tbuckley/cabot-search huggingface dataset:
How does moral objectification lead to correlated interactions?
Authors: Geoffrey P. Goodwin
Journal: Behavioral and Brain Sciences (2018)

Abstract The objectification of moral norms is purported to occur because it enables correlated interactions between individuals who share the same cooperative norms. But how does this process take place? I suggest two mechanisms beyond those Stanford identifies. I also ask whether there is predictable variation in which moral norms engender the strongest coupling between objectification and discomfort with disagreement.
<i>Notes from the Field</i>: Outbreak of <i>Vibrio cholerae</i> Associated with Attending a Funeral — Chegutu District, Zimbabwe, 2018
Authors: Jarred B. McAteer, Sydney Danda, Tonderai Nhende, Paul Manamike, Tonderai Parayiwa, Andrew Tarupihwa, Ottias Tapfumanei, Portia Manangazira, Gibson Mhlanga, Daniela B. Garone, Andrea Martinsen, Rachael D. Aubert, William Davis, Rupa Narra, Shirish Balachandra, Beth A. Tippett Barr, Eric Mintz
Journal: MMWR Morbidity and Mortality Weekly Report (2018)
Learning from a Trial Stopped by a Data and Safety Monitoring Board
Authors: David Harrington, Jeffrey M. Drazen
Journal: New England Journal of Medicine (2018)

One of the reasons we conduct clinical trials to test specific aspects of patient care is to be sure that the interventions we do benefit patients. As clinicians, we are well aware that the outcomes of a treatment may vary substantially from one participant to another; a treatment that works spectacularly well in one person is ineffective in another. If a trial is too small, an average treatment effect favoring an intervention may be consistent with the play of chance. Trials with larger numbers of participants measure average treatment effects more precisely and are more likely to detect real intervention . . .
Moral externalisation fails to scale
Authors: Carl Joseph Brusse, Kim Sterelny
Journal: Behavioral and Brain Sciences (2018)

Abstract We argue that Stanford's picture of the evolution of externalised norms is plausible mostly because of the idealisations implicit in his defence of it. Once we take into account plausible amounts of normative disagreement, plausible amounts of error and misunderstanding, and the knock-on consequences of shunning, it is plausible that Stanford under-counts the costs of externalisation.
New NCCN Guidelines: Recognition and Management of Immunotherapy-Related Toxicity
Authors: John A. Thompson
Journal: Journal of the National Comprehensive Cancer Network (2018)

<section class="abstract"><p id="P1">Immune checkpoint inhibitors (ICIs) are now FDA-approved for the treatment of 8 different cancers, and more approvals are likely, including use of these drugs in combinations. Although ICIs represent a true advance in cancer care, they can cause a range of immune-related adverse events. As more experience with ICIs is gained, more information is becoming available on immunotoxicity and optimal management. Physicians and patients need to be educated about potential adverse events and management of ICI-associated toxicity. In recognition of the need for better information, NCCN in collaboration with ASCO has developed the first set of NCCN Guidelines for Management of Immunotherapy-Related Toxicities. </section>
Demographic History and Genetic Adaptation in the Himalayan Region Inferred from Genome-Wide SNP Genotypes of 49 Populations
Authors: Elena Arciero, Thirsa Kraaijenbrink, None Asan, Marc Haber, Massimo Mezzavilla, Qasim Ayub, Wei Wang, Zhaxi Pingcuo, Huanming Yang, Jian Wang, Mark A Jobling, George van Driem, Yali Xue, Peter de Knijff, Chris Tyler-Smith
Journal: Molecular Biology and Evolution (2018)

We genotyped 738 individuals belonging to 49 populations from Nepal, Bhutan, North India, or Tibet at over 500,000 SNPs, and analyzed the genotypes in the context of available worldwide population data in order to investigate the demographic history of the region and the genetic adaptations to the harsh environment. The Himalayan populations resembled other South and East Asians, but in addition displayed their own specific ancestral component and showed strong population structure and genetic drift. We also found evidence for multiple admixture events involving Himalayan populations and South/East Asians between 200 and 2,000 years ago. In comparisons with available ancient genomes, the Himalayans, like other East and South Asian populations, showed similar genetic affinity to Eurasian hunter-gatherers (a 24,000-year-old Upper Palaeolithic Siberian), and the related Bronze Age Yamnaya. The high-altitude Himalayan populations all shared a specific ancestral component, suggesting that genetic adaptation to life at high altitude originated only once in this region and subsequently spread. Combining four approaches to identifying specific positively selected loci, we confirmed that the strongest signals of high-altitude adaptation were located near the Endothelial PAS domain-containing protein 1 and Egl-9 Family Hypoxia Inducible Factor 1 loci, and discovered eight additional robust signals of high-altitude adaptation, five of which have strong biological functional links to such adaptation. In conclusion, the demographic history of Himalayan populations is complex, with strong local differentiation, reflecting both genetic and cultural factors; these populations also display evidence of multiple genetic adaptations to high-altitude environments.
Abstract A28: Understanding the role of the tumor suppressor p53 in pancreatic cancer development
Authors: Brittany M. Flowers, Patty B. Garcia, Barbara M. Grüner, Monte M. Winslow, Laura D. Attardi
Journal: Cancer Research (2018)

Abstract In the next decade, pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer-related death. This high rate of mortality is attributed to late-stage diagnosis and lack of effective therapeutic strategies. The tumor-suppressor gene TP53 is mutated in ~75% of PDAC patients. The most frequently observed TP53 mutations in PDAC occur within the DNA binding domain at codons 175 and 273. TP53 mutations may induce loss of wild-type p53 function and gain of novel, oncogenic functions. We aim to use different mouse models of PDAC to identify the molecular pathways deregulated when wild-type p53 is lost and mutant p53 is expressed, to elucidate the molecular mechanisms driving PDAC development. While previous studies have suggested that point mutant p53 drives gain-of-function phenotypes, our studies of aging Pdx1-Cre;KrasLSL-G12D/+;Rosa26LSL-tdTomato/LSL-tdTomato mice with conditional p53 knockout (p53Flox/Flox or p53Flox/Null) or p53 mutation (p53LSL-R172H/Flox or p53LSL-R172H/Null) did not demonstrate a clear mutant p53 gain-of-function phenotype in tumor latency. We hypothesize that tumor latency is too rapid in these models to manifest a clear gain-of-function phenotype, requiring the establishment of different model systems. Indeed, our preliminary studies using tumor-derived p53R172H cell lines and isogenic p53 null cell lines suggest a role for mutant p53 gain of function in later-stage tumorigenesis, specifically in metastatic seeding. Furthermore, we are evaluating the role of the putative PDAC cells of origin, pancreatic acinar and ductal cells, in PDAC development. Using both tumor-derived mouse cell lines and pancreatic lineage-specific genetically engineered mouse models of PDAC, we can evaluate the consequences of loss of wild-type p53 expression and gain of mutant p53 expression in different pancreatic compartments. Ultimately, using these systems we aim to elucidate the target genes and molecular pathways controlled by wild-type p53 or by mutant p53 to regulate PDAC initiation. Understanding the molecular mechanisms driving PDAC initiation is critical for the development of new therapeutic strategies for early detection and effective intervention in PDAC patients. Citation Format: Brittany M. Flowers, Patty B. Garcia, Barbara M. Grüner, Monte M. Winslow, Laura D. Attardi. Understanding the role of the tumor suppressor p53 in pancreatic cancer development [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A28.
David Oliver: Should advance care planning enter the mainstream?
Authors: David Oliver
Journal: BMJ (2018)

BerkshireContact with the acute care system, especially repeated contact, is often a sign that life expectancy is limited.Around a third of adult patients in an acute bed are in the last year of their lives, although many won't know it, and nor can doctors necessarily predict it.About 40% of over 65s will die within 12 months of leaving hospital.[1] [2] Those with severe frailty are four times more likely to die within 12 months.
Patterns of Potential Opioid Misuse and Subsequent Adverse Outcomes in Medicare, 2008 to 2012
Authors: Colleen M. Carey, Anupam B. Jena, Michael L. Barnett
Journal: Annals of Internal Medicine (2018)

Background: Providers are increasingly being expected to examine their patients' opioid treatment histories before writing new opioid prescriptions. However, little evidence exists on how patterns of potential opioid misuse are associated with subsequent adverse outcomes nationally. Objective: To estimate how a range of patterns of potential opioid misuse relate to adverse outcomes during the subsequent year. Design: Observational study comparing outcomes for Medicare enrollees with potential opioid misuse patterns versus those for beneficiaries with no such patterns, adjusting for patient characteristics. Setting: Medicare, 2008 to 2012. Patients: A 5% sample of beneficiaries who had an opioid prescription without a cancer diagnosis. Measurements: Several measures for opioid misuse were defined on the basis of drug quantity, overlapping prescriptions, use of multiple prescribers or pharmacies, and use of out-of-state prescribers or pharmacies. The primary outcome was a diagnosis of opioid overdose in the year after a 6-month index period. Secondary outcomes included subsequent opioid-related or overall mortality. Results: Overall, 0.6% to 8.5% of beneficiaries fulfilled a misuse measure. Subsequent opioid overdose was positively associated with successively greater numbers of prescribers or pharmacies or higher opioid quantities during the index period. For example, patients who obtained opioids from 2, 3, or 4 prescribers were increasingly more likely to have an opioid overdose (adjusted absolute risk per 1000 beneficiary-years [aAR], 3.5 [95% CI, 3.3 to 3.7]; 4.8 [CI, 4.5 to 5.2]; or 6.4 [CI, 5.8 to 6.9], respectively) than those with a single prescriber (aAR, 1.9 [CI, 1.8 to 2.0]). Subsequent overdose risk increased meaningfully with any deviation in the single prescriber–single pharmacy opioid use pattern. All misuse measures examined had a positive association with subsequent opioid overdose and death. Limitation: Risk estimates provide measures of association and may not generalize to non-Medicare populations. Conclusion: To fully assess patients' opioid overdose risk, clinicians should examine a wide range of misuse patterns. Primary Funding Source: National Institutes of Health.
Research on Underrepresented Populations—Reply
Authors: Catherine Y. Spong, Diana W. Bianchi
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
PTH-043 Ocular radiation exposure during ercp: a meta-analysis of studies
Authors: S Menon, R Mathew
Journal: Gut (2017)

Introduction  The increasing complexity involved in procedures requiring fluoroscopy, such as ERCP, results in heightened screening times with attendant radiation exposure during these procedures. Deterministic effects are directly correlated with radiation dose and can be adjusted for during fluoroscopy but stochastic effects such as cataract due to ocular exposure are more difficult to determine. The International Commission of on Radiation Protection (ICRP) recommends a total body radiation threshold of no greater than 50mSv/year with an ocular dose limit of 20mSv/year.  Method  A literature search was performed on PubMed to identify studies involving ERCP in which radiation exposure was reported. Demographic data and data on fluoroscopy time and ocular exposure were extracted. A fixed and random effects meta-analyses was conducted.  Results  22 studies (7750 procedures) were identified, of which 8 studies (739 procedures) contained data on ocular exposure. The mean screening time per procedure was 3.9 min with a mean of 3 images captured per procedure. The mean ocular exposure per procedure was 0.26mSv. On fixed effects meta-analysis, the point estimate for ocular exposure per procedure was 0.017 (95% CI 0.015–0.018)mSv (Q 850.49, I2 98.4, p  Conclusion  Ocular radiation exposures are generally low during ERCP but operators performing high volumes (>200 per year) and complex ERCPs involving prolonged fluoroscopy need to exercise caution in relation to ocular exposure. Ocular shielding using lead-lined glasses may be reasonable in this group.  Disclosure of Interest  None Declared
Impact of pretreatment P53 gene mutation in locally advanced cervical cancer patients treated with definitive chemoradiation on treatment outcomes.
Authors: Prarthana Dalal, Tamer Refaat, Eric Donald Donnelly, Sean Sachdev, Vamsi Parimi, Samar Elachy, Ahmed Elgowily, Irene B. Helenowski, Jeffrey Gross, John Robert Lurain, Jonathan Blake Strauss, Gayle Woloschak, Jian-Jun Wei, William Small
Journal: Journal of Clinical Oncology (2015)

e16506 Background: This study aimed to assess the association between pretreatment P53 gene mutation in local-regional advanced cervical cancer patients treated definitively with concurrent chemoradiation (CRT) and treatment outcomes including overall survival (OS), progression free survival (PFS), distant metastases free survival (DMFS), and local-regional control (LC). Methods: This IRB approved study included cervical cancer patients treated definitively and consecutively with CRT. Evaluation of nuclear immunoreactivity for P53 was performed and scored semi-quantitatively by three pathologists, blinded to the treatment outcomes. Treatment-outcomes were reviewed and reported. Outcomes were stratified by P53 gene mutation (strong P53 immunoreactivity in ≥ 30% of cells, i.e. < 30% vs. ≥ 30%). OS, PFS, LC, and DC rates were obtained via the Kaplan-Meier method and differences between groups were evaluated by the log-rank test. Results: The mean age was 51 + 10 years, and the 5-year OS, PFS, LC, and DMFS were 57.18%, 48.07%, 72.11%, and 62.85%, respectively. Most of the patients (53.57%) had FIGO stage IIB disease. Almost two thirds of the patients (64.29%) had clinical node negative disease. 89.3% had squamous cell carcinoma and 10.7% had adenocarcinoma. Fifteen (53.6%), and 13 patients (46.4%) had P53 gene nuclear immunoreactivity < 30% and ≥ 30%, respectively. For patients with P53 gene nuclear immunoreactivity ≥ 30%, and < 30%, the 5-year OS were 42.86 % (CI 12.64%, 70.67%), and 69.84% (CI 37.79%, 87.60%) (P-value = 0.30), PFS were 25% (CI 4.35%, 54.18%), and 71.50% (CI 40.40%, 88.32%) (P-value = 0.15), LC were 56.25% (CI 24.37%, 79.10%), and 86.67% (CI 56.39%, 96.49%) (P-value = 0.15), and DMFS were 43. 75% (CI 8.50%, 75.79%), and 78% (CI 45.52%, 92.46%) (P-value = 0.40), respectively. There was a trend toward a worse LC, PFS, DMFS, and OS among patients with P53 gene mutation that was not statistically significant. Conclusions: This study demonstrated that pretreatment P53 gene mutation had a trend towards, but not statistically significant association with, poor treatment outcomes in locally advanced cervical cancer patients treated definitively with CRT.
Abstract IA21: Interrogating cancer drivers and dependencies using non-germline mouse models
Authors: Scott W. Lowe
Journal: Cancer Research (2018)

Abstract Cancer is a heterogeneous disease involving various genetic and epigenetic alterations that initiate and maintain the disease. Our laboratory is interested in understanding how such alterations contribute to tumorigenesis, alter treatment response, and create vulnerabilities that may be targeted therapeutically. To interrogate cancer in vivo, we have developed a range of non-germline mouse models that enable a wide variety of cancer genotypes to be produced in a fraction of the time and cost of traditional germline methods. Approaches vary depending on the particular question, and can involve genetic manipulation and retransplantation of tissue stem cells and/or organoid cultures, the generation of multi-allelic ES cells and subsequent use in chimeric mice, and direct somatic engineering of mutations in particular tissues. Additionally, we have incorporated RNAi and CRISPR/Cas9 technologies to expedite our ability to study gene function in these models. Collectively, the combination of these tools has allowed us to identify and characterize new cancer drives using one-by-one or multiplexed approaches, and to perform rapid in vivo validation of “hits” from functional genomic screens. Examples of each method and approach will be presented. Citation Format: Scott W. Lowe. Interrogating cancer drivers and dependencies using non-germline mouse models [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA21.
Abstract 297: GJA1-20k Protects the Heart From Ischemic Injury by Inducing Mitochondrial Metabolic Quiescence
Authors: Ying Fu, Wassim Basheer, Baiming Sun, Sosse Agvanian, Shaohua Xiao, TingTing Hong, Robin M Shaw
Journal: Circulation Research (2017)

The mRNA of the GJA1 gene that encodes gap junction protein connexin 43 (Cx43) undergoes alternative translation, producing N-terminal truncated smaller protein isoforms. Unlike the well-characterized full-length Cx43 (GJA1-43k), little is known about the function and regulation of the smaller isoforms. Here, we report that global ischemia/reperfusion injury in Langendorff-perfused mouse hearts upregulates endogenous GJA1-20k, the most abundant isoform of alternative translation. Biochemical fractionation indicates that the induced GJA1-20k is preferentially enriched in cardiomyocyte mitochondria. When introduced in vitro through adenovirus-medicated gene expression, exogenous GJA1-20k, but not full length protein GJA1-43k, localizes to mitochondria and improves the survival and viability of adult cardiomyocytes when subjected to oxidative stress. In vivo gene transfer of GJA1-20k through retro-orbital injection of AAV9 virus results in lower mitochondria-dependent basal oxygen consumption as well as maximal respiratory capacity in cardiomyocytes, unlike GFP or GJA1-43k controls. Thus GJA1-20k, but not GJA1-43k, protects the heart against ischemic injury induced by permanent LAD ligation. As compared to GFP control group, myocardial infarct size in GJA1-20k treated hearts is reduced by 30% at 72 hours post LAD ligation. These results indicate that endogenous GJA1-20k is induced upon stress and has strong tropism to mitochondria. Increased GJA1-20k induces mitochondrial metabolic quiescence and affords cardioprotection in vitro and in vivo. Alternatively translated GJA1-20k acts as a novel mitochondrial stress protein and demonstrates therapeutic potential against ischemic injury.
Performance of a Genomic Sequencing Classifier for the Preoperative Diagnosis of Cytologically Indeterminate Thyroid Nodules
Authors: Kepal N. Patel, Trevor E. Angell, Joshua Babiarz, Neil M. Barth, Thomas Blevins, Quan-Yang Duh, Ronald A. Ghossein, R. Mack Harrell, Jing Huang, Giulia C. Kennedy, Su Yeon Kim, Richard T. Kloos, Virginia A. LiVolsi, Gregory W. Randolph, Peter M. Sadow, Michael H. Shanik, Julie A. Sosa, S. Thomas Traweek, P. Sean Walsh, Duncan Whitney, Michael W. Yeh, Paul W. Ladenson
Journal: JAMA Surgery (2018)

<h3>Importance</h3> Use of next-generation sequencing of RNA and machine learning algorithms can classify the risk of malignancy in cytologically indeterminate thyroid nodules to limit unnecessary diagnostic surgery. <h3>Objective</h3> To measure the performance of a genomic sequencing classifier for cytologically indeterminate thyroid nodules. <h3>Design, Setting, and Participants</h3> A blinded validation study was conducted on a set of cytologically indeterminate thyroid nodules collected by fine-needle aspiration biopsy between June 2009 and December 2010 from 49 academic and community centers in the United States. All patients underwent surgery without genomic information and were assigned a histopathology diagnosis by an expert panel blinded to all genomic information. There were 210 potentially eligible thyroid biopsy samples with Bethesda III or IV indeterminate cytopathology that constituted a cohort previously used to validate the gene expression classifier. Of these, 191 samples (91.0%) had adequate residual RNA for validation of the genomic sequencing classifier. Algorithm development and independent validation occurred between August 2016 and May 2017. <h3>Exposures</h3> Thyroid nodule surgical histopathology diagnosis by an expert panel blinded to all genomic data. <h3>Main Outcomes and Measures</h3> The primary end point was measurement of genomic sequencing classifier sensitivity, specificity, and negative and positive predictive values in biopsies from Bethesda III and IV nodules. The secondary end point was measurement of classifier performance in biopsies from Bethesda II, V, and VI nodules. <h3>Results</h3> Of the 183 included patients, 142 (77.6%) were women, and the mean (range) age was 51.7 (22.0-85.0) years. The genomic sequencing classifier had a sensitivity of 91% (95% CI, 79-98) and a specificity of 68% (95% CI, 60-76). At 24% cancer prevalence, the negative predictive value was 96% (95% CI, 90-99) and the positive predictive value was 47% (95% CI, 36-58). <h3>Conclusions and Relevance</h3> The genomic sequencing classifier demonstrates high sensitivity and accuracy for identifying benign nodules. Its 36% increase in specificity compared with the gene expression classifier potentially increases the number of patients with benign nodules who can safely avoid unnecessary diagnostic surgery.
The complexities and successes of the NHS
Authors: Kamran Abbasi
Journal: BMJ (2018)

Amid your feverish royal wedding celebrations spare a thought for the NHS. Firmly wedded to us, the NHS is enigmatic, infuriating, and complex. For its many lovers it is also loyal, beautiful, and impossible to live without. It may be easy to find fault with the NHS, as with a difficult partner, but might we do better by dwelling on its successes?

To that end, we seek your opinions on the NHS’s greatest achievement in its first 70 years. Our editorial team has shortlisted 12 of the many nominations from readers. …