tbuckley/cabot-search huggingface dataset:
BUSPIRONE IS EFFECTIVE ON CENTRAL APNEAS IN PATIENTS WITH SYSTOLIC HEART FAILURE
Authors: Chiara Borrelli, Gianluca Mirizzi, Claudio Passino, Francesca Bramanti, Giovanni Iudice, Eleonora Benelli, Assunta Agazio, Francesco Grotti, Michele Emdin, Alberto Giannoni
Journal: Journal of the American College of Cardiology (2018)
Role of mTORC2 and nitric oxide in bladder cancer invasion.
Authors: Divya Sahu, Donna E. Hansel, Richard Klemke, Gerry Boss
Journal: Journal of Clinical Oncology (2018)

504 Background: In the United States, bladder cancer is the fourth most common cancer, with an estimated 79,000 new diagnoses and 17,000 deaths in 2017, and the eleventh most common cancer worldwide. The key driver of bladder cancer stage progression is tumor cell invasion which has limited response to current chemotherapy options and hence, newer therapies directed against invasion are key to improving the treatment of bladder cancer. Our laboratory has identified mammalian target of rapamycin complex 2 (mTORC2) as a driver of bladder cancer cell invasion. We have also recently shown that arginine, the nitric oxide (NO) precursor, is implicated in bladder cancer progression. We evaluated the interaction between these two pathways to promote invasion. Methods: Expression of inducible and endothelial nitric oxide synthases (iNOS and eNOS) in FFPE tissue sections of progressive disease was assessed by IHC and correlated with histopathology, progression and stage based on moderate to strong expression (2+, 3+) compared to absent to weak expression (0, 1+).We utilized gene silencing methods and NOS inhibitors and NO scavenger for effects on bladder cancer invasion and migration. We assessed mTORC2 pathway activity and NOS levels in invasive cell tip protrusions called “invadopodia” and evaluated if mTORC2 regulates NOS localization and/or activity. We used a novel zebrafish model to characterize the effects of mTORC2 and NO on bladder cancer metastases. Results: We found that eNOS and iNOS are elevated in invasive human bladder tumors and cell lines and their ablation reduces bladder cancer cell migration and invasion. mTORC2 silencing can affect levels of iNOS and eNOS in bladder cancer cell lines. Silencing of mTORC2, eNOS or iNOS reduced metastases of bladder cancer cells within zebrafish. Conclusions: mTORC2 pathway is a key driver of bladder cancer invasion and metastases by regulating the NO pathway and both mTORC2 and NO can be targets for bladder cancer therapy, which would benefit patient outcomes.
Treatment effects measured by restricted mean survival time in trials of immune checkpoint inhibitors for cancer
Authors: F. Liang, S. Zhang, Q. Wang, W. Li
Journal: Annals of Oncology (2018)

The hazard ratio (HR) is used routinely to quantify the treatment effect for time-to-event end points in oncology trials, but its use requires that there be proportional hazards in the treatment arms. Non-proportional hazards are observed frequently in cancer immunotherapy trials due to the long-term survival and delayed clinical effect. Although values of HR are quoted in such trials, they are not valid measures of outcome.Reports of parallel group randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors with overall survival data were eligible. For each trial, the ratio of restricted mean survival time (RMST) between the arms was based on reconstructed individual patient data for overall survival.Twenty-five RCTs totaling 12 870 patients were included in this study. Overall survival was used as primary or coprimary end point in 18 trials (72%). In all trials, there was agreement between the ratio of RMST or RMTL and the reported HR about the direction of treatment effect. Estimates of HR provided larger estimates of treatment effect than the ratio of RMST or RMTL in all these trials. The estimated HR and RMST-based measures were in agreement regarding the statistical significance of the effect in all but two trials.Ratio of RMST is a complementary technique that provides alternative method of summarizing treatment effects. Proportional hazards of the treatment effect should not be assumed in RCTs evaluating immune checkpoint inhibitors, and RMST analysis should be reported in such trials.
Ethnic differences in the association between maternal vitamin D status and offspring asthma and wheeze: Findings from the Born in Bradford cohort study
Authors: G. Santorelli, J. Wright, A. Sheikh
Journal: Allergy (2018)

The authors declare that they have no conflicts of interest. 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.
A TOOL FOR PERSONALIZED DECISION MAKING: A CLINICAL PREDICTION MODEL FOR ANTHRACYCLINE CARDIOTOXICITY IN EARLY STAGE BREAST CANCER
Authors: Jenica Upshaw, Robin Ruthazer, Kathy Miller, Susan Parsons, John Erban, Anne O’Neill, Lynne Wagner, George Sledge, Bonnie Ky, David Kent
Journal: Journal of the American College of Cardiology (2018)
ELEVATED END-DIASTOLIC WALL STRESS AFTER ACUTE MYOCARDIAL INFARCTION PREDICTS ADVERSE CARDIOVASCULAR OUTCOMES AND LONGER HOSPITAL LENGTH OF STAY
Authors: Wassim Mosleh, Tanvi Shah, Roshan Karki, Milind Chaudhari, Charl Khalil, Kevin Frodey, Dahal Suraj, Umesh Sharma
Journal: Journal of the American College of Cardiology (2018)
EVALUATION OF THE RIGHT VENTRICULAR SYSTOLIC FUNCTION RECOVERY AND REMODELING AFTER PERCUTANEOUS CORONARY INTERVENTION IN PATIENTS WITH INFERIOR WALL AND RIGHT VENTRICULAR MYOCARDIAL INFARCTION
Authors: Xue Yao, Bo Hu, Tuan-Tuan Tan, Qing Zhou, Rui-Qiang Guo
Journal: Journal of the American College of Cardiology (2018)
Sex differences in delayed antiretroviral therapy initiation among adolescents and young adults living with HIV in DR Congo
Authors: Sarina Dane, Tania Tchissambou, Désiré Dibulundu, Caitlin Madevu-Matson, Bibola Ngalamulume-Roberts, Faustin Malele Bazola, Juliana Soares Linn
Journal: The Lancet Global Health (2018)

BackgroundIn DR Congo, adolescent girls are disproportionately vulnerable to HIV. Nonetheless, females are often more engaged in the health-care system, including during antenatal care, when women enrolled on Option B+ for prevention of mother-to-child transmission of HIV initiate antiretroviral therapy (ART). We aimed to understand the extent of delayed ART initiation among adolescents and young adults newly enrolled in HIV care, and to assess whether there were any sex differences.MethodsAggregate data from 365 ICAP-supported sites in Kinshasa and Haut-Katanga provinces in DR Congo from April 2016 to May 2017 were reviewed to describe delayed ART uptake among adolescents and young adults aged 15–24 years. Delayed uptake was defined as not beginning treatment within 1 month of enrolling in care among those eligible for ART. Pregnant and non-pregnant women were combined since available data did not disaggregate by pregnancy status. DR Congo began implementing "test and start" during the study period. All analyses used group-level data and were conducted using multivariable logistic regression, adjusting for setting and age group.FindingsBetween April 2016 and May 2017, 861 adolescents and young adults (128 male and 733 female) enrolled in HIV care and treatment services. 21 (16%) males and 58 (8%) females had not begun treatment within 1 month of enrolling in care, despite eligibility for ART (odds ratio [OR] 2·28, 95% CI 1·33–3·92). The male predominance remained after controlling for setting (urban vs rural) and age group (15–19 years vs 20–24 years) (adjusted OR 2·03, 95% CI 1·17–3·53). Aggregate data did not allow for analysis of individual explanations, but reasons for delayed ART may include the need to stabilise patients before starting treatment and patients' preferences.InterpretationDespite being more vulnerable to HIV, female adolescents and young adults have faster ART initiation than males after enrolling in HIV treatment. It is likely that Option B+ expedites ART initiation for females. Going forwards, ICAP will strengthen its adolescent package of support with community-based adolescent-friendly interventions targeting males, with the goal to enrol all adolescents and young adults on ART in accordance with DRC's test and start guidelines.FundingCDC/PEPFAR.
IMPACT OF HYDROSTATIC PRESSURE ON FRACTIONAL FLOW RESERVE: IN VIVO EXPERIMENTAL STUDY MEASURING HEIGHT DIFFERENCES WITHIN SWINE CORONARY ARTERIES
Authors: Suguru Nagamatsu, Kenji Sakamoto, Ryota Sato, Takayoshi Yamashita, Seiji Takashio, Yasuhiro Izumiya, Daisuke Utsunomiya, Kenichi Tsujita
Journal: Journal of the American College of Cardiology (2018)
EV-103 study: A phase 1b dose-escalation and dose-expansion study of enfortumab vedotin in combination with immune checkpoint inhibitor (CPI) therapy for treatment of patients with locally advanced or metastatic urothelial cancer.
Authors: Christopher J. Hoimes, Daniel Peter Petrylak, Thomas W. Flaig, Anne-Sophie Carret, Amal Melhem-Bertrandt, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2018)

TPS532 Background: Immune checkpoint inhibitors (CPIs) are approved for patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) who progress on prior platinum or are ineligible for first line cisplatin. However, only a minority of pts respond to CPI monotherapy and a combination approach may be beneficial. Enfortumab vedotin (EV), an antibody-drug conjugate (ADC), delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) to tumors expressing Nectin-4, which is overexpressed in mUC. Preliminary results from an ongoing phase 1 study of EV monotherapy in pts with mUC (Petrylak ASCO 2017) showed that EV was well tolerated in pts with mUC. EV showed a 41% (29 out of 71 pts) objective response rate (ORR) across all doses (24 wks median response duration). In pts with liver metastasis the ORR was 47% (9 out 19 pts) across all doses. Preclinical data show that an MMAE ADC, but not the unconjugated antibody, increases tumor immunogenicity by inducing immunogenic cell death, antigen presentation and tumor immune infiltration (Gardai 2015). Based on encouraging phase 1 study results and potential enhanced immune response, combining EV with a CPI may result in improved response rates with longer durability. Methods: This phase 1b study (NCT03288545) evaluates the safety/activity of EV + CPI in pts with la/mUC who have not previously received a CPI. The study has 2 parts: dose escalation (EV + pembrolizumab) and dose expansion (EV + CPI [pembrolizumab or atezolizumab]). Pts must have la/m transitional cell carcinoma of the urothelium, be eligible for treatment with a CPI, and be either ineligible for first-line cisplatin-based chemotherapy or have disease progression during or following treatment with ≥1 platinum-containing regimen. The primary objective is to assess the safety/tolerability of EV + CPI. Secondary objectives include determining a recommended dose of EV + CPI in pts with la/mUC, antitumor activity as measured by ORR, disease control rate, duration of response, PFS, and OS. Response is assessed per RECIST v1.1 and iRECIST. Study enrollment began in Oct 2017. Clinical trial information: NCT03288545.
PRIMARY LV UNLOADING WITH A TRANS-VALVULAR AXIAL FLOW PUMP REDUCES INFARCT SIZE BY INCREASING MYOCARDIAL LEVELS OF STROMAL DERIVED FACTOR ONE ALPHA (SDF-1A) IN ACUTE MYOCARDIAL INFARCTION AND LIMITS THE DEVELOPMENT OF ISCHEMIC HEART FAILURE
Authors: Michele Esposito, Yali Zhang, Xiaoying Qiao, Lara Reyelt, Kevin Morine, Shiva Annamalai, Courtney Bogins, Peter Natov, Ayan Patel, Ethan Rowin, Richard Karas, Navin Kapur
Journal: Journal of the American College of Cardiology (2018)
Automation of quantifying and mapping of stromal and malignant cells in pancreatic adenocarcinoma using deep learning.
Authors: Sunyoung S. Lee, Jin Cheon Kim, Jillian Dolan, Andrew Baird
Journal: Journal of Clinical Oncology (2018)

266 Background: The characteristic histological feature of pancreatic adenocarcinoma (PAD) is extensive desmoplasia alongside leukocytes and cancer-associated fibroblasts. Desmoplasia is a known barrier to the absorption and penetration of therapeutic drugs. Stromal cells are key elements for a clinical response to chemotherapy and immunotherapy, but few models exist to analyze the spatial and architectural elements that compose the complex tumor microenvironment in PAD. Methods: We created a deep learning algorithm to analyze images and quantify cells and fibrotic tissue. Histopathology slides of PAD patients (pts) were then used to automate the recognition and mapping of adenocarcinoma cells, leukocytes, fibroblasts, and degree of desmoplasia, defined as the ratio of the area of fibrosis to that of the tumor gland. This information was correlated with mutational burden, defined as mutations (mts) per megabase (mb) of each pt. Results: The histopathology slides (H&amp;E stain) of 126 pts were obtained from The Cancer Genome Atlas (TCGA) and analyzed with the deep learning model. Pt with the largest mutational burden (733 mts/mb, n = 1 pt) showed the largest number of leukocytes (585/mm 2 ). Those with the smallest mutational burden (0 mts/mb, n = 16 pts) showed the fewest leukocytes (median, 14/mm 2 ). Mutational burden was linearly proportional to the number of leukocytes (R 2 of 0.7772). The pt with a mutational burden of 733 was excluded as an outlier. No statistically significant difference in the number of fibroblasts, degree of desmoplasia, or thickness of the first fibrotic layer (the smooth muscle actin-rich layer outside of the tumor gland), was found among pts of varying mutational burden. The median distance from a tumor gland to a leukocyte was inversely proportional to the number of leukocytes in a box of 1 mm 2 with a tumor gland at the center. Conclusions: A deep learning model enabled automated quantification and mapping of desmoplasia, stromal and malignant cells, revealing the spatial and architectural relationship of these cells in PAD pts with varying mutational burdens. Further biomarker driven studies in the context of immunotherapy and anti-fibrosis are warranted.
Where can I access a list of all locum agencies and contact details?
Authors: Adam Harrison
Journal: BMJ (2004)

<h3>ABSTRACT</h3> Since SARS-Cov-2 started spreading in China and turned into a pandemic disease called Covid-19, many articles about prediction with mathematical model have appeared in the literature. In addition to models in specialized journals, a significant amount of software was made available, presenting with dashboards spreading of the pandemic for each new. These models are solved by computer simulation of traditional exponential models as a representation of the growth of cases and deaths. Some more accurate models are based on existing variations of SIR model (Susceptible, Infected and Recovered). A third class of study is developed in spatial or probabilistic models as a way of forecasting the effect of Covid-19 around the world. Data on the number of positive cases in all countries, show that SARS-Cov-2 shows great resistance even after strategies of lockdown or social distancing. The purpose of this article is to show how the bifurcation theory, known as Catastrophe Theory, can help to understand why Covid-19 expansion rates change so much and even with low values for a longtime trigger contagion quickly and abruptly. The Catastrophe Theory was conceived by the mathematician René Thom in the 60s with wide applications in works in the 70s. The outbreak of spruce budworm in Canada revealed a very interesting opportunity to test Catastrophe Theory whose explanation for the phenomenon was widely debated in the academic world. Inspired by the same mathematical approach to this phenomenon in Canada in the 1970s, we applied the Catastrophe Theory in the current Covid-19 pandemic. We observed that sudden outbreaks occur when the carrying capacity and the rate of expansion of the virus reach a region of bifurcation on the cusp surface. With actual Covid-19 data obtained from WHO, we fitted the dynamic model using the particle swarm technique and compared the results in the bifurcation plan with the Covid-19 outbreaks in different regions of the world. It is possible in many cases to observe the trajectory of the parameters between limit points in the bistable region and the consequent explosion of cases observed for each country assessed.
CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer
Authors: J. Smeby, A. Sveen, M.A. Merok, S.A. Danielsen, I.A. Eilertsen, M.G. Guren, R. Dienstmann, A. Nesbakken, R.A. Lothe
Journal: Annals of Oncology (2018)

BackgroundThe prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression–based consensus molecular subtypes (CMSs) of CRC define molecularly and clinically distinct subgroups, and represent a novel stratification framework in biomarker analysis. We investigated the prognostic value of these mutations within the CMS groups.Patients and methodsTotally 1197 primary tumors from a Norwegian series of CRC stage I–IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 12, 13 and 61) and BRAF (codon 600). A subset was analyzed for gene expression and confident CMS classification was obtained for 317 samples. This cohort was expanded with clinical and molecular data, including CMS classification, from 514 patients in the publically available dataset GSE39582. Gene expression signatures associated with KRAS and BRAFV600E mutations were used to evaluate differential impact of mutations on gene expression among the CMS groups.ResultsBRAFV600E and KRAS mutations were both associated with inferior 5-year overall survival (OS) exclusively in MSS tumors (BRAFV600E mutation versus KRAS/BRAF wild-type: Hazard ratio (HR) 2.85, P< 0.001; KRAS mutation versus KRAS/BRAF wild-type: HR 1.30, P= 0.013). BRAFV600E-mutated MSS tumors were strongly enriched and associated with metastatic disease in CMS1, leading to negative prognostic impact in this subtype (OS: BRAFV600E mutation versus wild-type: HR 7.73, P= 0.001). In contrast, the poor prognosis of KRAS mutations was limited to MSS tumors with CMS2/CMS3 epithelial-like gene expression profiles (OS: KRAS mutation versus wild-type: HR 1.51, P= 0.011). The subtype-specific prognostic associations were substantiated by differential effects of BRAFV600E and KRAS mutations on gene expression signatures according to the MSI status and CMS group.ConclusionsBRAFV600E mutations are enriched and associated with metastatic disease in CMS1 MSS tumors, leading to poor prognosis in this subtype. KRAS mutations are associated with adverse outcome in epithelial (CMS2/CMS3) MSS tumors.
Lords and ministers raise concerns about career progression of female doctors
Authors: Caroline White
Journal: BMJ (2012)

The career progression of women doctors in the NHS is “a serious and significant issue,” a senior health minister has said.

Speaking during a debate in the House of Lords on Tuesday, prompted by concerns voiced by Baroness Deech about women doctors’ career paths, parliamentary under secretary of state Earl Howe said that far too few women made it to the top of the NHS, which represented a huge loss of talent.

He cited figures showing a 75% surge in women doctors working in the NHS over the past decade, including a 105% rise in the number of female consultants, a 58% increase …
PROGNOSTIC IMPACT OF CORONARY VASOSPASM RELATED TYPE 2 MYOCARDIAL INFARCTION IN JAPANESE: RESULTS FROM J-MINUET SUB-STUDY
Authors: Kenji Sakamoto, Kenichi Tsujita, Koichi Kaikita, Koichi Nakao, Yukio Ozaki, Kazuo Kimura, Junya Ako, Teruo Noguchi, Satoshi Yasuda, Satoru Suwa, Kazuteru Fujimoto, Yasuharu Nakama, Takashi Morita, Wataru Shimizu, Yoshihiko Saito, Atsushi Hirohata, Yasuhiro Morita, Teruo Inoue, Atsunori Okamura, Toshiaki Mano, Kunihiro Nishimura, Yoshihiro Miyamoto, Hisao Ogawa, Masaharu Ishihara
Journal: Journal of the American College of Cardiology (2018)
Severe cutaneous adverse reactions due to inappropriate medication use
Authors: G. Chaby, L. Valeyrie-Allanore, T.A. Duong, B. Lebrun-Vignes, B. Milpied, B. Sassolas, F. Tetart, P. Wolkenstein, O. Chosidow, L. Fardet
Journal: British Journal of Dermatology (2018)

The proportion of severe cutaneous adverse reactions (SCARs) that could be avoided if medication use was consistent with good medical practice is unknown.To estimate the proportion of SCARs related to inappropriate medication use.We carried out a retrospective study of all validated SCARs collected in a French registry between 2003 and 2016. For each case, all plausible drugs suspected of inducing SCARs (i.e. not just the drug regarded as 'the most probable') were considered with regard to (i) prescription for an inappropriate indication, (ii) unintentional rechallenge despite a previous allergy to the drug or (iii) self-medication with prescription medicines.In total, 602 cases were included in the analyses. Antibiotics, anticonvulsants and allopurinol were the drugs most frequently involved, accounting for more than 50% of all cases. All suspected medications were considered to have been appropriately used for 417 of the 602 individuals included in the study population [69·3%, 95% confidence interval (CI) 65·6-73·0] and inappropriately used for 144 individuals (23·9%, 95% CI 20·5-27·3). These inappropriate uses were due mainly to prescriptions for an inappropriate indication (65·8%, 95% CI 58·4-73·2) or unintentional rechallenge (20·9%, 95% CI 14·6-27·2). Allopurinol and co-trimoxazole were the drugs most frequently involved in inappropriate indications. Antibiotics were the largest group involved in unintentional rechallenge. Nonsteroidal anti-inflammatory drugs, available on prescription, were most frequently involved in inappropriate self-medication.Our results underline the need for respecting the appropriate indication for drugs in order to reduce the incidence of SCARs. Reducing unintentional rechallenge also seems to be a necessary preventive measure.
An HIV Behavioral Intervention Gets It Right—and Shows We Must Do Even Better
Authors: Lisa R. Metsch, Tracy Pugh, Grant Colfax
Journal: JAMA Internal Medicine (2018)

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