULTS We described selected factors contributing to poor trial accrual and possible solutions. We focused on patient and community factors, disparities, physician and provider factors, clinical trial factors, and site and organizational factors CONCLUSIONS We will implement strategies with the intent to double accrual to neuro-oncology trials over the next 5 years.

Importance Objectively measuring how Mohs defect reconstruction changes casual observer attention has important implications for patients and facial plastic surgeons. Objective To use eye-tracking technology to objectively measure the ability of Mohs facial defect reconstruction to normalize facial attention. Design, Setting, and Participants This observational outcomes study was conducted at an academic tertiary referral center from January to June 2016. An eye-tracking system was used to record how 82 casual observers directed attention to photographs of 32 patients with Mohs facial defects of varying sizes and locations before and after reconstruction as well as 16 control faces with no facial defects. Statistical analysis was performed from November 2018 to January 2019. Main Outcomes and Measures First, the attentional distraction caused by facial defects was quantified in milliseconds of gaze time using eye tracking. Second, the eye-tracking data were analyzed using mixed-effects linear regression to assess the association of facial defect reconstruction with normalized facial attention. Results The 82 casual observers (63 women and 19 men; mean [SD] age, 34 [12] years) viewed control faces in a similar and consistent fashion, with most attention (65%; 95% CI, 62%-69%) directed at the central triangle, which includes the eyes, nose, and mouth. The eyes were the most visually important feature, capturing a mean of 60% (95% CI, 57%-64%) of fixation time within the central triangle and 39% (95% CI, 36%-43%) of total observer attention. The presence of Mohs defects was associated with statistically significant alterations in this pattern of normal facial attention. The larger the defect and the more centrally a defect was located, the more attentional distraction was observed, as measured by increased attention on the defect and decreased attention on the eyes, ranging from 729 (95% CI, 526-931) milliseconds for small peripheral defects to 3693 (95% CI, 3490-3896) milliseconds for large central defects. Reconstructive surgery was associated with improved gaze deviations for all faces and with normalized attention directed to the eyes for all faces except for those with large central defects. Conclusions and Relevance Mohs defects are associated with altered facial perception, diverting attention from valuable features such as the eyes. Reconstructive surgery was associated with normalized attentional distraction for many patients with cutaneous Mohs defects. These data are important to patients who want to know how reconstructive surgery could change the way people look at their face. The data also point to the possibility of outcomes prediction based on facial defect size and location before reconstruction. Eye tracking is a valuable research tool for outcomes assessment that lays the foundation for understanding how reconstructive surgery may change perception and normalize facial deformity.

X-linked reticulate pigmentary disorder (XLPDR, Mendelian Inheritance in Man #301220) is a rare syndrome characterized by recurrent infections and sterile multiorgan inflammation. The syndrome is caused by an intronic mutation in POLA1, the gene encoding the catalytic subunit of DNA polymerase-α (Pol-α), which is responsible for Okazaki fragment synthesis during DNA replication. Reduced POLA1 expression in this condition triggers spontaneous type I interferon expression, which can be linked to the autoinflammatory manifestations of the disease. However, the history of recurrent infections in this syndrome is as yet unexplained. Here we report that patients with XLPDR have reduced NK cell cytotoxic activity and decreased numbers of NK cells, particularly differentiated, stage V, cells (CD3 – CD56 dim ). This phenotype is reminiscent of hypomorphic mutations in MCM4 , which encodes a component of the minichromosome maintenance (MCM) helicase complex that is functionally linked to Pol-α during the DNA replication process. We find that POLA1 deficiency leads to MCM4 depletion and that both can impair NK cell natural cytotoxicity and show that this is due to a defect in lytic granule polarization. Altogether, our study provides mechanistic connections between Pol-α and the MCM complex and demonstrates their relevance in NK cell function.

Despite its rank as the fourth healthiest state in the United States, Minnesota has clear cardiovascular disease disparities between African-Americans and whites. Culturally-tailored interventions implemented using community-based participatory research (CBPR) principles have been vital to improving health and wellness among African-Americans. This paper delineates the establishment, impact, and lessons learned from the formation of a community steering committee (CSC) to guide the Fostering African-American Improvement in Total Health (FAITH!) Program, a CBPR cardiovascular health promotion initiative among African-Americans in Minnesota. The theory-informed CSC implementation process included three phases: (1) Membership Formation and Recruitment, (2) Engagement, and (3) Covenant Development and Empowerment. The CSC is comprised of ten diverse community members guided by mutually agreed upon bylaws in their commitment to FAITH!. Overall, members considered the CSC implementation process effective and productive. A CBPR conceptual model provided an outline of proximal and distal goals for the CSC and FAITH!. The CSC implementation process yielded four lessons learned: (1) Have clarity of purpose and vision, (2) cultivate group cohesion, (3) employ consistent review of CBPR tenets, and (4) expect the unexpected. A robust CSC was established and was instrumental to the success and impact of FAITH! within African-American communities in Minnesota.

AbstractBackgroundSolid organ transplant (SOT) recipients are a special group of patients who require comprehensive evaluation for preventable infectious diseases before transplantation. The main aim of our study was to investigate the number of heart, lung, and liver (HLL) transplant recipients who were evaluated for their immune status against measles, mumps, rubella (MMR), and varicella (VZV). As a secondary aim, we investigated whether pre‐transplant infectious disease consultation (IDC) improves vaccination rates.MethodsThis study was an institution‐based retrospective analysis of HLL transplant recipients born in or after 1957 and evaluated at Mayo Clinic, FL Transplant Center between January 1st, 2016 and December 31st, 2017. Data collection was obtained from electronic medical records. The vaccination rates were compared by univariate analysis based on IDC and no ID consultation (NIDC).ResultsOne hundred and eighty‐seven (77%) of a total 242 patients received an IDC pre‐transplantation. Varicella IgG levels were screened in all 187 IDC candidates. Among the 187 IDC patients, mumps, measles, and rubella IgG serologies were performed in 9 (5%), 21 (11%), and 51 (27%), respectively. Among all 242 patients, vaccines given included 2 (0.8%) MMR, 10 (4.1%) varicella and 85 (35.12%) Zostavax. Univariate analysis revealed that Zostavax was given to 76 (40.6%) pre‐transplant IDC patients and only in 9 (16.7%) NIDC patients (P < .001).ConclusionsDespite the relatively high IDC rate, patients’ screened numbers for MMR IgG levels were low. Results pointed out the need for MMR protocol‐driven serologic screening as well as for VZV and IDC prior to transplantation to increase vaccination rates.

Abstract Background Rapid blood culture diagnostics increase cost and have unclear benefit for patients with Gram-negative bacilli (GNB) bloodstream infections (BSIs). We conducted a multicenter, prospective randomized controlled trial (RAPIDS-GN), comparing outcomes of patients with GNB BSI who had blood culture testing with standard of care (SOC) culture and antibiotic susceptibility testing (AST) vs. rapid organism identification (ID) and phenotypic AST using the Accelerate Pheno System (AXDX). Methods Subjects with blood culture Gram stain showing GNB were randomized to receive SOC testing with antimicrobial stewardship review (AS) or AXDX plus SOC testing with AS, at two academic medical centers between October 2017 and October 2018. SOC testing included rapid MALDI-TOF mass spectrometry ID and agar dilution or broth microdilution AST. In a modified intention to treat analysis, subjects were excluded if: Gram stain was erroneous, culture was positive during off-hours, blood culture in the prior week had GNB, they were deceased/on comfort care, or admitted to a nonparticipating hospital. The primary outcome was time to first antibiotic modification within 72 hours after randomization. Subjects without antibiotic modifications were assigned a time of 72 hours. No censoring was observed. T-tests and Wilcoxon rank-sum tests were used for statistical analyses. Results Of 500 randomized subjects, 448 were included (226 SOC, 222 AXDX). Groups did not differ in baseline characteristics (Table 1). Median (IQR) hours to first antibiotic modification was faster in the AXDX vs. SOC group [8.6 (2.6, 27.6) vs. 14.9 (3.3, 41.1)], P = 0.02 (Figure 1). Median (IQR) hours to first Gram-negative antibiotic modification (including escalation and de-escalation) was faster in the AXDX than SOC group [17.4 (4.9, 72) vs. 42.1 (10.1, 72)], P < 0.001 (Figure 2). Groups did not differ in clinical outcomes (Table 2). Mean (S.D.) time to results was faster for AXDX than SOC for organism ID [2.7 (1.2) h vs. 15.6 (20.3) h, P < 0.001] and AST [13 (55.7) h vs. 54.6 (45.5) h, P < 0.001]. Conclusion In the largest trial to evaluate the clinical impact of a blood culture diagnostic for GNB BSI, we found that rapid organism ID and phenotypic AST led to faster changes in antibiotic therapy for Gram-negative bacteremia. Disclosures Ritu Banerjee, MD, PhD, Accelerate Diagnostics: Grant/Research Support; BioFire: Research Grant; Biomerieux: Research Grant; Roche: Research Grant Robin Patel, MD, ASM and IDSA: Other Financial or Material Support, Travel reimbursement, editor’s stipends; CD Diagnostics, Merck, Hutchison Biofilm Medical Solutions, Accelerate Diagnostics, ContraFect, TenNor Therapeutics Limited, Shionogi: Grant/Research Support; Curetis, Specific Technologies, NextGen Diagnostics, PathoQuest, Qvella: Consultant; NBME, Up-to-Date, the Infectious Diseases Board Review Course: Honorarium recipient, Other Financial or Material Support; Patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued: Other Financial or Material Support, Patents.

Key Points Five-year follow-up of S1106 demonstrates similar efficacy, MRD negativity, and 5-year survival with RH or RB, but RH was more toxic than RB. RB showed excellent efficacy and survival and less toxicity compared with a cytarabine-based regimen in transplant-eligible MCL patients.

Abstract Context Central and peripheral administration of peptide YY (PYY) has potent anorectic effects, and PYY analogs are under development as antiobesity treatments. Recent animal data suggest PYY may also influence the reproductive axis; however the effects of PYY on the human reproductive system are unknown. Objective To investigate the effects of PYY administration on the reproductive axis in healthy young men. Design Single-blind, randomized, placebo-controlled crossover study. Setting Clinical Research Facility, Imperial College Healthcare NHS Trust. Participants Eighteen healthy eugonadal men (mean age 24.1 ± 0.9 years, mean body mass index 22.2 ± 0.4 kg/m2). Intervention Eight-hour intravenous infusion of 0.4 pmol/kg/min PYY3-36 or rate-matched vehicle infusion. Main Outcome Measures Number of luteinizing hormone (LH) pulses, LH, follicle stimulating hormone (FSH), and testosterone levels. Results The number of LH pulses (mean number of LH pulses/8 hours: PYY 4.4 ± 0.3 vs vehicle 4.4 ± 0.4, P &gt; .99), LH area under the curve (AUC) (PYY 1503 ± 79 IU.min/L vs vehicle 1574 ± 86 IU.min/L, P = .36), FSH AUC (PYY 1158 ± 513 IU.min/L vs vehicle 1199 ± 476 IU.min/L, P = .49) and testosterone AUC (PYY 10 485 ± 684 IU.min/L vs vehicle 11 133 ± 803 IU.min/L, P = .24) were similar during PYY and vehicle infusions. Conclusions Acute intravenous infusion of 0.4 pmol/kg/min PYY does not affect the reproductive axis in healthy men.