tbuckley/cabot-search huggingface dataset:
Ultrastructural features resembling those of harlequin ichthyosis in patients with severe congenital ichthyosiform erythroderma
Authors: E. Virolainen, K-M. Niemi, A. Gånemo, J. Kere, A. Vahlquist, U. Saarialho-Kere
Journal: British Journal of Dermatology (2008)

Congenital ichthyoses are a group of heterogeneous disorders of cornification. Autosomal recessive congenital ichthyosis (ARCI) can be clinically subdivided into congenital ichthyosiform erythroderma and lamellar ichthyosis. Ultrastructurally, ARCI is classified into four groups: ichthyosis congenita (IC) types I–IV. The genetic background of the ARCI disorders is heterogeneous, but only one disease gene, transglutaminase 1, has been detected so far. We describe six patients with severe congenital ichthyosis from six different Scandinavian families. They could not be classified ultrastructurally into the four IC groups because of atypical findings of electron microscopy. These included abnormal lamellar bodies, alterations in keratohyalin, remnant organelles and lipid inclusions in the upper epidermal cells, which resembled the ultrastructural findings of harlequin ichthyosis (HI), although the HI phenotype was not present at birth. Some clinical features, such as thick scales, erythroderma, alopecia and ectropion were common to all patients. Ichthyosis was usually accentuated in the scalp and four patients had clumped fingers and toes. None of the patients carried the transglutaminase 1 mutation. We conclude that ultrastructural findings resembling those detected in previous HI cases (type 1 and 2) can also be found in patients who do not have classic clinical features of that rare ichthyosis. This may be due to lack of specificity of ultrastructural markers for HI or to its clinical heterogeneity.
Comparative Approaches to Drug Pricing
Authors: So-Yeon Kang, Ge Bai, Michael J. DiStefano, Mariana P. Socal, Farah Yehia, Gerard F. Anderson
Journal: Annual Review of Public Health (2019)

The United States relies primarily on market forces to determine prices for drugs, whereas most other industrialized countries use a variety of approaches to determine drug prices. Branded drug companies have patents and market exclusivity periods in most industrialized countries. During this period, pharmaceutical companies are allowed to set their list price as high as they prefer in the United States owing to the absence of government price control mechanisms that exist in other countries. Insured patients often pay a percentage of the list price, and cost sharing creates some pressure to lower the list price. Pharmacy benefit managers negotiate with drug companies for lower prices by offering the drug company favorable formulary placement and fewer utilization controls. However, these approaches appear to be less effective, compared with other countries' approaches to containing branded drug prices, because prices are substantially higher in the United States. Other industrialized countries employ various forms of rate setting and price regulation, such as external reference pricing, therapeutic valuation, and health technology assessment to determine the appropriate price.
Adherence to the 2017 French dietary guidelines and adult weight gain: A cohort study
Authors: Dan Chaltiel, Chantal Julia, Moufidath Adjibade, Mathilde Touvier, Serge Hercberg, Emmanuelle Kesse-Guyot
Journal: PLoS Medicine (2019)

The French dietary guidelines were updated in 2017, and an adherence score to the new guidelines (Programme National Nutrition Santé Guidelines Score 2 [PNNS-GS2]) has been developed and validated recently. Since overweight and obesity are key public health issues and have been related to major chronic conditions, this prospective study aimed to measure the association between PNNS-GS2 and risk of overweight and obesity, and to compare these results with those for the modified Programme National Nutrition Santé Guidelines Score (mPNNS-GS1), reflecting adherence to 2001 guidelines.Participants (N = 54,089) were recruited among French adults (≥18 years old, mean baseline age = 47.1 [SD 14.1] years, 78.3% women) in the NutriNet-Santé web-based cohort. Mean (SD) score was 1.7 (3.3) for PNNS-GS2 and 8.2 (1.6) for mPNNS-GS1. Selected participants were those included between 2009 and 2014 and followed up to September 2018 (median follow-up = 6 years). Collected data included at least three 24-hour dietary records over a 2-year period following inclusion, baseline sociodemographics, and anthropometric data over time. In Cox regression models, PNNS-GS2 was strongly and linearly associated with a lower risk of overweight and obesity (HR for quintile 5 versus quintile 1 [95% CI] = 0.48 [0.43-0.54], p < 0.001, and 0.47 [0.40-0.55], p < 0.001, for overweight and obesity, respectively). These results were much weaker for mPNNS-GS1 (HR for quintile 5 versus quintile 1 = 0.90 [0.80-0.99], p = 0.03, and 0.98 [0.84-1.15], p = 0.8, for overweight and obesity, respectively). In multilevel models, PNNS-GS2 was negatively associated with baseline BMI and BMI increase over time (β for a 1-SD increase in score [95% CI] = -0.040 [-0.041; -0.038], p < 0.001, and -0.00080 [-0.00094; -0.00066], p < 0.001, respectively). In "direct comparison" models, PNNS-GS2 was associated with a lower risk of overweight and obesity, lower baseline BMI, and lower BMI increase over time than mPNNS-GS1. Study limitations include possible selection bias, reliance on participant self-report, use of arbitrary cutoffs in data analyses, and residual confounding, but robustness was tested in sensitivity analyses.Our findings suggest that adherence to the 2017 French dietary guidelines is associated with a lower risk of overweight and obesity. The magnitude of the association and the results of the direct comparison reinforced the validity of the updated recommendations.The NutriNet-Santé Study ClinicalTrials.gov (NCT03335644).
Lung and Diaphragm Protection during Noninvasive Respiratory Support
Authors: Elena Spinelli, Tommaso Mauri
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

n = 11).Two networks affirmed conducting studies that were unfunded or self-funded.Collaborations in critical care have expanded from activities largely conducted within research networks to include collaborations between research networks (Figure 2).Several key findings arise from our survey.First, research collaborations in critical care originated from a need for investigators to work together to advance the science behind caring for critically ill patients.Second, critical care collaborations largely focus on the design and implementation of randomized controlled trials.Third, most critical care research networks developed after 2005.Since this time, alliances have evolved in scope to include global collaborations between research networks.Fourth, most critical care research networks either conduct one or a few large studies or coordinate multiple research programs concurrently.Fifth, collaborative critical care research networks depend on peer-reviewed funding to cover infrastructure costs, with one-fourth of research networks being self-funded or unfunded.Sixth, financial support for studies is fragile and dependent on contributions from multiple funding partners.Collaborative research networks have transformed how critical care research has been conducted over the past three decades.The future critical care research agenda will be increasingly accountable to patient and family priorities and societal expectations for research investments to translate into better health care and outcomes (8).As the human and financial costs of research increase, we anticipate greater emphasis on strategies that will simplify the logistics and costs of conducting critical care research.Novel study designs and greater collaborations among research networks will be integral to advancing future research in critical care.
Abstract 16287: Fatty Acid-Based Medium Promoted Metabolic Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Chengzhong Cai, Feng Wei, Qiang Shi, Xi Yang, David G Strauss, Norman Stockbridge, Li Pang
Journal: Circulation (2018)

Introduction: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great potential for cardiovascular disease modeling, drug discovery, and precision medicine; however, the r...
Controlled release of adenosine from core-shell nanofibers to promote bone regeneration through STAT3 signaling pathway
Authors: Xin Cheng, Gu Cheng, Xin Xing, Chengcheng Yin, Yuet Cheng, Xue Zhou, Shan Jiang, Fenghua Tao, Hongbing Deng, Zubing Li
Journal: Journal of Controlled Release (2019)
Two unique HLA-A*0201 restricted peptides derived from cyclin E as immunotherapeutic targets in leukemia
Authors: Hong He, Yukio Kondo, Ken Ishiyama, Gheath Alatrash, Sijie Lu, Kathryn Cox, Na Qiao, Karen Clise-Dwyer, Lisa St. John, Pariya Sukhumalchandra, Qing Ma, Jeffrey J. Molldrem
Journal: Leukemia (2020)
99mTc-MIP-1404 SPECT/CT for Patients With Metastatic Prostate Cancer
Authors: Christian Schmidkonz, Armin Atzinger, Theresa Ida Goetz, Michael Beck, Philipp Ritt, Olaf Prante, Torsten Kuwert, Tobias Bäuerle, Michael Cordes
Journal: Clinical Nuclear Medicine (2019)

Background 99m Tc-MIP-1404 is a SPECT-suitable prostate-specific membrane antigen (PSMA) ligand for detection of prostate cancer. In patients with metastatic prostate cancer, there are no data as yet on interobserver and intraobserver variability when assessing PSMA-positive lesions for longitudinal changes of tracer uptake. Methods 99m Tc-MIP-1404 SPECT/CT scans of 22 patients with metastatic prostate cancer were analyzed, and each subject was imaged at 2 separate points in time, before and after treatment. Mean interval between scans was 10 months. Three independent observers visually assessed a total of 96 PSMA-positive metastases (bone, 69; lymph node, 22; viscera, 3) or local recurrences (n = 2) for longitudinal changes in tracer uptake on planar scintigraphy and SPECT/CT. All lesions were categorized as regressive, stable, or progressive based on visual findings and on peak SUV (SUVpeak) of quantitative SPECT/CT (progressive, &gt;30% SUVpeak increase; regressive, &lt;30% SUVpeak decrease; or stable, all others). Results Quantitative analysis of PSMA-positive lesions yielded significantly higher interobserver agreement (90.6%; 95% confidence interval [CI], 0.83%–0.96%) than visual assessments by either SPECT/CT (76.0%; 95% CI, 0.66%–0.84%) or planar scintigraphy (56.3%; 95% CI, 0.46%–0.66%). Intermethod comparison of aggregated results yielded significantly higher agreement between quantitative and visual SPECT/CT (85.1%; 95% CI, 0.80%–0.89%), as opposed to quantitative SPECT/CT and planar scintigraphy (53.1%; 95% CI, 0.47%–0.59%) or visual SPECT/CT and planar scintigraphy (54.9%; 95% CI, 0.49%–0.61%). In visual and quantitative analysis of 96 PSMA-positive lesions, the number of discrepancies ranged from 9 (9.4%) for quantitative SPECT/CT to 42 (43.8%) for planar scintigraphy. Overall reader confidence was higher for SPECT/CT than for planar scintigraphy ( P &lt; 0.001). Intraobserver agreement was near-perfect for all methods, whether SPECT/CT (visual, all κ = 0.94–0.97; quantitative κ = 0.94–0.98) or planar scintigraphy (all κ = 0.90–0.94). Conclusions Quantitative evaluation of longitudinal change in tracer uptake by PSMA-positive lesions measured via SPECT/CT is superior to visual interpretation of images by planar scintigraphy or SPECT/CT. Compared with visual evaluation, quantitative SPECT/CT is highly reproducible, showing near-perfect agreement among observers and higher reader confidence.
Phase II trial of paclitaxel in front-line therapy of hormone refractory metastatic prostate cancer
Authors: T. Kolevska, D. Goldstein, C. Davis, L. Fehrenbacher
Journal: Journal of Clinical Oncology (2007)

15628 Hormone refractory prostate cancer patients have poor prognosis with median survival of only 16 months. They are frequently elderly men with many co-morbid conditions unable to tolerate treatments with substantial toxicity. Docetaxel, the only drug shown to prolong survival causes significant toxicities, requires steroids administration, may cause poorly reversible neuropathy and requires long infusion times, all limiting its use in elderly men that are mostly affected by hormone refractory prostate cancer. Abraxane is a novel agent delivering paclitaxel without steroids, requires only 30 minutes infusion times and low toxicity potential that may be effective and more tolerable in patients with prostate cancer. The goal of our study is to evaluate the effectiveness and toxicity of Abraxane in first line chemotherapy of men with hormone refractory prostate cancer. Considering the favorable toxicity profile of Abraxane and in an effort to make our results applicable to the majority of prostate cancer patients we are including men with performance status of 2. Main eligibility criteria are: hormone refractory metastatic prostate cancer documented by PSA progression, no prior chemotherapy, PSA &gt;5 and performance status 0–2. Primary endpoint is efficacy based on PSA response. Secondary endpoints are time to PSA progression, overall survival, and toxicities. The clinical trial has been opened at Kaiser Permanente Northern California since September 2005. There are 15 patients enrolled. All have been evaluable for toxicity and the drug is very well tolerated so far by this population of patients. Out of 15 patients 12 are evaluable for response. Two patients have recently started the protocol therapy and have not met the time point for disease assessment. One patient discontinued the treatment after one infusion due to toxicity (elevated LFTs). One patient completed 11 cycles of Abraxane, while maintaining stable disease on bone scan and achieved a PR by PSA. Ten patients have come off study due to progressive disease based on clinical presentation, rising PSA or signs of radiological progression. There are currently 4 patients actively receiving therapy. Updated results will be presented at the time of ASCO 2007 meeting. No significant financial relationships to disclose.
Emergency bowel surgery: organisational change is needed to improve outcomes
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Just a fifth of patients (19.4%) who underwent emergency laparotomy and who had signs of sepsis on admission received antibiotics within the recommended 60 minutes, an audit has shown.1

The 2017-2018 national emergency laparotomy audit, carried out on behalf of the Royal College of Anaesthetists, said that this outcome had not improved over the past five years and had worsened since the last audit (24% in 2016-17).

The report found that progress on other outcomes had also stalled, including average 30 day mortality after emergency laparotomy, which remained static at 9.6%. This had previously been improving, from 11.8% in 2013 to 9.5% in 2017.

The Royal College of Anaesthetists said that …
AI system outperforms radiologists in first reading of breast cancer screening, study claims
Authors: Elisabeth Mahase
Journal: BMJ (2020)

An artificial intelligence (AI) system designed to read mammogram images and identify breast cancer “outperformed” radiologists in the first reading, a study has claimed.1

The research, funded by Google and carried out by Google employees (who own stock) and consultants, tested the AI model using two datasets from the UK (25 856 mammograms) and US (3097 mammograms) and found it reduced the number of false negatives and positives, compared with radiologists.

The study, published in Nature , said that in the UK, where mammograms are read by two radiologists during screening, this model could reduce the workload for the second reader by 88%.

The Royal College of Radiologists said that while AI programmes can be helpful as a “second pair of eyes,” it will not solve the workforce crisis because “radiologists and imaging teams do far more …
Tracheal Intubation in the Critically Ill. Where We Came from and Where We Should Go
Authors: Jarrod M. Mosier, John C. Sakles, J. Adam Law, Calvin A. Brown, Peter G. Brindley
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Section:ChooseTop of pageAbstract <<History of Emergency Airw...Current Challenges with E...Future Research Direction...Key MessagesReferencesCITING ARTICLES
Solar Ultraviolet Radiation and Breast Cancer Risk: A Systematic Review and Meta-Analysis
Authors: Troy W. R. Hiller, Dylan E. O’Sullivan, Darren R. Brenner, Cheryl E. Peters, Will D. King
Journal: Environmental Health Perspectives (2020)

Background: A protective relationship has been hypothesized between exposure to solar ultraviolet radiation (UVR) and the development of breast cancer. Objective: The objective of this study was to conduct a systematic literature review and meta-analysis of studies examining the association of exposure to solar UVR and breast cancer risk. Methods: We searched Medline, EMBASE, and Web of Science for all studies investigating exposure to solar UVR and breast cancer risk. Separate analyses were performed using estimates of time spent in the sun, and ambient UVR. Associations were estimated using DerSimonian and Laird random-effect models. Heterogeneity was investigated through subgroup analyses and I2 statistics. Results: Fourteen studies were included in the review and 13 in the meta-analysis, with the majority (n=8) conducted in North America. We observed a decreased risk of breast cancer for individuals spending ≥1h/d in the sun during summer months over a lifetime or usual adulthood compared with <1h/d [pooled relative risk (RR)=0.84; 95% CI: 0.77, 0.91]. Spending ≥2h/d in the sun had a similar protective effect as 1 to <2h/d when compared with <1h/d (RR=0.83; 95% CI: 0.75, 0.93 vs. 0.83; 95% CI: 0.78, 0.89). Exposure during adolescence was suggestive of a lower risk of breast cancer than exposure later in life (≥45 years of age) (RR=0.83; 95% CI: 0.71, 0.98 vs. 0.97; 95% CI: 0.85, 1.11). Ambient UVR was not associated with the risk of breast cancer (RR=1.00; 95% CI: 0.93, 1.09). Discussion: To our knowledge, this was the first meta-analysis to estimate the risk of developing breast cancer associated with time spent in the sun. The results suggest that obtaining greater than an hour a day in the sun during the summer months could decrease the risk of developing breast cancer. https://doi.org/10.1289/EHP4861
Smooth muscle SIRT1 reprograms endothelial cells to suppress angiogenesis after ischemia
Authors: Yong-Qing Dou, Peng Kong, Chang-Lin Li, Hong-Xing Sun, Wei-Wei Li, Yuan Yu, Lei Nie, Li-Li Zhao, Sui-Bing Miao, Xiao-Kun Li, Chen Dong, Jin-Wen Zhang, Yang Liu, Xiao-Xia Huo, Kui Chi, Xiang Gao, Ning Zhang, Lin Weng, Hongyuan Yang, Fan Zhang, Mei Han
Journal: Theranostics (2020)

Objective: Vascular smooth muscle cells (VSMCs) undergo the phenotypic changes from contractile to synthetic state during vascular remodeling after ischemia.SIRT1 protects against stress-induced vascular remodeling via maintaining VSMC differentiated phenotype.However, the effect of smooth muscle SIRT1 on the functions of endothelial cells (ECs) has not been well clarified.Here, we explored the role of smooth muscle SIRT1 in endothelial angiogenesis after ischemia and the underlying mechanisms.Methods: We performed a femoral artery ligation model using VSMC specific human SIRT1 transgenic (SIRT1-Tg) and knockout (KO) mice.Angiogenesis was assessed in in vivo by quantification of the total number of capillaries, wound healing and matrigel plug assays, and in vitro ECs by tube formation, proliferation and migration assays.The interaction of HIF1α with circRNA was examined by using RNA immunoprecipitation, RNA pull-down and in situ hybridization assays.Results: The blood flow recovery was significantly attenuated in SIRT1-Tg mice, and markedly improved in SIRT1-Tg mice treated with SIRT1 inhibitor EX527 and in SIRT1-KO mice.The density of capillaries significantly decreased in the ischemic gastrocnemius of SIRT1-Tg mice compared with SIRT1-KO and WT mice, with reduced expression of VEGFA, which resulted in decreased number of arterioles.We identified that the phenotypic switching of SIRT1-Tg VSMCs was attenuated in response to hypoxia, with high levels of contractile proteins and reduced expression of the synthetic markers and NG2, compared with SIRT1-KO and WT VSMCs.Mechanistically, SIRT1-Tg VSMCs inhibited endothelial angiogenic activity induced by hypoxia via the exosome cZFP609.The cZFP609 was delivered into ECs, and detained HIF1α in the cytoplasm via its interaction with HIF1α, thereby inhibiting VEGFA expression and endothelial angiogenic functions.Meantime, the high cZFP609 expression was observed in the plasma of the patients with atherosclerotic or diabetic lower extremity peripheral artery disease, associated with reduced ankle-brachial index.Knockdown of cZFP609 improved blood flow recovery after hindlimb ischemia in SIRT1-Tg mice.Conclusions: Our findings demonstrate that SIRT1 may impair the plasticity of VSMCs.cZFP609 mediates VSMCs to reprogram endothelial functions, and serves as a valuable indicator to assess the prognosis and clinical outcomes of ischemic diseases.
Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β–mediated colitis
Authors: Liming Mao, Atsushi Kitani, Eitaro Hiejima, Kim Montgomery-Recht, Wenchang Zhou, Ivan Fuss, Adrian Wiestner, Warren Strober
Journal: Journal of Clinical Investigation (2020)

Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus have important non-B cell functions. Here, we explored the function of this kinase in macrophages with studies of its regulation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. We found that bone marrow-derived macrophages (BMDMs) from BTK-deficient mice or monocytes from patients with X-linked agammaglobulinemia (XLA) exhibited increased NLRP3 inflammasome activity; this was also the case for BMDMs exposed to low doses of BTK inhibitors such as ibrutinib and for monocytes from patients with chronic lymphocytic leukemia being treated with ibrutinib. In mechanistic studies, we found that BTK bound to NLRP3 during the priming phase of inflammasome activation and, in doing so, inhibited LPS- and nigericin-induced assembly of the NLRP3 inflammasome during the activation phase of inflammasome activation. This inhibitory effect was caused by BTK inhibition of protein phosphatase 2A-mediated (PP2A-mediated) dephosphorylation of Ser5 in the pyrin domain of NLRP3. Finally, we show that BTK-deficient mice were subject to severe experimental colitis and that such colitis was normalized by administration of anti-IL-β or anakinra, an inhibitor of IL-1β signaling. Together, these studies strongly suggest that BTK functions as a physiologic inhibitor of NLRP3 inflammasome activation and explain why patients with XLA are prone to develop Crohn's disease.