tbuckley/cabot-search huggingface dataset:
Disruption of the white matter structural network and its correlation with baseline progression rate in patients with sporadic amyotrophic lateral sclerosis
Authors: Wenbin Li, Qianqian Wei, Yanbing Hou, Du Lei, Yuan Ai, Kun Qin, Jing Yang, Graham J. Kemp, Huifang Shang, Qiyong Gong
Journal: Translational Neurodegeneration (2021)

Abstract Objective There is increasing evidence that amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease impacting large-scale brain networks. However, it is still unclear which structural networks are associated with the disease and whether the network connectomics are associated with disease progression. This study was aimed to characterize the network abnormalities in ALS and to identify the network-based biomarkers that predict the ALS baseline progression rate. Methods Magnetic resonance imaging was performed on 73 patients with sporadic ALS and 100 healthy participants to acquire diffusion-weighted magnetic resonance images and construct white matter (WM) networks using tractography methods. The global and regional network properties were compared between ALS and healthy subjects. The single-subject WM network matrices of patients were used to predict the ALS baseline progression rate using machine learning algorithms. Results Compared with the healthy participants, the patients with ALS showed significantly decreased clustering coefficient C p ( P = 0.0034, t = 2.98), normalized clustering coefficient γ ( P = 0.039, t = 2.08), and small‐worldness σ ( P = 0.038, t = 2.10) at the global network level. The patients also showed decreased regional centralities in motor and non-motor systems including the frontal, temporal and subcortical regions. Using the single-subject structural connection matrix, our classification model could distinguish patients with fast versus slow progression rate with an average accuracy of 85%. Conclusion Disruption of the WM structural networks in ALS is indicated by weaker small-worldness and disturbances in regions outside of the motor systems, extending the classical pathophysiological understanding of ALS as a motor disorder. The individual WM structural network matrices of ALS patients are potential neuroimaging biomarkers for the baseline disease progression in clinical practice.
Projecting the impact of triple CFTR modulator therapy on intravenous antibiotic requirements in cystic fibrosis using patient registry data combined with treatment effects from randomised trials
Authors: Ruth H Keogh, Rebecca Cosgriff, Eleni-Rosalina Andrinopoulou, Keith G Brownlee, Siobhán B Carr, Karla Diaz-Ordaz, Emily Granger, Nicholas P Jewell, Alex Lewin, Clemence Leyrat, Daniela K Schlüter, Maarten van Smeden, Rhonda D Szczesniak, Gary J Connett
Journal: Thorax (2021)

Background Cystic fibrosis (CF) is a life-threatening genetic disease, affecting around 10 500 people in the UK. Precision medicines have been developed to treat specific CF-gene mutations. The newest, elexacaftor/tezacaftor/ivacaftor (ELEX/TEZ/IVA), has been found to be highly effective in randomised controlled trials (RCTs) and became available to a large proportion of UK CF patients in 2020. Understanding the potential health economic impacts of ELEX/TEZ/IVA is vital to planning service provision. Methods We combined observational UK CF Registry data with RCT results to project the impact of ELEX/TEZ/IVA on total days of intravenous (IV) antibiotic treatment at a population level. Registry data from 2015 to 2017 were used to develop prediction models for IV days over a 1-year period using several predictors, and to estimate 1-year population total IV days based on standards of care pre-ELEX/TEZ/IVA. We considered two approaches to imposing the impact of ELEX/TEZ/IVA on projected outcomes using effect estimates from RCTs: approach 1 based on effect estimates on FEV 1 % and approach 2 based on effect estimates on exacerbation rate. Results ELEX/TEZ/IVA is expected to result in significant reductions in population-level requirements for IV antibiotics of 16.1% (~17 800 days) using approach 1 and 43.6% (~39 500 days) using approach 2. The two approaches require different assumptions. Increased understanding of the mechanisms through which ELEX/TEZ/IVA acts on these outcomes would enable further refinements to our projections. Conclusions This work contributes to increased understanding of the changing healthcare needs of people with CF and illustrates how Registry data can be used in combination with RCT evidence to estimate population-level treatment impacts.
KS01.4.A NK cells as key orchestrators in mediating the anti-tumour response to immune checkpoint blockade in melanoma brain metastases
Authors: C M Fife, J Williams, R Brownlie, T Andreou, A Sunderland, C McKimmie, R Salmond, M Lorger
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Brain metastases (BrM) are an unmet clinical need with poor prognosis. 60% of melanoma patients develop BrM. BrM are strongly understudied due to frequent exclusion from clinical trials, and hence treatment options commonly lag behind. Antibodies targeting the immune-inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have demonstrated efficacy against melanoma BrM. Despite this, therapeutic responses are highly variable, and it is unknown why therapy fails in a high proportion of patients. Improved therapeutic strategies require a thorough understanding of potentially exploitable mechanisms of therapeutic efficacy. Our data previously implicated different immune cells, foremost CD8+ T cells, but also NK cells, in the intracranial efficacy and enhanced survival benefit of immune checkpoint blockade (ICB). Our aim here is to investigate the role of NK cells in mediating the response to ICB in melanoma BrM. MATERIAL AND METHODS To study the role of NK cells in the response to ICB in melanoma BrM, a tumour transplantation model of B16 melanoma with simultaneous extracranial (i.e., flank) and brain tumours in C57BL/6 mice was utilised. NK cells were depleted through administration of anti-asialo-GM1 NK cell-depleting antibodies. Confirmation of NK cell depletion and quantification of intratumoral immune cell populations was performed using flow cytometry. Intratumoral gene expression of key chemokines and immune mediator genes was assessed using RT-qPCR and mRNA-seq. RESULTS Highly variable response to ICB with respect to intratumoral accumulation of CD8+ T cells allowed separation of mice into responders and non-responders and revealed genes and pathways associated with response to ICB. NK cell depletion reversed the ICB-mediated increase in the accumulation of CD8+ T cells and significantly reduced the expression of genes associated with response in intracranial and extracranial tumours. The ICB-mediated significant increase in gene expression of various chemokines (i.e., Cxcl9/10) and immune mediators (i.e., Ifng, Prf1 and Gzmb) was significantly abrogated upon NK cell depletion. CONCLUSION NK cells play a critical role in the underlying mechanisms of ICB efficacy through their modulation of the tumour microenvironment and enhancement of CD8+ T cell accumulation in intracranial tumours. Targeting of NK cells may allow potentiation of ICB therapy in the brain, as well as at extracranial sites.
Disaggregating Data to Measure Racial Disparities in COVID-19 Outcomes and Guide Community Response — Hawaii, March 1, 2020–February 28, 2021
Authors: Joshua J. Quint, Miriam E. Van Dyke, Hailey Maeda, J. Keʻalohilani Worthington, May Rose Dela Cruz, Joseph Keaweʻaimoku Kaholokula, Chantelle Eseta Matagi, Catherine M. Pirkle, Emily K. Roberson, Tetine Sentell, Lisa Watkins-Victorino, Courtni A. Andrews, Katherine E. Center, Renee M. Calanan, Kristie E.N. Clarke, Delight E. Satter, Ana Penman-Aguilar, Erin M. Parker, Sarah Kemble
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Native Hawaiian and Pacific Islander populations have been disproportionately affected by COVID-19 (1-3). Native Hawaiian, Pacific Islander, and Asian populations vary in language; cultural practices; and social, economic, and environmental experiences,† which can affect health outcomes (4).§ However, data from these populations are often aggregated in analyses. Although data aggregation is often used as an approach to increase sample size and statistical power when analyzing data from smaller population groups, it can limit the understanding of disparities among diverse Native Hawaiian, Pacific Islander, and Asian subpopulations¶ (4-7). To assess disparities in COVID-19 outcomes among Native Hawaiian, Pacific Islander, and Asian populations, a disaggregated, descriptive analysis, informed by recommendations from these communities,** was performed using race data from 21,005 COVID-19 cases and 449 COVID-19-associated deaths reported to the Hawaii State Department of Health (HDOH) during March 1, 2020-February 28, 2021.†† In Hawaii, COVID-19 incidence and mortality rates per 100,000 population were 1,477 and 32, respectively during this period. In analyses with race categories that were not mutually exclusive, including persons of one race alone or in combination with one or more races, Pacific Islander persons, who account for 5% of Hawaii's population, represented 22% of COVID-19 cases and deaths (COVID-19 incidence of 7,070 and mortality rate of 150). Native Hawaiian persons experienced an incidence of 1,181 and a mortality rate of 15. Among subcategories of Asian populations, the highest incidences were experienced by Filipino persons (1,247) and Vietnamese persons (1,200). Disaggregating Native Hawaiian, Pacific Islander, and Asian race data can aid in identifying racial disparities among specific subpopulations and highlights the importance of partnering with communities to develop culturally responsive outreach teams§§ and tailored public health interventions and vaccination campaigns to more effectively address health disparities.
Abstract 260: Associations of Chest Compression Release Velocity and Age, Weight, and Gender During Cardiac Resuscitation
Authors: John H Sutter, Samuel Beger, Chengcheng Hu, Daniel W Spaite, Annemarie Silver, Robyn McDannold, Margaret Mullins, Tyler Vadeboncoeur, Bentley J Bobrow
Journal: Circulation (2018)

Background: Higher chest compression release velocity (CCRV) is associated with better outcomes after OHCA. Patient age and gender have been associated with variations in chest wall compliance and compressibility which may impact outcomes. Hypothesis: To evaluate the association between CCRV and OHCA patient age, weight, and gender. Methods: Observational study of prospectively collected OHCA quality improvement data in two suburban EMS agencies in Arizona between 10/1/2008 and 12/31/2016. Patient age and weight were categorized into quartiles for the analysis. CCRV was summarized at each level of the categorical variable by median and inter-quartile range (IQR), and was then compared between different levels by the Kruskal-Wallis test. Results: During the study period, 2,661 OHCA cases were treated. After exclusion criteria, 1,140 cases remained for analysis. Median duration of compressions was 8.70 minutes. Mean CCRV was negatively correlated with age and positively correlated with weight (Table). Male patients exhibited a greater mean CCRV compared to female patients [344.4 mm/s (IQR 307.3-384.6) vs. 331.5 (285.3-385.5), p=0.0133]. Conclusion: Patient characteristics including younger age, male gender, and increased weight were associated with a higher CCRV during OHCA resuscitation.
Biosimilar uptake of filgrastim and impact on spending in Medicare Part D from 2015 to 2019.
Authors: Syed Hussaini, Arjun Gupta, Kelly E. Anderson, Jeromie M. Ballreich, Lauren H. Nicholas, Caleb Alexander
Journal: Journal of Clinical Oncology (2021)

67 Background: The introduction of a filgrastim biosimilar in 2014 was associated with substantial cost savings in Medicare Part B and Medicaid programs. However, Medicare Part D is unique since it is unable to directly negotiate prices with drug manufacturers. We sought to investigate the uptake of filgrastim biosimilars and impact on spending among Part D beneficiaries. Methods: We evaluated utilization trends for filgrastim (Neupogen), filgrastim-sndz (Zarxio), and tbo-filgrastim (Granix) using the 2015-2019 Medicare Part D Prescription Drug Event data. We conducted a retrospective cross-sectional review of annual spending, number of beneficiaries, number of claims, spending per beneficiary, and spending per dosage unit. We excluded filgrastim-aafi (Nivestym) due to recent approval and adjusted for inflation using 2019 dollars. Results: In 2019, total aggregate Part D spending on filgrastim products was $78 million. From 2015 to 2019, the biosimilar share of total aggregate spending increased from $1.8 million (2%) to $44 million (56%), with combined biosimilar spending (Zarxio and Granix) eclipsing originator Neupogen in 2018 (within 4 years of FDA approval of Zarxio). Total spending on Neupogen reduced 58% from 2015 to 2019. While biosimilar uptake progressively increased every year, total aggregate spending on all filgrastim forms reduced only 7% from 2015 to 2019 ($84 million to $78 million). For all 3 forms, from 2015 to 2019, trends in spending were: average spending per claim ($3193 to $2549, -20%), average spending per beneficiary ($5880 to $6722, +15%), and average spending per dosage unit of filgrastim ($583 vs $571, -2%). Detailed results in Table. Conclusions: We demonstrate that the significant uptake of biosimilar filgrastim products in Medicare Part D from 2015 to 2019 was associated with a small decrease in aggregate spending, essentially unchanged per unit spending, and increased spending per beneficiary on filgrastim products. Our findings contrast with experiences across Medicare Part B and Medicaid, that demonstrated significant cost savings with biosimilar filgrastim uptake. This may be due to inability of Medicare Part D to directly negotiate prices with manufacturers (in contrast to Medicare Part B and Medicaid), supporting ongoing Congressional policy being debated in the United States Senate (H.R. 3).[Table: see text]
A dual lox/cox inhibitor, licofelone, suppresses pancreatic cancer xenografts in athymic nude mice
Authors: Sunil Patel, Suresh Guruswamy, Chang Choi, Yuting Zhang, Vernon Steele, Howard Ozer, C V Rao
Journal: Cancer Research (2008)

LB-324  Currently, therapeutic strategies for pancreatic cancer (PC) are very limited and most of the first-line therapies had limited survival benefit. Eicosanoids generated from 5-Lipoxygenase (5-LOX) and cyclooxygenase (COX)- pathways are involved in tumor promotion, progression and metastasis of several cancers, including PC. Thus, inhibition of both COX and 5-LOX pathways may be an important strategy for the prevention and treatment of PC. In this study, we compared the effect of Licofelone (LF), a 5-LOX/ COX-inhibitor, therapeutic efficacy in comparison to standard therapeutic agents, Gemcitabine (GT) and Oxaliplatin (OP) in PC xenografts.  Athymic NCr-nu/nu mice were divided into 4 treatment groups (5/group) and fed AIN-76A diet. LF was administered at 200 ppm in diet, while GT (25mg/Kg BW, twice weekly) and OP (5mg/kg BW, once in 4 weeks) was administered by i.p. All mice were given s.c. injection of BxPC-3 pancreatic cancer cells to initiate xenograft tumors. After 10 weeks of treatment, mice were sacrificed and the final Tumor Volume (TV) and tumor weight were measured. Tumor xenografts were assessed for cell proliferation, apoptosis, expression of COX-2, 5-LOX, and VEGFR-1/2 by western blot and Immunohistochemical (IHC) methods.  None of the experimental agents induced any toxicity or weight loss. Treatmentwith GT significantly suppressed TV (37%) and weight (32.4%), whereas OP did not provide any effect. Interestingly, LF showed a very significant decrease in TV (68%) and weight (64%). Further, tumor xenograft treated with GT and LF showed significant suppression of cell proliferation by PCNA staining (66% and 88%, respectively) and induction of apoptosis by TUNEL method (3-fold and 8-fold, respectively) compared to control. IHC & Western blot analysisof tumors from GT and LF treated mice revealed a significant inhibition of COX-2, 5-LOX, and VEGFR-1/2. In summary, our results are the first to show that dietary LF possesses PC inhibitory properties and had better efficacy than GT.
P14.40 Trends in distribution of glioblastoma care and patient’s travel distance; results from the Dutch Brain Tumor Registry
Authors: M E De Swart, V K Y Ho, F J Lagerwaard, D Brandsma, M P Broen, P French, A Gijtenbeek, M Geurts, M C J Hanse, B Idema, M Klein, J A F Koekkoek, S K Polman, C W Samuels, T Seute, A E J Sijben, M Smits, M J Vos, A M E Walenkamp, P Wesseling, P C De Witt Hamer, M C M Kouwenhoven
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Over the past years, increasing worldwide attention towards centralization of complex cancer care has been pursued as higher volume centers have shown improved outcomes. Changes in distribution of care and the impact on travel distance in glioblastoma patients have not been determined yet. In this study, we determine trends in distribution of glioblastoma care in the Netherlands over the last three decades and assess whether the observed trends affected travel distance for individual patients. MATERIAL AND METHODS Data were obtained from the Dutch Brain Tumor Registry from 1989 to 2018. All glioblastoma patients (≥18 years) were included for analysis. Patients, neurosurgical centers and radiotherapy centers were geocoded. Data were analyzed in six time intervals of 5 years. High volume hospitals were defined as &amp;gt;50 cases per year. Travel distance was examined in two categories, ≤60km and &amp;gt;60km respectively. Trend analyses for proportions were used to analyze hospital volume changes and travel distances. RESULTS A total of 16.477 glioblastoma patients were registered, with an annual increase from 203 patients in 1989 to 917 patients in 2018. Neurosurgical centers increased from 16 to 17 and for radiotherapy from 19 to 22 centers between 1989–1993 and 2014–2018. Mean neurosurgical- and radiotherapy center volumes increased from 12 to 39 (P=0.025) and 7 to 27 (P=0.025) patients per hospital per year from 1989–1993 to 2014–2018. High volume neurosurgical centers were observed since 2004, and an increased number of patients were treated in these centers, 27.8%, 52.6% and 64.1% in the time periods 2004–2008, 2009–2013, and 2014–2018 (P&amp;lt;0.001). High volume radiology centers were observed since 2009, and 15.0% and 27.3% of patients were treated in these centers in the time periods 2009–2013 and 2014–2018 (P&amp;lt;0.001). Patients with a travel distance &amp;gt;60km to the neurosurgical center reduced from 15.8% to 13.2% (P=0.033). Travel distance &amp;gt;60km to the radiotherapy center did not reduce significantly (10.4% to 8.8%, P=0.601). CONCLUSION An increasing number of glioblastoma patients were differentially treated in high volume neurosurgery and radiotherapy centers. The observation that this did not translate into increased travel distances, indicates accessible specialized Neuro-Oncology care for glioblastoma patients in The Netherlands.
OS08.5.A Proteomic analysis of meningioma
Authors: C O Hanemann, J Dunn, Y Akther, E Ercolano, C Adams, M Banton, V Sharma, D Hilton
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Meningioma is the most common primary intracranial tumor. Although ~80% are benign some WHO grade I are clinically aggressive. Chemotherapies are ineffective and biomarkers for clinical management are lacking. Approximately 60% sporadic meningiomas harbor mutations in the NF2 gene andutations in TRAF7, KLF4, AKT1, SMO and PIK3CA have been identified in the majority NF2-positive tumors esp lower grade. However, the molecular mechanisms behind meningioma tumourigenesis is still unclear. We aim to identify novel biomarkers and therapeutic targets of meningioma by characterizing the proteomic landscape. MATERIAL AND METHODS We analysed grade I, II and III frozen meningioma specimens and three different mutational groups: AKT1/TRAF7, KLF4/TRAF7 and NF2 -/- using LC-MS/MS to analyse global proteins, enriched phosphoproteins and phosphopeptides. Differential expression and functional annotation of proteins was completed using Perseus, IPA® and DAVID. For mutational subtypes quantitative phosphoproteomics was performed using TMT 10plex labeling approach followed by motif analysis using motif-X algorithm. We validated differential expression of proteins and phosphoproteins by Western blot and immunohistochemistry. RESULTS We quantified 3888 proteins and 3074 phosphoproteins across all meningioma grades. Bioinformatics analysis revealed commonly upregulated (phospho)proteins to be enriched in Gene Ontology terms associated with RNA metabolism. Validation confirmed significant overexpression of proteins such as EGFR, CKAP4, the nuclear proto-oncogene SET, the splicing factor SF2/ASF as well as total and activated phosphorylated form of the NIMA-related kinase, NEK9, involved in mitotic progression. Hexokinase 2 was overexpressed in higher grades. For the mutation subtypes we have quantified 4162 proteins across all mutational meningioma subgroups. Analysis showed distinct proteomic profiles of mutational subgroups. Comparative analysis showed 10 proteins were commonly significantly upregulated among all mutational subtypes vs. normal meninges. 257 proteins were commonly significantly downregulated and enriched with molecular functions including aldehyde dehydrogenase and oxido-reductase. Mutational subtype-specific analysis identified 162 proteins significantly upregulated in AKT1/TRAF7 vs. remaining sample groups to be enriched in the oxidative phosphorylation pathway. 14 and 7 proteins were commonly significantly upregulated in KLF4/TRAF7 and NF2 -/- mutant meningioma subtypes respectively. Several of these up-regulated proteins including ANNEXIN-3, CRABP2, CLIC3 and Endoglin were verified via WB. Lastly, analyses of 6600 phosphosites predicted regulatory kinases CONCLUSION We show extensive proteomic and phospophoproteomics analysis of meningioma and suggest new therapeutic and biomarker candidates.
Does mass drug administration of azithromycin reduce child mortality?
Authors: Samwel Maina Gatimu, Rachel Wangari Kimani
Journal: The Lancet Global Health (2021)

Child mortality remains prevalent in low-income and middle-income countries, with the sub-Saharan Africa region accounting for the largest under-5 mortality rates.1 Although under-5 mortality rates have significantly decreased, most countries in sub-Saharan Africa with high mortality rates are unlikely to achieve the Sustainable Development Goal of at least as low as 25 deaths per 1000 livebirths by 2030.2