tbuckley/cabot-search huggingface dataset:
P040 Involvement of the anti-ageing protein klotho in chondrocyte autophagy and apoptosis during osteoarthritis
Authors: E Le Tilly, T Ong, J Abadie, J Guicheux, L Beck, C Vinatier
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> The pathogenesis of OA is not fully characterised, but is thought to be due to perturbation of chondrocytes homeostasis including an impairment in the autophagy process particularly during ageing. Among the anti-ageing factors, Klotho has been shown to regulate autophagy in a variety of cell types, and Klotho polymorphisms have been associated with higher risks of OA. <h3>Objectives</h3> The aim of this project was to investigate the role of Klotho in OA. <h3>Methods</h3> The expression of Klotho and autophagy markers (LC3b and Beclin-1) and OA onset were evaluated in ageing C57BL/6 mice as an age-related spontaneous model of OA. The cartilage integrity, autophagy and apoptosis status in Klotho-deficient mice knee joints were also analysed. In parallel, to investigate the relationship between Klotho and autophagy, immature murine articular chondrocytes (iMACs) were stimulated with increasing doses of soluble recombinant Klotho. The effect of Klotho on autophagy was also evaluated in a pathological context, i.e. following IL1-β stimulation (10 ng/ml) for 24 hours. Bax/Bcl-2 ratio, a marker of the intrinsic apoptotic pathway, was also evaluated in IL1-β-treated chondrocytes. <h3>Results</h3> In the knee joints of mice from escalating ages, the expression of Klotho correlated with LC3b and Beclin-1 expression and gradually decreased with age while OA features appear. Articular cartilage of KL-/- mice revealed an increase in the OARSI score, associated with increased chondrocyte death and LC3b expression, as well as caspase 3 and TUNEL expression. In IL1-β-treated chondrocytes, the autophagy markers and Bax/Bcl-2 ratio were overexpressed, while the addition of Klotho counteracted this effect. <h3>Conclusions</h3> In summary, we described an early articular cartilage degradation in the absence of Klotho, suggesting a potential protective role of Klotho in OA development. The increase in autophagic process in Klotho mutant mice associated with the decrease in autophagy and Klotho expression with age clearly indicate intimate relationships between these two players. <i>In vitro</i> experiments suggested that Klotho may not have a direct effect on autophagy but rather through reducing apoptosis induced by pro-inflammatory cytokines such as IL1-β. Our study revealed the close relationship between the anti-ageing Klotho protein and chondrocyte death in articular cartilage, unveiling Klotho as a potential target to enhance chondrocyte survival. <h3>Disclosure of interest</h3> None declared
Diagnosis of sepsis from a drop of blood by measurement of spontaneous neutrophil motility in a microfluidic assay
Authors: Felix Ellett, Julianne Jorgensen, Anika L. Marand, Yuk Ming Liu, Myriam M. Martinez, Vicki Sein, Kathryn L. Butler, Jarone Lee, Daniel Irimia
Journal: Nature Biomedical Engineering (2018)
Age Effects on Cerebral Oxygenation and Behavior in Children with Sleep-disordered Breathing
Authors: Knarik Tamanyan, Lisa M. Walter, Aidan Weichard, Margot J. Davey, Gillian M. Nixon, Sarah N. Biggs, Rosemary S. C. Horne
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Childhood sleep-disordered breathing ranges in severity from primary snoring to obstructive sleep apnea and is associated with behavioral and neurocognitive deficits. It remains unknown why children with primary snoring, who do not experience peripheral oxygen desaturation or sleep fragmentation, experience similar daytime deficits as those with obstructive sleep apnea or why effects are age-dependent.To examine cerebral tissue oxygenation and oxygen extraction as an explanation for daytime deficits in children with primary snoring.Children referred for suspected sleep-disordered breathing and nonsnoring control subjects underwent overnight polysomnography with near-infrared spectroscopy. Children were categorized into 3- to 6-year (n = 87) and 7- to 12-year (n = 72) old groups, and according to the obstructive apnea-hypopnea index into primary snoring (≤1 event/h), mild (>1-5 events/h), and moderate/severe obstructive sleep apnea (>5 events/h). Cognitive and behavioral performance were assessed.In the 3- to 6-year group, there were no differences in cerebral oxygenation or oxygen extraction between severity groups. In the 7- to 12-year group, cerebral oxygenation was significantly lower, although these differences were small, in control subjects versus primary snoring during quiet wakefulness before sleep onset, N1, and REM. Oxygen extraction was significantly higher in control subjects versus primary snoring during N1 sleep, with no differences between primary snoring and obstructive sleep apnea groups. Cerebral oxygenation was not associated with cognitive performance in either age group or behavior in the 3- to 6-year group; however, it was associated with behavior in the school-aged children.Children with sleep-disordered breathing are able to maintain cerebral oxygenation, and the small changes observed are not related to cognitive deficits. However, in older children these differences were related to behavioral measures.
Abstract P3-06-04: Bcl-2 functional converters inhibit tumor growth and metastatic potential in zebrafish xenografts
Authors: J Gamble, M Pearce, P Kopparapu, HS Jang, R Tanguay, J Greenwood, S Kolluri
Journal: Cancer Research (2018)

Abstract While potential therapies might have pronounced success in the simplified settings in cell culture medium, many drugs fail or underperform when cancer cells are encased in a complex 3D microenvironment. Although, rat and mouse models will continue to be the gold standard for in vivo data in drug discovery, zebrafish xenograft models have emerged as a powerful model that can quickly and efficiently deliver in vivo drug efficacy data before commitment to expensive and time consuming rodent models. We have discovered several compounds that work as B-cell lymphoma 2 (Bcl-2) functional converters and activate Bcl-2 into a killer instead of its native anti-apoptotic role. In this study, we use a zebrafish xenograft model to evaluate the ability of these compounds to inhibit xenograft tumor growth of Bcl-2 expressing cancer cells, including triple negative breast cancers. Live fluorescent imaging of cancer cells within zebrafish embryos revealed a decrease in cancer cell growth while under treatment of compounds. Furthermore, the agents that converted Bcl-2 into pro-apoptotic protein also inhibited the metastatic potential of the cancer cells. Therefore, this study demonstrates zebrafish xenograft techniques that can be used to quickly and efficiently obtain in vivo drug discovery data. Moreover, we report novel Bcl-2 functional converter compounds that can effectively reduce xenograft tumor growth and its ability to invade tissue in a living 3D environment and establish the role of Bcl-2 in cancer progression. Citation Format: Gamble J, Pearce M, Kopparapu P, Jang HS, Tanguay R, Greenwood J, Kolluri S. Bcl-2 functional converters inhibit tumor growth and metastatic potential in zebrafish xenografts [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-06-04.
NHS reorganisation forces GPs to choose between patients and CCGs, warns BMA
Authors: Helen Jaques
Journal: BMJ (2013)

The Health and Social Care Act has created an “untenable conflict” between GPs’ professional obligations to patients and their statutory obligations to local commissioning groups, the BMA has warned.

The BMA said that practices’ responsibility to comply with the statutory obligations of their local clinical commissioning group (CCG) include staying within budget and meeting managerially driven targets. This will place “significant obstacles” in the way of …
P074 Il-10 regulates skin thickness and scaling in imiquimod-induced psoriasis-like skin inflammation in mice
Authors: X Xu, E Prens, E Florencia, L Boon, P Asmawidjaja, A-M Otten-Mus, E Lubberts
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Psoriasis is an autoimmune skin disease affecting around 0.6% to 3% of the whole population with detrimental physical and societal impacts. Previously, we established a psoriasis-like skin inflammation model in mice using topical application of imiquimod (IMQ). This model successfully re-captures all critical features of clinical psoriasis such as keratinocyte hyperproliferation, munro's microabscesses, and shares a similar infiltration profile of various immune cells. Previous data suggest up-regulation of IL-10, but its role in this psoriasiform model is not clear. <h3>Objectives</h3> To investigate the role of IL-10 in the IMQ-induced psoriasis-like skin inflammation. <h3>Methods</h3> Psoriasis-like skin inflammation was induced by topical application of imiquimod (Aldara) for 5 or 10 days. Mice were injected intraperitoneally with anti-IL-10 or an isotype control antibody or subcutaneously with dexamethasone. Back skin of mice was scored for up to 10 days using a modified Psoriasis Area and Severity Index (PASI) score system adapted from clinical PASI score. Inflammation and skin thickness were scored histologically. Gene expression and immune cells in the skin were analysed using RT-PCR and flow cytometry, respectively. <h3>Results</h3> At day 10, both skin thickness and scaling score were significantly higher after neutralising IL-10 compared to isotype control, or either group compared to dexamethasone-treated animals. At days 5 and 10, H and E staining confirmed that epidermal thickness was more prominent in anti-IL-10 treated mice compared to isotype control or dexamethasone-treated mice, with more profound differences at day 10. Ki-67 staining for proliferating keratinocytes showed more proliferation at the epidermal basal layer after neutralising IL-10. In addition, significant more infiltration of neutrophils was found in skin at day 10. At day 5, IL-23/IL-17 pathway cytokines were more significantly upregulated in anti-IL-10 group than the isotype control group, while at day 10, a significant upregulation of IL-19, IL-24 expression were found in anti-IL-10 group compared to isotype control. <h3>Conclusions</h3> IL-10 regulates skin thickness and scaling during psoriasis-like skin inflammation. Furthermore, our data suggested that IL-10 might influence psoriatic symptoms through dampening of IL-23/IL-17 axis in early phase (day 5) and reducing IL-19 and IL-24 expression at late stage (day 10). The negative feedback signal of IL-10 partially explains the observed decrease of inflammation in imiquimod-induced skin inflammation after day 5. <h3>Disclosure of interest</h3> X. Xu: None declared, E. Prens: None declared, E. Florencia: None declared, L. Boon: None declared, P. Asmawidjaja: None declared, A.-M. Otten-Mus: None declared, E. Lubberts Grant/research support from: Novartis
EXPRESS study: A multicenter, prospective trial in progress exploring the association between low level of genomic alteration and exceptional and unexpected response to targeted therapies in patients with solid tumors
Authors: O. Le Saux, A. Italiano, D. Spaeth, P.-E. Heudel, T. Filleron, V. Pezzella, M. Jimenez, F. Legrand, C. Ferté
Journal: Annals of Oncology (2018)
Scottish and Northern Irish doctors to be revalidated by GMC number
Authors: Helen Jaques
Journal: BMJ (2012)

The first cohort of doctors in Scotland and Northern Ireland to be revalidated from April next year will be picked randomly on the basis of their GMC registration number.

In Scotland doctors who have either 4 or 6 as the penultimate digit of their registration number will form the first 20% to be revalidated. The Scotland Revalidation Delivery Board says that this approach will guarantee the fair and indiscriminate selection of doctors for revalidation.

Doctors in Northern Ireland will …
Return to pivoting sport after ACL reconstruction: association with osteoarthritis and knee function at the 15-year follow-up
Authors: Britt Elin Øiestad, Inger Holm, May Arna Risberg
Journal: British Journal of Sports Medicine (2018)

Objectives To examine the associations between return to pivoting sport following ACL reconstruction (ACLR) and knee osteoarthritis (OA), and self-reported knee symptoms, function and quality of life after 15 years. Methods Study sample included 258 participants with ACLR 15 years previously. Return to pivoting sport (handball, soccer and basketball) data were collected by interviews, and symptomatic OA was defined as Kellgren and Lawrence grade ≥2 plus almost daily knee pain in the last month. Self-reported symptoms, function and quality of life were assessed with the Knee Injury and Osteoarthritis Outcome Score. Adjusted regression models were used to analyse the associations between return to pivoting sport and OA (present or not), and self-reported outcomes. P values ≤0.05 were considered statistically significant. Results Two hundred and ten (81%) participants (57% men) with a mean age of 39.1 (±8.7) years completed the 15-year follow-up, and 109 (52%) had returned to pivoting sport. Returning to pivoting sport was associated with less symptomatic OA (OR 0.28, 95% CI 0.09 to 0.89) and radiographic OA (OR 0.40, 95% CI 0.17 to 0.98), adjusted for age, sex, combined injury, self-reported knee function, and time between injury and surgery. Those who returned to pivoting sport had better function in activities of daily living (ADL). Conclusion The participants with ACLR who returned to pivoting sport had lower odds of knee OA and better self-reported ADL function. Further investigation is required to understand the clinical significance of these findings.
Postgraduate certificate in managing medical careers
Authors: Kavita Das
Journal: BMJ (2011)

With career support in medicine gaining importance, the certificate course in managing medical careers is highly relevant. The course is designed by the Institute of Postgraduate Medicine of Brighton and Sussex Medical School and delivered by Kent Surrey and Sussex Deanery. The course, which has been running since 2008, has recently been developed into a diploma and masters degree for those who are interested in progressing.

The course is ideal for all levels of staff who provide career support to medical students and trainee doctors: faculty career leads, educational supervisors, educational advisers, and medical education managers, for example. The teaching staff come from Kent Surrey and Sussex Deanery and have substantial experience in career guidance and support and medical education. Given the …
Healthcare utilization and costs associated with GI cancers in the United States.
Authors: Aileen Deng, Atrayee Basu Mallick
Journal: Journal of Clinical Oncology (2018)

361 Background: In 2009, adults had 4.7 million cancer-related hospitalizations. Adult hospital stays with cancer identified as the principal diagnosis cost $20.1 billion and accounted for 6% of adult inpatient hospital costs. GI cancer-related healthcare utilization has not been well-defined. The aim of this study was to evaluate the trends in the incidence and costs of GI cancer-related hospital admissions in the U.S. Methods: We reviewed the National Inpatient Sample Database (NIS) from 1997-2014. All patients with principle discharge diagnoses of esophageal, stomach, colon, rectum and anus, liver and intrahepatic bile duct and pancreas cancer were analyzed. Temporal trends in the number of hospital admissions, length of stay, hospitalization cost and mortality rates were obtained by HCUPnet. Results: GI cancer-related hospital admissions decreased from 230,537 in 1997 to 221,220 in 2014. Although the number of hospital admissions decreased for esophageal (12,157 to 11,885), stomach (23,528 to 21,800), colon (110,939 to 90,135), rectum and anus cancer (43,807 to 40,160), it has increased for liver and intrahepatic bile duct (11,243 to 21,775, p &lt; 0.001) and pancreas cancer (28,862 to 35,465, p &lt; 0.001). While the mean length of stay decreased from 9.6 days in 1997 to 7.6 days in 2014, the mean hospital charges per patient (adjusted for inflation) increased 127% from $34,747 in 1997 to $78,742 in 2014. The highest increase in mean hospital charges per patient were in liver and intrahepatic bile duct ($27,128 to $74,619 (175%), p &lt; 0.001), rectum and anus ($32,566 to $80,789 (148%), p &lt; 0.001) and pancreas cancer ($33,562 to $75,981 (126%), p &lt; 0.001). Conclusions: GI cancer-related hospital admissions decreased from 1997 to 2014. Despite decrease in the mean length of hospital stay, the costs of hospitalizations have increased substantially, especially in liver and intrahepatic bile duct, rectum and anus and pancreas cancer. Our study suggests that shorter length of stay alone has not reduced costs of hospitalizations in GI cancers. There remains a growing need to understand healthcare costs and to develop effective value-based interventions in GI cancer-related hospital admissions.
Analysis of Cell-Free DNA to Assess Risk of Tumoremia Following Endoscopic Ultrasound Fine-Needle Aspiration of Pancreatic Adenocarcinomas
Authors: Michael J. Levy, Benjamin R. Kipp, Dragana Milosevic, Amber R. Schneider, Jesse S. Voss, Rajeswari Avula, Sarah E. Kerr, Michael R. Henry, Edward Highsmith, Minetta C. Liu, Ferga C. Gleeson
Journal: Clinical Gastroenterology and Hepatology (2018)
Abstract 18039: Resource Utilization for Initial Hospitalization in Pediatric Heart Transplantation in the United States
Authors: Dana M Boucek, Ashwin K Lal, Nelangi M Pinto, Hsin-Yi Cindy Weng, Jacob F Wilkes, Shaji C Menon
Journal: Circulation (2015)

Background: Pediatric heart transplantation (HT) is resource intensive. Event driven pediatric HT databases do not capture data on resource use. The objective of this study was to evaluate resource utilization and identify associated factors during initial hospitalization for pediatric HT in a large multi-institutional cohort. Methods: This is a multicenter retrospective cohort study using the PHIS database (43 US children’s hospitals) of children ≤ 19 years of age who underwent HT between 1/07 and 7/13. Data collected: Demographic variables including site, payer, distance and time to center, clinical pre and post-transplant variables, mortality, cost and charge. Total length of stay (LOS) and charge for initial hospitalization were used as surrogates for resource use. Charges were inflation adjusted to 2013 $. Gamma regression analysis was performed to evaluate factors associated with resource use. Results: Of 1629 subjects, 54% were male, and the median age at HT was 5 years (IQR 0-13). The median total and ICU LOS were 51 (IQR: 23-98) and 23 (IQR: 9-58) days respectively, and mortality occurred in 82 (5%). Total charge and cost for hospitalization were $852,713 ($464,900-$1,609,300) and $383,600 ($214,900-$681,000) respectively. Factors associated with resource use on multivariate analysis are shown in Table 1. Younger age, lower center volume, southern region, and comorbidities prior to HT were associated with higher resource use. In later years, costs increased despite shorter LOS. Conclusions: This large multicenter study provides novel insight into factors associated with resource use in pediatric HT that cannot be assessed in alternative event driven transplant databases. Peri-transplant morbidities are associated with increased cost and LOS. Reducing costs in line with LOS will improve health care value. Regional and center volume differences need further investigation for optimizing value-based care and efficient use of scarce resources.
I am a Malaysian citizen thinking of going to the United Kingdom or the Republic of Ireland to study medicine. Is a UK degree recognised in the Republic of Ireland, and vice versa? Would I have to take exams before seeking jobs in the other country?
Authors: Jim Sherifi
Journal: BMJ (2006)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site. <b>www.bmjcareers.com/advicezone</b>
Death by Gun Violence—Guns Are Not the Problem—Reply
Authors: Howard Bauchner, Frederick P. Rivara
Journal: JAMA Dermatology (2018)

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GPs’ income fell 3% in a year, official data show
Authors: Abi Rimmer
Journal: BMJ (2015)

GPs’ average income before tax in 2013-14 was £90 200, a 3% decrease on the 2012-13 figure, shows an analysis by the NHS Health and Social Care Information Centre.1 The figures relate to UK GPs on the general medical services (GMS) contract and the primary medical services (PMS) contract and to salaried GPs.

The average taxable income of contractor GPs working under a GMS or PMS contract in the United Kingdom was £99 800 in 2013-14. This was a …