tbuckley/cabot-search huggingface dataset:
Assessment of the FDA Risk Evaluation and Mitigation Strategy for Transmucosal Immediate-Release Fentanyl Products
Authors: Jeffrey Eric Rollman, James Heyward, Lily Olson, Peter Lurie, Joshua Sharfstein, G. Caleb Alexander
Journal: JAMA (2019)

Transmucosal immediate-release fentanyls (TIRFs), indicated solely for breakthrough cancer pain in opioid-tolerant patients, are subject to a US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) to prevent them from being prescribed inappropriately.To evaluate knowledge assessments of pharmacists, prescribers, and patients regarding appropriate TIRF use; to describe sponsor assessments, based on claims data, of whether the REMS program was meeting its goals; and to characterize how the FDA responded to REMS assessments.Qualitative analysis of 4877 pages of FDA documents obtained through a Freedom of Information Act request, including 6 annual REMS assessment reports (2012-2017), FDA evaluations of these reports, and FDA-sponsor correspondence about safety issues.A REMS program to reduce the risk of adverse outcomes, including misuse, abuse, addiction, and overdose, arising from use of TIRFs.(1) Knowledge assessments of pharmacists, prescribers, and patients; (2) survey and claims-based prescribing assessments; (3) FDA and TIRF sponsor communications; (4) modifications to the REMS program; and (5) disenrollment of noncompliant prescribers.Twelve months after initiation of the program, 24 of 302 pharmacists (7.9%), 35 of 302 prescribers (11.6%), and 5 of 192 patients (2.6%) incorrectly reported that TIRFs can be prescribed to opioid-nontolerant patients, with similar levels of misunderstanding maintained in the subsequent reports. At 60 months, product-specific analyses of claims data indicated that between 34.6% and 55.4% of patients prescribed TIRFs were opioid-nontolerant. In the 48-month survey, 106 of 310 prescribers (34.2%) reported prescribing TIRFs for opioid-tolerant patients with chronic, noncancer pain; at 60 months, 54 of 302 prescribers (18.4%) and 148 of 310 patients (47.7%) erroneously reported that TIRFs were FDA-approved for such use. Over the 60-month period examined, there were few substantive changes made to the REMS to address evidence of high rates of off-label TIRF use, and, although the REMS program had a noncompliance plan, there was no report of prescribers being disenrolled for inappropriate prescribing.In this review of FDA documents pertaining to the TIRF REMS, surveys of pharmacists, prescribers, and patients reflected generally high levels of knowledge regarding proper TIRF prescribing, yet some survey items as well as claims-based analyses indicated substantial rates of inappropriate TIRF use. Despite these findings, the FDA did not require substantive changes to the program.
West Nile Virus and Other Nationally Notifiable Arboviral Diseases — United States, 2016
Authors: Alexis Burakoff, Jennifer Lehman, Marc Fischer, J. Erin Staples, Nicole P. Lindsey
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Arthropod-borne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease in the continental United States (1,2). Other arboviruses, including La Crosse, Powassan, Jamestown Canyon, St. Louis encephalitis, and eastern equine encephalitis viruses, cause sporadic cases of disease and occasional outbreaks. This report summarizes surveillance data reported to CDC for 2016 for nationally notifiable arboviruses. It excludes dengue, chikungunya, and Zika viruses, as these are primarily nondomestic viruses typically acquired through travel. Forty-seven states and the District of Columbia (DC) reported 2,240 cases of domestic arboviral disease, including 2,150 (96%) WNV disease cases. Of the WNV disease cases, 1,310 (61%) were classified as neuroinvasive disease (e.g., meningitis, encephalitis, acute flaccid paralysis), for a national incidence of 0.41 cases per 100,000 population. After WNV, the most frequently reported arboviruses were La Crosse (35 cases), Powassan (22), and Jamestown Canyon (15) viruses. Because arboviral diseases continue to cause serious illness, maintaining surveillance is important to direct prevention activities.
Optimization of E. coli fermentation for plasmid DNA production
Journal: Molecular Therapy (2004)

Obtaining optimal yields of highly purified plasmid DNA is seen as an essential step toward efficient production of genetic drugs, such as DNA vaccines and therapeutic plasmids. To do so requires: 1) growth conditions optimized for efficient plasmid production; and 2) efficient downstream purification. To date, most efforts toward commercial method development have been placed on downstream purification, resulting in reported yields up to 100-200mg DNA/liter of culture medium. In order to address the initial and yield-limiting upstream steps, we optimized the plasmid growth conditions for both batch and fed-batch fermentation. The increased plasmid yield also improved the effectiveness of downstream purification by reducing the fraction of impurities.
Evaluation of Intense Androgen Deprivation Before Prostatectomy: A Randomized Phase II Trial of Enzalutamide and Leuprolide With or Without Abiraterone
Authors: Rana R. McKay, Huihui Ye, Wanling Xie, Rosina Lis, Carla Calagua, Zhenwei Zhang, Quoc-Dien Trinh, Steven L. Chang, Lauren C. Harshman, Ashley E. Ross, Kenneth J. Pienta, Daniel W. Lin, William J. Ellis, Bruce Montgomery, Peter Chang, Andrew A. Wagner, Glenn J. Bubley, Adam S. Kibel, Mary-Ellen Taplin
Journal: Journal of Clinical Oncology (2019)

Patients with locally advanced prostate cancer have an increased risk of cancer recurrence and mortality. In this phase II trial, we evaluate neoadjuvant enzalutamide and leuprolide (EL) with or without abiraterone and prednisone (ELAP) before radical prostatectomy (RP) in men with locally advanced prostate cancer.Eligible patients had a biopsy Gleason score of 4 + 3 = 7 or greater, prostate-specific antigen (PSA) greater than 20 ng/mL, or T3 disease (by prostate magnetic resonance imaging). Lymph nodes were required to be smaller than 20 mm. Patients were randomly assigned 2:1 to ELAP or EL for 24 weeks followed by RP. All specimens underwent central pathology review. The primary end point was pathologic complete response or minimal residual disease (residual tumor ≤ 5 mm). Secondary end points were PSA, surgical staging, positive margins, and safety. Biomarkers associated with pathologic outcomes were explored.Seventy-five patients were enrolled at four centers. Most patients had high-risk disease by National Comprehensive Cancer Network criteria (n = 65; 87%). The pathologic complete response or minimal residual disease rate was 30% (n = 15 of 50) in ELAP-treated patients and 16% (n = four of 25) in EL-treated patients (two-sided P = .263). Rates of ypT3 disease, positive margins, and positive lymph nodes were similar between arms. Treatment was well-tolerated. Residual tumors in the two arms showed comparable levels of ERG, PTEN, androgen receptor PSA, and glucocorticoid receptor expression. Tumor ERG positivity and PTEN loss were associated with more extensive residual tumors at RP.Neoadjuvant hormone therapy followed by RP in locally advanced prostate cancer resulted in favorable pathologic responses in some patients, with a trend toward improved pathologic outcomes with ELAP. Longer follow-up is necessary to evaluate the impact of therapy on recurrence rates. The potential association of ERG and PTEN alterations with worse outcomes warrants additional investigation.
Estimating cholera incidence with cross-sectional serology
Authors: Andrew S. Azman, Justin Lessler, Francisco J. Luquero, Taufiqur Rahman Bhuiyan, Ashraful Islam Khan, Fahima Chowdhury, Alamgir Kabir, Marc Gurwith, Ana A. Weil, Jason B. Harris, Stephen B. Calderwood, Edward T. Ryan, Firdausi Qadri, Daniel T. Leung
Journal: Science Translational Medicine (2019)

Cross-sectional Vibrio cholerae –related antibody measures can be used to estimate cholera incidence in a population.
P124/O27 Osteocyte-derived podoplanin is an important regulator of bone remodelling in the KBxN serum transfer model of rheumatoid arthritis
Authors: C Wehmeyer, AJ Naylor, K Moeller, G Poologasundarampillai, T Pap, CD Buckley
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Post-doctoral fellow. <h3>Introduction</h3> Osteocytes derive from bone-forming osteoblasts and are located deep inside the bone matrix. They are encysted in cavities (lacunae) and form dendritic extensions to develop a dense sentinel network inside the bone. Osteocytes are not passive cells. They modulate bone remodelling through regulation of both osteoclast and osteoblast activity. Immature osteocytes express the transmembrane glycoprotein podoplanin (PDPN/gp38)<sup>1</sup> which is important for dendrite elongation and osteocyte function.<sup>2</sup> Moreover it has been reported that PDPN expression is regulated by inflammatory cytokines including TNFα, IL-6, IL-22, TGF-β1, IFN-γ<sup>3</sup> and is highly expressed in synovial tissues from RA patients.<sup>4</sup> However the role of PDPN in osteocytes during inflammatory disease has not previously been investigated. <h3>Objectives</h3> In this study we investigated the effect of osteocyte-specific deletion of PDPN in the KBxN serum transfer (ST) mouse model of rheumatoid arthritis. <h3>Methods</h3> Dmp1 Cre mice were crossed with PDPN<sup>flox/flox</sup> mice to generate osteocyte specific conditional knockout mice as well as appropriate PDPN<sup>flox/fox</sup> controls. KBxN ST arthritis was used to study the effect of PDPN deletion on mouse arthritis progression. PDPN expression was assessed by immunohistochemistry. Osteoclast numbers were calculated by TRAP staining. Loss of cartilage and pannus formation was evaluated by Safranin-O and H and E staining. Standard microCT and synchrotron microCT analysis was used to assess bone density parameters, osteocyte location and bone erosions. <h3>Results</h3> PDPN is expressed in osteocytes at sites of bone erosions in inflamed joints of KBxN ST mouse model. Osteocyte-specific PDPN deletion has no effect on trabecular and cortical bone density parameters in mouse tibiae under resting conditions, as has been previously reported.<sup>2</sup> However, loss of PDPN on osteocytes leads to significantly more bone erosions in the resolving phase of the KBxN ST model compared to non-deleted controls. Deletion of osteocyte PDPN has no effect on pannus formation, cartilage loss and osteoclast numbers. <h3>Conclusions</h3> Osteocyte-derived PDPN has been suggested as an important sensor for bone damage and this study demonstrates its bone-protective function during inflammatory arthritis. <h3>References</h3> Zhang KQ, <i>et al. Molecular and Cellular Biology</i> 2006;26:4539–4552. Staines KA, <i>et al. J Cell Physiol</i> 2017;232:3006–3019. Honma M, Minami-Hori M, Takahashi H, Iizuka HP. <i>J Dermatol Sci</i> 2012;65:134–140. Del Rey MJ, <i>et al. Plos One</i> 2014;9:e99607. <h3>Disclosure of Interest</h3> None declared.
Surveillance for Waterborne Disease Outbreaks Associated with Drinking Water — United States, 2011–2012
Authors: Karlyn D. Beer, Julia W. Gargano, Virginia A. Roberts, Vincent R. Hill, Laurel E. Garrison, Preeta K. Kutty, Elizabeth D. Hilborn, Timothy J. Wade, Kathleen E. Fullerton, Jonathan S. Yoder
Journal: MMWR Morbidity and Mortality Weekly Report (2015)

Advances in water management and sanitation have substantially reduced waterborne disease in the United States, although outbreaks continue to occur. Public health agencies in the U.S. states and territories* report information on waterborne disease outbreaks to the CDC Waterborne Disease and Outbreak Surveillance System (http://www.cdc.gov/healthywater/surveillance/index.html). For 2011-2012, 32 drinking water-associated outbreaks were reported, accounting for at least 431 cases of illness, 102 hospitalizations, and 14 deaths. Legionella was responsible for 66% of outbreaks and 26% of illnesses, and viruses and non-Legionella bacteria together accounted for 16% of outbreaks and 53% of illnesses. The two most commonly identified deficiencies† leading to drinking water-associated outbreaks were Legionella in building plumbing§ systems (66%) and untreated groundwater (13%). Continued vigilance by public health, regulatory, and industry professionals to identify and correct deficiencies associated with building plumbing systems and groundwater systems could prevent most reported outbreaks and illnesses associated with drinking water systems.
Malaria Surveillance — United States, 2015
Authors: Kimberly E. Mace, Paul M. Arguin, Kathrine R. Tan
Journal: MMWR Surveillance Summaries (2018)

Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles species mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is occasionally acquired by persons who have not traveled out of the country through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission. Malaria surveillance in the United States is conducted to provide information on its occurrence (e.g., temporal, geographic, and demographic), guide prevention and treatment recommendations for travelers and patients, and facilitate transmission control measures if locally acquired cases are identified.
Lower Extremity Amputation and Health Care Utilization in the Last Year of Life among Medicare Beneficiaries with ESRD
Authors: Catherine R. Butler, Margaret L. Schwarze, Ronit Katz, Susan M. Hailpern, William Kreuter, Yoshio N. Hall, Maria E. Montez Rath, Ann M. O'Hare
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Although lower extremity amputation is common among patients with ESRD and often portends a poor prognosis, little is known about end-of-life care among these patients. The authors’ analysis of a national cohort of Medicare beneficiaries finds that patients with ESRD are far more likely than those without ESRD to undergo amputation during their final year of life. Among patients with ESRD, having a lower extremity amputation was associated with admission to and prolonged stays in acute and subacute care settings during their last year of life, as well as with dying in the hospital, discontinuing dialysis, and fewer days receiving hospice services. These findings likely signal unmet palliative care needs among seriously ill patients with ESRD who undergo lower extremity amputation. Background Lower extremity amputation is common among patients with ESRD, and often portends a poor prognosis. However, little is known about end-of-life care among patients with ESRD who undergo amputation. Methods We conducted a mortality follow-back study of Medicare beneficiaries with ESRD who died in 2002 through 2014 to analyze patterns of lower extremity amputation in the last year of life compared with a parallel cohort of beneficiaries without ESRD. We also examined the relationship between amputation and end-of-life care among the patients with ESRD. Results Overall, 8% of 754,777 beneficiaries with ESRD underwent at least one lower extremity amputation in their last year of life compared with 1% of 958,412 beneficiaries without ESRD. Adjusted analyses of patients with ESRD showed that those who had undergone lower extremity amputation were substantially more likely than those who had not to have been admitted to—and to have had prolonged stays in—acute and subacute care settings during their final year of life. Amputation was also associated with a greater likelihood of dying in the hospital, dialysis discontinuation before death, and less time receiving hospice services. Conclusions Nearly one in ten patients with ESRD undergoes lower extremity amputation in their last year of life. These patients have prolonged stays in acute and subacute health care settings and appear to have limited access to hospice services. These findings likely signal unmet palliative care needs among seriously ill patients with ESRD who undergo amputation as well as opportunities to improve their care.
Epidemiology and dermatological comorbidity of seborrhoeic dermatitis: population‐based study in 161 269 employees
Authors: N. Zander, R. Sommer, I. Schäfer, R. Reinert, N. Kirsten, B.‐C. Zyriax, J.‐T. Maul, M. Augustin
Journal: British Journal of Dermatology (2019)

BACKGROUND:

Seborrhoeic dermatitis is a common but epidemiologically poorly researched chronic skin disease.
OBJECTIVES:

To characterize the prevalence and dermatological comorbidity of seborrhoeic dermatitis in Germany.
METHODS:

In the course of voluntary company skin checks, full-body examinations were carried out in more than 500 companies by experienced dermatologists and documented electronically.
RESULTS:

In total, 161 269 participants were included (men 55·5%, mean age 43·2 ± 10·9 years). Seborrhoeic dermatitis was identified in 3·2% (men 4·6%, women 1·4%). A significant difference was found between age groups (2·0% in < 35; 3·6% in 35-64; 4·4% ≥ 65 years). The most frequent concomitant skin conditions were: folliculitis [17·0%, 95% confidence interval (CI) 15·9-18·1], onychomycosis (9·1%, 95% CI 8·3-10·0), tinea pedis (7·1%, 95% CI 6·3-7·8), rosacea (4·1%, 95% CI 3·6-4·7), acne (4·0%, 95% CI 3·4-4·5) and psoriasis (2·7%, 95% CI 2·3-3·2). Regression analysis revealed the following relative dermatological comorbidities when controlling for age and sex: folliculitis [odds ratio (OR) 2·1, 95% CI 2·0-2·3], contact dermatitis (OR 1·8, 95% CI 1·1-2·8), intertriginous dermatitis (OR 1·8, 95% CI 1·4-2·2), rosacea (OR 1·6, 95% CI 1·4-1·8), acne (OR 1·4, 95% CI 1·2-1·7), pyoderma (OR 1·4, 95% CI 1·1-1·8), tinea corporis (OR 1·4, 95% CI 1·0-2·0), pityriasis versicolor (OR 1·3, 95% CI 1·0-1·7) and psoriasis (OR 1·2, 95% CI 1·0-1·5).
CONCLUSIONS:

Seborrhoeic dermatitis is a common disease, which is more prevalent in men and older people, and it has an increased rate of dermatological comorbidity. However, absolute differences in the prevalence of comorbidities are small and negligible. Nevertheless, the findings underline the need for integrated, complete dermatological diagnostics and therapy.
Single-cell analysis reveals congruence between kidney organoids and human fetal kidney
Authors: Alexander N. Combes, Luke Zappia, Pei Xuan Er, Alicia Oshlack, Melissa H. Little
Journal: Genome Medicine (2019)

Human kidney organoids hold promise for studying development, disease modelling and drug screening. However, the utility of stem cell-derived kidney tissues will depend on how faithfully these replicate normal fetal development at the level of cellular identity and complexity. Here, we present an integrated analysis of single cell datasets from human kidney organoids and human fetal kidney to assess similarities and differences between the component cell types. Clusters in the combined dataset contained cells from both organoid and fetal kidney with transcriptional congruence for key stromal, endothelial and nephron cell type-specific markers. Organoid enriched neural, glial and muscle progenitor populations were also evident. Major transcriptional differences between organoid and human tissue were likely related to technical artefacts. Cell type-specific comparisons revealed differences in stromal, endothelial and nephron progenitor cell types including expression of WNT2B in the human fetal kidney stroma. This study supports the fidelity of kidney organoids as models of the developing kidney and affirms their potential in disease modelling and drug screening.
A gene expression assay for simultaneous measurement of microsatellite instability and anti-tumor immune activity
Authors: Patrick Danaher, Sarah Warren, SuFey Ong, Nathan Elliott, Alessandra Cesano, Sean Ferree
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Clinical benefit from checkpoint inhibitors has been associated in a tumor-agnostic manner with two main tumor traits. The first is tumor antigenicity, which is typically measured by tumor mutation burden, microsatellite instability (MSI), or Mismatch Repair Deficiency using gene sequence platforms and/or immunohistochemistry. The second is the presence of a pre-existing adaptive immune response, typically measured by immunohistochemistry (e.g. single analyte PD-L1 expression) and/or gene expression signatures (e.g. tumor “inflamed” phenotype). These two traits have been shown to provide independent predictive information. Here we investigated the potential of using gene expression to predict tumor MSI, thus enabling the measurement of both tumor antigenicity and the level of tumor inflammation in a single assay, possibly reducing sample requirement, turn-around time, and overall cost. <h3>Methods</h3> Using The Cancer Genome Atlas RNA-seq datasets with the greatest MSI-H incidence, i.e. those from colon (<i>n</i> = 208), stomach (<i>n</i> = 269), and endometrial (<i>n</i> = 241) cancers, we trained an algorithm to predict tumor MSI from under-expression of the mismatch repair genes MLH1, PMS2, MSH2, and MSH6 and from 10 additional genes with strong pan-cancer associations with tumor hypermutation. The algorithms were validated on the NanoString nCounter™ platform in independent cohorts of colorectal (<i>n</i> = 52), endometrial (<i>n</i> = 11), and neuroendocrine (<i>n</i> = 4) tumors pre-characterized using the MMR immunohistochemistry assay. <h3>Results</h3> In the validation cohorts, the algorithm showed high prediction accuracy of tumor MSI status, with sensitivity of at least 88% attained at thresholds chosen to achieve 100% specificity. Furthermore, MSI status was compared to the Tumor Inflammation Signature (TIS), an analytically validated diagnostic assay which measures a suppressed adaptive immune response in the tumor and enriches for response to immune checkpoint blockade. TIS score was largely independent of MSI status, suggesting that measuring both parameters may identify more patients that would respond to immune checkpoint blockade than either assay alone. <h3>Conclusions</h3> Development of a gene expression signature of MSI status raises the possibility of a combined diagnostic assay on a single platform which measures both tumor antigenicity and presence of a suppressed adaptive immune response. Such an assay would have significant advantages over multi-platform assays for both ease of use and turnaround time and could lead to a diagnostic test with improved clinical performance.
The Not-My-Problem Problem
Authors: Lisa Rosenbaum
Journal: New England Journal of Medicine (2019)

Audio roundtable discussion on learning to foster better teams. (32:51)Download In cases in which the "bystander effect" seems to be at play in medicine, inaction by a group of clinicians usually takes the form of tacit acceptance of the status quo when the status quo isn't working. What can social psychology teach us about such group failures?