Institutional Research Support Research Articles

Barriers to Publishing Scholarship: A Study on Neurology Physician Residents and Fellows.

Background Scholarly activity by trainees is required for US-accredited graduate medical education (GME) programs. Several factors, including financial barriers to open access (OA) journals, may impact trainees' successful completion of scholarly activity, but little is known to what extent, particularly for neurology trainees. Method The authors implemented a cross-sectional, web-based 17-item survey of US-accredited neurology residency and fellowship programs during the 2022-2023 academic year. Participant responses for producing scholarly activity during GME were analyzed by mixed methods and examined by trainee motivation and perceived barriers, available institutional research support, and OA awareness and compared against socio-demographics (i.e., disadvantaged status history, underrepresented in medicine (URiM) status, international medical school graduate (IMG))and prior research experience. Results Seventy-two respondents from 63 neurology programs completed the survey. Participants represented all US census regions and mostly from academic health centers and in advanced years of training. Overall, 17 (23.6%) self-reported as URiM and 20 (27.8%) as an IMG. Sixty-two (86.1%) were familiar with OA. Prior publications were associated with OA awareness (X2 = 5.3, p<0.05), and 27 (37.5%) reported financial barriers to publishing. IMGs reported less motivation to publish based on a journal's impact factor (odds ratio [OR] = 0.15, 95% confidence interval [CI], 0.03-0.65, p<0.01) but were nearly 5 times more likely to report financial barriers to OA publishing (OR = 4.62, 95% CI 1.31-16.80, p<0.01). Trainees successfully publishing while training reported prior research experience (OR = 7.27, 95% CI 1.71-42.64, p<0.05) and access to mentors (OR = 4.67, 95% CI 1.52-14.64, p<0.001).Dedicated time for scholarly activity and publishing were reported as significant barriers in open-ended responses. Conclusions One-third of the study participants reported financial barriers to publishing scholarship, with these barriers disproportionately affecting IMGs. Prior research experience and access to mentors were associated with a higher likelihood of publishing.

EU, 미국, 중국시장에서 한국 신재생에너지 산업의 품목별 수출 품질경쟁력과 시장점유율 변화 요인 분석

This study applied product and market segment analysis (PMSA) and intra-industry trade (IIT) indices to capture the quality and price competitiveness and high- and low-quality IIT of new renewable energy (NRE) items in Korea’s trade with major economic powers (i.e., European Union [EU], United States, and China) for the period 2012-2022. Additionally, this study used the constant market share (CMS) technique to divide the causes of fluctuations in Korea's market share in large economies’ import markets into demand side, supply side, and adaptation side. The empirical results can be summarized in the following three points. First, PMSA of quality and price competitiveness confirmed Korea’s weakness in securing price and quality competitiveness in trade with the EU and the United States and Korea’s inability to secure price competitiveness in trade with China. Additionally, analysis of high- and low quality IIT showed that in trade with the EU, low-quality vertical IIT and horizontal IIT were mixed, whereas in trade with the United States and China, the majority of items showed low-quality vertical IIT and high-quality vertical IIT patterns, respectively. More importantly, the CMS results by item in the NRE industry based on the 2017/2022 period showed that in the EU and US import markets, supply factors caused most of the market share changes for the majority of items, and in the Chinese import market, the main causes were a mixture of supply and demand factors. In conclusion, policy and institutional support for research and development of independent and convergence technologies are needed to strengthen the NRE industry’s quality competitiveness, and market expansion of the NRE industry can be accomplished by expanding direct investment in the United States and the EU, as well as through government financial support.

2579. Pneumonia Severity Index and CURB-65 scoring for the evaluation of community associated pneumonia in patients with cancer at a major cancer center

Abstract Background Cancer patients with pneumonia (PNA) have 2 to 21 times higher mortality rate compared to the general population. The Pneumonia Severity Index (PSI) and CURB-65 scale have been used to predict mortality for patients with community acquired pneumonia (CAP). While these scales are well studied in the general population, there is a paucity of research on the utility of PSI and CURB-65 for predicting outcomes from CAP in patients with cancer. In this study, we assessed the relationship between PSI and CURB-65 score and 30-day mortality of CAP in cancer patients at Memorial Sloan Kettering Cancer Center (MSKCC). Methods A prospective study at MSKCC was conducted between 01/2023 and 06/2023 on patients who presented with clinical symptoms consistent with PNA and had a urine streptococcus antigen test sent for evaluation. PNA was defined as pulmonary infiltrates on chest X-ray or CT &amp;lt; 48 hours of index event and ≥ 1 clinical symptoms (fever, cough, dyspnea, increased sputum production, hypoxemia). Descriptive statistics were performed to report participant outcomes based on PSI and CURB-65 score and to identify the factors associated with CAP in this population. PSI and CURB-65 scores were derived as described in the literature, based on patient comorbidities (including neoplasia), clinical signs and laboratory values. Higher score is associated with worsening 30-day mortality. Results For 86 participants with who presented with symptoms of PNA and had a urine antigen test sent, 43 (50%) were diagnosed with CAP (Figure 1). The median age was 70 (range: 29-88), 21 (49%) were male, and 16 (37%) had hematologic malignancies (Table 1). Etiologies of CAP were identified in 8 patients (bacteria in 4 patients, virus in 3 patients, fungus in 1 patient). Of the 28 patients with 30-day outcome data available, 5 (18%) died within 30 days of CAP diagnosis. All 5 deceased participants were categorized as PSI Class IV or V (moderate to high risk); however, these participants only scored 0-2 (low to moderate risk) on the CURB-65 scale (Table 2). Conclusion We observed a 30-day overall mortality (n=28) of 18%. For cancer patients who present with CAP, PSI class provides a better means to assess mortality risk than CURB-65 score. Further study is needed to validate our findings. Disclosures Yeon Joo Lee, MD, MPH, AiCuris: institutional research support for clinical trials|Karius: institutional research support for clinical trials|Merck: Grant/Research Support|Scynexis: institutional research support for clinical trials Susan K. Seo, MD, Merck: Grant/Research Support

IMPACT OF RESPONSE TO SYSTEMIC BRIDGING THERAPY ON CLINICAL OUTCOMES AND CYTOKINE PROFILE IN PATIENTS RECEIVING CAR T‐CELL THERAPY FOR AGGRESSIVE B‐CELL LYMPHOMA

Background: It is unclear whether a deeper response to bridging therapy (BT) before chimeric antigen receptor (CAR) T cell therapy improves CAR-T treatment outcome in large B cell lymphoma (LBCL). We studied the impact of response to systemic BT on clinical outcomes and cytokine profiles of LBCL patients (pts) treated with CD19-directed CAR-T. Methods: We included LBCL pts treated with systemic BT before receiving commercial CD19-CAR-T at two academic centers, and excluded those who received monotherapy with glucocorticosteroids or isolated radiation therapy. BT was classified as Polatuzumab- (pola) based, intensive chemotherapy, lenalidomide/ Bruton tyrosine kinases inhibitors (len/BTKi), or other. PET/CT scans obtained before and after BT, and after CAR-T were evaluated using Lugano 2014 response criteria. Association between BT and response rates (RR) were examined using Fisher’s exact test, and the associations with cytokine levels were examined using Kruskal Wallis tests. Kaplan Meier analysis was used to estimate overall (OS) and progression free survival (PFS) from time of CAR T infusion. Cox proportional hazards models were used for univariable and multivariable analyses. Results: We identified 148 pts whose median age was 65 (range 23–85), and 96 (65%) were male. BTs included: 62 (42%) pola-based, 48 (32%) intensive chemotherapy, 25 (17%) len/BTKi, and 13 (9%) other BT. Among all pts, 77 (52%) received Axicel, 42 (28%) received Tisacel and 29 (20%) received Lisocel. Median time from apheresis to CAR-T was 35 days. Among evaluable pts RR to BT were: 10 (7%) complete responses (CR), 39 (29%) partial responses (PR), 87 (64%) either stable disease (SD) or progressive disease (PD). RR did not differ among different BT regimens (p = 0.27). At day 100 post-CAR-T, RR were: 74 (50%) CR, 27 PR (18%) and 44 (30%) SD/PD. With a median follow up of 18.9 months, PFS was 5.03 months (95% CI: 3.25, 9.53) and median (OS) was 16.1 months (95% CI 12.2–31.3) (Figure 1A). In multivariable analysis, poor response to BT (SD/PD) and elevated LDH prior to CAR-T infusion were associated with worse PFS, but not with OS. LDH (Figure 1B), ferritin, IL-6, IL-10 and C-reactive protein measured prior to lymphodepletion (LD) and at day 0 of CAR-T infusion were significantly higher in pts with SD/PD compared to pts achieving a CR/PR to BT. Ferritin levels prior to LD were higher in pts who received intensive chemotherapy compared to other BT. Keywords: aggressive B-cell non-Hodgkin lymphoma, cellular therapies Conflicts of interests pertinent to the abstract G. L. Shah Research funding: Janssen, Amgen, Beyond Spring, and BMS. DSMB for ArcellX M. Scordo Consultant or advisory role: McKinsey & Company, Angiocrine Bioscience, Inc., and Omeros Corporation; served on ad hoc advisory boards for Kite—A Gilead Company Honoraria: Received honoraria from i3Health and Medscape for CME-related activity Research funding: received research funding from Angiocrine Bioscience, Inc., and Omeros Corporation R. J. Lin Consultant or advisory role: Kite G. Salles Consultant or advisory role: Abbvie, Atbtherapeutics, Bayer, Beigene, BMS/Celgene, Debiopharm, Epizyme, Genentech/Roche, Genmab, Incyte, Ipsen, Janssen, Kite/Gilead, Loxo/Lilly, Molecular Partners, Morphosys, Nordic Nanovector, Novartis, Regeneron, Takeda H Stock ownership: Owkin M. Perales Consultant or advisory role: Adicet, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Syncopation, VectivBio AG, and Vor Biopharma. He serves on DSMBs for Cidara Therapeutics, Medigene, and Sellas Life Sciences, and the scientific advisory board of NexImmune. Research funding: He has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis. Other remuneration: He has ownership interests in NexImmune, Omeros and OrcaBio. M. L. Palomba Consultant or advisory role: Synthekine, Cellectar, Beigene, Kite, BMS

Readmission with infective endocarditis within 90 days following transcatheter aortic valve implantation.

Transcatheter aortic valve implantation (TAVI) continues to be the most common modality of treating aortic stenosis in the United States. While infective endocarditis (IE) and its outcomes have been well documented after surgical aortic valve replacement, the incidence and outcomes of early IE after TAVI have not been well described. All patients who underwent TAVI from 2012 through 2018 were identified using the National Readmission Database. Among them, patients who underwent TAVI at the index admission and readmitted within 90 days were included. Patients who died or had IE during the index admission were excluded. Clinical outcomes were compared between patients readmitted with IE (IE group) and those without (non-IE group). A total of 168,283 patients were readmitted to a hospital within 90 days after TAVI. The median age of the IE group and non-IE group were 81 and 82 years old, respectively (p = 0.21). Of those, 525 (0.3%) were readmitted with IE. The median time from TAVI to readmission was 20 days. During readmissions, 11.6% of the IE group died while only 3.15% of the non-IE group experienced death (p < 0.001). The most common causative organism of IE was enterococcus (22.1%). Multivariable analysis revealed that congestive heart failure, cerebrovascular disease, dialysis, concomitant valve disease, Medicaid, and discharge to a facility were independently associated with readmission with IE within 90 days. The incidence of readmission with IE is low after TAVI. However, the mortality was markedly high during readmissions. Surgical intervention was rarely performed for IE during the first admission. Enterococcus was the most common organism observed in IE after TAVI. IS receives institutional research support from Abbott, Atricure, cryolife, and Medtronic. None related to this manuscript. Not applicable.

Voicing student recovery: Embracing diversity in collegiate recovery programs

Objective: To discuss the engagement of patients and stakeholders (ie, faculty, staff, healthcare providers, and university administrators) in capacity building activities to prepare for future patient-centered research on collegiate recovery. Participants: 502 attended capacity building activities and provided input on priorities for future research in collegiate recovery and 77 participated in the deliberative democracy forum process. Methods: We used surveys and the deliberative democracy forum method, which includes framing sessions and forums for data collection. This method enables individuals with diverse backgrounds to share and learn about differing viewpoints to build consensus for decision making. Results: Forum participants prioritized barriers to recovery for future research and discussed the need to address diversity in collegiate recovery programs, including racial/ethnic diversity in the student recovery population and diversity in pathways to recovery, to decrease barriers to recovery. Conclusions: Institutional support for research on collegiate recovery is critical to move the field forward.

Long-term Outcomes With Ibrutinib Treatment for Patients With Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis of 3 Clinical Trials With Nearly 10 Years of Follow-up.

Long-term Outcomes With Ibrutinib Treatment for Patients With Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis of 3 Clinical Trials With Nearly 10 Years of Follow-up.

Precision medicine in aggressive thyroid cancer: Moving beyond multitargeted tyrosine kinase inhibitors

Precision medicine in aggressive thyroid cancer: Moving beyond multitargeted tyrosine kinase inhibitors

Myocarditis Associated with mRNA COVID-19 Vaccination.

Myocarditis Associated with mRNA COVID-19 Vaccination.

Effectiveness of BNT162b2 mRNA COVID-19 Vaccine Against SARS-CoV-2 Variant Beta (B.1.351) Among Persons Identified Through Contact Tracing in Israel

Background: SARS-CoV-2 variant Beta (B.1.351) was designated as a Variant of Concern (VoC) after becoming the dominant strain in South Africa and spreading internationally. BNT162b2 showed lower levels of neutralizing antibodies against Beta than against other strains raising concerns about effectiveness of vaccines against infections caused by Beta. We estimated BNT162b2 effectiveness against Beta infections in Israel, a country with high vaccine uptake. Methods: The Ministry of Health (MoH) identified Beta cases through mandatory reporting of SARS-CoV-2 cases and whole genome sequencing (WGS) of specimens from vaccination-breakthrough infections, reinfections, arriving international travelers, and a selection of other infected persons. A cohort analysis was conducted of exposure events of contacts of primary Beta cases. WGS was conducted on available PCR-positive specimens collected from contacts. VE estimates with 95% confidence intervals (CIs) against confirmed and probable Beta infections were determined by comparing infection risk between unvaccinated and fully-vaccinated ( > 7 days after the second dose) contacts, and between unvaccinated and partially-vaccinated (Findings: MoH identified 310 Beta cases through Jun 27, 2021. During the study period (Jan 1, 2021 – Mar 25, 2021), 164 non-institutionalized primary Beta cases, with 552 contacts aged > 16 years, were identified. 343/552 (62%) contacts were interviewed and tested. 71/343 (21%) contacts were PCR-positive. WGS was performed on 7/71 (10%) PCR-positive specimens; all were Beta. Among SARS-CoV-2-infected contacts, 48/71 (68%) were symptomatic, 10/71 (14%) hospitalized, and 2/71 (3%) died. Fully-vaccinated VE against confirmed or probable Beta infections was 72% (95% CI -5 - 97%; p =0.04) and against symptomatic confirmed or probable Beta infections was 100% (95% CI 19 - 100%; p =0.01). There was no evidence of protection in partially-vaccinated contacts. Interpretation: Two doses of BNT162b2 conferred protection against Beta infections and disease. Introductions of Beta did not interrupt control of the pandemic in Israel. Funding: None to declare. Declaration of Interest: Frederick Angulo, David Swerdlow, John McLaughlin, Farid Khan, Gabriel Mircus, Kaijie Pan, Jo Southern, and Luis Jodar hold stock and stock options in Pfizer Inc. Marc Lipsitch has provided advice on COVID-19 free of charge to Janssen, Astra-Zeneca, Pfizer, and COVAXX (United Biomedical), as well as to the nonprofit One Day Sooner and has received consulting income or honoraria from Merck, Pfizer, Bristol Meyers Squibb, Janssen, and Sanofi, and institutional research support from Pfizer. He is on the Scientific Advisory Committee of the Coalition for Epidemic Preparedness and Innovations (CEPI). All other authors report no conflicts.Ethical Approval: This study was approved by MoH’s Institutional Review Board (CoR-MoH-080-2021).

Infections, Hospitalizations, and Deaths Averted Via Direct Effects of the Pfizer-BioNTech BNT162b2 mRNA COVID-19 Vaccine in a Nationwide Vaccination Campaign, Israel

Background: Israel recently initiated a rapid nationwide COVID-19 vaccination campaign to immunize persons ≥16 years of age and used exclusively Pfizer–BioNTech BNT162b2 mRNA COVID-19 vaccine according to schedule (two doses, 21 days apart). We provide the first estimates of the number of COVID-19 cases, hospitalizations, and deaths averted by a nationwide vaccination campaign. Methods: We used national surveillance data from the first 112 days (Dec 20, 2020 ‒ Apr 10, 2021) of Israel’s vaccination campaign to estimate averted burden of four outcomes: SARS-CoV-2 infections and COVID-19-related hospitalizations, severe or critical hospitalizations, and deaths. The direct effects of the immunization program were estimated for all susceptible individuals (i.e., no previous evidence of laboratory-confirmed SARS-CoV-2 infection) who were at least partially vaccinated (defined as receipt of at least one dose with ≥14 days after the first dose). Cases averted were estimated based on cumulative daily, age-specific rate differences comparing rates among unvaccinated to those who were at least partially vaccinated for each of the four outcomes and the (age-specific) size of the susceptible population and proportion that was at least partially vaccinated. Findings: Through Apr 10, 2021, we estimated that Israel’s vaccination campaign averted 158,665 (95% uncertainty range: 115,899‒201,431) SARS-CoV-2 infections, 24,597 (6,622‒42,571) hospitalizations, 17,432 (3,065‒31,799) severe and critical hospitalizations, and 5,533 (-1,146‒12,213) deaths. Of these, 66% of hospitalizations and 91% of deaths averted were among those ≥65 years of age. Seventy-three percent of SARS-CoV-2 infections and 79% of COVID-19-related hospitalizations and deaths averted stemmed from the protective effects in fully vaccinated persons. Interpretations: Without vaccination, Israel would have likely experienced triple the number of hospitalizations and deaths compared to what actually occurred during their largest wave of SARS-CoV-2 to date, which would have likely overwhelmed the healthcare system. Indirect effects and long-term benefits of the program, which could be substantial, were not included in these estimates and warrant future research. Funding: None.Declaration of Interest: John McLaughlin, Frederick Angulo, Farid Khan, Gabriel Mircus, Kaijie Pan, Jo Southern, David Swerdlow, and Luis Jodar hold stock and stock options in Pfizer Inc. Marc Lipsitch has provided advice on COVID-19 free of charge to Janssen, Astra-Zeneca, Pfizer, and COVAXX (United Biomedical), as well as to the nonprofit One Day Sooner and has received consulting income or honoraria from Merck, Bristol Meyers Squibb, and Sanofi, and institutional research support from Pfizer. All other authors report no conflicts.

Deep Learning Model to Quantify Left Atrium Volume on Routine Non-Contrast Chest Ct and Predict Adverse Outcomes

Background: Non-contrast chest CTs (NCCT) are performed routinely for coronary artery calcium (CAC) scoring and lung cancer screening. However, a large amount of noncoronary and nonpulmonary data from these scans remain unassessed. We aimed to validate a deep learning model to automatically segment and measure left atrial (LA) volumes from routine NCCT and evaluate prediction for cardiovascular outcomes. Methods: We retrospectively evaluated 273 patients (median age 69 years, 55.5% male) who underwent a routine non-ECG gated NCCT for lung cancer screening. LA volumes were quantified by three expert cardiothoracic radiologists and a prototype AI algorithm. LA volumes were then indexed to the body surface area (BSA). Expert and AI LA volume index (LAVi) were compared and used to predict cardiovascular outcomes within five years. Logistic regression with appropriate univariate statistics were used for modelling outcomes. Findings: There was excellent correlation between AI and expert results with an LAV intraclass correlation of 0.950 (0.936-0.960). Bland-Altman plot demonstrated the AI underestimated LAVi by a mean 5.86 mL/m 2 . AI-LAVi was associated with new-onset atrial fibrillation (AUC 0.86; OR 1.12, 95% CI 1.08-1.18, p<0.001), HF hospitalization (AUC 0.90; OR 1.07, 95% CI 1.04-1.13, p<0.001), and MACE (AUC 0.68; OR 1.04, 95% CI 1.01-1.07, p=0.01). Interpretation: This novel deep learning algorithm for automated measurement of LA volume on routine NCCT had excellent agreement with manual quantification. AI-LAVi is significantly associated with new-onset atrial fibrillation, HF hospitalization, and MACE within 5 years. Funding: None to declare. Declaration of Interest: AJ, MAG, PS, and PS are employees of Siemens Healthineers. UJS has received institutional research support and/or honoraria for speaking and consulting from Astellas, Bayer, Bracco, Elucid BioImaging, General Electric, Guerbet, HeartFlow Inc., and Siemens Healthineers. TE has received a speaker fee and travel support from Siemens Healthineers. MEF reports research support from Boston Scientific, Biosense Webster, and Medtronic. JRB owns equity at YellowDot Innovations, LLC., and has received institutional research support and/or honoraria for consulting from Siemens Healthineers. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

Background: It is unclear how multiple sclerosis (MS) affects the severity of Covid-19.Methods: Hospitalization, Intensive Care Unit (ICU) admission and death after Covid-19 diagnosis of 1362 MS patients were compared to the age and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher-risk: EDSS>3 or at least one comorbidity, lower-risk: EDSSFindings: The risk of severe events was about twice the risk in the age and sex-matched Italian population: RR=2·12 for hospitalization (pInterpretation: Overall the MS cohort had a risk of severe events that is twice the risk in the age and sex-matched Italian population. This excess of risk is mainly explained by EDSS and comorbidities, while a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon.Funding Information: None.Declaration of Interests: MP. Sormani reports grants from Roche, during the conduct of the study; personal fees from Biogen, Merck, Roche, Sanofi, Novartis, Medday, Geneuro, Celgene, Mylan outside the submitted work.N. De Rossi received speaker honoraria from Biogen Idec, Genzyme, Novartis, Sanofi-Aventis; received funding for participation in advisory board to Novartis, Biogen and Genzyme-Sanofi and for travel to scientific meetings from Biogen Idec, Teva, Sanofi-Genzyme, Roche, Almirall and Novartis.M Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Associate Editor of Radiology, and Associate Editor of Neurological Sciences; received compensation for consulting services and/or speaking activities from Alexion, Almirall, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). He received speaker’s honoraria from the following companies: Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and TEVA.M. Radaelli received speaker honoraria from Biogen Idec, Sanofi-Genzyme, Novartis and Merck Serono and funding for travel to scientific meetings from Biogen Idec, Sanofi-Genzyme, Novartis, Merck Serono, Teva and Roche.P. Immovilli reports personal fees from Roche, personal fees from Biogen, personal fees from Merck, outside the submitted work.M. Capobianco reports personal fees and non-financial support from Biogen, personal fees and non-financial support from Merck Serono, personal fees and non-financial support from Roche, personal fees and non-financial support from Novartis, personal fees and non-financial support from Sanofi, personal fees from Almirall, outside the submitted work.P. Confalonieri has received honoraria for speaking or consultation fees from Novartis and Biogen, has received funding for travel to attend scientific events or speaker honoraria from Merck Serono, Biogen Idec, Teva and Roche. He has also received institutional research support from Merk-Serono, Novartis and Roche. He is also principal investigator in clinical trials for Biogen, Merck Serono, Roche.M.Inglese received research grants from NIH, DOD, NMSS, FISM, and Teva Neuroscience; received fees for participating in advisory boards from Roche, Biogen, Merck and Genzyme.M. Trojano reports grants and personal fees from Biogen, grants and personal fees from Novartis, grants and personal fees from Roche, grants and personal fees from Merck, personal fees from Sanofi, personal fees from TEVA, from null, outside the submitted work.G. Comi reports personal fees from Novartis, Teva Pharmaceutical Industries Ltd, Teva Italia Srl, Sanofi Genzyme, Genzyme Corporation, Genzyme Europe, Merck KGgA, Merck Serono SpA, Celgene Group, Biogen Idec, Biogen Italia Srl, F. Hoffman-La Roche, Roche SpA, Almirall SpA, Forward Pharma, Medday, Excemed, outside the submitted work.F. Patti reports grants from Biogen, grants from Merck, grants from FISM, grants from Onlus association, grants from University of Catania, personal fees from Almirall, personal fees from Bayer, personal fees from Biogen, personal fees from Merck, personal fees from Roche, personal fees from Sanofi, personal fees from TEVA, outside the submitted work.M. Salvetti reports grants and personal fees from Biogen, grants and personal fees from Merck, grants and personal fees from Novartis, grants and personal fees from Roche, grants and personal fees from Sanofi, grants and personal fees from Teva, grants from Italian Multiple Sclerosis Foundation, grants from Sapienza University of Rome, outside the submitted work.I .Schiavetti, L. Carmisciano, C. Cordioli, G Brichetto, E Cocco, P Cavalla, I Pesci, A Zito, GA Marfia, P Perini, V Brescia Morra, G. Tedeschi, C. Scandellari, M. Battaglia have nothing to disclose.Ethics Approval Statement: The study was approved by the Regional Ethics Committee of Liguria (University of Genoa) (n 130/2020 – DB id 10433) and at a national level by Agenzia Italiana del Farmaco (AIFA).

Development of university–industry partnerships in Kazakhstan: Innovation under constraint

This paper examines university–industry partnerships (UIPs) in Kazakhstan. The study described here explored the kinds of collaborations with industry that universities have undertaken, their purposes and benefits, and the contextual barriers to such partnerships. Our findings suggest that UIPs in Kazakhstan remain weak and are largely limited to employers’ involvement in teaching, the provision of internships for students, and technical consultancies. We argue that the goal of policy makers to develop robust research partnerships that contribute to innovation and economic growth is constrained by heavy faculty teaching loads, poor institutional support for research, constant reforms in the higher education system, and little consistency in the priorities of the fast-changing Ministers of Education.

Pretreatment Neutrophil-to-Lymphocyte Ratio as a Predictor of Survival and Response to Therapy in Patients Treated with Immune Checkpoint Inhibitors

Background: Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients benefit, there is a strong need for predictive biomarkers. The aim of this study was to analyze the predictive capacity of neutrophil-to-lymphocyte ratio (NLR) in cancer patients treated with ICI, and to analyze the predictive value of combining NLR with tumor mutational burden (TMB). Methods: Retrospective cohort study of patients treated during 2015-2018. A total of 1714 patients with 16 different cancer types, who had complete blood count within 30 days prior to first ICI infusion, and whose tumors underwent next-generation sequencing were included. Overall survival, progression-free survival, response to ICI, and clinical benefit (response or stable disease ≥6 months) were the primary endpoints. Findings: Patients with NLR in the top 20th percentile within cancer type had significantly poorer overall survival (HR = 2·17; 95% CI, 1·89-2·50; P<0·001), progression-free survival (HR = 1·60; 95% CI, 1·41-1·81; P<0·001), response rate (18% vs 29%; P<0·001), and clinical benefit rate (21% vs 35%; P<0·001). Consistent results were obtained stratifying by cancer type. In multivariable analyses, NLR and TMB demonstrated independent association with clinical benefit. A combined variable of NLR and TMB was strongly associated with outcome. The probability of clinical benefit from ICI was 4 times higher in the NLR-low/TMB-high group compared to the NLR-high/TMB-low group (OR = 3·88; 95% CI, 2·72-5·54; P<0·001). Interpretation: In cancer patients, higher NLR was associated with poorer survival and lower likelihood of response to ICI. NLR is a suitable candidate for a cost-effective and widely accessible predictive biomarker, and can be combined with TMB for additional predictive capacity. Funding Statement: Fundacion Alfonso Martin Escudero (to CV), NIH K08 DE024774 and R01 DE027738 (to LGTM), and the NIH/NCI Cancer Center Support Grant P30 CA008748. Declaration of Interests:DH receives funding from AstraZeneca. MAP reports consulting fees from BMS, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, and Aduro, honoraria from BMS and Merck, and research support from RGenix, Infinity, BMS, Merck, Array BioPharma, Novartis, and AstraZeneca. ANS reports advisory board position with BMS, Immunocore, and Castle Biosciences, and institutional research support from BMS, Immunocore, and Xcovery. VPB is a recipient of an immuno-oncology translational research grant from Bristol-Myers Squibb and is an inventor on a patent application related to work on neoantigen modelling. AMC reports advisory board position with Springworks Therapeutics. JJS has received travel support from Intuitive Surgical Inc. for fellow education and has served as a clinical advisor to Guardant Health, Inc. SGP has a patent PCT/US2016/026717 Methods of Cancer Detection Using PARPIFL pending, holds equity in Summit Biomedical Imaging, has a patent US 10,016,238B2 Apparatus, system and method for providing laser steering and focusing for incision, excision and ablation of tissue in minimally-invasive surgery, and holds equity in ColdSteel Laser Inc. NR reports research support from Pfizer and BMS, and consulting fees from REPARE Therapeutics, Mirati Therapeutics and Illumina. AZ reports honoraria from Illumina. TAC acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai, has served as an advisor for Bristol-Myers Squibb, Illumina, Eisai, and An2H, holds equity in An2H, and is a co-founder of Gritstone Oncology and holds equity. LGTM reports laboratory research funding from Illumina, Inc. and AstraZeneca. Ethics Approval Statement: The study was approved by the Memorial Sloan Kettering Cancer Center institutional review board (IRB).

Why do Human Femoral Stents Fail? First In-man Pathology and Multimodality Imaging of Acute and Chronic Femoral Stenting in Human

Introduction: Lower extremity peripheral arterial disease (PAD) is a major cause of morbidity. Endovascular therapy remains the gold standard to treat PAD1. While pathology of coronary stenting has been well studied2, pathology of lower extremity femoral stenting remains poorly understood. The objective was to comprehensively evaluate the pathology of acute and chronic femoral stenting in symptomatic atherosclerotic patients and to understand the causes of stent failures (SF) using multi-modality imaging including micro-computed tomography (microCT). Methods: Twelve stents were obtained from 10 patients with history of PAD (mean age 74 ± 9.3; 7 male and three female); all the stented arteries underwent radiography, microCT and histologic assessment. Dissected arteries were embedded in Spurr and sawed at 3-5 mm intervals and Exact slides were prepared at 60 to 100 mm and a total of 78 sections examined following co-registration with microCT. Results are reported as median and interquartile (25 to 75th percentile, IQR). Results: Duration was 150 days (30 - 365, IQR), diameter was 5.90 mm (5.44 - 7.16, IQR) and stented length was 39.5 mm (27 - 107.5, IQR). Two of 12 stents were drug-eluting stents, 10 of 12 were bare-metal stents. Half of them were overlapping stents. Indications for stenting were intermittent claudication (40%), chronic limb ischemia (50%), and acute limb ischemia (10%). Morphometric analysis of the histologic sections showed stent success [(defined as < 75% cross sectional area narrowing and absence a thrombus (>30% narrowing from thrombus)] in 4 of 12 stents with 31.0% stenosis (22.16 - 35.0, IQR). The causes of SF in the remaining 8 were: stent-thrombosis (Figure 1), 3; in-stent restenosis, 2; and chronic total occlusions, 3, with 91.5% stenosis (78.3 - 100, IQR). Histologic malapposition3 occurred in 8 of the 12 stented lesions. Underlying nodular calcification (NC) was observed in half of the lesions, medial calcifications observed in 67% of cases with the median arch of calcification of 63° (0-283, IQR). Intimal calcification was observed in 11/12 cases, degree of calcification was 126° (38 - 248, IQR). The duration of implantation was divided into short-term (≤90 days) and long-term (>90 days) stenting. The extent of medial calcification was significantly different in short-term vs. long-term stenting [126° (18.0 - 195.8) vs 0 (0 - 2.25) respectively, p=0.003]. Malapposition (Figure 2) was observed more frequently in the short-term vs. long-term groups [50.0% (25.0 - 87.5) vs 0% (0-11.9) respectively, p=0.02]. Stent fractures were observed in 3 stents (3/11, 27.7%) and all of them were associated with SF. Also, SF had a higher medial injury score4: 2 (1 - 3, IQR) vs 1 (1 - 2, IQR), p=0.04. Conclusion: This descriptive histologic study is the first series of explanted human femoral stents, removed at surgery (n=10) and autopsy (n=2). Medial calcification and malapposition play an important role in long-term stent patency. Excessive injury and stent fracture also contributes to SF. Use of microCT in this study illustrates the advantages of high-resolution CT to detect SF, especially stent fractures. This study also enlightens the necessity to evaluate any explanted material in the future5.Figure 2Multi-modality imaging showing stent malapposition.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Disclosure: Sho Torii receives research grants from SUNRISE lab. Renu Virmani and Aloke V. Finn have received institutional research support from Abbott Vascular, Boston Scientific, Cook Medical, Cardiovascular Systems, Inc., Medtronic, and Terumo Corporation; Renu Virmani is a consultant for 480 Biomedical, Abbott Vascular, Medtronic, and W.L. Gore. Other authors report no conflicts of interest.

Sex Comparison of Drug‐seeking Behavior after Limited‐Access Methamphetamine‐taking in a Socio‐sexual Context in Rats

Vulnerability to develop a substance use disorder is influenced by social context, including sexual experience, in both male and female drug users. Methamphetamine (Meth) is associated with increased sexual pleasure, driving further drug use. Our laboratory has demonstrated in male rats that limited access to Meth in a socio‐sexual context during consecutive daily sessions enhances drug‐seeking behavior during extinction and reinstatement tests. The goal of this study was to investigate the effects of Meth‐taking in a socio‐sexual context in female rats, which differ from males in behavioral and pharmacological responses to Meth in an estrus‐cycle dependent manner. Female Sprague Dawley rats were ovariectomized and implanted with IV catheters. They underwent 5 sessions of limited‐access Meth self‐administration (maximum drug intake 1 mg/kg/session) each separated by three days. Two days and 4 hours prior to each session, females received estradiol benzoate (10μg) and progesterone (500μg) respectively. Females either mated immediately after each session (concurrent females, n=7) or were returned to home cage (Meth only females, n=7). The male mating partners of the concurrent females were also tested for operant behavior (concurrent males, n=8) to determine whether concurrent Meth self‐administration and mating only once every four days is sufficient to enhance drug‐seeking behavior. After Meth self‐administration, all groups underwent 8 operant extinction sessions followed by cue reinstatement. Both concurrent groups (female and male) readily acquired Meth self‐administration, while Meth only females were delayed in acquiring Meth self‐administration compared to concurrent females. No differences in operant behavior were detected between groups during extinction. Next, it was determined that both female groups exhibited significant cue‐induced reinstatement of drug‐seeking behavior with no effects of prior concurrent sex behavior. In contrast, concurrent males did not significantly reinstate drug‐seeking. Together these results suggest that Meth‐taking in a socio‐sexual context may facilitate initial drug‐taking behavior in female rats, and that females have a higher vulnerability to relapse than males. However, the lack of enhanced vulnerability to relapse due to concurrent sexual behavior in concurrent males suggests that imposing a 3‐day interval between sessions mitigated the development of addiction‐like behavior in this model compared to our previous findings using daily sessions. Therefore, potential effects of concurrent socio‐sexual behavior may have also gone undetected in females using the current experimental design. Findings here provide useful insight into behavioral responses to limited‐access Meth self‐administration in female rats, however further development of experimental procedures is necessary to investigate the effect of Meth‐taking in a socio‐sexual context on extinction and relapse behavior in females.Support or Funding InformationSupported by Institutional Research Support Program at University of Mississippi Medical Center.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

LB21. Preemptive Therapy (PET) vs. Prophylaxis for Prevention of Cytomegalovirus (CMV) Disease in High-Risk Donor Seropositive/Recipient Seronegative (D+R−) Liver Transplant Recipients (LTR): A NIH-Sponsored, Randomized, Controlled, Multicenter Trial

BackgroundCurrent guidelines preferentially recommend valganciclovir (VGCV) prophylaxis over PET in most D+R− organ transplant populations, but adequately powered direct comparative clinical trials are lacking.MethodsD+R− LTR were randomly assigned (1:1, stratified by site and T-cell depleting induction) to receive either PET (weekly plasma CMV DNAemia at central laboratory for 100 days, with VGCV 900 mg bid for DNAemia at any level, until two consecutive negative weekly tests) or prophy (VGCV 900 mg qd for 100 days). The primary outcome was CMV disease by 12 months as adjudicated by an independent, blinded, endpoint committee in ITT population. Secondary outcomes were opportunistic infections (OIs) (invasive fungal and bacterial), neutropenia (ANC < 1000/µL), acute rejection, graft loss, and mortality assessed at12 months.ResultsFrom October 2012 to June 2017, 205 patients were randomized at six centers; 100 to PET, 105 to prophy. The incidence of CMV disease was 9% (9/100) in PET and 19% (20/105) in prophy (P = 0.039) with majority of difference due to post-prophylaxis disease: 6% in PET vs. 17% in prophy (P = 0.027). CMV disease included syndrome in 55% (16/29) and end-organ in 45% (13/29), with similar proportions in two groups. Secondary outcomes were not different for PET and prophy groups: OIs (19% vs. 21%), neutropenia (34% vs.. 28%), acute rejection (27% vs. 27%), graft loss (2% vs. 2%), and mortality (10% vs. 6%), respectively, P > 0.05 for all comparisons. Mortality at last follow-up (median 3.2 years) was not different for PET vs. prophy (14% vs. 18%, P = 0.43).ConclusionsPET significantly reduced the incidence of CMV disease compared with prophy in D+R- LTR, and was associated with similar other clinical outcomes. Current guidelines should be revised to recommend PET over prophylaxis in this setting, and similar trials conducted in other D+R− transplant populations. (Funded by NIAID; ClinicalTrials.gov# NCT01552369.) Disclosures D. Winston, Merck: Investigator, Research support. Chimerix: Investigator, Research support. Shire: Investigator, Research support. Gilead: Investigator, Research support. Oxford Immunotech: Investigator, Research support. G. M. Lyon III, Shire: Investigator, institutional research support. Hookipa: Investigator, institutional research support. Merck: Investigator, institutional research support. F. P. Silveira, Shire: contracted clinical research, site investigator. A. P. Limaye, Merk: Consultant and Investigator, Consulting fee and Research grant. Astellas Pharma Inc.: Consultant and Investigator, Consulting fee. Helocyte Inc.: Consultant, Consulting fee.

LBA3 - Maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients (pts) with advanced ovarian cancer (OC) and a BRCA1/2 mutation (BRCAm): Phase III SOLO1 trial

Background: Pts with newly diagnosed advanced OC are treated with cytoreductive surgery and platinum-based chemotherapy. Most relapse within the first 3 years and have further chemotherapy, but once relapsed are largely not curable. SOLO1 (NCT01844986) is the first Phase III trial to evaluate PARP inhibitor (olaparib [Lynparza®]) maintenance therapy after platinum-based chemotherapy in newly diagnosed advanced OC with a BRCAm. Methods: SOLO1 is a randomized, controlled, double-blind trial. Eligible pts had newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid ovarian, primary peritoneal and/or fallopian tube cancer with a BRCAm, had received platinum-based chemotherapy and were in clinical complete or partial response. Pts were randomized 2:1 to olaparib tablets 300 mg bd or placebo. The primary endpoint was investigator-assessed progression-free survival (PFS; modified RECIST v1.1). Results: Of 391 randomized pts, 260 received olaparib and 130 placebo (one pt did not receive placebo). Median follow-up was 41 months. Baseline characteristics were well balanced. Primary PFS analysis showed a significant 70% reduction in the risk of progression or death with olaparib versus placebo (Table). PFS sensitivity analyses, second PFS and time to first subsequent therapy or death support the primary analysis. Overall survival datTableLBA3Median, monthsHR (95% CI)Olaparib (N = 260)Placebo (N = 131)Between-group differenceP valuePFS, investigator assessedNR13.8NC0.30 (0.23–0.41)P < 0.0001(51% maturity)PFS, BICR*Sensitivity analysis using BICR BICR, blinded independent central review; HR, hazard ratio; NC, not calculable; NR, not reached; PFS, progression-free survival; PFS2, time from randomization to second progression or death; TFST, time to first subsequent therapy or deathNR14.1NC0.28 (0.20–0.39)(38% maturity)P < 0.0001TFST51.815.136.70.30 (0.22–0.40)P < 0.0001PFS2NR41.9NC0.50 (0.35–0.72)(31% maturity)P = 0.0002* Sensitivity analysis using BICR BICR, blinded independent central review; HR, hazard ratio; NC, not calculable; NR, not reached; PFS, progression-free survival; PFS2, time from randomization to second progression or death; TFST, time to first subsequent therapy or death Open table in a new tab a are immature. Adverse events were mostly low grade. The most common grade ≥3 toxicities with olaparib were anaemia (22%) and neutropenia (8%). Olaparib dose reductions, interruptions and discontinuations occurred in 28%, 52% and 12%, respectively. There was no change from baseline in health-related quality of life scores with olaparib. Conclusions: Maintenance olaparib led to a substantial, unprecedented improvement in PFS, with an estimated difference in median PFS for olaparib versus placebo of approximately 3 years. Editorial acknowledgement: Gillian Keating, MBChB, from Mudskipper Business Ltd, funded by AstraZeneca and Merck & Co., Inc. Clinical trial identification: NCT01844986, 26 August 2013. Legal entity responsible for the study: AstraZeneca. Funding: AstraZeneca. Disclosure: M. Friedlander: Personal fees for advisory boards: AZ and MSD. K. Moore: Consultancy: Tesaro, Genentech Roche, Clovis, Immunogen, VBL Therapeutics, Janssen (honorarium, ad board), AstraZeneca - honorarium, ad board (for agents not involved in the SOLO-1 study). N. Colombo: Honoraria: Genentech, Astra Zeneca, PharmaMar; Consulting or advisory role: Genentech, PharmaMar, AstraZeneca, Clovis Oncology, Pfizer, MSD, Tesaro; Research funding: AstraZeneca. G. Scambia: Fees for advisory role: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro. A. Oaknin: Fees for advisory board: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro; Travel/accommodation: Roche, AstraZeneca, PharmaMar. A. Floquet: Fees for advisory board: Astra Zeneca, Roche, Tesaro; Support travel: Roche. A. Leary: Ad boards: Clovis, AstraZeneca, Gamamabs, Pfizer, Gridstone; Travel costs: AstraZeneca; Preclinical research support: Merus, Gamamabs, Sanofi. G.S. Sonke: Institutional research support: AstraZeneca, Merck, Novartis, Roche. C. Gourley: Fees for advisory role: Roche, AstraZeneca, Tesaro, Nucana, Clovis, Foundation One; Lecture fees: AstraZeneca; Research funding (to my institution): Novartis, Aprea, AstraZeneca, Nucana, Tesaro. S. Banerjee: Research funding: AstraZeneca; Advisory boards: AstraZeneca, Tesaro, Clovis. A.M. Oza: Steering committees for trials: AstraZeneca, Clovis, Tesaro (all non-compensated); Honoraria: Intas Pharma. A. González-Martín: Grants as speaker/advisory board participants (last 36 months): AstraZeneca, Tesaro, Roche, Clovis, Pharmamar. C. Aghajanian: Consultancy: Tesaro, Cerulean, Bayer, VentiRx (honorarium, ad board); Mateon Therapeutics (honorarium steering committee meetings); Clovis (honorarium ad boards and steering committee meeting). W. Bradley: Fee for advisory role: Celsion E.S. Lowe, R. Bloomfield: Employee and stockholder: AstraZeneca. P. Disilvestro: Consulting fees: AstraZeneca and Tesaro (over last 2 years). All other authors have declared no conflicts of interest.

Research and innovation field as an area for creating an innovation infrastructure for the development of today’s society

The paper examines social and economic aspects of the research and innovation field within which an infrastructure for the development of today’s society is being created. An idea of creating an innovation infrastructure based on innovation and modernization of the social and economic system is developed. It is demonstrated that creating an innovation infrastructure for further growth by applying the modernization theory is associated with updating the existing business patterns and introducing new ones into technical and technological, economic and social, spiritual and cultural areas of society. This necessitates the development and implementation of an economic model of investment for modernization; attraction and expansion of investment through providing intermediary services by infrastructure institutions. It is emphasized that the growth in the research and innovation field contributes to the national capacity-building that ensures the development and implementation of domestic innovative products and supports the national identity. It is pointed out that for creating an innovation infrastructure for the development of today’s society the following measures should be taken: addressing social and economic challenges of the state and raising living standards; funding and improving research studies; establishing a market infrastructure; developing integration links between educational, research and manufacturing organizations; providing community-based and institutional support for research and innovation field; increasing the investment attractiveness of the country on the world stage.