Improving Patient\Population Health: Using ‘Why’ to Develop a Transformative Research Center

Introduction Novel approaches to address the most vexing problems facing patients and vulnerable populations are needed. The purpose of this project was to establish an innovative research Center based on the principles of transformational organizations. Methods A new Center formed included faculty members with expertise in cancer, serious illness, and population health. Applying Sinek’s “why, how, and what” framework, members developed and refined a purpose statement and strategic objectives. The Center now includes members representing diverse disciplines. Year 1 accomplishments included a refined mission and vision statement, two funded research proposals, one submitted training grant, one administrative hire, and active recruitment of two-research faculty to support Center activities. Conclusions The newly-formed Center for Improving Patient and Population Health has enabled scholars within a research-intensive school of nursing to forge new partnerships to compete successfully for larger, complicated grant proposals on shorter deadlines. Opportunities exist to integrate students and research staff more fully into Center operations.

Non-invasive myocardial work reference ranges in healthy children

Background Myocardial work (MW) estimation by pressure-strain loops (PSL) allows a non-invasive assessment of myocardial performance, as recently demonstrated in adult patients. Aim Aim of this study is to provide the reference values for global myocardial work index (MWI), constructive work (MCW), wasted work (MWW), and work efficiency (MWE) in a group of healthy children. Methods Assessment of MW was performed using a commercially available software package. MW was measured from PSLs areas, derived from non-invasive LVP curves combined with strain acquired speckle tracking echocardiography (STE). After calculating GLS, values of brachial blood pressure were inserted and the time of valvular events by echocardiography were indicated, then the software was able to measure non-invasive PSLs. Results Two-dimensional (2D) standard and speckle-tracking echocardiography were performed in 90 healthy children (mean age 9.9±4.9 [1–17] years, females: 57%) together with the assessment of MW by means of PSLs. Mean ± standard deviation, 5° and 95° percentile values for global MWI, MCW, MWW, and MWE in the whole population were 1769±254 mm Hg, (1354–2193); 2201±290 mm Hg, (1657–2658); 78±47 (29–163) mm Hg%; 96±1.8 (92–99)%, respectively. Conclusions The assessment of MW is feasible in healthy children. This study provides useful 2-dimensional echocardiographic reference ranges for novel indices of non-invasive MW. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): ESC Training Grant 2019

786 Distinct efficacy and immunological responses to aPD-1, aPD-L1 and aPD-L2 immunotherapy in B16 melanoma in aged versus young hosts includes T-cell stem cell effects and PD-L2 expression differences

BackgroundAging is the biggest risk factor for cancer, yet little is known about cancer immunotherapy effects. ?PD-1 can block PD-L1 and PD-L2 while ?PD-L1 blocks PD-1 and CD80.1 A recent key finding in young hosts including humans is that melanoma response to aPD-1/aPD-L1 correlates with CD8+TCF-1+ T cell stem cell (TCSC) generation.2MethodsWe tested aPD-1 (100 or 200 µg/mouse), aPD-L1 (100 µg/mouse) or aPD-L2 (200 µg/mouse) in aged (18-33 months) and young (3-8 months) mice challenged orthotopically with B16 (WT or PD-L1ko) melanoma (SQ) or ID8agg ovarian cancer (IP). Tumors were analyzed by flow. Bone marrow-derived DC were generated with GM-CSF.ResultsWe reported that aPD-1 treats young and aged with B16 and aPD-L1 treats young not aged.3 aPD-L2 treated B16 in aged but, remarkably, not young, the first anti-cancer single agent immunotherapy exhibiting this property [figure 1]. Efficacy in young (aPD-1, aPD-L1) and aged (aPD-L2) correlated with increased tumor TCSC [figure 3], but TCSC differed by age and treatment (e.g., distinct CCR2, CXCR5, CXCR3) [figure 2]. aPD-L2 efficacy against B16 in aged mice required host IFN-g and IL-17 [figure 4]. IP ID8agg ovarian cancer did not respond to aPD-L2 in aged or young mice. Aged expressed up to 40-fold more PD-L2 versus young on various immune cells suggesting high PD-L2 helps aPD-L2 response [figure 6]. Host IFN-g contributed to aged PD-L2 expression, which did not appear cell-autonomous [figure 6]. PD-L1KO aged but not young mice challenged with PD-L1KO B16 responded to aPD-1 [figure 5], consistent with PD-L2 block as a mechanism.Abstract 786 Figure 1aPD-L2 treats B16 in aged but not young miceIn the image.Abstract 786 Figure 2aPD-1, aPD-L1 and aPD-L2 elicit distinct TCSCIn the image.Abstract 786 Figure 3Treatment efficacy correlate with increased TCSCIn the image.Abstract 786 Figure 4Lack of host IFN-g and IL-17 eliminates aPD-L2 efficacyIn the image.Abstract 786 Figure 5PD-L1 KO aged mice challenged with PD-L1 KO B16In the image.Abstract 786 Figure 6Immune cell immune checkpoint expressionIn the image.ConclusionsTreatment differences in aged versus young could depend on immune checkpoint or TCSC differences, which could be related to CD8+ T-cell infiltration, including TCSC. aPD-1 efficacy in aged PD-L1KO mice challenged with PD-L1KO B16 suggests that aPD-1 efficacy is through PD-L2 block in aged. PD-L2 expression differences and anatomical compartment differences in tumor microenvironment may also contribute to treatment efficacy differences. We are now identifying mechanisms for increased PD-L2 and other mechanisms for aPD-L2 efficacy in aged, and testing TCSC effects. Our work can improve cancer immunotherapy in aged hosts and provides insights in treatment failures, including in young hosts.AcknowledgementsSouth Texas MSTP training grant (NIH T32GM113896), TL1TR002647, Graduate Research in Immunology Program training grant(NIH T32 AI138944), R01 CA231325, Samuel Waxman Cancer Research Foundation GrantEthics ApprovalThe study was approved by UTHSA IACUC, approval number 20180021.ReferencesSchildberg FA, Klein SR, Freeman GJ, Sharpe AH. Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity 2016;44(5):955-72.Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 2016;537(7620):417-21.Padron A, Hurez V, Gupta HB, Clark CA, Pandeswara SL, Yuan B, et al. Age effects of distinct immune checkpoint blockade treatments in a mouse melanoma model. Exp Gerontol 2018;105:146-54.

From bench to bedside: trends in National Institutes of Health funding for neurosurgeons from 1991 to 2015

OBJECTIVENeurosurgeons play an important role in advancing medicine through research, the funding of which is historically linked to the National Institutes of Health (NIH). The authors defined variables associated with neurosurgical NIH funding, prevalence of funded topics by neurosurgical subspecialty, and temporal trends in NIH neurosurgical funding.METHODSThe authors conducted a retrospective review of NIH-funded American Association of Neurological Surgeons members using NIH RePORTER (http://report.nih.gov/) for the years 1991–2015.RESULTSThe authors followed 6515 neurosurgeons from 1991 to 2015, including 6107 (94%) non–MD-PhD physicians and 408 (6%) MD-PhDs. NIH grants were awarded to 393 (6%) neurosurgeons, with 23.2% of all first-time grants awarded to the top 5 funded institutions. The average total funded grant-years per funded neurosurgeon was 12.5 (range 1–85 grant-years). A higher percentage of MD-PhDs were NIH funded than MDs (22% [n = 91] vs 5% [n = 297], p < 0.0001). The most common grants awarded were R01 (128, 33%), K08 (69, 18%), F32 (60, 15%), M01 (50, 13%), and R21 (39, 10%). F32 and K08 recipients were 9-fold (18% vs 2%, p < 0.001) and 19-fold (38% vs 2%, p < 0.001) more likely to procure an R01 and procured R01 funding earlier in their careers (F32: 7 vs 12 years after residency, p = 0.03; K08: 9 vs 12 years, p = 0.01). Each year, the number of neurosurgeons with active grants linearly increased by 2.2 (R2 = 0.81, p < 0.001), whereas the number of total active grants run by neurosurgeons increased at nearly twice the rate (4.0 grants/year) (R2 = 0.91, p < 0.001). Of NIH-funded neurosurgical grants, 33 (9%) transitioned to funded clinical trial(s). Funded neurosurgical subspecialties included neuro-oncology (33%), functional/epilepsy (32%), cerebrovascular (17%), trauma (10%), and spine (6%). Finally, the authors modeled trends in the number of active training grants and found a linear increase in active R01s (R2 = 0.95, p < 0.001); however, both F32 (R2 = 0.36, p = 0.01) and K08 (R2 = 0.67, p < 0.001) funding had a significant parabolic rise and fall centered around 2003.CONCLUSIONSThe authors observed an upward trend in R01s awarded to neurosurgeons during the last quarter century. However, their findings of decreased K08 and F32 training grant funding to neurosurgeons and the impact of these training grants on the ultimate success and time to success for neurosurgeons seeking R01 funding suggests that this upward trend in R01 funding for neurosurgeons will be difficult to maintain. The authors’ work underscores the importance of continued selection and mentorship of neurosurgeons capable of impacting patient care through research, including the MD-PhDs, who are noted to be more represented among NIH-funded neurosurgeons.

1014 Relationship Between Lung Function and Obstructive Sleep Apnea in Cystic Fibrosis

Introduction The frequency of obstructive sleep apnea (OSA) may be high among patients with cystic fibrosis (CF), a life-shortening, genetic respiratory disease that affects approximately 30,000 Americans. Yet, the potential relationship between OSA and lung function has not been thoroughly explored. Methods Single-center retrospective review of polysomnography (PSG) results from 2009-2017 in referred patients with CF and available pulmonary function data (PFTs) obtained at time of PSG and at 3, 6, 9, and 12-months prior. Results Mean ages were 11.1±3.9 (sd) and 37.1±14.1 years, among 18 children and 16 adults, respectively. Mean body mass index (BMI) was normal in both groups (62.5±26.6% in children; 25.1±6.4 kg/m2 in adults). Twenty-six subjects (76%) had OSA (apnea-hypopnea index &gt;1 in children, ≥5 in adults). Mean forced expiratory volume in 1 second percent predicted (FEV1 PPD) was higher among subjects with vs. without OSA at PSG and at each time-point in the year prior, independent of age and BMI at PSG (longitudinal mixed effects model, β=19.0, SE=8.1, p=0.028). While FEV1 PPD remained unchanged in the non-OSA group, FEV1 PPD at PSG was lower, in comparison to the year prior in subjects with OSA, with the greatest difference observed at 9-months prior to PSG (2-sample t-test, difference of -6.6% vs 0.6% in OSA vs. non-OSA groups respectively, p=0.078). Conclusion The PFTs, as daytime markers of CF lung disease severity, do not seem to reliably predict risk for OSA. In our sample, CF patients with vs. without OSA had better PFTs at baseline but they also showed a greater tendency for decline in PFTs over the year prior to OSA diagnosis. Larger sample size and longer duration of assessment may help, going forward, to assess any potential adverse impact of OSA on lung function decline. Support NIH Training Grant (T32NS007222, F32HL145915)