tbuckley/cabot-search huggingface dataset:
Are adenoma and serrated polyp detection rates correlated with endoscopists’ sensitivity of optical diagnosis?
Authors: Maxime E. S. Bronzwaer, Jasper L. A. Vleugels, Sascha C. van Doorn, Marcel G. W. Dijkgraaf, Paul Fockens, Evelien Dekker
Journal: Endoscopy (2020)

Abstract Introduction Endoscopists with a high adenoma detection rate (ADR) and proximal serrated polyp detection rate (PSPDR) detect these polyps more frequently, which may be attributable to better recognition of their endoscopic features. Little is known about the association between endoscopic lesion detection and differentiation skills. Therefore, we evaluated the correlation between the ADR, PSPDR, and the sensitivity of optical diagnosis for adenomas and serrated polyps. Methods We performed an exploratory post-hoc analysis of the DISCOUNT-2 study, including complete colonoscopies after a positive fecal immunochemical test (FIT) performed by endoscopists who performed ≥ 50 colonoscopies. The correlations between the ADR, PSPDR, and the sensitivity of optical diagnosis were calculated using Pearson’s rho correlation coefficient. Results 24 endoscopists performed ≥ 50 colonoscopies, resulting in a total of 2889 colonoscopies. The overall ADR was 84.5 % (range 71.4 % – 95.3 %) and overall PSPDR was 13.7 % (4.3 % – 29.0 %). The sensitivity of optical diagnosis for adenomas and serrated polyps were 94.5 % (83.3 % – 100 %) and 74.0 % (37.5 % – 94.1 %), respectively. No correlation could be demonstrated between the ADR and the sensitivity of optical diagnosis for adenomas (−0.20; P = 0.35) or between the PSPDR and the sensitivity of optical diagnosis for serrated polyps (−0.12; P = 0.57). Conclusions In a homogeneous FIT-positive population, no correlation between the ADR, PSPDR, and the sensitivity of optical diagnosis for adenomas and serrated polyps could be demonstrated. These exploratory results suggest that lesion detection and differentiation require different endoscopic skills. Further prospective studies are needed; until then, monitoring of both performance indicators is important to secure optimal efficacy of FIT-based colorectal cancer screening.
Computer-Aided Design of Microfluidic Circuits
Authors: Elishai Ezra Tsur
Journal: Annual Review of Biomedical Engineering (2020)

Microfluidic devices developed over the past decade feature greater intricacy, increased performance requirements, new materials, and innovative fabrication methods. Consequentially, new algorithmic and design approaches have been developed to introduce optimization and computer-aided design to microfluidic circuits: from conceptualization to specification, synthesis, realization, and refinement. The field includes the development of new description languages, optimization methods, benchmarks, and integrated design tools. Here, recent advancements are reviewed in the computer-aided design of flow-, droplet-, and paper-based microfluidics. A case study of the design of resistive microfluidic networks is discussed in detail. The review concludes with perspectives on the future of computer-aided microfluidics design, including the introduction of cloud computing, machine learning, new ideation processes, and hybrid optimization.
Ankyrin Is An Intracellular Tether for TMC Mechanotransduction Channels
Authors: Yi-Quan Tang, Sol Ah Lee, Mizanur Rahman, Siva A. Vanapalli, Hang Lu, William R. Schafer
Journal: Neuron (2020)

Mechanotransduction channels have been proposed as force sensors in various physiological processes, such as hearing and touch. In particular, TMC1 has been shown to constitute the pore of hair cell mechanotransduction channels, but little is known about how force is sensed by TMC channels. Here, we identify UNC-44/ankyrin as an essential component of the TMC-1 mechanotransduction channel complex in the sensory cilia of Caenorhabditis elegans mechanoreceptor neurons. Ankyrin binds indirectly to TMC-1 via evolutionarily conserved CIB proteins, which are required for TMC-1-mediated mechanosensation in C. elegans OLQ neurons and body wall muscles. Mechanosensory activity conferred by ectopically expressed TMCs in mechanoinsensitive neurons depends on both ankyrin and CIB proteins, indicating that the ankyrin-CIB subcomplex is required for TMC mechanosensitivity. Our work indicates that ankyrin is a long-sought intracellular tether that transmits force to TMC mechanotransduction channels.
Hepatic Vascular Malformation Mimics PSMA-Positive Prostate Cancer Metastasis
Authors: Sebastian Hoberück, Sebastian Driesnack, Danilo Seppelt, Enrico Michler, Tobias Hölscher, Jörg Kotzerke
Journal: Clinical Nuclear Medicine (2020)

Abstract An 80-year-old man developed high-risk prostate cancer after 7 years of active surveillance. For staging and treatment planning, a 68 Ga-PSMA PET/MRI was performed. Besides the PSMA-positive primary tumor and a solitary bone metastasis in the fifth thoracic vertebral body, an intensive intrahepatic PSMA expression (SUV max , 16.3) was suspicious for a liver metastasis. The results of a previously performed contrast-enhanced CT, a consecutively performed contrast-enhanced ultrasound, and a follow-up PSMA PET/CT after 4 months with a stable lesion during androgen deprivation lead to the diagnosis of a vascular malformation metabolically mimicking a hepatic metastasis of the prostate tumor.
Cardiac Microtissues: Maladaptive Contractility of 3D Human Cardiac Microtissues to Mechanical Nonuniformity (Adv. Healthcare Mater. 8/2020)
Authors: Chenyan Wang, Sangmo Koo, Minok Park, Zacharias Vangelatos, Plansky Hoang, Bruce R. Conklin, Costas P. Grigoropoulos, Kevin E. Healy, Zhen Ma
Journal: Advanced Healthcare Materials (2020)

In article number 1901373 by Kevin E. Healy, Zhen Ma, and co-workers, a “pathologically-inspired” 3D cardiac microtissue model is established based on human induced pluripotent stem cells and laser-based 3D printing technology. This engineered in vitro model system can facilitate better understanding of the correlation between cardiac contractile dysfunctions and nonuniform tissue mechanical environments.
Clinical impact of splicing in neurodevelopmental disorders
Authors: Stephan J. Sanders, Grace B. Schwartz, Kyle Kai-How Farh
Journal: Genome Medicine (2020)

Abstract Clinical exome sequencing is frequently used to identify gene-disrupting variants in individuals with neurodevelopmental disorders. While splice-disrupting variants are known to contribute to these disorders, clinical interpretation of cryptic splice variants outside of the canonical splice site has been challenging. Here, we discuss papers that improve such detection.
Macular Telangiectasia Type 2: Visual Acuity, Disease End Stage, and the MacTel Area
Authors: Tjebo F.C. Heeren, Emily Y. Chew, Traci Clemons, Marcus Fruttiger, Konstantinos Balaskas, Roy Schwartz, Catherine A. Egan, Peter Charbel Issa
Journal: Ophthalmology (2020)
MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial
Authors: Debashis Sarker, Ruth Plummer, Tim Meyer, Mikael H. Sodergren, Bristi Basu, Cheng Ean Chee, Kai-Wen Huang, Daniel H. Palmer, Yuk Ting Ma, T.R. Jeff Evans, Duncan R.C. Spalding, Madhava Pai, Rohini Sharma, David J. Pinato, James Spicer, Sarah Hunter, Vineet Kwatra, Joanna P. Nicholls, David Collin, Robert Nutbrown, Helen Glenny, Sonia Fairbairn, Vikash Reebye, Jon Voutila, Stephanie Dorman, Pinelopi Andrikakou, Peter Lloyd, Steve Felstead, Jenni Vasara, Robert Habib, Chris Wood, Pal Saetrom, Hans E. Huber, David C. Blakey, John J. Rossi, Nagy Habib
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. Patients and Methods: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). Results: Thirty-eight participants have been treated across six dose levels (28–160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment–related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. Conclusions: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.
Finding a Way Out: S1P Signaling and Immune Cell Migration
Authors: Audrey A.L. Baeyens, Susan R. Schwab
Journal: Annual Review of Immunology (2020)

The signaling lipid sphingosine 1-phosphate (S1P) plays critical roles in an immune response. Drugs targeting S1P signaling have been remarkably successful in treatment of multiple sclerosis, and they have shown promise in clinical trials for colitis and psoriasis. One mechanism of these drugs is to block lymphocyte exit from lymph nodes, where lymphocytes are initially activated, into circulation, from which lymphocytes can reach sites of inflammation. Indeed, S1P can be considered a circulation marker, signaling to immune cells to help them find blood and lymphatic vessels, and to endothelial cells to stabilize the vasculature. That said, S1P plays pleiotropic roles in the immune response, and it will be important to build an integrated view of how S1P shapes inflammation. S1P can function so effectively because its distribution is exquisitely tightly controlled. Here we review how S1P gradients regulate immune cell exit from tissues, with particular attention to key outstanding questions in the field.
Abstract 17127: Clockwise Rotation With Left Ventricular High Voltage is Significantly Associated With Increased Risk of Cardiovascular Diseases in a Population-based Cohort Study
Authors: Takashi Kobayashi, Makoto Watanabe, Aya Higashiyama, Yoshihiro Kokubo, Shiro Kamakura, Kengo Kusano, Kunihiro Nishimura, Misa Takegami, Yoko M. Nakao, Takuya Watanabe, Yoshihiro Miyamoto
Journal: Circulation (2017)

Introduction: Left ventricular high voltage (LVH) is closely associated with cardiovascular diseases (CVDs). No prospective study has examined the combined effect of LVH and cardiac rotation on the...
Iron bioavailability and cardiopulmonary function during ascent to very high altitude
Authors: David A. Holdsworth, Matthew C. Frise, Josh Bakker-Dyos, Christopher Boos, Keith L. Dorrington, David Woods, Adrian Mellor, Peter A. Robbins
Journal: European Respiratory Journal (2020)

<b>Intravenous iron supplementation at sea level is associated with enhanced stroke volume and higher <i>S</i><sub>pO<sub>2</sub></sub> on ascent to very high altitude (5100 m). These effects appear to result from reduced pulmonary vascular resistance and improved right heart function.</b>https://bit.ly/2VQX5fR
Preliminary recommendations of the German Society of Rheumatology (DGRh eV) for the management of patients with inflammatory rheumatic diseases during the SARS-CoV-2/COVID-19 pandemic
Authors: Hendrik Schulze-Koops, Christof Specker, Christof Iking-Konert, Julia Holle, Frank Moosig, Klaus Krueger
Journal: Annals of the Rheumatic Diseases (2020)

<h3>Background</h3> There is a need to reduce antimicrobial uses in humans. Previous studies have found variations in antibiotic (AB) prescribing between practices in primary care. This study assessed variability of AB prescribing between clinicians. <h3>Methods</h3> Clinical Practice Research Datalink, which collects electronic health records in primary care, was used to select anonymised clinicians providing 500+ consultations during 2012–2017. Eight measures of AB prescribing were assessed, such as overall and incidental AB prescribing, repeat AB courses and extent of risk-based prescribing. Poisson regression models with random effect for clinicians were fitted. <h3>Results</h3> 6111 clinicians from 466 general practices were included. Considerable variability between individual clinicians was found for most AB measures. For example, the rate of AB prescribing varied between 77.4 and 350.3 per 1000 consultations; percentage of repeat AB courses within 30 days ranged from 13.1% to 34.3%; predicted patient risk of hospital admission for infection-related complications in those prescribed AB ranged from 0.03% to 0.32% (5th and 95th percentiles). The adjusted relative rate between clinicians in rates of AB prescribing was 5.23. Weak correlation coefficients (&lt;0.5) were found between most AB measures. There was considerable variability in case mix seen by clinicians. The largest potential impact to reduce AB prescribing could be around encouraging risk-based prescribing and addressing repeat issues of ABs. Reduction of repeat AB courses to prescribing habit of median clinician would save 21 813 AB prescriptions per 1000 clinicians per year. <h3>Conclusions</h3> The wide variation seen in all measures of AB prescribing and weak correlation between them suggests that a single AB measure, such as prescribing rate, is not sufficient to underpin the optimisation of AB prescribing.
The growth- and survival-effects of SLPI on ovarian cancer cells is independent of its protease-inhibitory function and relates to its ability to sustain GEP-activity
Authors: Nick Devoogdt, Nabila Rasool, Fiona Simpkins, Joshua Cohen, Nana Tchabo, Elise Kohn
Journal: Cancer Research (2006)

3456  Secretory Leukocyte Protease Inhibitor (SLPI), a member of the Whey Acidic Protein family and encoded by a locus on chromosome 20q13, is frequently genomically and transcriptionally amplified in ovarian cancer and is being considered as a biomarker for this disease. Previous studies by our group have demonstrated that the SLPI protein exerts growth and survival-promoting activities on ovarian cancer cells, and that this is related to its ability to bind to, and preserve the activity of granulin-epithelin precursor (GEP), a potent growth- and survival factor for these cells. However, although biologically the best characterized activity of SLPI is its ability to inhibit serine proteases such as elastase that are known to degrade GEP protein, it remained unclear whether SLPI’s growth-promoting and GEP-protecting activities were related to its protease-inhibitory function. Here we further extent our previous data by showing that transfection into Hey-A8 ovarian cancer cells of either wild type (WT) SLPI or F/R-mutant SLPI forms with impaired elastase inhibitory activities, provided these cells with increased growth and survival properties. WT and F/R-mutant SLPI expression in these cells enhanced their in vitro growth properties under both adherent and anchorage-independent conditions up to 80%. This coincided with the facts that F/R-mutant SLPI bound to GEP in a similar extent as WT SLPI, and that the bioavailability of GEP was higher in either SLPI or F/R-SLPI transfectants as compared to control cells. Moreover, elastase-mediated GEP-degradation and concomittant cell-cycle arrest and death of control Hey-A8 cells was significantly decreased in either WT or F/R-mutant SLPI transfectants. Interestingly, SLPI-transfection into Hey-A8 cells also increased their capacity to form solid tumors upon intraperitoneal injection into nude mice, independently of its protease-inhibitory activity. In conclusion, we could demonstrate that SLPI exerts growth- and survival functions on ovarian cancer cells in vitro under conditions that mimic hostile in vivo conditions (e.g. lack of anchorage and injury by proteases) and that this is related to SLPI’s ability to bind to and maintain GEP-activity. In addition, in vivo, SLPI-expressing ovarian cancer cells were more aggressive than non-expressing controls, validating our in vitro models. Hence, development of modi that can interfere with SLPI’s protective role on GEP-activity could potentially be useful as therapeutic tools against ovarian cancer.
Strategies to Prevent or Remediate Cancer and Treatment-Related Aging
Authors: Jennifer L Guida, Tanya Agurs-Collins, Tim A Ahles, Judith Campisi, William Dale, Wendy Demark-Wahnefried, Jorg Dietrich, Rebecca Fuldner, Lisa Gallicchio, Paige A Green, Arti Hurria, Michelle C Janelsins, Chamelli Jhappan, James L Kirkland, Ronald Kohanski, Valter Longo, Simin Meydani, Supriya Mohile, Laura J Niedernhofer, Christian Nelson, Frank Perna, Keri Schadler, Jessica M Scott, Jennifer A Schrack, Russell P Tracy, Jan van Deursen, Kirsten K Ness
Journal: JNCI Journal of the National Cancer Institute (2020)

Up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with an accumulation of chronic conditions, frailty, and/or cognitive impairments resulting from cancer and its treatment. Thus, survivors often show an accelerated development of multiple geriatric syndromes and need therapeutic interventions. To advance progress in this area, the National Cancer Institute convened the second of 2 think tanks under the auspices of the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative. Experts assembled to share evidence of promising strategies to prevent, slow, or reverse the aging consequences of cancer and its treatment. The meeting identified research and resource needs, including geroscience-guided clinical trials; comprehensive assessments of functional, cognitive, and psychosocial vulnerabilities to assess and predict age-related outcomes; preclinical and clinical research to determine the optimal dosing for behavioral (eg, diet, exercise) and pharmacologic (eg, senolytic) therapies; health-care delivery research to evaluate the efficacy of integrated cancer care delivery models; optimization of intervention implementation, delivery, and uptake; and patient and provider education on cancer and treatment-related late and long-term adverse effects. Addressing these needs will expand knowledge of aging-related consequences of cancer and cancer treatment and inform strategies to promote healthy aging of cancer survivors.
Lower Out-of-Pocket Insulin Costs for Medicare Plan D Beneficiaries
Authors: Rita Rubin
Journal: JAMA (2020)

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Click by Click Microporous Annealed Particle (MAP) Scaffolds
Authors: Nicole J. Darling, Weixian Xi, Elias Sideris, Alexa R. Anderson, Cassie Pong, S. Thomas Carmichael, Tatiana Segura
Journal: Advanced Healthcare Materials (2020)

Abstract Macroporous scaffolds are being increasingly used in regenerative medicine and tissue repair. While the recently developed microporous annealed particle (MAP) scaffolds have overcome issues with injectability and in situ hydrogel formation, limitations with respect to tunability to be able to manipulate hydrogel strength and rigidity for broad applications still exist. To address these key issues, here hydrogel microparticles (HMPs) of hyaluronic acid (HA) are synthesized using the thiol‐norbornene click reaction and then HMPs are subsequently annealed into a porous scaffold using the tetrazine‐norbornene click reaction. This assembly method allows for straightforward tuning of bulk scaffold rigidity by varying the tetrazine to norbornene ratio, with increasing tetrazine resulting in increasing scaffold storage modulus, Young's modulus, and maximum stress. These changes are independent of void fraction. Further incorporation of human dermal fibroblasts throughout the porous scaffold reveals the biocompatibility of this annealing strategy as well as differences in proliferation and cell‐occupied volume. Finally, injection of porous HA‐Tet MAP scaffolds into an ischemic stroke model shows this chemistry is biocompatible in vivo with reduced levels of inflammation and astrogliosis as previously demonstrated for other crosslinking chemistries.
Pregabalin and gabapentin for pain
Authors: Stephanie Mathieson, Chung-Wei Christine Lin, Martin Underwood, Sam Eldabe
Journal: BMJ (2020)

### What you need to know

A 65 year old woman presents with continuous dull back ache and leg pain over the past four years. She underwent lumbar decompression surgery three months ago, but the pain persists. She has no neurological deficits. She is on treatment for hypertension and chronic kidney disease and cannot take non-steroidal anti-inflammatory drugs. She has tried paracetamol, codeine, tramadol, and amitriptyline for her pain in the past with little benefit. You offer a trial of pregabalin and ask her to follow up if she feels dizzy or is not able to tolerate the drug. 

Pregabalin and gabapentin, collectively gabapentinoids, are primarily anticonvulsant drugs. Over the past decade, they have been increasingly prescribed for pain.1 They are recommended for neuropathic pain in adults23 (table 1), but are commonly used off-label for other pain disorders such as low back pain, sciatica, and migraine.910 Pregabalin was one of the highest selling drugs globally in 2017.11 In 2018, more than 14 million prescriptions of pregabalin and gabapentin were issued in England.12 This increase in gabapentinoid prescribing may be driven by a desire to avoid opioid analgesics.13

View this table:

Table 1 
Approved indications for pregabalin and gabapentin



Pregabalin and gabapentin were reclassified as Class C drugs in the UK in April 2019 following an increase in the number of deaths caused by gabapentinoid misuse and addiction.14 Under the UK’s Misuse …