tbuckley/cabot-search huggingface dataset:
Management of Depression in Older Adults
Authors: Rob M. Kok, Charles F. Reynolds
Journal: JAMA (2017)

<h3>Importance</h3> Depression in older adults is a common psychiatric disorder affecting their health-related quality of life. Major depression occurs in 2% of adults aged 55 years or older, and its prevalence rises with increasing age. In addition, 10% to 15% of older adults have clinically significant depressive symptoms, even in the absence of major depression. <h3>Observations</h3> Depression presents with the same symptoms in older adults as it does in younger populations. In contrast to younger patients, older adults with depression more commonly have several concurrent medical disorders and cognitive impairment. Depression occurring in older patients is often undetected or inadequately treated. Antidepressants are the best-studied treatment option, but psychotherapy, exercise therapy, and electroconvulsive therapy may also be effective. Psychotherapy is recommended for patients with mild to moderate severity depression. Many older patients need the same doses of antidepressant medication that are used for younger adult patients. Although antidepressants may effectively treat depression in older adults, they tend to pose greater risk for adverse events because of multiple medical comorbidities and drug-drug interactions in case of polypharmacy. High-quality evidence does not support the use of pharmacologic treatment of depression in patients with dementia. Polypharmacy in older patients can be minimized by using the Screening Tool of Older Persons Prescriptions and Screening Tool to Alert doctors to Right Treatment (STOPP/START) criteria, a valid and reliable screening tool that enables physicians to avoid potentially inappropriate medications, undertreatment, or errors of omissions in older people. Antidepressants can be gradually tapered over a period of several weeks, but discontinuation of antidepressants may be associated with relapse or recurrence of depression, so the patient should be closely observed. <h3>Conclusions and Relevance</h3> Major depression in older adults is common and can be effectively treated with antidepressants and electroconvulsive therapy. Psychological therapies and exercise may also be effective for mild-moderate depression, for patients who prefer nonpharmacological treatment, or for patients who are too frail for drug treatments.
Concordant testing results between various human papillomavirus assays in primary cervical cancer screening: systematic review
Authors: L. de Thurah, J. Bonde, J.U.H. Lam, M. Rebolj
Journal: Clinical Microbiology and Infection (2017)

Human papillomavirus (HPV) assays are increasingly used for primary cervical screening and HPV-vaccination-effect monitoring. We undertook a systematic literature review to determine the concordance in positive test results (i.e. detection of HPV infections) between Hybrid Capture 2 (HC2) and other assays.
Autophagy and Mitophagy in Cardiovascular Disease
Authors: José Manuel Bravo-San Pedro, Guido Kroemer, Lorenzo Galluzzi
Journal: Circulation Research (2017)

Autophagy contributes to the maintenance of intracellular homeostasis in most cells of cardiovascular origin, including cardiomyocytes, endothelial cells, and arterial smooth muscle cells. Mitophagy is an autophagic response that specifically targets damaged, and hence potentially cytotoxic, mitochondria. As these organelles occupy a critical position in the bioenergetics of the cardiovascular system, mitophagy is particularly important for cardiovascular homeostasis in health and disease. Consistent with this notion, genetic defects in autophagy or mitophagy have been shown to exacerbate the propensity of laboratory animals to spontaneously develop cardiodegenerative disorders. Moreover, pharmacological or genetic maneuvers that alter the autophagic or mitophagic flux have been shown to influence disease outcome in rodent models of several cardiovascular conditions, such as myocardial infarction, various types of cardiomyopathy, and atherosclerosis. In this review, we discuss the intimate connection between autophagy, mitophagy, and cardiovascular disorders.
IMMU-15. SPECIFIC EXPRESSION OF PD-L1 IN RELA-FUSION SUPRATENTORIAL EPENDYMOMA: IMPLICATIONS FOR PD1 TARGETED IMMUNOTHERAPY
Authors: Davis Witt, Andrew Donson, Vladimir Amani, Michael Handler, Lindsey Hoffman, Kathleen Dorris, Nicholas Foreman, Andrea Griesinger
Journal: Neuro-Oncology (2017)

Ependymoma (EPN) is the third most common pediatric central nervous system tumor, associated with poor survival and long-term morbidity. There is a critical need for new treatments and an untested avenue is immunotherapy. We have previously shown that immune cell infiltration is correlated with a favorable outcome in EPN and, in addition, that PD-1 was expressed by approximately 50% of tumor infiltrating T-cells suggesting an exhausted phenotype. We predict that EPN patients would therefore likely benefit from immune checkpoint inhibitors such as PD-1 antibodies nivolumab and pembrolizumab that are being tested in pediatric brain tumor clinical trials. These antibodies work by blocking the T-cell bound PD-1 receptor from binding PD-L1 and PD-L2, on tumor and/or antigen-presenting myeloid cells. Expression of PD-L1 is presently the best predictor of clinical response to PD-1 antibodies and is used for trial patient selection. To this end we screened a cohort of pediatric posterior fossa (PF) and supratentorial (ST) EPN patient samples for PD-L1 expression by protein (Western blot) and mRNA (microarray) analysis. RELA-fusion ST EPN express PD-L1 mRNA and protein at higher levels then PF EPN. Furthermore, PDL1 expression was absent in ST YAP-fusion tumors. This disparity between RELA and YAP fusion tumor PD-L1 mRNA levels was validated using a larger independent EPN cohort. Recent studies have demonstrated that the NF-ĸB pathway regulates transcription of PD-L1 through LMP1 and INF-gamma induced expression. It is therefore likely that the constitutive activation of NF-ĸB signaling resulting from RELA-fusion underlies PD-L1 over-expression in this EPN subgroup. Based on these data, it is critical that RELA-fusion ST EPN tumors be included in pediatric clinical trials for PD-1 targeted antibodies.
Senior NHS doctors face huge burden of work related illness, researchers find
Authors: Matt Limb
Journal: BMJ (2017)

Senior UK doctors have disclosed a huge burden of work related ill health and feelings of being unsupported by the NHS, a study has found.

Hundreds of doctors near the end of their careers reported experiencing chronic physical or mental stress, and many said that the NHS did not respond well when they became ill.

The researchers said that more GPs than hospital doctors reported problems and that older doctors in particular “need support to be able to continue successfully in their careers.”

The research was carried out by the UK Medical Careers Research Group at Oxford University’s Nuffield Department of Population Health and was published in the Journal of the Royal Society of Medicine .1 …
Unmanipulated haploidentical stem cell transplantation in adults with acute lymphoblastic leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT
Authors: Nicole Santoro, Annalisa Ruggeri, Myriam Labopin, Andrea Bacigalupo, Fabio Ciceri, Zafer Gülbaş, He Huang, Boris Afanasyev, William Arcese, Depei Wu, Yener Koc, Johanna Tischer, Stella Santarone, Sebastian Giebel, Mohamad Mohty, Arnon Nagler
Journal: Journal of Hematology & Oncology (2017)

Allogenic hematopoietic stem cell transplantation (allo-SCT) is the most effective post-remission treatment for adults with high-risk acute lymphoblastic leukemia (ALL). The aim of the study was to analyze results of unmanipulated haploidentical allo-SCT (haplo-SCT) for adults with ALL and to identify prognostic factors.We performed a retrospective analysis on 208 adults transplanted in EBMT centers from 2007 to 2014.Median age at haplo-SCT was 32 years and median follow-up, 31 months. Forty-four percent of the patients were in first complete remission (CR1). Stem cell source was the bone marrow (BM) for 43% and peripheral blood (PB) for 57% of patients. Myeloablative conditioning (MAC) was used for 66% and reduced intensity regimen (RIC) for 34% of patients. GVHD prophylaxis was based on post-transplant cyclophosphamide (PT-Cy) for 118 (57%) or on anti-thymocyte-globulin (ATG) for 90 (43%) plus standard prophylaxis. One hundred eighty-four (92%) patients achieved engraftment. Cumulative incidence (CI) of grade II-IV acute-graft-versus-host-disease (GVHD) was 31%, grade III-IV 11%, and chronic GVHD 29%. Non-relapse mortality (NRM) and relapse-incidence (RI) were 32 and 37%, respectively. Overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free-survival (GRFS) at 3 years were 33, 31, and 26%. For patients in CR1, OS, LFS, and GRFS were 52, 47, and 40%, respectively. Disease status was the main factor associated with transplant outcomes. Use of BM was independently associated with improvement in NRM, acute GVHD, GRFS, LFS, and OS.Unmanipulated haplo-SCT may be considered a valid option for adult patients with high-risk ALL lacking HLA identical donor preferably in early disease status.
Identification of a High‐Frequency Somatic <i>NLRC4</i> Mutation as a Cause of Autoinflammation by Pluripotent Cell–Based Phenotype Dissection
Authors: Yuri Kawasaki, Hirotsugu Oda, Jun Ito, Akira Niwa, Takayuki Tanaka, Atsushi Hijikata, Ryosuke Seki, Ayako Nagahashi, Mitsujiro Osawa, Isao Asaka, Akira Watanabe, Shigeo Nishimata, Tsuyoshi Shirai, Hisashi Kawashima, Osamu Ohara, Tatsutoshi Nakahata, Ryuta Nishikomori, Toshio Heike, Megumu K. Saito
Journal: Arthritis & Rheumatology (2016)

To elucidate the genetic background of a patient with neonatal-onset multisystem inflammatory disease (NOMID) with no NLRP3 mutation.A Japanese male child diagnosed as having NOMID was studied. The patient did not have any NLRP3 mutation, even as low-frequency mosaicism. We performed whole-exome sequencing on the patient and his parents. Induced pluripotent stem cells (iPSCs) were established from the patient's fibroblasts. The iPSCs were then differentiated into monocyte lineage to evaluate the cytokine profile.We established multiple iPSC clones from a patient with NOMID and incidentally found that the phenotypes of monocytes from iPSC clones were heterogeneous and could be grouped into disease and normal phenotypes. Because each iPSC clone was derived from a single somatic cell, we hypothesized that the patient had somatic mosaicism of an interleukin-1β-related gene. Whole-exome sequencing of both representative iPSC clones and the patient's blood revealed a novel heterozygous NLRC4 mutation, p.T177A (c.529A>G), as a specific mutation in diseased iPSC clones. Knockout of the NLRC4 gene using the clustered regularly interspaced short palindromic repeat/Cas9 system in a mutant iPSC clone abrogated the pathogenic phenotype.Our findings indicate that the patient has somatic mosaicism of a novel NLRC4 mutation. To our knowledge, this is the first case showing that somatic mutation of NLRC4 causes autoinflammatory symptoms compatible with NOMID. The present study demonstrates the significance of prospective genetic screening combined with iPSC-based phenotype dissection for individualized diagnoses.
Screening for hepatocellular carcinoma: A drug safety issue
Authors: Alain Braillon
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: Cadier et al.1 claim that "gold‐standard monitoring (for hepatocellular carcinoma) for patients with cirrhosis is cost‐effective."1 This deserves strong comment. First, the results of available randomized controlled trials are far from convincing, and the systemic review of retrospective observational studies is negative.2 Moreover, these studies have enduringly stated that screening for hepatocellular carcinoma (HCC) improved survival despite raw data showing that screened patients died several years younger than patients who had not been screened.3 Cadier et al. even dare to claim significant survival benefit after adjustment for lead‐time bias based on a tumor doubling time of 90 days, an incredible speed; here, the benefit is assumed to be 4 months over a 10‐year period. The recommendation for HCC screening is not evidence based, an exception among all cancers. Moreover, poor evidence is a leading cause of poor compliance, a situation precluding efficiency for any screening policy: in a recent series from highly specialized liver units in Italy, hepatologists only apply their recommendation to 40% of their patients. Second, the complexity of the model (Markov and Monte Carlo simulation) contrasted with the lack of account for the first avoidable cause of hepatocellular carcinoma: smoking. In a large European cohort, the population attributable fraction (the proportional reduction in population disease incidence that would occur if risk factor exposure were reduced to an alternative ideal exposure level) for tobacco use in HCC (48%) was more than twice that of the second most attributed risk factor (hepatitis C, 21%).4 Implementing smoking cessation treatment is the prerequisite to prevent HCC. Nevertheless, I urge HCC screening in patients with hepatitis who are treated with direct‐acting antiviral therapy. Indeed, this approach increases serum vascular endothelial growth factor levels by 4‐fold5 and thus deserves a close scrutiny.
Bacteriophage transfer during faecal microbiota transplantation in<i>Clostridium difficile</i>infection is associated with treatment outcome
Authors: Tao Zuo, Sunny H Wong, Kelvin Lam, Rashid Lui, Kitty Cheung, Whitney Tang, Jessica Y L Ching, Paul K S Chan, Martin C W Chan, Justin C Y Wu, Francis K L Chan, Jun Yu, Joseph J Y Sung, Siew C Ng
Journal: Gut (2017)

<h3>Objective</h3> Faecal microbiota transplantation (FMT) is effective for the treatment of recurrent <i>Clostridium difficile</i> infection (CDI). Studies have shown bacterial colonisation after FMT, but data on viral alterations in CDI are scarce. We investigated enteric virome alterations in CDI and the association between viral transfer and clinical outcome in patients with CDI. <h3>Design</h3> Ultra-deep metagenomic sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on stool samples from 24 subjects with CDI and 20 healthy controls. We longitudinally assessed the virome and bacterial microbiome changes in nine CDI subjects treated with FMT and five treated with vancomycin. Enteric virome alterations were assessed in association with treatment response. <h3>Results</h3> Subjects with CDI demonstrated a significantly higher abundance of bacteriophage <i>Caudovirales</i> and a lower <i>Caudovirales</i> diversity, richness and evenness compared with healthy household controls. Significant correlations were observed between bacterial families <i>Proteobacteria</i>, <i>Actinobacteria</i> and <i>Caudovirales</i> taxa in CDI. FMT treatment resulted in a significant decrease in the abundance of <i>Caudovirales</i> in CDI. Cure after FMT was observed when donor-derived <i>Caudovirales</i> contigs occupied a larger fraction of the enteric virome in the recipients (p=0.024). In treatment responders, FMT was associated with alterations in the virome and the bacterial microbiome, while vancomycin treatment led to alterations in the bacterial community alone. <h3>Conclusions</h3> In a preliminary study, CDI is characterised by enteric virome dysbiosis. Treatment response in FMT was associated with a high colonisation level of donor-derived <i>Caudovirales</i> taxa in the recipient. <i>Caudovirales</i> bacteriophages may play a role in the efficacy of FMT in CDI. <h3>Trial registration number</h3> NCT02570477
Margaret McCartney: Our politicians are wilfully failing the NHS
Authors: Margaret McCartney
Journal: BMJ (2017)

The NHS and, by logical extension, social care should be the defining touchstone of the 2017 general election. Whether or not there’s a “humanitarian crisis,” as the British Red Cross warned in January,1 the system is under unsustainable stress.

Under these circumstances, manifestos promising government that’s “strong and stable” or “for the many not the few” must be backed up with hard evidence and thorough cost effectiveness calculations. After all, the surreal, persistent political misrepresentation of weekend mortality—all supposedly to justify a Conservative manifesto pledge from the last election—led to strikes and an overflowing, bitter cup for junior doctors.

Sadly, the 2017 manifestos seem no less damaging than the last Conservative one. …
Quelle place pour la dissection sous-muqueuse endoscopique dans le traitement des cancers superficiels sur oesophage de Barrett?
Authors: M Barret, DT Cao, F Beuvon, S Leblanc, M Camus, R Coriat, S Chaussadel, F Prat
Journal: Endoscopy (2016)

La dissection sous-muqueuse endoscopique permet la résection carcinologique des cancers superficiels digestifs. Sa supériorité sur la mucosectomie endoscopique a été démontrée pour les cancers superficiels épidermoïdes de l'oesophage. L'intérêt de la dissection sous-muqueuse dans le traitement des adénocarcinomes superficiels de l'oesophage reste controversé. Nous avons évalué l'efficacité et le taux de complications de la dissection sous-muqueuse dans le traitement des cancers superficiels développés sur oesophage de Barrett.
TRTH-25. REDUCING TIME TO DIAGNOSIS OF PAEDIATRIC BRAIN TUMOURS IN THE UK – HEADSMART AWARENESS CAMPAIGN (WWW.HEADSMART.ORG.UK)
Authors: Jo-Fen Liu, Dhurgsharna Shanmugavadivel, Sophie Wilne, David A Walker
Journal: Neuro-Oncology (2017)

BACKGROUND: Public and professional concern about delays in diagnosis of childhood brain tumours has led to a clinical referral guidelines and the HeadSmart campaign to raise awareness of the early features of brain tumours and the need for timely imaging. As part of the outcome evaluation, we have collected data on total diagnostic intervals (TDI) i.e. intervals between symptom onset to diagnosis through a national service evaluation. The aims of the project are to (1) report the most recent TDI; and (2) identify the subgroup(s) with the longest symptom interval. METHODS: Paediatric brain tumour cases (aged 0–18 years) diagnosed between June 2014 and May 2015 were identified through a network of HeadSmart clinical champions. Age at diagnosis, dates of first symptom onset, first presentation to healthcare and diagnosis, tumour site, diagnosis were collected thorough an online data collection form. RESULTS: Data of 334 eligible cases, representing over 75% of incident cases in the UK of that year were recorded. TDI showed a right skewed distribution with a 90th percentile of 48 weeks and maximum of 313 weeks. Group median TDI had reduced significantly from 14.4 weeks in 2006, to 9.1 weeks in 2011 at the time HeadSmart was launched, and then to 6.5 weeks in 2015. Stratified analysis showed that there is still a significant difference between age groups. Median TDI is 3.9, 6.6 and 9.9 weeks for children under 5, 5–11 years and 12–18, respectively. CONCLUSIONS: These findings justifying a more targeted approach for the awareness campaign. With a rebranded website (www.headsmart.org.uk), new animation, posters to summarise symptom by subspecialty and quick reference guide, we hope to raise the awareness amongst young people aged 12–18 years and general practitioners, and reduce the median TDI further to national target of four weeks.
Rising incidence of young-onset colorectal cancer in Texas, 1995-2010.
Authors: Daniel Wang Ying, David R Risser, Patricia Thompson, Neda Zarrin-Khameh, Melissa Bondy, Benjamin Leon Musher
Journal: Journal of Clinical Oncology (2014)

1587 Background: Although colorectal cancer (CRC) has traditionally been considered a disease of the elderly, the incidence of CRC among young adults in the US has been steadily rising. Examining CRC trends in Texas may, by virtue of its diverse population, shed light on future CRC epidemiology in the US. Methods: In this retrospective cohort study, we used 1995-2010 Texas Cancer Registry data to calculate the annual percentage change (APC) of CRC incidence by age, race/ethnicity, and anatomic site. Results: Of the 125,987 cases identified, 11% occurred in people <50 years old. The APCs of CRC incidence for individuals >50, 40-49, and 20-39 years old were -2.1% (CI -2.7 to -1.5, p<.05), 0.2% (NS), and 1.7% (CI 1.0 to 2.4, p<.05), respectively. In the >50 cohort, the incidence of CRC in all colon subsites progressively decreased (see Table). In the 20-39 group, sigmoid/rectum tumors became increasingly more common among Hispanics (APC 2.7% [CI 1.1 to 4.2, p<.05]) and non-Hispanic whites (APC 3.4% [CI 1.9 to 4.6, p<.05]) but not among African-Americans (APC -0.7% [CI -2.9 to 1.7, NS]), and there was a non-significant rise in right-sided tumors among African-Americans (APC 2.4% [CI -0.5 to 5.4, NS]). Compared to the >50 cohort, patients 20-39 were more likely to present with Stage III/IV disease (65.8% vs 53.2% [p<.01]). Conclusions: While the incidence of CRC in older Texans has fallen, CRC has become progressively more common in individuals 20-39 years old, a trend largely attributable to a rise in distal tumors in Hispanics and non-Hispanic whites. Younger patients tend to present with more advanced disease, likely due to lack of routine screening and/or more aggressive biology. Young-onset CRC is an emerging disease that warrants further investigation. APCs in CRC incidence, 1995-2010. Age Race/ethnicity Whole colon Right colon Left colon Sigmoid/rectum 20-39 All 1.7* 1.5* 2.1* 2.3* NHW 2.3* 1.3 3.2* 3.4* AA 0.2 2.8 -1.9 -0.7 Hispanic 2.1* 1.8 2.6* 2.7* 40-49 All 0.2 0.5 0.1 0.1 NHW 1.0* 0.8 1.0* 1.3* AA -1.0 0.3 -1.6 -2.1* Hispanic -0.5 -0.1 -0.7 0.9 >50 All -2.1* -1.4* -2.5* -2.6* NHW -2.5* -1.6* -3.0* -3.0* AA -1.4* -0.5 -1.9* -2.0* Hispanic -0.7 0.1 -1.1* -1.1* *APC significantly different from zero (p<.05). AA = African American. NHW = Non-Hispanic whites.