tbuckley/cabot-search huggingface dataset:
Pharmacokinetics (PK) of eribulin mesylate in cancer patients (pts) with normal and impaired renal function.
Authors: Antoinette R. Tan, John Sarantopoulos, Lucy Lee, Larisa Reyderman, Yi He, Martin S. Olivo, Sanjay Goel
Journal: Journal of Clinical Oncology (2014)

2595 Background: Eribulin mesylate is a novel microtubule dynamics inhibitor. The effect of renal impairment on eribulin PK was evaluated following a single dose in adult pts with advanced solid tumors no longer responding to standard therapy. Methods: This phase 1 sequential cohort study grouped pts by renal function according to the Cockcroft-Gault formula: moderate impairment (creatinine clearance [CrCL]: 30–50 mL/min), severe impairment (CrCL: 15–29 mL/min), or matched-normal (CrCL: ≥80 mL/min). During cycle 1, the iv eribulin mesylate dose on days 1 and 8 were 1.4 mg/m2 and 1.1 mg/m2 for moderate; 0.7 mg/m2 days 1 and 8 for severe; 1.4 mg/m2 days 1 and 8 for normal; the dose for severely impaired pts was based on an interim PK analysis of the moderate group. Blood was collected up to 168 hours after the first dose (cycle 1); PK parameters were calculated by non-compartmental analysis. Results: Nineteen pts were enrolled (12 women; median [range] age 70 [33–82] years: moderate, n = 7; severe, n = 6; normal, n = 6). Mean dose-normalized (DN) area under the curve (AUC) was increased for pts with moderate and severe renal impairment when each was compared with pts with normal renal function (ratio for both: 1.49; 90% confidence interval [CI] 0.9, 2.45). The magnitude of increase in DN maximum plasma concentration was 1.31-fold (90% CI 0.84, 2.05) for pts with moderate impairment and 2.02-fold (90% CI 1.27, 3.21) for those with severe impairment. Renal impairment decreased eribulin clearance (CL). Regression analysis of CL and renal function showed a positive correlation with a numerically small slope (0.0184; 90% CI –0.00254, 0.0394), indicating a small effect of renal impairment on eribulin disposition. Simulations of expected AUC values showed that dose reduction to 1 mg/m2 for pts with moderate and severe renal impairment led to similar eribulin exposure as with 1.4 mg/m2 in pts with normal renal function. Similar toxicity profiles were observed between groups and there were no unexpected AEs. Conclusions: Renal impairment decreased eribulin clearance and increased eribulin exposure in pts with advanced solid tumors. PK evaluation supports eribulin dose reduction to 1 mg/m2 in pts with moderate and severe renal impairment. Clinical trial information: NCT01418677.
OP0168 THE ROLE OF VASCULAR INFLAMMATION MARKERS IN DEFICIENCY OF ADENOSINE DEAMINASE 2
Authors: U. Kaya Akca, E. Sag, Ş. Ünal, M. Kasap-Cuceoglu, Y. Bilginer, S. Özen
Journal: Annals of the Rheumatic Diseases (2021)

Background: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disease whose pathogenesis has not been clearly elucidated. Objectives: To investigate the role of vascular inflammatory factors in the pathogenesis of DADA2, to compare the vascular inflammation profiles of DADA2 patients with different phenotypes, and to compare DADA2 patients with classic polyarteritis nodosa (PAN). Methods: The study included eighteen DADA2 patients, ten PAN patients, and eight healthy controls. Plasma levels of sST2, sRAGE, Tie-2, sCD40L, Tie-1, sFlt-1, LIGHT, TNF-α, PlGF, IL-6, IL-18, IL-10, MCP-1 were studied by cytometric bead-based multiplex assay panel. Results: Among the DADA2 patients, five had hematological manifestations, 13 had vasculitic findings, and accompanying immunological findings were present in seven patients. Nine patients had neurological findings, five of whom had neuropathy. Hematological findings were Diamond-Blackfan anemia-like phenotype in four patients and bicytopenia (anemia and thrombocytopenia) in one patient. Disease characteristics of DADA2 and PAN patients revealed that neurological involvement and livedo reticularis were more frequent in DADA2 patients (p=0.034 and p=0.009, respectively), while myalgia was more common in PAN patients (p:0.001). Plasma levels of Tie-1 and sFlt-1 were higher in the overall DADA2 patients compared to healthy controls and PAN patients (p&lt;0.001 and p=0.004, respectively). DADA2 patients with PAN-like features had higher sRAGE, Tie-2, and TNF-α levels compared to PAN patients (p=0.013, p=0.003, and p=0.001, respectively). There was no significant difference in the levels of vascular inflammation markers between DADA2 patients with vasculitis and hematological involvement except IL-18. The plasma IL-18 levels were higher in the DADA2 patients with hematological findings compared to vasculitic phenotype (p=0.001). Finally DADA2 patients with neuropathy had higher sRAGE concentrations than patients without neuropathy and healthy controls (p=0.03 and p=0.008, respectively). Conclusion: We suggest that the high plasma IL-18 levels may be associated with an activated IFN pathway, the pathogenesis of hematologic manifestations, and unresponsive to anti-TNF treatment. Higher concentrations of Tie-1, Tie-2, sFlt-1, sRAGE, and TNF-α distinguished DADA2 patients with PAN-like features from PAN patients. We identified sRAGE as a potential biomarker of neuropathy in DADA2 patients. References: [1]Pesciotta EN, Lam H-S, Kossenkov A, et al. In-Depth, Label-Free analysis of the erythrocyte cytoplasmic proteome in Diamond Blackfan Anemia identifies a unique inflammatory signature. PLoS One 2015;10(10):e0140036. [2]Haslbeck KM, Bierhaus A, Erwin S, et al. Receptor for advanced glycation endproduct (RAGE)–mediated nuclear factor-κB activation in vasculitic neuropathy. Muscle Nerve 2004;29(6):853-60. Disclosure of Interests: None declared
POS0625 ASSOCIATIONS OF REMISSION AND PERSISTENCE OF BIOLOGICS AT 1 AND 12 YEARS
Authors: K. Murray, M. Turk, Y. Alammari, F. Young, P. Gallagher, T. P. Saber, U. Fearon, D. Veale
Journal: Annals of the Rheumatic Diseases (2021)

Background: Biologic therapies have greatly improved outcomes in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Yet, our ability to predict long-term remission and persistence or continuation of therapy remains limited. Objectives: To compare RA and PsA outcomes at 1 and 12 years after commencing biologic DMARDs and to identify predictors of remission and persistence of therapy. Methods: RA and PsA patients were prospectively recruited from a biologic clinic. Outcomes on commencing therapy, at 1 year and 12 years were reviewed. Demographics, medications, morning stiffness, patient global health score, tender and swollen joint counts, antibody status, CRP and HAQ were collected. Outcomes at 1 and 12 years are reported and predictors of EULAR-defined remission (DAS28-CRP &lt; 2.6) and biologic persistence are examined with univariate and multivariate analysis. Results: A total of 403 patients (274 RA and 129 PsA) were analysed. PsA patients were more likely to be male, in full-time employment and have completed higher education. PsA had higher remission rates than RA at both 1 year (60.3% versus 34.5%, p &lt; 0.001) and 12 years (91.3% versus 60.6%, p &lt; 0.001). This difference persisted when patients were matched for baseline disease activity ( p &lt; 0.001). Biologic continuation rates were high for RA and PsA at 1 year (49.6% versus 58.9%) and 12 years (38.2% versus 52.3%). In PsA, patients starting on etanercept had lower CRP at 12 years ( p = 0.041). Multivariate analysis showed 1-year continuation [OR 4.28 (1.28–14.38)] and 1-year low-disease activity [OR 3.90 (95% CI 1.05–14.53)] was predictive of a 12-year persistence. Persistence with initial biologic at 12 years [OR 4.98 (95% CI 1.83–13.56)] and male gender [OR 4.48 (95% CI 1.25–16.01)] predicted 12 year remission. Conclusion: This is the first real world data to show better response to biologic therapy in PsA compared to RA at 12 years. Long-term persistence with initial biologic agent was high and predicted by biologic persistence and low-disease activity at 1 year. Interestingly, PsA patients had higher levels of employment, educational attainment, and long-term remission rates compared to RA patients. Disclosure of Interests: Kieran Murray Grant/research support from: Bresnihan Molloy and Newman Fellowships, Matthew Turk: None declared, Yousef Alammari: None declared, Francis Young: None declared, Phil Gallagher: None declared, Tajvur Parveen Saber: None declared, Ursula Fearon: None declared, Douglas Veale: None declared
Whole genome sequencing data used for surveillance of Campylobacter infections: detection of a large continuous outbreak, Denmark, 2019
Authors: Katrine Grimstrup Joensen, Susanne Schjørring, Mette Rørbæk Gantzhorn, Camilla Thougaard Vester, Hans Linde Nielsen, Jørgen Harald Engberg, Hanne Marie Holt, Steen Ethelberg, Luise Müller, Gudrun Sandø, Eva Møller Nielsen
Journal: Eurosurveillance (2021)

Background Campylobacter is one of the most frequent causes of bacterial gastroenteritis. Campylobacter outbreaks are rarely reported, which could be a reflection of a surveillance without routine molecular typing. We have previously shown that numerous small outbreak-like clusters can be detected when whole genome sequencing (WGS) data of clinical Campylobacter isolates was applied. Aim Typing-based surveillance of Campylobacter infections was initiated in 2019 to enable detection of large clusters of clinical isolates and to match them to concurrent retail chicken isolates in order to react on ongoing outbreaks. Methods We performed WGS continuously on isolates from cases (n = 701) and chicken meat (n = 164) throughout 2019. Core genome multilocus sequence typing was used to detect clusters of clinical isolates and match them to isolates from chicken meat. Results Seventy-two clusters were detected, 58 small clusters (2–4 cases) and 14 large clusters (5–91 cases). One third of the clinical isolates matched isolates from chicken meat. One large cluster persisted throughout the whole year and represented 12% of all studied Campylobacter cases. This cluster type was detected in several chicken samples and was traced back to one slaughterhouse, where interventions were implemented to control the outbreak. Conclusion Our WGS-based surveillance has contributed to an improved understanding of the dynamics of the occurrence of Campylobacter strains in chicken meat and the correlation to clusters of human cases.
AB0868-HPR ADHERENCE TO DISEASE-MODIFYING ANTIRHEUMATIC DRUGS IN RHEUMATIC DISEASES DURING COVID-19 PANDEMIC
Authors: I. A. Moreno-Arquieta, G. G. Sánchez Mendieta, D. E. Flores Alvarado, J. A. Esquivel Valerio, D. Á. Galarza-Delgado
Journal: Annals of the Rheumatic Diseases (2021)

Background: The pandemic COVID-19 has set a new challenge in adherence to treatment in patients with rheumatic diseases. Prior studies in Latin America had reported adherence of 16.4% on Rheumatoid Arthritis (RA) and 45.9% in Systemic Lupus Erythematous (SLE). There is evidence that these patients believe their treatment increases the risk and gravity of COVID-19 and therefore, suspending the treatment could reduce this risk. It has been shown that a “Good adherence” is associated to a better survival. Objectives: Describe the adherence to DMARDs in patients with Rheumatic diseases during COVID-19. Methods: Descriptive, cross-sectional, self-report study conducted in rheumatology outpatient clinic of University Hospital in Monterrey, México. Consecutive patients with RA, SLE, Inflammatory Myopathies and Systemic Sclerosis, were approached during their routine appointments, March 2020 to December 2020 period during COVID-19 pandemic. They were asked how many days of the month they took the DMARD indicated in the previous appointment, with Based on this, adherence was classified into four categories: Good 100-75% (&gt; 21 days), Regular 74-50% (21-15 days), Bad 49-25% (14-8 days) and Null &lt;25% (&lt;7 days). Data was obtained from our internal electronic patient record registry and analyzed with SPSS V.22. Results: n (DMARDs) Good Regular Bad Null n (% ) n (% ) n (% ) n (% ) Rheumatoid Arthritis 302 255 (84.4) 13 (4.3) 20 (6.6) 14 (4.6) Systemic Lupus Erithematous 126 111 (88) 3 (2.3) 8 (6.3) 4 (3.1) Inflammatory Myopathies 11 10 (90.9) 0 (0) 1 (9) 0 (0) Systemic Sclerosis 30 27 (90) 2 (6.6) 1 (3.3) 0 (0) TOTAL 469 Conclusion: Despite what it is believed, patients are not changing therapeutic regimes. The adherence found in this group of patients was good, for the definition used in this study. It should be considered that the self-report method may overestimate adherence, so the data found must be correlated with objective methods in the future. References: [1]Resende Prudente L, Souza Diniz J, Matteucci Ferreira TXA, Marçal Lima D, Antônio Silva N, Saraiva G, et al. Medication adherence in patients in treatment for rheumatoid arthritis and systemic lupus erythematosus in a university hospital in Brazil. Patient Preference and Adherence. 2016:10 863–870. [2]Michaud K, Wipfler K, Shaw Y, et al. Experiences of patients with rheumatic diseases in the United States during early days of the COVID-19 pandemic. ACR Open Rheumatol 2020. doi:10.1002/acr2.11148. [3]Waimann ChA, Marengo MF, de Achaval S, Cox VL, Garcia-Gonzalez A, Reveille JD. Electronic Monitoring of Oral Therapies in Ethnically Diverse and Economically Disadvantaged Patients With Rheumatoid Arthritis. Arthritis &amp; Rheumatism. 2013:6 1421-1429. Disclosure of Interests: None declared
AB0402 SELF-ASSESSMENT OF SCLERODERMA SKIN THICKNESS: DEVELOPMENT AND VALIDATION OF THE PASTUL QUESTIONNAIRE
Authors: J. Spierings, V. Ong, C. Denton
Journal: Annals of the Rheumatic Diseases (2021)

<h3>Background:</h3> Evaluation of skin is central to both clinical practice and trials in systemic sclerosis (SSc). This is generally done with the modified Rodnan Skin Score (mRSS). Remote consultations are now widely implemented in response to the COVID-19 pandemic, which has inevitably limited evaluation of skin. To monitor skin during this pandemic and to further explore ways to assess skin, we developed the PASTUL (Patient self-Assessment of Skin Thickness in Upper Limb) questionnaire. <h3>Objectives:</h3> This study evaluated feasibility and validity of PASTUL in SSc. <h3>Methods:</h3> The PASTUL questionnaire uses a simple self-assessed grading of skin as normal, mild, moderate, or severely thickened at eight sites of upper limb corresponding to mRSS. Assessed grades were converted to an integer scale [0, 1, 2, 3]. Detailed instructions for patients were provided. Scleroderma Skin PRO (SSPRO) and Scleroderma Health Assessment Disability Index (SHAQ-DI) were also completed. For comparison, physician assessed mRSS was performed in a subgroup of patients. Construct validity was evaluated by examining the correlation between PASTUL, mRSS, SSPRO and SHAQ-DI using Pearson's correlation coefficient. Content validity was evaluated by scoring relevance, clarity and practical difficulty. Test-retest reliability was estimated using intraclass correlation coefficient (ICC). <h3>Results:</h3> 130 patients were invited of which 104 (80%) completed the questionnaires. The mRSS was undertaken in 78 patients (n=42, 54% limited cutaneous SSc (lcSSc)). The PASTUL was completed by patients (86%) or by a partner/friend (14%). Mean PASTUL score was 11 (SD 7), mean HAQ-DI 1.41 (SD 0.77) and mean SSPRO 48.3 (SD 27.0). PASTUL strongly correlated with total SSPRO and SSPRO subdomain physical limitations (r=0.60 and 0.62, respectively) (Figure 1A). Correlations between PASTUL and mRSS and mRSS upper limbs were moderate (r=0.56 and 0.58, respectively) (Figure 1B). An overview of all correlations is provided in Table 1. Correlation between PASTUL and mRSS was stronger in lcSSc compared to diffuse cutaneous SSc patients (r=0.53 vs 0.43) and when assessed by a partner/friend compared to patients themselves (r=0.90 vs 0.54). The PASTUL demonstrated excellent test-retest reliability (ICC of 0.93, p&lt;0.001) and good content validity. <h3>Conclusion:</h3> The significant correlation of PASTUL scores with total SSPRO and physical limitation scores and moderate correlation with mRSS support the potential of PASTUL for remote evaluation of skin thickness in virtual clinical settings. Future studies may explore sensitivity to change and utility in clinical trials. <h3>Disclosure of Interests:</h3> None declared
Sierra Leone: Ebola and war survivors failed by lack of mental health services, Amnesty finds
Authors: Elisabeth Mahase
Journal: BMJ (2021)

People in Sierra Leone are being failed by a lack of much needed mental health services to cope with the devastating and lasting effects of the civil war and the Ebola epidemic, Amnesty International has warned.

The report, They Are Forgetting About Us , included 55 interviews with health professionals, government officials, and 25 people who had experienced violence during the war or who had contracted the Ebola virus.1

From 1991 to 2002 the civil war in Sierra Leone killed tens of thousands of civilians and displaced more than two million people. Then in 2014 the country was hit by an Ebola outbreak that lasted until 2016 and …
A new era of atopic eczema research: Advances and highlights
Authors: Claudia Hülpüsch, Andreas B. Weins, Claudia Traidl‐Hoffmann, Matthias Reiger
Journal: Allergy (2021)

Atopic eczema (AE) is an inflammatory skin disease with involvement of genetic, immunological and environmental factors. One hallmark of AE is a skin barrier disruption on multiple, highly interconnected levels: filaggrin mutations, increased skin pH and a microbiome dysbiosis towards Staphylococcus aureus overgrowth are observed in addition to an abnormal type 2 immune response. Extrinsic factors seem to play a major role in the development of AE. As AE is a first step in the atopic march, its prevention and appropriate treatment are essential. Although standard therapy remains topical treatment, powerful systemic treatment options emerged in the last years. However, thorough endotyping of the individual patients is still required for ideal precision medicine approaches in future. Therefore, novel microbial and immunological biomarkers were described recently for the prediction of disease development and treatment response. This review summarizes the current state of the art in AE research.
Heterogeneous delivery across the blood-brain barrier limits the efficacy of an EGFR-targeting antibody drug conjugate in glioblastoma
Authors: Bianca-Maria Marin, Kendra A Porath, Sonia Jain, Minjee Kim, Jason E Conage-Pough, Ju-Hee Oh, Caitlyn L Miller, Surabhi Talele, Gaspar J Kitange, Shulan Tian, Danielle M Burgenske, Ann C Mladek, Shiv K Gupta, Paul A Decker, Madison H McMinn, Sylwia A Stopka, Michael S Regan, Lihong He, Brett L Carlson, Katrina Bakken, Terence C Burns, Ian F Parney, Caterina Giannini, Nathalie Y R Agar, Jeanette E Eckel-Passow, Jennifer R Cochran, William F Elmquist, Rachael A Vaubel, Forest M White, Jann N Sarkaria
Journal: Neuro-Oncology (2021)

Antibody drug conjugates (ADCs) targeting the epidermal growth factor receptor (EGFR), such as depatuxizumab mafodotin (Depatux-M), is a promising therapeutic strategy for glioblastoma (GBM) but recent clinical trials did not demonstrate a survival benefit. Understanding the mechanisms of failure for this promising strategy is critically important.PDX models were employed to study efficacy of systemic vs intracranial delivery of Depatux-M. Immunofluorescence and MALDI-MSI were performed to detect drug levels in the brain. EGFR levels and compensatory pathways were studied using quantitative flow cytometry, Western blots, RNAseq, FISH, and phosphoproteomics.Systemic delivery of Depatux-M was highly effective in nine of 10 EGFR-amplified heterotopic PDXs with survival extending beyond one year in eight PDXs. Acquired resistance in two PDXs (GBM12 and GBM46) was driven by suppression of EGFR expression or emergence of a novel short-variant of EGFR lacking the epitope for the Depatux-M antibody. In contrast to the profound benefit observed in heterotopic tumors, only two of seven intrinsically sensitive PDXs were responsive to Depatux-M as intracranial tumors. Poor efficacy in orthotopic PDXs was associated with limited and heterogeneous distribution of Depatux-M into tumor tissues, and artificial disruption of the BBB or bypass of the BBB by direct intracranial injection of Depatux-M into orthotopic tumors markedly enhanced the efficacy of drug treatment.Despite profound intrinsic sensitivity to Depatux-M, limited drug delivery into brain tumor may have been a key contributor to lack of efficacy in recently failed clinical trials.
Untargeted Molecular Analysis of Exhaled Breath as a Diagnostic Test for Ventilator-Associated Lower Respiratory Tract Infections (BreathDx)
Authors: Pouline MP van Oort, Tamara M Nijsen, Iain R White, Hugo H Knobel, Timothy Felton, Nicholas Rattray, Oluwasola Lawal, Murtaza Bulut, Waqar Ahmed, Antonio Artigas, Pedro R Povoa, Ignacio Martin-Loeches, Hans Weda, Royston Goodacre, Marcus J Schultz, Paul M Dark, Stephen J Fowler, Lieuwe D Bos
Journal: Thorax (2021)

Patients suspected of ventilator-associated lower respiratory tract infections (VA-LRTIs) commonly receive broad-spectrum antimicrobial therapy unnecessarily. We tested whether exhaled breath analysis can discriminate between patients suspected of VA-LRTI with confirmed infection, from patients with negative cultures. Breath from 108 patients suspected of VA-LRTI was analysed by gas chromatography-mass spectrometry. The breath test had a sensitivity of 98% at a specificity of 49%, confirmed with a second analytical method. The breath test had a negative predictive value of 96% and excluded pneumonia in half of the patients with negative cultures. Trial registration number: UKCRN ID number 19086, registered May 2015.
Global epidemiology, health burden and effective interventions for elevated blood pressure and hypertension
Authors: Bin Zhou, Pablo Perel, George A. Mensah, Majid Ezzati
Journal: Nature Reviews Cardiology (2021)

High blood pressure is one of the most important risk factors for ischaemic heart disease, stroke, other cardiovascular diseases, chronic kidney disease and dementia. Mean blood pressure and the prevalence of raised blood pressure have declined substantially in high-income regions since at least the 1970s. By contrast, blood pressure has risen in East, South and Southeast Asia, Oceania and sub-Saharan Africa. Given these trends, the prevalence of hypertension is now higher in low-income and middle-income countries than in high-income countries. In 2015, an estimated 8.5 million deaths were attributable to systolic blood pressure >115 mmHg, 88% of which were in low-income and middle-income countries. Measures such as increasing the availability and affordability of fresh fruits and vegetables, lowering the sodium content of packaged and prepared food and staples such as bread, and improving the availability of dietary salt substitutes can help lower blood pressure in the entire population. The use and effectiveness of hypertension treatment vary substantially across countries. Factors influencing this variation include a country's financial resources, the extent of health insurance and health facilities, how frequently people interact with physicians and non-physician health personnel, whether a clear and widely adopted clinical guideline exists and the availability of medicines. Scaling up treatment coverage and improving its community effectiveness can substantially reduce the health burden of hypertension. In this Review, Zhou and colleagues summarize the current data on the global epidemiology of blood pressure and hypertension and evaluate changes over time. They also present estimates of the mortality effects of elevated blood pressure and discuss interventions that can reduce the burden of high blood pressure.
Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB
Authors: Roy Maimon, Carlos Chillon-Marinas, Cedric E. Snethlage, Sarthak M. Singhal, Melissa McAlonis-Downes, Karen Ling, Frank Rigo, C. Frank Bennett, Sandrine Da Cruz, Thomas S. Hnasko, Alysson R. Muotri, Don W. Cleveland
Journal: Nature Neuroscience (2021)