tbuckley/cabot-search huggingface dataset:
Rosuvastatin Myotoxicity After Starting Canagliflozin Treatment
Authors: Eugene Brailovski, Richard B. Kim, David Juurlink
Journal: Annals of Internal Medicine (2021)

LettersMarch 2021Rosuvastatin Myotoxicity After Starting Canagliflozin TreatmentEugene Brailovski, MD, CM, Richard B. Kim, MD, David Juurlink, MD, PhDEugene Brailovski, MD, CMUniversity of Toronto, Toronto, Ontario, CanadaSearch for more papers by this author, Richard B. Kim, MDUniversity of Western Ontario, London, Ontario, CanadaSearch for more papers by this author, David Juurlink, MD, PhDUniversity of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-1456 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE: Dr. Alamer and colleagues rightly note that patients of Asian descent are more prone to rosuvastatin toxicity. Our patient's loss-of-function polymorphism in the gene encoding for BCRP would have been expected to impart greater rosuvastatin exposure for a given dose (1). However, it does not explain her clinical course, because she had tolerated the same dosage (40 mg/d) for more than 5 years without difficulty. The modest decline in renal function similarly does not explain her presentation, because rosuvastatin clearance is mediated primarily by the liver, with most of the drug recovered in feces and only approximately 10% ...References1. Hua WJ, Hua WX, Fang HJ. The role of OATP1B1 and BCRP in pharmacokinetics and DDI of novel statins. Cardiovasc Ther. 2012;30:e234-41. [PMID: 21884024] doi:10.1111/j.1755-5922.2011.00290.x CrossrefMedlineGoogle Scholar2. Martin PD, Warwick MJ, Dane AL, et al. Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther. 2003;25:2822-35. [PMID: 14693307] CrossrefMedlineGoogle Scholar3. Weibrecht K, Dayno M, Darling C, et al. Liver aminotransferases are elevated with rhabdomyolysis in the absence of significant liver injury. J Med Toxicol. 2010;6:294-300. [PMID: 20407858] doi:10.1007/s13181-010-0075-9 CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: University of Toronto, Toronto, Ontario, CanadaUniversity of Western Ontario, London, Ontario, CanadaDisclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-0549. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoRosuvastatin Myotoxicity After Starting Canagliflozin Treatment Rao N.V.S. Mamidi , Damayanthi Devineni , Don Sun , Yshai Yavin , and Norman Rosenthal Rosuvastatin Myotoxicity After Starting Canagliflozin Treatment Ahmad Alamer , Charisse Te , and Maryam T. Fazel Metrics Cited byClinical conundrums involving statin drug-drug interactions March 2021Volume 174, Issue 3Page: 432 ePublished: 16 March 2021 Issue Published: March 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
The CK1δ/ε-AES axis regulates tumorigenesis and metastasis in colorectal cancer
Authors: Zhongyuan Wang, Liang Zhou, Yejun Wang, Quanzhou Peng, Huan Li, Xin Zhang, Zijie Su, Jiaxing Song, Qi Sun, Sapna Sayed, Shanshan Liu, Desheng Lu
Journal: Theranostics (2021)

Background: Amino-terminal enhancer of split (AES) has been identified as a tumor and metastasis suppressor in some cancers including colorectal cancer (CRC), but very little is known about the regulation of AES expression. Methods: Bioinformatics analysis was used to investigate the expression patterns of AES, CK1δ and CK1ε. The co-immunoprecipitation, GST pull-down, Western Blot, real-time PCR and immunohistochemistry were performed to study the mechanism underlying the regulation of AES expression by CK1δ/ε. The biological function was assessed by in vitro colony formation, transwell, sphere formation, tumor organoids, in vivo tumor metastasis model and patient-derived colorectal tumor xenografts (PDTX) model. Results: A strong inverse relationship was observed between the expression of AES and the expression of CK1δ/ε. Mechanically, AES could interact with CK1δ/ε and SKP2 using its Q domain. SKP2 mediated the ubiquitination and degradation of AES in a CK1δ/ε-dependent manner. CK1δ/ε phosphorylated AES at Ser121 and accelerated the SKP2-mediated ubiquitination and degradation of AES. In colon cancer cells, CK1δ/ε antagonized the effect of wild-type AES but not that of its mutant (S121A) on Wnt and Notch signaling, leading to an increase in the expression of Wnt target genes and Notch target genes. By downregulating the expression of AES, CK1δ/ε enhanced anchorage-independent growth, migration, invasion and sphere formation in colon cancer cells. CK1δ/ε also promoted the growth of APCmin/+ colorectal tumor organoids and liver metastasis in colon cancer mouse models through the regulation of AES degradation. Furthermore, CK1 inhibitor SR3029 treatment suppressed tumor growth via stabilizing AES in APCmin/+ colorectal tumor organoids and patient-derived colorectal tumor xenografts (PDTX). Conclusions: Our results revealed that the CK1δ/ε-AES axis is important for CRC tumorigenesis and metastasis, and targeted inhibition of this axis may be a potential therapeutic strategy for CRC.
Discordance of High-Sensitivity Troponin Assays in Patients With Suspected Acute Coronary Syndromes
Authors: Júlia Karády, Thomas Mayrhofer, Maros Ferencik, John T Nagurney, James E Udelson, Andreas A Kammerlander, Jerome L Fleg, W Frank Peacock, James L Januzzi, Wolfgang Koenig, Udo Hoffmann
Journal: Journal of the American College of Cardiology (2021)
Neocortical Layer 1: An Elegant Solution to Top-Down and Bottom-Up Integration
Authors: Benjamin Schuman, Shlomo Dellal, Alvar Prönneke, Robert Machold, Bernardo Rudy
Journal: Annual Review of Neuroscience (2021)

Many of our daily activities, such as riding a bike to work or reading a book in a noisy cafe, and highly skilled activities, such as a professional playing a tennis match or a violin concerto, depend upon the ability of the brain to quickly make moment-to-moment adjustments to our behavior in response to the results of our actions. Particularly, they depend upon the ability of the neocortex to integrate the information provided by the sensory organs (bottom-up information) with internally generated signals such as expectations or attentional signals (top-down information). This integration occurs in pyramidal cells (PCs) and their long apical dendrite, which branches extensively into a dendritic tuft in layer 1 (L1). The outermost layer of the neocortex, L1 is highly conserved across cortical areas and species. Importantly, L1 is the predominant input layer for top-down information, relayed by a rich, dense mesh of long-range projections that provide signals to the tuft branches of the PCs. Here, we discuss recent progress in our understanding of the composition of L1 and review evidence that L1 processing contributes to functions such as sensory perception, cross-modal integration, controlling states of consciousness, attention, and learning.
Using key concepts from the Marmot review to frame covid-19 response
Authors: D Graham Mackenzie
Journal: BMJ (2021)

have helpfully updated the Marmot review, 2 highlighting "intervention generated inequalities" (IGIs) as unintentional consequences of health inequalities work in parts of the UK since the 1970s.Their discussion of commercial influences seems overly complicated, however.I would argue that the concentration of tobacco retailers, fast food outlets, bookies, pubs, and off licences in more deprived areas is simply an example of IGIs delivered intentionally by the commercial sector.The concept of IGIs extends the idea of "lifestyle drift" in the original Marmot review.Understanding other key terms from the Marmot review and its updates will be essential in responding to the covid-19 pandemic and recovery.
Advise non-pharmacological therapy as first line treatment for chronic insomnia
Authors: Christine Soong, Lisa Burry, Maria Greco, Cara Tannenbaum
Journal: BMJ (2021)

### What you need to know Guidelines recommend non-pharmacological approaches, including cognitive behavioural therapy, as first line treatment for chronic insomnia in adults (box 1).12345 Yet, sedatives are commonly prescribed to treat insomnia. Over a quarter of a million people in the UK receive sedatives for more than a year based on estimates from a primary care survey in 2017.6 A drug survey in the UK reported 2.4 million adults had received, and had dispensed, one or more prescriptions for sedatives written in 2017-18.7 In a study of 386 457 US outpatient visits, prescription rates for benzodiazepines doubled from 3.8% (95% confidence interval 3.2% to 4.4%) in 2003 to 7.4% (6.4% to 8.6%) in 2015, including co-prescribing with other sedating medications.8 Sedatives include medications licensed for insomnia—for example, benzodiazepine receptor agonists (such as estazolam, temazepam, eszopiclone, zaleplon, zolpidem), dual orexin receptor antagonists (such as lemborexant, suvorexant), and melatonin receptor agonists (such as ramelteon)—as well as those used off-label (such as quetiapine, trazodone, diphenhydramine). Sedatives are associated with serious harm, including cognitive deficits, falls, confusion, hip fracture,91011 dependency,1213 and mortality.814 Overdose deaths involving benazodiazepines increased in the US from 1135 in 1999 to 8791 in 2015.14 Box 1 ### Guidelines promoting a non-pharmacological approach to insomniaRETURN TO TEXT
Genetic and Epigenetic Interplay Within a <i>COLGALT2</i> Enhancer Associated With Osteoarthritis
Authors: Yulia S. Kehayova, Emily Watson, J. Mark Wilkinson, John Loughlin, Sarah J. Rice
Journal: Arthritis & Rheumatology (2021)

The osteoarthritis (OA)-associated single-nucleotide polymorphism (SNP) rs11583641 is located in COLGALT2, encoding a posttranslational modifier of collagen. In cartilage, the SNP genotype correlates with DNA methylation in a putative enhancer. This study was undertaken to characterize the mechanistic relationship between rs11583641, the putative enhancer, and COLGALT2 expression using cartilage samples from human patients and a chondrocyte cell model.Nucleic acids were extracted from articular cartilage samples obtained from patients with OA (n = 137). Samples were genotyped, and DNA methylation was quantified at 12 CpGs using pyrosequencing. The putative enhancer was deleted in Tc28a2 chondrocytes using clustered regularly interspaced short palindromic repeat/Cas9, and the impact on nearby gene expression was determined using real-time quantitative polymerase chain reaction. Targeted modulation of the epigenome using catalytically dead Cas9 (dCas9) constructs fused to DNA methyltransferase 3a or ten-eleven translocase 1 allowed for the investigation of a causal relationship between DNA methylation and enhancer activity.The genotype at rs11583641 correlated with DNA methylation at 3 CpGs, and the presence of the OA risk allele, C, corresponded to reduced levels of methylation. Deletion of the enhancer resulted in a 2.7-fold reduction in COLGALT2 expression. Targeted methylation and demethylation of the CpGs had antagonistic effects on COLGALT2 expression. An allelic imbalance in the expression of COLGALT2 was identified in the cartilage from patients with OA, with relative overexpression of the OA risk allele. Allelic expression ratios correlated with DNA methylation at 4 CpGs.COLGALT2 is a target of OA genetic risk at this locus. The genotype at rs11583641 impacts DNA methylation in a gene enhancer, which, in turn, modulates COLGALT2 expression. COLGALT2 encodes an enzyme that initiates posttranslational glycosylation of collagens and is therefore a compelling OA susceptibility target.
Fatal anaphylaxis: making sure all cases are counted
Authors: Vibha Sharma, Tomaz Garcez, Adam T Fox
Journal: BMJ (2021)

Baseggio Conrado and colleagues note that, although hospital admissions for food induced anaphylaxis increased between 1998 and 2018, the case fatality rate for confirmed food anaphylaxis decreased over this 20 year period, from 0.7% to 0.19%.1

Improved survival might result from better management, but misclassification of deaths should also be considered, especially as fatalities are rare. Having evaluated deaths for the United Kingdom Fatal Anaphylaxis Registry (UKFAR), we raise the …
Corrigendum to “MERTK in cancer therapy: Targeting the receptor tyrosine kinase in tumor cells and the immune system” [Pharmacology &amp; Therapeutics 213 (2020) 107577]
Authors: Justus M. Huelse, Diana M. Fridlyand, Shelton Earp, Deborah DeRyckere, Douglas K. Graham
Journal: Pharmacology & Therapeutics (2021)
Referral criteria to palliative care for patients with respiratory disease: a systematic review
Authors: Jennifer Philip, Anna Collins, Natasha Smallwood, Yuchieh Kathryn Chang, Li Mo, Ian A. Yang, Tamera Corte, Christine F. McDonald, David Hui
Journal: European Respiratory Journal (2021)

Aims Advanced nonmalignant respiratory diseases are associated with significant patient morbidity, yet access to palliative care occurs late, if at all. Our aim was to examine referral criteria for palliative care among patients with advanced nonmalignant respiratory disease, with a view to developing a standardised set of referral criteria. Methods We performed a systematic review of all studies reporting on referral criteria to palliative care in advanced nonmalignant respiratory disease, with a focus on chronic obstructive pulmonary disease and interstitial lung disease. The systematic review was conducted and reported according to the PRISMA guidelines, and was undertaken using electronic databases (Ovid, MEDLINE, Ovid Embase and PubMed). Results Searches yielded 2052 unique titles, which were screened for eligibility and resulted in 62 studies addressing referral criteria to palliative care in advanced nonmalignant respiratory disease. Of 18 categories put forward for referral to palliative care, the most commonly discussed factors were hospital use (69% of papers), indicators of poor respiratory status (47%), physical and emotional symptoms (37%), functional decline (29%), need for advanced respiratory therapies (27%), and disease progression (26%). Conclusion Clinicians consider referral to specialist palliative care for a wide range of disease- and needs-based criteria. Our findings highlight the need to standardise palliative care access by developing consensus referral criteria for patients with advanced nonmalignant respiratory illnesses.
Horizontal Gene Transfer and Gene Duplication of β-Fructofuranosidase Confer Lepidopteran Insects Metabolic Benefits
Authors: Xiangping Dai, Takashi Kiuchi, Yanyan Zhou, Shunze Jia, Yusong Xu, Susumu Katsuma, Toru Shimada, Huabing Wang
Journal: Molecular Biology and Evolution (2021)

Abstract Horizontal gene transfer (HGT) is a potentially critical source of material for ecological adaptation and the evolution of novel genetic traits. However, reports on posttransfer duplication in organism genomes are lacking, and the evolutionary advantages conferred on the recipient are generally poorly understood. Sucrase plays an important role in insect physiological growth and development. Here, we performed a comprehensive analysis of the evolution of insect β-fructofuranosidase transferred from bacteria via HGT. We found that posttransfer duplications of β-fructofuranosidase were widespread in Lepidoptera and sporadic occurrences of β-fructofuranosidase were found in Coleoptera and Hymenoptera. β-fructofuranosidase genes often undergo modifications, such as gene duplication, differential gene loss, and changes in mutation rates. Lepidopteran β-fructofuranosidase gene (SUC) clusters showed marked divergence in gene expression patterns and enzymatic properties in Bombyx mori (moth) and Papilio xuthus (butterfly). We generated SUC1 mutations in B. mori using CRISPR/Cas9 to thoroughly examine the physiological function of SUC. BmSUC1 mutant larvae were viable but displayed delayed growth and reduced sucrase activities that included susceptibility to the sugar mimic alkaloid found in high concentrations in mulberry. BmSUC1 served as a critical sucrase and supported metabolic homeostasis in the larval midgut and silk gland, suggesting that gene transfer of β-fructofuranosidase enhanced the digestive and metabolic adaptation of lepidopteran insects. These findings highlight not only the universal function of β-fructofuranosidase with a link to the maintenance of carbohydrate metabolism but also an underexplored function in the silk gland. This study expands our knowledge of posttransfer duplication and subsequent functional diversification in the adaptive evolution and lineage-specific adaptation of organisms.
Association Between Contact Precautions and Transmission of Methicillin-Resistant <i>Staphylococcus aureus</i> in Veterans Affairs Hospitals
Authors: Karim Khader, Alun Thomas, Vanessa Stevens, Lindsay Visnovsky, McKenna Nevers, Damon Toth, Lindsay T. Keegan, Makoto Jones, Michael Rubin, Matthew H. Samore
Journal: JAMA Network Open (2021)

<h3>Importance</h3> The effectiveness and importance of contact precautions for endemic pathogens has long been debated, and their use has broad implications for infection control of other pathogens. <h3>Objective</h3> To estimate the association between contact precautions and transmission of methicillin-resistant<i>Staphylococcus aureus</i>(MRSA) across US Department of Veterans Affairs (VA) hospitals. <h3>Design, Setting, and Participants</h3> This retrospective cohort study used mathematical models applied to data from a population-based sample of adults hospitalized in 108 VA acute care hospitals for at least 24 hours from January 1, 2008, to December 31, 2017. Data were analyzed from May 2, 2019, to December 11, 2020. <h3>Exposures</h3> A positive MRSA test result, presumed to indicate contact precautions use according to the VA MRSA Prevention Initiative. <h3>Main Outcomes and Measures</h3> The main outcome was the association between contact precautions and MRSA transmission, defined as the relative transmissibility attributed to contact precautions. A contact precaution effect estimate (&lt;1 indicates a reduction in transmission associated with contact precautions) was estimated for each hospital and then pooled over time and across hospitals using meta-regression. <h3>Results</h3> In this cohort study of 108 VA hospitals, more than 2 million unique individuals had over 5.6 million admissions, of which 14.1% were presumed to have contact precautions with more than 8.4 million MRSA surveillance tests. Pooled estimates found associations between contact precautions and transmission to be stable from 2008 to 2017, with estimated transmission reductions ranging from 43% (95% credible interval [CrI], 38%-48%) to 51% (95% CrI, 46%-55%). Over the entire 10-year study period, contact precautions reduced transmission 47% (95% CrI, 45%-49%), and the intrafacility autocorrelation coefficient estimate was 0.99, suggesting consistent estimates over time within facilities. Larger facilities and those with higher admission screening compliance observed additional reductions in transmission associated with contact precautions (relative rate, 0.84; 95% CI, 0.74-0.96 and 0.74; 95% CI, 0.58-0.96, respectively) compared with smaller facilities and those with lower admission screening compliance. Facilities in the southern US had a smaller transmission reduction attributable to contact precautions (relative rate, 1.14; 95% CI, 1.01-1.28) compared with facilities in other regions in the US. <h3>Conclusions and Relevance</h3> In this cohort study of adults in VA hospitals, transmissibility of MRSA was found to be reduced by approximately 50% among patients with contact precautions. These results provide an explanation for decreasing acquisition rates in VA hospitals since the MRSA Prevention Initiative.
Requirement of Gαi1 and Gαi3 in interleukin-4-induced signaling, macrophage M2 polarization and allergic asthma response
Authors: Jin-yu Bai, Ya Li, Guan-hua Xue, Ke-ran Li, Yu-Fan Zheng, Zhi-qing Zhang, Qin Jiang, Yuan-yuan Liu, Xiao-zhong Zhou, Cong Cao
Journal: Theranostics (2021)

IL-4 induces Akt activation in macrophages, required for full M2 (alternative) polarization. We examined the roles of Gαi1 and Gαi3 in M2 polarization using multiple genetic methods. Methods and Results: In MEFs and primary murine BMDMs, Gαi1/3 shRNA, knockout or dominant negative mutations attenuated IL-4-induced IL4Rα endocytosis, Gab1 recruitment as well as Akt activation, leaving STAT6 signaling unaffected. Following IL-4 stimulation, Gαi1/3 proteins associated with the intracellular domain of IL-4Rα and the APPL1 adaptor, to mediate IL-4Rα endosomal traffic and Gab1-Akt activation in BMDMs. In contrast, gene silencing of Gαi1/3 with shRNA or knockout resulted in BMDMs that were refractory to IL-4-induced M2 polarization. Conversely, Gαi1/3-overexpressed BMDMs displayed preferred M2 response with IL-4 stimulation. In primary human macrophages IL-4-induced Akt activation and Th2 genes expression were inhibited with Gαi1/3 silencing, but augmented with Gαi1/3 overexpression. In Gαi1/3 double knockout (DKO) mice, M2 polarization, by injection of IL-4 complex or chitin, was potently inhibited. Moreover, in a murine model of asthma, ovalbumin-induced airway inflammation and hyperresponsiveness were largely impaired in Gαi1/3 DKO mice. Conclusion: These findings highlight novel and essential roles for Gαi1/3 in regulating IL-4-induced signaling, macrophage M2 polarization and allergic asthma response.
Update in Critical Care 2020
Authors: Robinder G. Khemani, Jessica T. Lee, David Wu, Edward J. Schenck, Margaret M. Hayes, Patricia A. Kritek, Gökhan M. Mutlu, Hayley B. Gershengorn, Rémi Coudroy
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Update in Critical Care 2020." American Journal of Respiratory and Critical Care Medicine, 203(9), pp. 1088–1098
Polymer Conjugation of Docosahexaenoic Acid Potentiates Cardioprotective Therapy in Preclinical Models of Myocardial Ischemia/Reperfusion Injury
Authors: Sandra Tejedor, Irene Dolz‐Pérez, Caitlin G. Decker, Amparo Hernándiz, Jose L. Diez, Raquel Álvarez, Delia Castellano, Nahuel A. García, Imelda Ontoria‐Oviedo, Vicent J. Nebot, Hernán González‐King, Begoña Igual, Pilar Sepúlveda, María J. Vicent
Journal: Advanced Healthcare Materials (2021)

Abstract While coronary angioplasty represents an effective treatment option following acute myocardial infarction, the reperfusion of the occluded coronary artery can prompt ischemia–reperfusion (I/R) injury that significantly impacts patient outcomes. As ω ‐3 polyunsaturated fatty acids (PUFAs) have proven, yet limited cardioprotective abilities, an optimized polymer‐conjugation approach is reported that improves PUFAs bioavailability to enhance cardioprotection and recovery in animal models of I/R‐induced injury. Poly‐ l ‐glutamic acid (PGA) conjugation improves the solubility and stability of di‐docosahexaenoic acid (diDHA) under physiological conditions and protects rat neonatal ventricular myocytes from I/R injury by reducing apoptosis, attenuating autophagy, inhibiting reactive oxygen species generation, and restoring mitochondrial membrane potential. Enhanced protective abilities are associated with optimized diDHA loading and evidence is provided for the inherent cardioprotective potential of PGA itself. Pretreatment with PGA–diDHA before reperfusion in a small animal I/R model provides for cardioprotection and limits area at risk (AAR). Furthermore, the preliminary findings suggest that PGA–diDHA administration in a swine I/R model may provide cardioprotection, limit edema and decrease AAR. Overall, the evaluation of PGA–diDHA in relevant preclinical models provides evidence for the potential of polymer‐conjugated PUFAs in the mitigation of I/R injury associated with coronary angioplasty.