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Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a randomized controlled trial.Setting & Participants: Participants in the CREDENCE trial.Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (Results: The mean age of the cohort was 63.0 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791.

Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications.A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine.None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).

Background Therapeutic options are limited in pediatric CNS malignancies. CheckMate 908 (NCT03130959) is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO + ipilimumab (IPI) in pediatric patients with high-grade CNS malignancies. Methods Patients (N = 166) in 5 cohorts received NIVO 3 mg/kg every 2 weeks (Q2W) or NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks (4 doses) followed by NIVO 3 mg/kg Q2W. Primary endpoints included overall survival (OS; newly diagnosed diffuse intrinsic pontine glioma [DIPG]) and progression-free survival (PFS; other recurrent/progressive or relapsed/resistant CNS cohorts). Secondary endpoints included other efficacy metrics and safety. Exploratory endpoints included pharmacokinetics and biomarker analyses. Results As of January 13, 2021, median OS (80% CI) was 11.7 (10.3–16.5) and 10.8 (9.1–15.8) months with NIVO and NIVO + IPI, respectively, in newly diagnosed DIPG. Median PFS (80% CI) with NIVO and NIVO + IPI was 1.7 (1.4–2.7) and 1.3 (1.2–1.5) months, respectively, in recurrent/progressive high-grade glioma; 1.4 (1.2–1.4) and 2.8 (1.5–4.5) months in relapsed/resistant medulloblastoma; and 1.4 (1.4–2.6) and 4.6 (1.4–5.4) months in relapsed/resistant ependymoma. In patients with other recurrent/progressive CNS tumors, median PFS (95% CI) was 1.2 (1.1–1.3) and 1.6 (1.3–3.5) months, respectively. Grade 3/4 treatment-related adverse-event rates were 14.1% (NIVO) and 27.2% (NIVO + IPI). NIVO and IPI first-dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor programmed death ligand 1 expression was not associated with survival. Conclusions NIVO ± IPI did not demonstrate clinical benefit relative to historical data. The overall safety profiles were manageable with no new safety signals.

ImportanceMedicare Advantage is associated with improved health outcomes, increased care efficiency, and lower out-of-pocket costs compared with fee-for-service (FFS) Medicare. When engaged in 2-sided risk arrangements, physicians are incented to offer high value for patients; however, no studies have explored the quality and efficiency outcomes in 2-sided risk Medicare Advantage models compared with FFS Medicare.ObjectiveTo compare quality and efficiency of care between physicians using a Medicare Advantage 2-sided risk model and FFS Medicare.Design, Setting, and ParticipantsThis retrospective cohort analysis with exact and propensity score–matched design used claims data from January 1, 2018, to December 31, 2019. Participants included beneficiaries enrolled in a Medicare Advantage 2-sided risk model (ie, physicians assumed the financial risk of total costs of care) and those in an FFS Medicare program in a 5% limited data set with part A and B coverage residing in 6 states (Arizona, California, Florida, Nevada, Texas, and Utah). Data were analyzed from February 1 to June 15, 2022.ExposuresMedicare Advantage 2-sided risk model seen in practices that are part of a nationwide health care delivery organization compared with traditional FFS Medicare.Main Outcomes and MeasuresComparative analysis of 8 quality and efficiency metrics in populations enrolled in a 2-sided risk-model Medicare Advantage program and 5% FFS Medicare.ResultsIn this analytic cohort of 316 312 individuals (158 156 in each group), 46.11% were men and 53.89% were women; 32.72% were aged 65-69 years, 29.44% were aged 70-74 years, 19.05% were aged 75-79 years, 10.84% were aged 80-85 years, and 7.95% were 85 years or older. The Medicare Advantage model was associated with care of higher quality and efficiency in all 8 metrics compared with the FFS model. This included lower odds of inpatient admission (−18%; odds ratio [OR], 0.82 [95% CI, 0.79-0.84]), inpatient admission through the emergency department (ED) (−6%; OR, 0.94 [95% CI, 0.91-0.97]), ED visits (−11%; OR, 0.89 [95% CI, 0.86-0.91]), avoidable ED visits (−14%; OR, 0.86 [95% CI, 0.82-0.89]), 30-day inpatient readmission (−9%; rate ratio, 0.91 [95% CI, 0.86-0.98]), admission for stroke or myocardial infarction (−10%; OR, 0.90 [95% CI, 0.83-0.98]), and hospitalization for chronic obstructive pulmonary disease or asthma exacerbation (−44%; OR, 0.56 [95% CI, 0.50-0.62]).Conclusions and RelevanceThe improvements observed in this study may be partly or fully attributed to the Medicare Advantage model. The Medicare Advantage risk adjustment system appears to be meeting its intended goal by aligning the capitation payments to the health care burden of the individual beneficiary and aggregate population served, thus providing revenue to develop infrastructure that supports improvements in quality and efficiency for the patients enrolled in Medicare Advantage models with 2-sided risk.

Background: Cerebral venous sinus thrombosis (CVST) secondary to vaccine-induced thrombotic thrombocytopenia is an extremely rare side effect of adenovirus-based COVID-19 vaccines. CVST incidence associated with COVID-19 itself has not been widely reported. We report the incidence of CVST in patients hospitalized with COVID-19 during the first year of the pandemic. Methods: We analyzed de-identified electronic medical records of a retrospective cohort of patients admitted with COVID-19 to >200 hospitals between March 2020 and March 2021. We used International Classification of Diseases, Tenth Revision codes and natural language processing extracts to identify patients with a new CVST diagnosis during COVID-19 hospitalization. The primary outcome was CVST incidence in hospitalized, COVID-19-positive patients. Secondary outcomes included CVST incidence and mortality. Incidence rates were calculated using the DerSimonian-Laird estimator method. Results: Ninety-one thousand seven hundred twenty-seven patients were evaluated; 22 had new CVST diagnoses by electronic medical record review. CVST incidence in the hospitalized COVID-19 cohort was 231 per 1 000 000 person-years (95% CI, 152.1–350.8). FemalesP =0.012) and males (44.4% of males versus 7.7% of females, P =0.023) were more likely to die in hospital. Conclusions: CVST incidence in COVID-19–positive hospitalized patients is high. Advanced age and male gender were associated with likelihood of death in hospital; further studies are required to confirm these findings.

To understand primary care visits and medication utilization among older patients with hypertension to gauge opportunity for service redesign.Data came from 1,880,331 Medicare Advantage members with hypertension who had a primary care visit and a pharmacy claim for an antihypertensive, antidiabetic, or antilipemic medication. To determine activities associated with a primary care visit, we analyzed 43,258,454 medical claims, 245 procedure codes, and medication management associated with those visits. Models for predicting both hypertension visits and medication management were evaluated and applied.Logistic regression was used to identify which features were predictive of a medication change or a provider visit.Almost 40% of visits were consultation only, not associated with a procedure, and 26.5% of individuals had no medication change in a year. For prescription changes, 75% were a return to a previously prescribed medication or a medication discontinuation. Twenty percent of the population accounted for 47.9% of visits. Type 2 diabetes and a prior medication change were the strongest predictors of a medication change. A previous medication change was also the strongest predictor of a subsequent provider visit.Our analysis suggests that a significant portion of care-consultation-only visits-may be relatively low value. Further, much of medication management may not require an office-based visit. Finally, utilization behavior of patients with hypertension and predictive models are likely to allow informed provisioning of new service models to specific population segments.

Girlhood (It’s complicated) is an exhibition at the National Museum of American History (NMAH), part of the Smithsonian Institution, which opened in October of 2020. Created with federal funding as part of the American Women’s History Initiative (AWHI), the exhibition commemorates the centennial of women’s suffrage. To put a fresh spin on this anniversary and draw attention to larger, intertwining issues of gender and politics in the United States, the exhibition team chose to explore the history of girlhood and girls as political actors as the focus of the show. Drawing on the rich, interdisciplinary literature of girlhood studies and inspired by zines as a form of identity creation and political self-expression, the show aims to create a public history of girlhood that unveils the public lives of girls in the past and showcases the many ways in which they, even without the vote or formal political power, have had a political voice in American history. The exhibition is open at the NMAH from October 2020 to January 2023, and will travel with the Smithsonian Institution Traveling Exhibition Service through 2026.

One-third of health care in the United States is wasted. Despite this recognition, solutions are sparse. The Optimal Care model combines evidence-based medicine, patient-centered technology, and outcomes reporting to transform health care.

Importance Real-world analysis of the incidence of SARS-CoV-2 infection post vaccination is important in determining the comparative efficacy of the available vaccines. Objective To study the incidence of SARS-CoV-2 infection in individuals fully vaccinated with either the BNT162b2 or the mRNA-1273 at 30-, 60-, and 90-days post vaccination Design Retrospective cohort study Setting Deidentified administrative claims for Medicare Advantage and commercially insured individuals in a research database. Participants Over 3.5 million fully-vaccinated individuals including 6,434 individuals with SARS-CoV-2 infection with a follow up period between 14 and 151 days after their second dose. Exposure Vaccination by either mRNA-1273 or BNT162b2. Main Outcome and Measures The rate of Covid-19 infection occurring at 30, 60, and 90 days at least 14 days after the second dose of either the mRNA-1273 vaccine or the BNT162b2 vaccine. Sub analyses included the incidence of hospitalization, ICU admission, and death/hospice transfer. Separate analysis was conducted for individuals ≥ age 65 and those without a prior diagnosis of Covid-19 and both yielded results similar to the general population. Results The mRNA-1273 vaccine provided slightly superior protection against SARS-CoV-2 infection compared to the BNT162b2 vaccine. In the full population, there were no significant differences in the risk of hospitalization, ICU admission, or death/hospice transfer. Conclusion Immunization with mRNA-1273, compared to BNT162b2, provided slightly more protection against SARS-CoV-2 infection that reached statistical significance at 90 days with a number needed to vaccinate of ≥292.There were no differences in vaccine efficacy for protection against hospitalization, ICU admission, or death/hospice transfer.

BACKGROUND The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral PARP1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy. Preclinical data indicates that veliparib crosses the blood-brain-barrier and enhances the efficacy of radiotherapy and temozolomide in IDH mutant and wild-type HGG models. ACNS1721 was a single-arm, non-randomized phase 2 clinical trial designed to determine whether treatment with veliparib and radiotherapy, followed by the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and temozolomide, improves progression-free survival (PFS) in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features. METHODS Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients without somatic H3 K27M or BRAF mutations were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant). Protocol radiochemotherapy consisted of involved field radiotherapy with concurrent veliparib at 65 mg/m2 twice daily. Adjuvant chemotherapy consisted of up to 10 cycles of veliparib 25 mg/m2 twice daily and temozolomide 135 mg/m2 once daily for 5 days every 4 weeks. RESULTS Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year progression-free survival (PFS) was 0.29 (SE = 0.09) and 1-year overall survival (OS) was 0.67 (SE = 0.10). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year PFS was 0.57 (SE = 0.15) and 1-year OS was 0.90 (SE = 0.09). CONCLUSION Rapid central pathology review and molecular testing was feasible. The protocol therapy was well tolerated but failed to improve outcome compared to clinically and molecularly matched historical control cohorts.

BACKGROUND Pharmacokinetic modeling for previously reported phase 1A data of pan-RAF inhibitor DAY101 in RAS/RAF/MEK/ERK pathway-altered tumors suggested a correlation between higher doses and improved efficacy without clear safety data. The protocol was amended to explore differential dosing across different body surface areas (BSA). METHODS Eligible patients were < 25 years old with radiographically recurrent/progressive RAS/RAF/MEK/ERK pathway-altered tumors. We applied a novel modification of a TITE-BOIN design to determine recommended phase 2 dosing of oral, weekly DAY101 in evaluable patients within two BSA subgroups: ≤ 1.5 m2 or > 1.5 m2. Target toxicity probability was closest to 20%. We tested 420 and 530 mg/m2. Dose limiting toxicities (DLTs) were determined within Cycle 1. Evaluable patients had either ‘complete’ or ‘partial’ information. Complete information meant patient had a DLT or received 3 of 4 planned doses with no DLT. Partial information meant patient received only 1 or 2 doses or did not complete the DLT observation period. Three patients with complete information at a given dose level were required before dose escalation. The primary endpoint driving dose escalation was time from start of Cycle 1 to first DLT or, if no DLT, time from start of Cycle 1 to minimum of date of last contact or end of Cycle 1. RESULTS We treated 35 eligible patients: 21 KIAA1549:BRAF-, 9 BRAFV600E-, 4 novel RAF- and one FGFR1-altered tumors. Histologically, cohort included 30 LGGs, 4 high grade gliomas and 1 soft tissue sarcoma. There were 6 DLTs: 3 in each BSA subgroup, all at 530 mg/m2/dose, all grade 3, and 5 known side effects ( 2 fatigue, 3 rash, 1 menorrhagia). CONCLUSIONS Oral weekly DAY101 is well tolerated. The TITE model recommends 530 mg/m2/dose PO weekly for patients with BSA < 1.5m2 and 420 mg/m2/dose PO weekly for patients with BSA >1.5m2.

BACKGROUND: Limited data exist regarding checkpoint inhibitor efficacy for pediatric CNS malignancies. METHODS: CheckMate 908 is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO + ipilimumab (IPI) in 5 cohorts of pediatric patients previously treated with standard-of-care (NCT03130959). Patients received NIVO-3mg/kg Q2W or NIVO-3mg/kg + IPI-1mg/kg Q3W (4 doses) followed by NIVO-3mg/kg Q2W. Primary endpoints included OS (newly diagnosed DIPG) and PFS (other CNS cohorts); secondary endpoints included other efficacy metrics/safety. Exploratory endpoints included pharmacokinetics/biomarker analyses. Comparisons between treatments/cohorts were not planned. RESULTS: At data cutoff (13-Jan-2021), 166 patients received NIVO (n=85) or NIVO+IPI (n=81) at median (m) ages of 10.0yrs (range, 1-21) and 11.0yrs (1-21), respectively. In newly diagnosed DIPG, mOS (80% CI) was 11.7mos (10.3-16.5) with NIVO (n=23) and 10.8mos (9.1-15.8) with NIVO+IPI (n=22). In recurrent/progressive HGG, mPFS (80% CI) was 1.7mos (1.4-2.7) with NIVO (n=16) and 1.3mos (1.2-1.5) with NIVO+IPI (n=15). In relapsed/resistant medulloblastoma, mPFS (80% CI) was 1.4mos (1.2-1.4) with NIVO (n=15) and 2.8mos (1.5-4.5) with NIVO+IPI (n=15). In relapsed/resistant ependymoma, mPFS (80% CI) was 1.4mos (1.4-2.6) with NIVO (n=12) and 4.6mos (1.4-5.4) with NIVO+IPI (n=10). In other recurrent/progressive CNS tumors, mPFS (95% CI) was 1.2mos (1.1-1.3) with NIVO (n=19) and 1.6mos (1.3-3.5) with NIVO+IPI (n=19). Median treatment duration was 2.1mos (range, 0-41.7+ [NIVO]/0-29.6+ [NIVO+IPI]). Grade 3/4 treatment-related AEs occurred in 14.1% (NIVO) and 27.2% (NIVO+IPI) of patients. NIVO and IPI first dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor PD-L1 expression was not associated with survival. Tumor mutational burden was high in 1 patient (NIVO+IPI) with HGG (OS=11.0mos). CONCLUSIONS: NIVO±IPI demonstrated no clinical benefit in pediatric patients with high-grade CNS malignancies, consistent with available historical data. The safety profiles were manageable.

BACKGROUND RAS/RAF/MEK/ERK pathway activation is the primary driver for most pediatric low-grade gliomas (pLGG). MEK162 (binimetinib) is an orally bioavailable MEK1/2 inhibitor with superior brain penetration in a preclinical model. The primary objective of this multi-institutional phase II and target validation study was to assess stratum-specific efficacy of binimetinib in progressive pLGG. METHODS Eligible children aged 1-18 years with previously treated radiographically progressive pLGG were enrolled and treated with binimetinib, starting dose 32mg/m2/dose twice daily. Stratum 1 included patients with pLGG with documented BRAF fusion; stratum 2, neurofibromatosis 1 (NF1)-associated pLGG; stratum 3, sporadic pLGG without documented BRAF fusion; and stratum 4, patients undergoing planned tumor biopsy who began binimetinib preoperatively. Partial and minor responses (PR and MR) were defined as ≥50% and ≥25% decrease in maximal two-dimensional measurements. RESULTS Of 86 patients enrolled, 85 were evaluable for response. Of these, 48 (56%) showed a radiographic response (30 PR and 18 MR) in the first year of treatment. Response rate for stratum 1 (n=28) was 50% (12 PR and 2 MR); 12 (43%) had stable disease (SD) and 2 (7%) progressive disease (PD). Stratum 2 (n=21) response rate was 43% (5 PR, 4 MR), with 12 (57%) SD and no PD. Stratum 3 (n=29) response rate was 69% (10 PR, 10 MR), 4 (14%) SD and 5 (17%) PD. Stratum 4 (n=7) include 3 PR, 2 MR, 2 SD. Nineteen (22%) discontinued treatment for toxicity (most commonly dermatologic), and an additional 42 (49%) required dose reduction. Median dose at the time of PR/MR was 28mg/m2; responses were seen at doses as low 16mg/m2. CONCLUSION Binimetinib is highly effective in the treatment of both NF1-associated and sporadic pLGG, with or without documented BRAF fusion. Modified dosing strategies to improve tolerability may be considered in future trials.

BACKGROUND: The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral PARP1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy. Preclinical data indicates that veliparib crosses the blood-brain-barrier and enhances the efficacy of radiotherapy and temozolomide in IDH mutant and wild-type HGG models. ACNS1721 was a single-arm, non-randomized phase 2 clinical trial designed to determine whether treatment with veliparib and radiotherapy, followed by the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and temozolomide, improves progression-free survival (PFS) in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features. METHODS: Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients without somatic H3 K27M or BRAF mutations were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant). Protocol radiochemotherapy consisted of involved field radiotherapy with concurrent veliparib at 65 mg/m2 twice daily. Adjuvant chemotherapy consisted of up to 10 cycles of veliparib 25 mg/m2 twice daily and temozolomide 135 mg/m2 once daily for 5 days every 4 weeks. RESULTS: Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year progression-free survival (PFS) was 0.29 (SE = 0.09) and 1-year overall survival (OS) was 0.67 (SE = 0.10). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year PFS was 0.57 (SE = 0.15) and 1-year OS was 0.90 (SE = 0.09). CONCLUSION: Rapid central pathology review and molecular testing was feasible. The protocol therapy was well tolerated but failed to improve outcome compared to clinically and molecularly matched historical control cohorts.

This research examines the perceived quality of experience for safari tourists within the Ngorongoro Conservation Area in relation to wildlife viewing proximities and the potential of an educational intervention as a management strategy to mitigate adverse impacts of safari participant crowding. Crowding originates from the safari tourists’ preference to obtain close proximity to large mammals, in this case, lions. Recognizing these preferences and the associated impacts to animal behavior defined in the previous research, we developed and delivered a survey instrument designed to measure the perceived quality of experience of the safari tourist while controlling for the viewing proximity variable. The survey instrument involves participants responding to stock photos selected to represent the safari-tour experience, using a Likert type rating scale. Using a ‘pre-treatment’ and ‘post treatment’ protocol, we measure an educational management intervention that correlates the impact of intervention on safari participants’ perceptions of the quality of safari experience based on proximity to animals. Our findings revealed a statistically significant relationship between an educational intervention conveying the adverse impacts of crowding on lion behavior and safari tourists’ perception of a quality experience in relation of proximity to lions. Management implications • To support the findings of Ngrongoro Conservation Area Environmental Impact Assessment (EIA). • To inform the wildlife viewing policies and practices • To establish the validity of an education intervention. • To mediate visitor perceptions. • To ameliorate concerns related to tensions between revenue generation and conservation practices. • To model an environmental education intervention. • To generate a platform for understanding visitor preferences for safari guides. • To demonstrate the efficacy of precise environmental information on tourists understanding of complex environmental systems. • To inform management policies with respect to vehicular congestion as a variable of environmental concern.

BACKGROUND/RATIONAL: Following initial irradiation sparing therapy, many young children with relapsed medulloblastoma can be salvaged with craniospinal irradiation (CSI). However, the interval to relapse is short and neurocognitive sequelae remain a major concern. The contribution of molecular subgrouping may help refine indications and modalities of salvage strategies in this population. METHOD: From a cohort of 151 young children with molecularly characterized relapsed medulloblastoma, subset analysis of the SHH medulloblastoma was conducted to describe the practice of salvage radiotherapy and associated post-relapse survival (PRS). RESULTS: Sixty-seven SHH medulloblastoma patients (46 M0; 54 GTR; 11 non-ND/MBEN) received salvage therapy with curative intent. Before relapse, 54 (80.6%) received conventional chemotherapy (CC), 13 (19.4%) high-dose chemotherapy (HDC), while seven had additional focal radiotherapy (fRT). Median time to relapse was 11.1 months (range 3.8-41.0) and 43.3% were localized. Thirty patients (16 localized relapse) underwent surgery. Forty-seven (71.2%) received salvage radiotherapy (20 with CC; 10 with HDC; 15 alone, two unknown). CSI and fRT accounted for 82% and 18% respectively. CSI median dose was 36Gy (range 18-39Gy). Ten patients (eight with localized relapse) received CSI doses ≤23.4Gy. Nineteen patients (28.8%) did not receive any radiotherapy (nine HDC; 10 CC only). Radiotherapy was associated with better 3-year PRS (73.0% versus 36.1%; p=0.001). All patients treated with CSI ≤ 23.4Gy were alive at median follow-up of 69 months(24-142). Six of nine patients treated with HDC without irradiation were alive at last follow-up. Sixty-three percent of patients received reduced dose CSI(≤23.4Gy), fRT, or no radiotherapy, and their PRS did not significantly differ from those who received CSI ≥ 30.6Gy (p = 0.54). CONCLUSION: While salvage CSI provided PRS benefit in this SHH medulloblastoma cohort, we report the use of reduced salvage radiotherapy and irradiation avoidance in 63% of the patients, with 60% alive at last follow-up.

Background: Ketogenic diets and intermittent fasting (IF) are popularly used for weight loss. Generation of ketone bodies for fuel from fatty acid oxidation underlies both diets, combined or separately. We present a case of a prediabetic patient admitted for DKA after starting a combination keto/IF diet. Clinical Case: A 63-year-old man with hypertension, prediabetes, and alcohol use was admitted from clinic after receiving lab test results consistent with diabetic ketoacidosis (DKA). Two months ago, he had started a keto diet with IF (5 days/week, 18 hour fast/day) and achieved weight loss of 20 pounds. He reported polyuria and polydipsia, which was attributed to the recent initiation of chlorthalidone. Laboratory testing revealed glucose 519 (/= 40 mg/dL). Workup for precipitating causes of DKA was negative including normal lactate, lipase and troponin. The patient was managed with an insulin drip and discharged on subcutaneous insulin (Lantus 45 units/day, Aspart 13 units with meals) and metformin. The patient re-introduced carbohydrates into his diet after meeting with the nutritionist. Eight weeks later, the HbA1c decreased to 6.6% and insulin was significantly reduced to Lantus 25 units/day. Sixteen weeks after discharge, the HbA1c further declined to 5.1% and Lantus was reduced to 10 units/day. Beta cell function at that time was preserved as evidenced by c-peptide 1.82 ng/mL. Insulin therapy was discontinued and the patient was closely monitored for urinary ketones and recurrence of hyperglycemia, neither which have developed. Conclusion: This is a unique case of DKA precipitated by a keto/intermittent fasting diet, without the use of SGLT2 inhibitor. Interestingly, previous metabolic studies show that nutritional ketosis typically generates low levels of serum ketones without a clinically significant anion gap metabolic acidosis. With negative beta cell autoantibodies and preserved beta cell function, this presentation is also consistent with ketosis-prone diabetes type 2B. It is possible that nutritional ketosis triggered the onset of KPD, although the mechanism remains unclear particularly since it is known that lipotoxicity is not pathogenic in the development of KPD. References: 1. Bueno NB et al. Br J Nutr. 2013;110(7):1178-1187. 2. Cahill GF Jr. Annu Rev Nutr. 2006;26:1-22. 3. Gaba R et al. Expert Rev Endocrinol Metab. 2019;14(1):43-48.

VISUAL ABSTRACT

In this book, the author introduces readers to a panoply of small‐time itinerants who have not gotten much attention from historians of early America. By scouring the advertisements in Readex's dig...

BACKGROUND: Molecular subclassification of medulloblastoma identifies Wnt-positive medulloblastoma (WPM) as a highly favorable subtype with event-free survival (EFS) exceeding 90% when treating patients following near total or complete resection with standard dose craniospinal irradiation and boost radiation to the posterior fossa (XRT) followed by adjuvant chemotherapy. This pilot study explored the safety of omitting XRT in children with standard-risk WPM. METHODS: Subjects had to meet usual standard-risk criteria (< 1.5 cm2 residual tumor, no metastatic spread, no anaplasia) and have a WPM. Initial criteria for determination of WPM included nuclear beta-catenin immunopositivity, monosomy 6 and absence of myc-amplification by FISH. Following the first two subject enrollments, criteria for WPM was revised to no longer require nuclear beta-catenin immunopositivity, and substituted gene-expression profiling by Nanostring. Upon consent, eligible subjects received adjuvant chemotherapy following the Children’s Oncology Group ACNS0331 AAB-AAB-AAB (A=cisplatin/CCNU/VCR; B=cyclophosphamide/vincristine) backbone and followed for EFS. RESULTS: Fourteen children underwent prescreening of which six children who met molecular criteria for WPM elected to enroll on study treatment. Subject #1 completed planned protocol therapy, requiring a 50% reduction in cisplatin for most of therapy for ototoxicity, but relapsed 3 months following the completion of therapy. Subject #2 completed planned protocol therapy without dose reductions or delays, but relapsed 6 months following the completion of therapy. In both cases, relapse was local and disseminated. Following the second relapse, further accrual was halted. Of the remaining 4 subjects, two have recently completed protocol therapy and remain free of disease. The final two subjects are in the midst of protocol therapy. Additional therapy in the form of XRT and/or chemotherapy dose intensification has been recommended to these remaining 4 subjects. CONCLUSIONS: Chemotherapy following ACNS0331, in the absence of XRT, appears to be insufficient for the treatment of non-metastatic WPM.

INTRODUCTION: There is an urgent need to expedite the development of new or repurposed drugs for children’s cancer. An additional challenge in the developing brain is to ensure the drug is delivered to the tumour at therapeutic and non-toxic concentrations for sufficient duration to achieve the biological effect. Children’s brain tumours account for over 20% of childhood cancers and differ significantly in their biological characteristics from their adult counterparts. METHODS: The authors participated in an international CNS drug delivery workshop funded by the charity Children with Cancer UK in February 2016, where different experimental techniques aimed at optimising CNS drug delivery in children’s brain tumours were discussed. RESULTS: The workshop was reported by e-cancer (http://ecancer.org/journal/10/full/630-highlights-of-children-with-cancer-uk-s-workshop-on-drug-delivery-in-paediatric-brain-tumours.php; http://ecancer.org/conference/831-drug-delivery-in-paediatric-brain-tumours.php). We were encouraged to develop a proposal to establish an international research consortium to raise awareness and promote collaboration in the field. This is now funded for two years by Children with Cancer UK. The Children’s Brain Tumour Drug Delivery Consortium seeks to strengthen collaborative developments by working closely with the international children’s brain tumour community, encouraging and facilitating discussions between a multi-disciplinary network of clinicians and researchers within pharma and academia as well as a range of funders and stakeholders. As of March 2018, we have 94 individuals from 11 nations registered as members, with diverse stakeholders represented by academics, clinical academics, charities, public/patient groups, industry and regulatory bodies. CONCLUSION: We present this abstract to the BNOS conference to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event, and to extend our invitation for collaborators to join the consortium.