tbuckley/cabot-search huggingface dataset:
Endothelial SIRT6 Is Vital to Prevent Hypertension and Associated Cardiorenal Injury Through Targeting Nkx3.2-GATA5 Signaling
Authors: Jian Guo, Ziying Wang, Jichao Wu, Min Liu, Mengmeng Li, Yu Sun, Wei Huang, Yujia Li, Yan Zhang, Wei Tang, Xiaoyan Li, Chun Zhang, Fanzhen Hong, Ningjun Li, Jing Nie, Fan Yi
Journal: Circulation Research (2019)

Endothelial dysfunction is an important determinant risk factor for the development of hypertension and its complications. Thus, identification of potential therapeutic targets for preventing endothelial dysfunction has major clinical importance. Emerging evidence indicates that epigenetic modifications are closely associated with the regulation of endothelial function. Among them, HDAC (histone deacetylase)-mediated epigenetic processes in vascular homeostasis and cardiovascular disease have attracted much attention. SIRT6 (sirtuin 6) is one member of SIRTs (class III HDAC) that are highly conserved NAD+-dependent deacetylases.This study was designed to elucidate the role of SIRT6 in the pathogenesis of hypertension, discover the new targets of SIRT6, and explore related mechanisms on the regulation of endothelial function.The levels of endothelial SIRT6 were significantly reduced in 2 independent hypertension models: desoxycorticosterone acetate/salt-induced and Ang II (angiotensin II)-induced hypertensive mice. Utilizing genetically engineered endothelial-specific SIRT6 knockout (Cre+/SIRT6fl/fl) mice, we found that endothelial-specific deletion of SIRT6 significantly enhanced blood pressure, exacerbated endothelial dysfunction and cardiorenal injury in experimental hypertension. Functionally, SIRT6 has pleiotropic protective actions in endothelial cells, which include promoting endothelium-dependent vasodilatation and vascular NO bioavailability, reducing cellular permeability, ameliorating endothelial senescence and apoptosis, and facilitating autophagy. Mechanistically, SIRT6 induced the expression of GATA5 (GATA-binding protein 5), a novel regulator of blood pressure, through inhibiting Nkx3.2 (NK3 homeobox 2) transcription by deacetylating histone H3K9 (histone H3 lysine 9), thereby regulating GATA5-mediated signaling pathways to prevent endothelial injury. Finally, we provide direct evidence for the therapeutic potential of SIRT6 in desoxycorticosterone acetate/salt-induced hypertensive mice by overexpression of SIRT6 in vivo.This study for the first time demonstrates that SIRT6 prevents hypertension and its complications by maintaining endothelial function. Pharmacological targeting of SIRT6 may be an innovative therapeutic strategy for treating patients with hypertension.
Hypoallergenicity of a whey‐based, extensively hydrolyzed infant formula prepared with nonporcine enzymes
Authors: Anna Nowak‐Węgrzyn, Laura Czerkies, Martinas Kuslys, Sophie Nutten, Peter J. Simons, Barbara Collins, Ralf G. Heine
Journal: Allergy (2019)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Deciphering the chronology of copy number alterations in Multiple Myeloma
Authors: Anil Aktas Samur, Stephane Minvielle, Masood Shammas, Mariateresa Fulciniti, Florence Magrangeas, Paul G. Richardson, Philippe Moreau, Michel Attal, Kenneth C. Anderson, Giovanni Parmigiani, Hervé Avet-Loiseau, Nikhil C. Munshi, Mehmet Kemal Samur
Journal: Blood Cancer Journal (2019)

Abstract Multiple myeloma (MM) and its precursor condition MGUS are characterized by chromosomal aberrations. Here, we comprehensively characterize the order of occurrence of these complex genomic events underlying MM development using 500 MGUS, and MM samples. We identify hyperdiploid MM (HMM) and non-HMM as genomically distinct entities with different evolution of the copy number alterations. In HMM, gains of 9,15 or 19 are the first and clonal events observed as clonal even at MGUS stage. These events are thus early and may underlie initial transformation of normal plasma cells to MGUS cells. However, CNAs may not be adequate for progression to MM except in 15% of the patients in whom the complex subclonal deletion events are observed in MM but not MGUS. In NHMM, besides the driver translocations, clonal deletion of 13 and 1q gain are early events also observed in MGUS. We combined this information to propose a timeline for copy number alteration.
Withdrawal Aversion and the Equivalence Test
Authors: Dominic Wilkinson, Ella Butcherine, Julian Savulescu
Journal: The American Journal of Bioethics (2019)

If a doctor is trying to decide whether or not to provide a medical treatment, does it matter ethically whether that treatment has already been started? Health professionals sometimes find it harder to stop a treatment (withdraw) than to refrain from starting the treatment (withhold). But does that feeling correspond to an ethical difference? In this article, we defend equivalence-the view that withholding and withdrawal of treatment are ethically equivalent when all other factors are equal. We argue that preference for withholding over withdrawal could represent a form of cognitive bias-withdrawal aversion. Nevertheless, we consider whether there could be circumstances in which there is a moral difference. We identify four examples of conditional nonequivalence. Finally, we reflect on the moral significance of diverging intuitions and the implications for policy. We propose a set of practical strategies for helping to reduce bias in end-of-life decision making, including the equivalence test.
Abstract 3566: Confirmed Influence Of The <i>LPIN1</i> Gene On Traits Of The Metabolic Syndrome In Human
Authors: Silke Wiedmann, Marcus Fischer, Martina Koehler, Katharina Neureuther, Angela Doering, Günter Riegger, Christian Hengstenberg, Andrea Baessler
Journal: Circulation (2007)

Lipin, a molecular protein expressed by adipocytes, has marked effects on adipose tissue mass, insulin sensitivity, and glucose homeostasis. Genetic variants within the lipin gene, LPIN1 , may be associated with traits of the metabolic syndrome (MetS) as we have shown previously in a sample of the general population. Methods: 15 SNPs densely covering the LPIN1 gene region were genotyped in an age- and sex- stratified sample of the general population (MONICA study Augsburg, DNA and phenotypes of 1,416 Caucasians). Ten of these SNPs were also genotyped for replication in an independent sample of 1,030 subjects recruited throughout Germany. The MetS was defined via the sum of its core components and additionally by a factor score derived from factor analysis. Permutation based methods were used to test the association between genetic LPIN1 variants and metabolic traits for empirical significance. Results: Linkage disequilibrium (LD) analysis revealed three LD blocks encompassing LPIN1 . We identified three associated three-marker haplotypes: one common haplotype (26.8% frequency) increases the risk for the MetS (OR=1.6, 95% CI[1.2–2.2]), while the other two being less common (5.7% and 4.0%) are strongly associated with lower blood pressure (p&lt;0.0001), a lower BMI and waist circumference (p&lt;0.0001), lower HbA1c (p&lt;0.01) as well as a lower MetS factor score (p&lt;0.0001). Furthermore, the frequencies of arterial hypertension (p&lt;0.0001), obesity (p&lt;0.0001), diabetes (p&lt;0.05), and the presence of ≥3 MetS components (p&lt;0.0006) were significantly lower than in subjects not carrying one of these protective haplotypes. These findings could be largely confirmed in the replication sample. Specifically, the same haplotypes were significantly associated with fasting triglyceride levels (p=0.00008), HDL cholesterol levels (p=0.00012), diabetes (p=0.00007), and the MetS factor score (p=0.002). Conclusion: These data confirm that allelic variants of the LPIN1 gene have significant effects in human metabolic traits and highlight the importance of lipin in the pathophysiology of the MetS. Permutation-based low p-values and the consistent findings in several populations across multiple phenotypes of the MetS reflect the robustness of these results.
CLO19-029: Dosing Patterns of Nilotinib Use in SIMPLICITY, an Observational Study in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients (Pts) in Routine Clinical Practice
Authors: Jorge Cortes, Clara Chen, Michael Mauro, Neela Kumar, Catherine Davis, Stuart L. Goldberg
Journal: Journal of the National Comprehensive Cancer Network (2019)

Introduction: Dosing patterns of nilotinib (NIL) in chronic phase chronic myelogenous leukemia (CP-CML) patients (Pts) have not been well documented outside of clinical trials. SIMPLICITY (NCT01244750) is an ongoing observational study exploring tyrosine kinase inhibitor (TKI) use in routine clinical practice among CP-CML pts receiving TKIs in the US and Europe since 2010. This analysis reports NIL dosing patterns and explores predictors of dose reductions. A subset analysis focusing on the first-line (1L) approved dose of 300 mg twice daily (BID) will also be presented. Methods: Only SIMPLICITY pts receiving 1L NIL BID (n=349/408) were included. Baseline demographics and dosing patterns (starting dose, dose changes, time to dose reduction, and duration of therapy [DoT]) were analyzed descriptively. Statistical comparisons were made using t-tests, the Mann-Whitney U test for continuous variables, and chi-square for categorical variables. Logistic regression models were used to identify factors associated with dose reductions. Results: Of the 349 pts treated with 1L NIL, 281 (80.5%) started at the standard dose of 300 mg (BID) or the 400 mg (BID) dose for imatinib-resistance/intolerance, and 37 (10.6%) and 31 pts (8.9%) started on 150‒200 mg BID and 450‒800 mg BID. European pts were more likely to start on a dose &gt;400 mg BID than US pts (P&lt;.0001). Pts at academic centers were more likely to start on &gt;400 mg BID than those treated at community practices (P&lt;.0029). Among the pts starting NIL at 300 or 400 mg (BID) in 1L, 70.9% remained on these doses; 26.6% received a dose reduction (median time to dose reduction: 80.5 days); and 2.5% received a dose increase. Median DoT with NIL was 30.4 vs 43.9 months for pts with vs without a dose reduction (P=NS). The main reason for dose reduction was intolerance (n=51; 68.9%); in 51% of pts, a specific side effect was cited. Dose reductions were more likely in patients at academic centers (odds ratio=1.996; P =.021), but not in pts experiencing baseline fatigue (OR=1.799; P =0.072). Conclusions: Most pts treated with 1L NIL were started on 300 or 400 mg (BID); however, 1 in 4 pts required a dose reduction, most often due to intolerance. Physicians at academic centers were more likely to reduce the NIL dose than those in community practices. DoT with NIL for pts who received a dose reduction was shorter than that for those who did not. These findings will aid clinical decisions on dose optimization and maintaining response, whilst improving the patient quality of life.
Tuberculosis — United States, 2018
Authors: Amish Talwar, Clarisse A. Tsang, Sandy F. Price, Robert H. Pratt, William L. Walker, Kristine M. Schmit, Adam J. Langer
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

World TB Day is observed each year on March 24.This observance provides an opportunity to raise awareness about tuberculosis (TB) and the measures needed to find, treat, and prevent this devastating disease.In 2018, a provisional total of 9,029 TB cases were reported in the United States (incidence = 2.8 cases per 100,000 persons) (1), a decline from the 9,094 cases reported in 2017 and the lowest number of cases on record in the United States since reporting began in 1953.Increased diagnosis and treatment of latent TB infection remains essential to eliminating TB in the United States.Worldwide, an estimated 10 million cases of TB were reported in 2017, a decline of 1.8% from 2016.Approximately 1.57 million persons died from TB in 2017, a 3.9% decrease from 2016 (2).The implementation of effective strategies, including expansion of TB preventive treatment, defined in the global setting as treatment for those who might be infected with TB and are at risk for progressing to TB disease, including persons living with human immunodeficiency virus infection, is necessary to reach global targets.CDC is working with domestic and global partners to diagnose and treat TB in the United States and around the world.Additional information about World TB Day and CDC's TB activities is available at https://www.cdc.gov/tb/worldtbday.
Influenza surveillance: determining the epidemic threshold for influenza by using the Moving Epidemic Method (MEM), Montenegro, 2010/11 to 2017/18 influenza seasons
Authors: Bozidarka Rakocevic, Anita Grgurevic, Goran Trajkovic, Boban Mugosa, Sandra Sipetic Grujicic, Sanja Medenica, Olivera Bojovic, José Eugenio Lozano Alonso, Tomas Vega
Journal: Eurosurveillance (2019)

In 2009, an improved influenza surveillance system was implemented and weekly reporting to the World Health Organization on influenza-like illness (ILI) began. The goals of the surveillance system are to monitor and analyse the intensity of influenza activity, to provide timely information about circulating strains and to help in establishing preventive and control measures. In addition, the system is useful for comparative analysis of influenza data from Montenegro with other countries.We aimed to evaluate the performance and usefulness of the Moving Epidemic Method (MEM), for use in the influenza surveillance system in Montenegro.Historical ILI data from 2010/11 to 2017/18 influenza seasons were modelled with MEM. Epidemic threshold for Montenegro 2017/18 season was calculated using incidence rates from 2010/11-2016/17 influenza seasons.Pre-epidemic ILI threshold per 100,000 population was 19.23, while the post-epidemic threshold was 17.55. Using MEM, we identified an epidemic of 10 weeks' duration. The sensitivity of the MEM epidemic threshold in Montenegro was 89% and the warning signal specificity was 99%.Our study marks the first attempt to determine the pre/post-epidemic threshold values for the epidemic period in Montenegro. The findings will allow a more detailed examination of the influenza-related epidemiological situation, timely detection of epidemic and contribute to the development of more efficient measures for disease prevention and control aimed at reducing the influenza-associated morbidity and mortality.
Negative Co-stimulation Constrains T Cell Differentiation by Imposing Boundaries on Possible Cell States
Authors: Spencer C. Wei, Roshan Sharma, Nana-Ama A.S. Anang, Jacob H. Levine, Yang Zhao, James J. Mancuso, Manu Setty, Padmanee Sharma, Jing Wang, Dana Pe’er, James P. Allison
Journal: Immunity (2019)
Abstract 14666: Relative Impact of Congenital Heart Disease on Morbidity and Mortality in Infancy Around the Globe: The Global Burden of Disease Study
Authors: Meghan Zimmerman, Alison Smith, Craig A Sable, Michelle Echko, Moshen Naghavi, Christopher Hugo-Hamman, Raman Krishna Kumar, Bistra Zheleva, Jackie Boucher, Kathy Jenkins, Theo Vos, Christopher Murray, Liesl Zulke, Gerard Martin, Nicholas Kassebaum
Journal: Circulation (2017)

Background: The absolute and relative contribution of congenital heart disease (CHD) to mortality and morbidity varies by Socio-Demographic Index (SDI) region. Location-specific data is crucial to ...
Evaluation of the Collaborative Use of an Evidence-Based Care Bundle in Emergency Laparotomy
Authors: Geeta Aggarwal, Carol J. Peden, Mohammed A. Mohammed, Anne Pullyblank, Ben Williams, Timothy Stephens, Suzanne Kellett, James Kirkby-Bott, Nial Quiney
Journal: JAMA Surgery (2019)

<h3>Importance</h3> Patients undergoing emergency laparotomy have high mortality, but few studies exist to improve outcomes for these patients. <h3>Objective</h3> To assess whether a collaborative approach to implement a 6-point care bundle is associated with reduction in mortality and length of stay and improvement in the delivery of standards of care across a group of hospitals. <h3>Design, Setting, and Participants</h3> The Emergency Laparotomy Collaborative (ELC) was a UK-based prospective quality improvement study of the implementation of a care bundle provided to patients requiring emergency laparotomy between October 1, 2015, and September 30, 2017. Participants were 28 National Health Service hospitals and emergency surgical patients who were treated at these hospitals and whose data were entered into the National Emergency Laparotomy Audit (NELA) database. Post-ELC implementation outcomes were compared with baseline data from July 1, 2014, to September 30, 2015. Data entry and collection were performed through the NELA. <h3>Interventions</h3> A 6-point, evidence-based care bundle was used. The bundle included prompt measurement of blood lactate levels, early review and treatment for sepsis, transfer to the operating room within defined time goals after the decision to operate, use of goal-directed fluid therapy, postoperative admission to an intensive care unit, and multidisciplinary involvement of senior clinicians in the decision and delivery of perioperative care. Change management and leadership coaching were provided to ELC leadership teams. <h3>Main Outcome and Measures</h3> Primary outcomes were in-hospital mortality, both crude and Portsmouth Physiological and Operative Severity Score for the enumeration of Mortality and morbidity (P-POSSUM) risk-adjusted, and length of stay. Secondary outcomes were the changes after implementation of the separate metrics in the care bundle. <h3>Results</h3> A total of 28 hospitals participated in the ELC and completed the project. The baseline group included 5562 patients (2937 female [52.8%] and a mean [range] age of 65.3 [18.0-114.0] years), whereas the post-ELC group had 9247 patients (4911 female [53.1%] and a mean [range] age of 65.0 [18.0-99.0] years). Unadjusted mortality rate decreased from 9.8% at baseline to 8.3% in year 2 of the project, and so did risk-adjusted mortality from a baseline of 5.3% to 4.5% post-ELC. Mean length of stay decreased from 20.1 days during year 1 to 18.9 days during year 2. Significant changes in 5 of the 6 metrics in the care bundle were achieved. <h3>Conclusions and Relevance</h3> A collaborative approach using a quality improvement methodology and a care bundle appeared to be effective in reducing mortality and length of stay in emergency laparotomy, suggesting that hospitals should adopt such an approach to see better patient outcomes and care delivery performance.
Bayer and Janssen pay $775m to settle Xarelto misinformation claims
Authors: Owen Dyer
Journal: BMJ (2019)

The German drug maker Bayer and the Johnson & Johnson subsidiary Janssen Pharmaceuticals will jointly pay $775m (£587m; €687m) to settle more than 25 000 lawsuits in US federal and state courts, representing almost all of the outstanding claims against the bestselling anticoagulant rivaroxaban (Xarelto).

Janssen holds a licence to sell rivaroxaban in the United States, while Bayer developed the blood thinner and sells it elsewhere.

Neither company admitted liability, and both expressed their continuing confidence in rivaroxaban, which still sells robustly around the world. Bayer’s revenue from the drug last year was $4.07bn, and Janssen’s rivaroxaban sales totalled $2.47bn.

Bayer said that it “continues to believe these claims …
QIM19-139: Reflex Testing of Oncotype DX Recurrence Score: A Single Institution Review of a Quality Improvement Protocol
Authors: Mara A. Piltin, Kathryn Eckert, Margaret Wight, Alan J. Shienbaum, Jeanine Chiffarano, Trina A. Poretta, Tamara A. LaCouture, Monica N. Khattak, Michele E. Gaguski, Alyssa Imperatore, Sruti Golthi, Kahyun Yoon-Flannery
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Implementation of genomic assays has led to treatment of early-stage breast cancers with high risk of recurrence with adjuvant systemic chemotherapy while sparing those with a low risk of recurrence from systemic therapy with minimal benefit. Genomic assays are becoming a more widely used tool, evident by the eighth edition of the American Joint Committee on Cancer (AJCC) Breast Cancer Staging System, which includes recurrence score as part of the treatment algorithm in certain subgroups of tumors. Our institution identified the time to assay result as a quality improvement opportunity. We instituted a protocol to have a reflex testing of Oncotype DX based on certain criteria to decrease time to assay results and ultimately time to treatment. Methods: Our Multidisciplinary Breast Leadership Committee instituted a policy for reflex Oncotype DX testing on patients under the age of 70 with estrogen receptor positive, HER2-neu protein–negative, and node-negative invasive breast cancers measuring between 0.5 cm to 5 cm in January 2018. We compared our data available from pre- and postimplementation using the single factor analysis of variance (ANOVA) as well as an independent t-test and a post-hoc Tukey-Kramer test. Results: We have observed 45 cases that met the criteria for reflex Oncotype Dx testing since the initiation of this quality improvement protocol. The recurrence scores ranged from 0 to 55. There was a statistically significant difference in the number of days from operation to result day from 2016 to 2018 (55 days vs 18 days; P &lt;.001). The number of days from the test order date to result date also saw a significant improvement from 2016 to 2018 (12 vs 9 days; P &lt;.05). Conclusions: Breast cancer treatment options continue to evolve, particularly with the use of genomic assays. Our single institution review confirms the utility of our reflex Oncotype DX protocol with a decreased time to result with reflex testing of patients in the appropriate clinical setting. Further development of similar pathways may be necessary to streamline our patients’ care in the treatment of breast cancer.
Primary care will not meet demand unless practices take on more clinical support staff, say experts
Authors: Abi Rimmer
Journal: BMJ (2019)

The NHS cannot recruit as many GPs as it needs, so practices should employ other staff to help with their workload, says a report by three leading healthcare think tanks.1

The report said that, despite national efforts to increase GP numbers, “the stark reality is that even with a major focus on increasing the number of GPs in training, we project the numbers of GPs in the NHS will fall substantially short of demand and of the government’s target of an additional 5000 GPs.”

The only way to meet demand would be to expand the multidisciplinary team and draw on the skills …
Excellent Response to Lower Dose of 177Lu-PSMA-617 in a Metastatic Castration–Resistant Prostate Cancer Patient With a Transplanted Kidney
Authors: Ghazal Norouzi, Ramin Akbarian Aghdam, Hamidreza Hashemifard, Elahe Pirayesh
Journal: Clinical Nuclear Medicine (2019)

A 68-year-old man with metastatic castration-resistant prostate cancer and widespread bone metastases as well as a history of kidney transplant, underwent 5 cycles of Lu-prostate-specific membrane antigen 617 therapies in our department. Being more cautious of the radiation burden imposed on the transplanted kidney, a lower average dose of 4 GBq per cycle was administered (instead of the more routine 6.0-7.4 GBq per cycle). However, excellent response was noted and serum creatinine level of 0.8 mg/dL remained stable.
Is elimination of vertical transmission of HIV in high prevalence settings achievable?
Authors: Ameena Goga, Yagespari Singh, Debra Jackson, Yogan Pillay, Sanjana Bhardwaj, Witness Chirinda, Chika Hayashi, Shaffiq Essajee, Priscilla Idele
Journal: BMJ (2019)

Ameena Goga and colleagues argue that more realistic targets are needed to maintain momentum on reducing vertical transmission in countries with a high HIV prevalence