tbuckley/cabot-search huggingface dataset:
Self-Defeating Codes of Medical Ethics and How to Fix Them: Failures in COVID-19 Response and Beyond
Authors: Alex John London
Journal: The American Journal of Bioethics (2020)

Statements of the core ethical and professional responsibilities of medical professionals are incomplete in ways that threaten fundamental goals of medicine. First, in the absence of explicit guidance for responding to cases in which there is significant uncertainty or disagreement about the relative therapeutic, prophylactic or diagnostic merits of available interventions they perpetuate self-defeating practices. Second, without addressing the role of advertising in shaping patient and community preferences they risk creating moral loopholes that bypass and undermine professional duties of fidelity, honesty and transparency. In both cases, these flaws are exacerbated by an individualism that ignores the critical role of health systems in managing and reducing uncertainty and conflict over best practices, and in communicating with and shaping the expectations of the public. These points are illustrated with examples from the response to COVID-19 and suggestions for reform are proposed.
An Intensive Transition Navigator Intervention Improves Transition Readiness to Adult Care in Youth with Sickle Cell Disease
Authors: Deepa Manwani, Lynn Davidson, Ellen Silver, Rosy Chhabra, Caterina Minniti, Deepa Rastogi, Maya Doyle, Kerry A Morrone, Ruth Stein, Suzette Oyeku, Laurie Bauman
Journal: Blood (2017)
Abstract 15249: Association of Coronary Artery and Extra-coronary Calcification With Reduced Physical Function and Frailty in Older Adults: The Atherosclerosis Risk in Communities Study
Authors: Ning Ding, Frances Wang, Miguel Cainzos Achirica, Nancy Schoenborn, Cynthia Boyd, Lynne E Wagenknecht, Kenneth R Butler, Aaron R Folsom, Josef Coresh, B Gwen Windham, Michael J Blaha, Kunihiro Matsushita
Journal: Circulation (2020)

Introduction: Coronary artery calcium (CAC) and extra-coronary calcification (ECC) have been associated with age-related phenotypes such as cognitive impairment. However, their relationship with poor physical function and frailty/pre-frailty in older adults is unclear. Hypothesis: CAC and ECC (aortic valve, aortic valve ring, mitral valve, ascending aorta, and descending aorta) are associated with poor physical function and frailty/pre-frailty. Methods: We defined poor physical function as a Short Physical Performance Battery (SPPB) score ≤9 and frailty/pre-frailty as the presence of at least one frailty criterion: weight loss, slow walking speed, exhaustion, low grip strength, and low physical activity. The number of vascular beds with any calcification (CAC and five ECC sites [0-6]) was calculated for a composite measure of calcification. Logistic regression was used to quantify cross-sectional associations with SPPB or frailty/pre-frailty among 1,564 ARIC participants aged 74-92 without prior CVD at visit 7 (2018-19). Results: The prevalence of low SPPB, frailty, and pre-frailty was 50%, 5%, and 56%, respectively. Highest (vs. lowest) quartile of aortic valve and mitral valve calcification was associated with low SPPB (OR 1.47 [1.15, 1.88] and 1.53 [1.19,1.97]) and frailty/pre-frailty (1.34 [1.05, 1.71] and 1.41 [1.10, 1.80]). Aortic valve ring calcification was associated with frailty/pre-frailty, and descending aorta calcification with low SPPB. The total number of calcified vascular beds demonstrated a dose-response relationship to both outcomes (Table), with 5-6 calcified vascular beds demonstrating ~2-fold higher odds. Conclusions: Cardiovascular calcification, especially aortic valve and mitral valve calcification, was robustly associated with higher risk of poor physical function and frailty/pre-frailty, suggesting the potential etiological link between cardiovascular calcification and functional decline at older age.
Identifying human trafficking in adults
Authors: Jane Hunt, Rachel Witkin, Cornelius Katona
Journal: BMJ (2020)

### What you need to know

A 24 year old woman from Nigeria presents to a male GP in the UK with vaginal discharge and inter-menstrual bleeding. She speaks limited English. Her notes show that she has received three diagnoses of sexually transmitted infections in the last year. She is accompanied by a man who looks older than she is, who offers to interpret for her. She responds without emotion to introductions and questions, and stares out of the window much of the time. An abusive or exploitative situation is suspected. The need for an intimate examination and further investigations is explained, and the accompanying man is politely asked to wait outside. The woman declines a chaperone. Further medical history is elicited through a telephone interpreter. The doctor asks gently whether she feels safe with the man and where she lives. The woman then becomes distressed and tearful and refuses to say anything further. 

Trafficked adults experience, or have experienced, complex physical and/or emotional trauma, and are usually considered to be adults at risk. The UK’s Care and Support Statutory Guidance, first published in 2014,1 cites modern slavery as one of the 10 …
SIRT6 Protects Smooth Muscle Cells From Senescence and Reduces Atherosclerosis
Authors: Mandy O.J. Grootaert, Alison Finigan, Nichola L. Figg, Anna K. Uryga, Martin R. Bennett
Journal: Circulation Research (2020)

Rationale: Vascular smooth muscle cell (VSMC) senescence promotes atherosclerosis and features of plaque instability, in part, through lipid-mediated oxidative DNA damage and telomere dysfunction. SIRT6 (Sirtuin 6) is a nuclear deacetylase involved in DNA damage response signaling, inflammation, and metabolism; however, its role in regulating VSMC senescence and atherosclerosis is unclear. Objective: We examined SIRT6 expression in human VSMCs, the role, regulation, and downstream pathways activated by SIRT6, and how VSMC SIRT6 regulates atherogenesis. Methods and Results: SIRT6 protein, but not mRNA, expression was markedly reduced in VSMCs in human and mouse atherosclerotic plaques, and in human VSMCs derived from plaques or undergoing replicative or palmitate-induced senescence versus healthy aortic VSMCs. The ubiquitin ligase CHIP (C terminus of HSC70-interacting protein) promoted SIRT6 stability, but CHIP expression was reduced in human and mouse plaque VSMCs and by palmitate in a p38- and c-Jun N-terminal kinase-dependent manner. SIRT6 bound to telomeres, while SIRT6 inhibition using shRNA or a deacetylase-inactive mutant (SIRT6 H133Y ) shortened human VSMC lifespan and induced senescence, associated with telomeric H3K9 (histone H3 lysine 9) hyperacetylation and 53BP1 (p53 binding protein 1) binding, indicative of telomere damage. In contrast, SIRT6 overexpression preserved telomere integrity, delayed cellular senescence, and reduced inflammatory cytokine expression and changes in VSMC metabolism associated with senescence. SIRT6, but not SIRT6 H133Y , promoted proliferation and lifespan of mouse VSMCs, and prevented senescence-associated metabolic changes. ApoE −/− (apolipoprotein E) mice were generated that overexpress SIRT6 or SIRT6 H133Y in VSMCs only. SM22α-hSIRT6/ApoE −/− mice had reduced atherosclerosis, markers of senescence and inflammation compared with littermate controls, while plaques of SM22α-hSIRT6 H133Y /ApoE −/− mice showed increased features of plaque instability. Conclusions: SIRT6 protein expression is reduced in human and mouse plaque VSMCs and is positively regulated by CHIP. SIRT6 regulates telomere maintenance and VSMC lifespan and inhibits atherogenesis, all dependent on its deacetylase activity. Our data show that endogenous SIRT6 deacetylase is an important and unrecognized inhibitor of VSMC senescence and atherosclerosis.
Ca <sup>2+</sup> -CaM Dependent Inactivation of RyR2 Underlies Ca <sup>2+</sup> Alternans in Intact Heart
Authors: Jinhong Wei, Jinjing Yao, Darrell Belke, Wenting Guo, Xiaowei Zhong, Bo Sun, Ruiwu Wang, John Paul Estillore, Alexander Vallmitjana, Raul Benitez, Leif Hove-Madsen, Enrique Alvarez-Lacalle, Blas Echebarria, S.R. Wayne Chen
Journal: Circulation Research (2020)

Ca2+ alternans plays an essential role in cardiac alternans that can lead to ventricular fibrillation, but the mechanism underlying Ca2+ alternans remains undefined. Increasing evidence suggests that Ca2+ alternans results from alternations in the inactivation of cardiac RyR2 (ryanodine receptor 2). However, what inactivates RyR2 and how RyR2 inactivation leads to Ca2+ alternans are unknown.To determine the role of CaM (calmodulin) on Ca2+ alternans in intact working mouse hearts.We used an in vivo local gene delivery approach to alter CaM function by directly injecting adenoviruses expressing CaM-wild type, a loss-of-function CaM mutation, CaM (1-4), and a gain-of-function mutation, CaM-M37Q, into the anterior wall of the left ventricle of RyR2 wild type or mutant mouse hearts. We monitored Ca2+ transients in ventricular myocytes near the adenovirus-injection sites in Langendorff-perfused intact working hearts using confocal Ca2+ imaging. We found that CaM-wild type and CaM-M37Q promoted Ca2+ alternans and prolonged Ca2+ transient recovery in intact RyR2 wild type and mutant hearts, whereas CaM (1-4) exerted opposite effects. Altered CaM function also affected the recovery from inactivation of the L-type Ca2+ current but had no significant impact on sarcoplasmic reticulum Ca2+ content. Furthermore, we developed a novel numerical myocyte model of Ca2+ alternans that incorporates Ca2+-CaM-dependent regulation of RyR2 and the L-type Ca2+ channel. Remarkably, the new model recapitulates the impact on Ca2+ alternans of altered CaM and RyR2 functions under 9 different experimental conditions. Our simulations reveal that diastolic cytosolic Ca2+ elevation as a result of rapid pacing triggers Ca2+-CaM dependent inactivation of RyR2. The resultant RyR2 inactivation diminishes sarcoplasmic reticulum Ca2+ release, which, in turn, reduces diastolic cytosolic Ca2+, leading to alternations in diastolic cytosolic Ca2+, RyR2 inactivation, and sarcoplasmic reticulum Ca2+ release (ie, Ca2+ alternans).Our results demonstrate that inactivation of RyR2 by Ca2+-CaM is a major determinant of Ca2+ alternans, making Ca2+-CaM dependent regulation of RyR2 an important therapeutic target for cardiac alternans.
Prospective Correlation of Prognostic Immunohistochemical Markers With SUV and ADC Derived From Dedicated Hybrid Breast 18F-FDG PET/MRI in Women With Newly Diagnosed Breast Cancer
Authors: Janna Morawitz, Julian Kirchner, Ole Martin, Nils-Martin Bruckmann, Frederic Dietzel, Yan Li, Christoph Rischpler, Ken Herrmann, Lale Umutlu, Ann-Kathrin Bittner, Svjetlana Mohrmann, Marc Ingenwerth, Lena Häberle, Irene Esposito, Gerald Antoch, Christian Buchbender, Lino M. Sawicki
Journal: Clinical Nuclear Medicine (2020)

The aim of this study was to correlate prognostically relevant immunohistochemical parameters of breast cancer with simultaneously acquired SUVs and apparent diffusion coefficient (ADC) values derived from hybrid breast PET/MRI.Fifty-six women with newly diagnosed, therapy-naive, histologically proven breast cancer (mean age, 54.1 ± 12.0 years) underwent dedicated prone 18F-FDG breast PET/MRI. Diffusion-weighted imaging (b-values: 0, 500, 1000 s/mm2) was performed simultaneously with the PET acquisition. A region of interest encompassing the entire primary tumor on each patient's PET/MRI scan was used to determine the glucose metabolism represented by maximum and mean SUV as well as into corresponding ADC maps to assess tumor cellularity represented by mean and minimum ADC values. Histopathological tumor grading and prognostically relevant immunohistochemical markers, that is, Ki67, progesterone receptor, estrogen receptor, and human epidermal growth factor receptor 2 (HER2), were assessed. Pearson correlation coefficients were calculated to compare SUV and ADC values as well as the immunohistochemically markers and molecular subtype. For the comparison with the tumor grading, a Wilcoxon test was used.A significant inverse correlation between SUV and ADC values derived from breast PET/MRI (r = -0.49 for SUVmean vs ADCmean; r = -0.43 for SUVmax vs ADCmin; both P's < 0.001) was found. Tumor grading and Ki67 both showed a positive correlation with SUVmean from breast PET/MRI (r = 0.37 and r = 0.32, P < 0.01). For immunohistochemical markers, HER2 showed an inverse correlation with ADC values from breast PET/MRI (r = -0.35, P < 0.01). Molecular subtypes significantly correlate with SUVmax and SUVmean (r = 0.52 and r = 0.42, both P's < 0.05). In addition, estrogen receptor expression showed an inverse correlation with SUVmax and SUVmean from breast PET/MRI (r = -0.45 and r = -0.42, P < 0.001).The present data show a correlation between increased glucose metabolism, cellularity, tumor grading, estrogen and HER2 expression, as well as molecular subtype of breast cancer primaries. Hence, simultaneous 18F-FDG PET and diffusion-weighted imaging from hybrid breast PET/MRI may serve as a predictive tool for identifying high-risk breast cancer patients in initial staging and guide-targeted therapy.
Recent progress in sono-photodynamic cancer therapy: From developed new sensitizers to nanotechnology-based efficacy-enhancing strategies
Authors: Yilin Zheng, Jinxiang Ye, Ziying Li, Haijun Chen, Yu Gao
Journal: Acta Pharmaceutica Sinica B (2020)

Many sensitizers have not only photodynamic effects, but also sonodynamic effects. Therefore, the combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT) using sensitizers for sono-photodynamic therapy (SPDT) provides alternative opportunities for clinical cancer therapy. Although significant advances have been made in synthesizing new sensitizers for SPDT, few of them are successfully applied in clinical settings. The anti-tumor effects of the sensitizers are restricted by the lack of tumor-targeting specificity, incapability in deep intratumoral delivery, and the deteriorating tumor microenvironment. The application of nanotechnology-based drug delivery systems (NDDSs) can solve the above shortcomings, thereby improving the SPDT efficacy. This review summarizes various sensitizers as sono/photosensitizers that can be further used in SPDT, and describes different strategies for enhancing tumor treatment by NDDSs, such as overcoming biological barriers, improving tumor-targeted delivery and intratumoral delivery, providing stimuli-responsive controlled-release characteristics, stimulating anti-tumor immunity, increasing oxygen supply, employing different therapeutic modalities, and combining diagnosis and treatment. The challenges and prospects for further development of intelligent sensitizers and translational NDDSs for SPDT are also discussed.
Covid-19: Hospitals in crisis as ambulances queue and staff are asked to cancel leave
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Covid-19: Hospitals in crisis as ambulances queue and staff are asked to cancel leave Elisabeth MahaseHospitals across London and the South East and East of England are struggling to meet rising demand as covid-19 hospital admissions rise to the highest point in the pandemic and the new, more transmissible variant of the virus spreads across the country. 1 NHS England.Covid-19 hospital activity.31 Dec 2020.https://www.england.nhs.uk/statistics/statistical-work-areas/covid-19-hospital-activity.
Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission
Authors: Andrew H. Wei, Hartmut Döhner, Christopher Pocock, Pau Montesinos, Boris Afanasyev, Hervé Dombret, Farhad Ravandi, Hamid Sayar, Jun-Ho Jang, Kimmo Porkka, Dominik Selleslag, Irwindeep Sandhu, Mehmet Turgut, Valentina Giai, Yishai Ofran, Merih Kizil Çakar, Aida Botelho de Sousa, Justyna Rybka, Chiara Frairia, Lorenza Borin, Germana Beltrami, Jaroslav Čermák, Gert J. Ossenkoppele, Ignazia La Torre, Barry Skikne, Keshava Kumar, Qian Dong, C.L. Beach, Gail J. Roboz
Journal: New England Journal of Medicine (2020)

Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor.
Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5
Authors: Christelle Dufour, Stephanie Foulon, Anne Geoffray, Julien Masliah-Planchon, Dominique Figarella-Branger, Valerie Bernier-Chastagner, Laetitia Padovani, Léa Guerrini-Rousseau, Cecile Faure-Conter, Celine Icher, Anne-Isabelle Bertozzi, Pierre Leblond, Tasnime Akbaraly, Franck Bourdeaut, Nicolas André, Celine Chappé, Pascale Schneider, Emilie De Carli, Pascal Chastagner, Claire Berger, Julien Lejeune, Christine Soler, Natacha Entz-Werlé, Marie-Bernadette Delisle
Journal: Neuro-Oncology (2020)

High-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5-19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5. All children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m2) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1-3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy). Fifty-one patients (median age, 8 y; range, 5-19) were enrolled. The median follow-up was 7.1 years (range: 3.4-9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65-88) and 76% (63-86), and the 3 and 5-year OS were 84% (72-92) and 76% (63-86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated. This treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.
Abstract 15306: Low-Grade Endotoxemia by Escherichia Coli Accelerates Artery Thrombus Growth via Toll-Like Receptor 4
Authors: Cristina Nocella, Roberto Carnevale, Sebastiano Sciarretta, Valentina Valenti, Flavio Di Nonno, Vittoria Cammisotto, Camilla Calvieri, Giacomo Frati, Giulia d’Amati, Maria Gemma, Anna Severino, Roberto Cangemi, Alessio Arrivi, Marcello Dominici, Enrico Mangeri, Carlo Gaudio, Gaetano Tanzilli, Francesco Violi
Journal: Circulation (2019)

Introduction: Escherichia Coli (EC) lipopolysaccharide, which is a component of gut microbiota, is detectable in human circulation at concentrations potentially eliciting platelet aggregation; howe...
Author Correction: Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors
Authors: Mark K. Bakker, Rick A. A. van der Spek, Wouter van Rheenen, Sandrine Morel, Romain Bourcier, Isabel C. Hostettler, Varinder S. Alg, Kristel R. van Eijk, Masaru Koido, Masato Akiyama, Chikashi Terao, Koichi Matsuda, Robin G. Walters, Kuang Lin, Liming Li, Iona Y. Millwood, Zhengming Chen, Guy A. Rouleau, Sirui Zhou, Kristiina Rannikmäe, Cathie L. M. Sudlow, Henry Houlden, Leonard H. van den Berg, Christian Dina, Olivier Naggara, Jean-Christophe Gentric, Eimad Shotar, François Eugène, Hubert Desal, Bendik S. Winsvold, Sigrid Børte, Marianne Bakke Johnsen, Ben M. Brumpton, Marie Søfteland Sandvei, Cristen J. Willer, Kristian Hveem, John-Anker Zwart, W. M. Monique Verschuren, Christoph M. Friedrich, Sven Hirsch, Sabine Schilling, Jérôme Dauvillier, Olivier Martin, Gregory T. Jones, Matthew J. Bown, Nerissa U. Ko, Helen Kim, Jonathan R. I. Coleman, Gerome Breen, Jonathan G. Zaroff, Catharina J. M. Klijn, Rainer Malik, Martin Dichgans, Muralidharan Sargurupremraj, Turgut Tatlisumak, Philippe Amouyel, Stéphanie Debette, Gabriel J. E. Rinkel, Bradford B. Worrall, Joanna Pera, Agnieszka Slowik, Emília I. Gaál-Paavola, Mika Niemelä, Juha E. Jääskeläinen, Mikael von Und Zu Fraunberg, Antti Lindgren, Joseph P. Broderick, David J. Werring, Daniel Woo, Richard Redon, Philippe Bijlenga, Yoichiro Kamatani, Jan H. Veldink, Ynte M. Ruigrok
Journal: Nature Genetics (2020)
Design of a biofluid-absorbing bioactive sandwich-structured Zn–Si bioceramic composite wound dressing for hair follicle regeneration and skin burn wound healing
Authors: Zhaowenbin Zhang, Wenbo Li, Ying Liu, Zhigang Yang, Lingling Ma, Hui Zhuang, Endian Wang, Chengtie Wu, Zhiguang Huan, Feng Guo, Jiang Chang
Journal: Bioactive Materials (2020)

The deep burn skin injures usually severely damage the dermis with the loss of hair follicle loss, which are difficult to regenerate. Furthermore, severe burns often accompanied with large amount of wound exudates making the wound moist, easily infected, and difficult to heal. Therefore, it is of great clinical significance to develop wound dressings to remove wound exudates and promote hair follicle regeneration. In this study, a sandwich-structured wound dressing (SWD) with Janus membrane property was fabricated by hot compression molding using hydrophilic zinc silicate bioceramics (Hardystonite, ZnCS) and hydrophobic polylactic acid (PLA). This unique organic/inorganic Janus membrane structure revealed excellent exudate absorption property and effectively created a dry wound environment. Meanwhile, the incorporation of ZnCS bioceramic particles endowed the dressing with the bioactivity to promote hair follicle regeneration and wound healing through the release of Zn2+ and SiO32− ions, and this bioactivity of the wound dressing is mainly attributed to the synergistic effect of Zn2+ and SiO32− to promote the recruitment, viability, and differentiation of hair follicle cells. Our study demonstrates that the utilization of the Janus membrane and synergistic effect of different type bioactive ions are effective approaches for the design of wound dressings for burn wound healing.