tbuckley/cabot-search huggingface dataset:
Covid-19: GP surgeries close for two weeks after staff test positive
Authors: Gareth Iacobucci
Journal: BMJ (2020)

A costimulatory member of the TNFR family, 4-1BB, is expressed on activated T cells. Although some reports have suggested that 4-1BB is primarily involved in CD8 T cell activation, in this report we demonstrate that both CD4 and CD8 T cells respond to 4-1BB ligand (4-1BBL) with similar efficacy. CD4 and CD8 TCR transgenic T cells up-regulate 4-1BB, OX40, and CD27 and respond to 4-1BBL-mediated costimulation during a primary response to peptide Ag. 4-1BBL enhanced proliferation, cytokine production, and CTL effector function of TCR transgenic T cells. To compare CD4 vs CD8 responses to 4-1BBL under similar conditions of antigenic stimulation, we performed MLRs with purified CD4 or CD8 responders from CD28<sup>+/+</sup> and CD28<sup>−/−</sup> mice. We found that CD8 T cells produced IL-2 and IFN-γ in a 4-1BBL-dependent manner, whereas under the same conditions the CD4 T cells produced IL-2 and IL-4. 4-1BBL promoted survival of CD4 and CD8 T cells, particularly at late stages of the MLR. CD4 and CD8 T cells both responded to anti-CD3 plus s4-1BBL with a similar cytokine profile as observed in the MLR. CD4 and CD8 T cells exhibited enhanced proliferation and earlier cell division when stimulated with anti-CD3 plus anti-CD28 compared with anti-CD3 plus 4-1BBL, and both subsets responded comparably to anti-CD3 plus 4-1BBL. These data support the idea that CD28 plays a primary role in initial T cell expansion, whereas 4-1BB/4-1BBL sustains both CD4 and CD8 T cell responses, as well as enhances cell division and T cell effector function.
Erratum: Corrigendum: Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis
Authors: Unnur Styrkarsdottir, Hannes Helgason, Asgeir Sigurdsson, Gudmundur L Norddahl, Arna B Agustsdottir, Louise N Reynard, Amanda Villalvilla, Gisli H Halldorsson, Aslaug Jonasdottir, Audur Magnusdottir, Asmundur Oddson, Gerald Sulem, Florian Zink, Gardar Sveinbjornsson, Agnar Helgason, Hrefna S Johannsdottir, Anna Helgadottir, Hreinn Stefansson, Solveig Gretarsdottir, Thorunn Rafnar, Ina S Almdahl, Anne Brækhus, Tormod Fladby, Geir Selbæk, Farhad Hosseinpanah, Fereidoun Azizi, Jung Min Koh, Nelson L S Tang, Maryams Danesphour, Jose I Mayordomo, Corrine Welt, Peter S Braund, Nilesh J Samani, Lambertus A Kiemeney, L Stefan Lohmander, Claus Christiansen, Ole A Andreassen, arcOGEN consortium, Olafur Magnusson, Gisli Masson, Augustine Kong, Ingileif Jonsdottir, Daniel Gudbjartsson, Patrick Sulem, Helgi Jonsson, John Loughlin, Thorvaldur Ingvarsson, Unnur Thorsteinsdottir, Kari Stefansson
Journal: Nature Genetics (2017)
The Use of a Smart Bolus Calculator Informed by Real-time Insulin Sensitivity Assessments Reduces Postprandial Hypoglycemia Following an Aerobic Exercise Session in Individuals With Type 1 Diabetes
Authors: Chiara Fabris, Ralf M. Nass, Jennifer Pinnata, Kelly A. Carr, Chaitanya L.K. Koravi, Charlotte L. Barnett, Mary C. Oliveri, Stacey M. Anderson, Daniel R. Chernavvsky, Marc D. Breton
Journal: Diabetes Care (2020)

OBJECTIVE Insulin dosing in type 1 diabetes (T1D) is oftentimes complicated by fluctuating insulin requirements driven by metabolic and psychobehavioral factors impacting individuals’ insulin sensitivity (IS). In this context, smart bolus calculators that automatically tailor prandial insulin dosing to the metabolic state of a person can improve glucose management in T1D. RESEARCH DESIGN AND METHODS Fifteen adults with T1D using continuous glucose monitors (CGMs) and insulin pumps completed two 24-h admissions in a hotel setting. During the admissions, participants engaged in an early afternoon 45-min aerobic exercise session, after which they received a standardized dinner meal. The dinner bolus was computed using a standard bolus calculator or smart bolus calculator informed by real-time IS estimates. Glucose control was assessed in the 4 h following dinner using CGMs and was compared between the two admissions. RESULTS The IS-informed bolus calculator allowed for a reduction in postprandial hypoglycemia as quantified by the low blood glucose index (2.02 vs. 3.31, P = 0.006) and percent time &amp;lt;70 mg/dL (8.48% vs. 15.18%, P = 0.049), without increasing hyperglycemia (high blood glucose index: 3.13 vs. 2.09, P = 0.075; percent time &amp;gt;180 mg/dL: 13.24% vs. 10.42%, P = 0.5; percent time &amp;gt;250 mg/dL: 2.08% vs. 1.19%, P = 0.317). In addition, the number of hypoglycemia rescue treatments was reduced from 12 to 7 with the use of the system. CONCLUSIONS The study shows that the proposed IS-informed bolus calculator is safe and feasible in adults with T1D, appropriately reducing postprandial hypoglycemia following an exercise-induced IS increase.
Hospital trust at centre of inquiry into babies’ deaths to repay £1m it received for “good care”
Authors: Clare Dyer
Journal: BMJ (2020)

A hospital trust at the centre of an investigation into avoidable deaths of babies is to repay a reward of nearly £1m it received for providing good maternity care.

Shrewsbury and Telford Hospital NHS Trust was given £953 391 by NHS Resolution’s maternity incentive scheme after reporting that it met 10 standards for safe services. But two months after the payment in September 2018 the trust’s …
Military medical response of the French gendarmerie to terrorist events
Authors: Simon-Pierre Corcostegui, Julien Galant, Pierre Pasquier, Kourosh Kazemzadegan, Luc Saint-Jean, Damien Commeau, Cédric Boutillier du Retail
Journal: BMJ (2020)

Park and colleagues discuss medical responses to a terrorist attack, mentioning the model used by the French National Police Special Intervention Unit.1 Another model is the one chosen by the French gendarmerie in association with the French Military Health Service. All gendarmes are trained in the first level of forward combat casualty care (SC1; sauvetage au combat de niveau 1).2 Simple care procedures can be carried out by the first responders.

In …
Sentinel lymph node biopsy is associated with a significantly improved survival compared to level Iand II axillary lymph node dissection in node-negative breast cancer patients
Authors: I. Langer, U. Guller, S. Hsu Schmitz, A. Ladewig, C. T. Viehl, H. Moch, E. Wight, F. Harder, D. Oertli, M. Zuber
Journal: Journal of Clinical Oncology (2007)

609 Background: The sentinel lymph node (SLN) biopsy has emerged as the standard of care in evaluating the axillary lymph node status in early stage breast cancer patients. It is well known that step sectioning and immunohistochemistry of the SLN allow for a more accurate histopathologic examination. Conversely, it remains to be elucidated whether or not the more accurate SLN staging is associated with improved survival. Therefore, the objective of the present investigation was to evaluate if patients undergoing a SLN biopsy have an improved disease-free and overall survival compared to those undergoing ALND. Methods: From our prospective database 355 node negative patients with early stage breast cancer (pT1 und pT2 &lt;=3cm, pN0/pNSN0) were assessed. Patients underwent either ALND (n=178) in the years 1990–1997 or a SLN biopsy (n=177) in 1998–2004. Long-term disease-free and overall survival were analysed for both groups. Log-rank tests were used for unadjusted analyses, a Cox proportional hazard regression model for risk-adjusted analyses. Results: The median follow- up was 48.2 months in the SLN group and 120.0 months in the ALND group. Patients in the SLN group had a significantly better disease-free (p=0.012) and overall survival (p=0.04) compared to the ALND group. In Cox proportional hazard regression analysis, the performed procedure (SLN compared to ALND) was an independent predictor for improved disease-free survival (hazard ratio 0.28, 95% confidence interval 0.11–0.75, p=0.011) and overall survival (hazard ratio 0.36, 95% confidence interval 0.14–0.89, p=0.027). Conclusion: The present analysis - the first one in the literature - provides compelling evidence that patients with a negative SLN have a significantly improved disease-free and overall survival compared to node negative patients undergoing ALND. This relevant finding is most likely due to an improved histopathologic staging accuracy. The significant survival benefit of node negative patients having SLN biopsy highlights yet another important advantage of the SLN concept in breast cancer. No significant financial relationships to disclose.
Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non–Small-Cell Lung Cancer
Authors: Shirish Gadgeel, Delvys Rodríguez-Abreu, Giovanna Speranza, Emilio Esteban, Enriqueta Felip, Manuel Dómine, Rina Hui, Maximilian J. Hochmair, Philip Clingan, Steven F. Powell, Susanna Yee-Shan Cheng, Helge G. Bischoff, Nir Peled, Francesco Grossi, Ross R. Jennens, Martin Reck, Edward B. Garon, Silvia Novello, Belén Rubio-Viqueira, Michael Boyer, Takayasu Kurata, Jhanelle E. Gray, Jing Yang, Tuba Bas, M. Catherine Pietanza, Marina C. Garassino
Journal: Journal of Clinical Oncology (2020)

In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680).Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis.As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups.First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.
Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving 5-fluorouracil (FU)/oxaliplatin (OX) as first-line chemotherapy
Authors: E. Marcuello, L. Pare, A. Altes, E. Del Rio, L. Sedano, A. Barnadas, M. Baiget
Journal: Journal of Clinical Oncology (2007)

2509 Background: Chemotherapy using oxaliplatin, 5-fluorouracil is known to be effective in the treatment of CRC patients. Optimization of this therapy is complicated due to wide variability in drug response that may be due to functional genomic polymorphisms in genes related to the drug target, to the metabolizing or to the DNA repair. We report the evaluation of polymorphisms in the TS, MTHFR (drug target) ERCC1, XPD and GSTP1 (repair enzymes) genes. Methods: We treated 109 CRC patients with a first line oxaliplatin/5-FU chemotherapeutic regimen. Genetic polymorphisms were determined by PCR based RFLP or by Real-Time PCR on an ABI PRISM 7000, using DNA from peripheral blood. The investigated polymorphisms were: TS (VNTR in the 5’ UTR, the 3R G&gt;C SNP and the 1494del6), ERCC1 (Asn118Asn, 8092C&gt;A, 19716 G&gt;C), GSTP1 (Ile105Val) and XPD (Lys751Gln). Clinical response (CR), progression free survival (PFS) and overall survival (OS) were evaluated according to each genotype. Results: The patients were classified according to the clinical risk assessment (CRA) defined by EORTC in three groups with different DFS (12, 9, 7 months; P= 0.008) and different OS (41,19,11 months; P= 0.0002). In the univariate analysis for CR, ERCC1 and XPD polymorphisms were significant (P=0.03, P= 0.047, respectively). After adjustment for the mentioned clinical risk assessment, only ERCC1 retained significance (P=0.037; HR: 4.2, C/C vs T/T). In the univariate analysis for PFS, only ERCC1 polymorphism was significant (P=0.034). After adjustment for the clinical risk, this genotype did not retained its significance (P=0.37). Finally, TS, ERCC1 and XPD polymorphisms were significant in the univariate analysis for overall survival, (P=0.032, P=0.003, P=0.016 respectively). Following the adjustement for the clinical risk, all three genotype variables retained significance (P=0.019, P=0.002, P= 0.024, respectively). Conclusions: i) The EORTC risk assessment classification was a very useful predictor of DFS and OS in our group of patients; ii) Germline genetic polymorphism of ERCC1 predicted response to FU/OX in CRC patients and iii) Polymorphisms in the TS, ERCC1 and XPD genes were good predictors of overall survival. No significant financial relationships to disclose.
A randomized, multicenter phase III trial comparing doxorubicin + cyclophosphamide followed by paclitaxel or doxorubicin + paclitaxel followed by weekly paclitaxel as adjuvant therapy for high-risk breast cancer
Authors: D. M. Loesch, F. Greco, J. O’Shaughnessy, J. D. Hainsworth, S. J. Vukelja, J. Sandbach, K. A. Boehm, D. Ilegbodu, L. Asmar, N. J. Robert
Journal: Journal of Clinical Oncology (2007)

517 Background: This study compared the disease-free survival (DFS) obtained with 2 regimens of adjuvant therapy for patients (pts) with high-risk breast cancer Methods: Women PS 0–1 with local, operable, confirmed stage I-III adenocarcinoma were eligible. Pts may have had primary surgery, with no residual tumor. Therapy was as follows:Arm 1 (AC→T) - doxorubicin 60 mg/m 2 plus cyclophosphamide 600 mg/m 2 repeated every 3 weeks for 4 cycles → paclitaxel 175 mg/m 2 repeated every 3 weeks for 4 cycles; Arm 2 (AT→T) - doxorubicin 50 mg/m 2 plus paclitaxel 200 mg/m 2 repeated every 3 weeks for 4 cycles → paclitaxel 80 mg/m 2 weekly ×12. Results: 1,830 pts were enrolled and treated; n=915 Arm 1 (AC→T) and n=915 Arm 2 (AT→T). Pts were: PS=0 (70%/Arm), ER+/PR+ (54% and 50%, Arms 1 and 2 respectively), ER-/PR- (35% and 34%) with 0 positive nodes (N+) (28% and 27%), 1–3 (N+) (44% and 46%), 4–9 (N+) (21% and 18%) and 10+ (N+) (7% and 8.5%). Most were postmenopausal (57%/Arm); median age was 52 years/Arm. To date 1,655 pts (90%) are alive. 5-year DFS was 80% vs 81% for Arms 1 and 2 Overall 5-year survival was 86% vs 89%, in Arms 1 and 2. Cause of death was recurrence for 76 pts in Arm 1 and 56 pts in Arm 2. The main reasons for pts being taken off study treatment were toxicity (85 pts Arm 1 vs 128 pts Arm 2), recurrence (79 pts Arm 1 vs 52 pts Arm 2), and consent withdrawal (18 pts Arm 1 vs 30 pts Arm 2). The most frequent toxicities were neutropenia, leukopenia, neuropathy, febrile neutropenia, nausea, vomiting, arthralgia, and myalgia. GI toxicities were more frequent in Arm 1. Alopecia occurred in both Arms (77%). Conclusions: At 5-years, the AT→T produced significantly better OS (p=0.054) and improved DFS (p=0.19). Clinically important toxicities were more frequent with AC→T. Given this, AT→T in the adjuvant treatment of breast cancer is well tolerated and warranted in place of AC→T in these pts. Research support provided by Bristol-Myers Squibb (Princeton, NJ). No significant financial relationships to disclose.
Reirradiation for inoperable in-field recurrences of malignant gliomas
Authors: U. Schäfer
Journal: Journal of Clinical Oncology (2007)

12527 Background: To evaluate the effect of sequential radiochemotherapy in preirradiated malignant gliomas in a phase II study. Methods: Sixteen patients (median age 61 years) were treated according to a standardized treatment protocol consisting of sequential radiochemotherapy. The chemotherapy (temozolomide) was carried out over a duration of 5 consequential days (Mon-Fri) with a dose of 200 mg/m 2 /d. Chemotherapy courses were repeated in 4 week intervals (day 1, 29, 57, etc.) until clinical progression. Radiotherapy with 30 Gy over 3 weeks (5 x 2 Gy/week) was interposed between the first two chemotherapy courses (days 8–26). Results: 14/16 patients had no acute side effects. One patient suffered from acute thrombocytopenia (6000x10 6 /l) and leukocytopenia (0,6x10 6 /l), a further patient developed mental degradation (treatment stopped at 24 Gy). All patients have died due to disease progression. Median event-free survival (Kaplan/Meier method) amounts to 6 months. 7/16 patients survived longer than 10 months and one patient longer than 2 years. Late treatment sequelae have not been observed so far. Conclusions: The reported radiochemotherapy protocol is feasible for these otherwise difficult to treat patients without a remarkable increase in toxicity. In individual cases it can lead to stable disease over a period of 10 months and more. No significant financial relationships to disclose.
Abstract 14358: A Novel Therapeutic Combination With Rivaroxaban and Spironolactone Attenuates Cardiovascular Remodeling in PAH Through Suppression of Protease-Activated Receptor-2 and Steroidogenic Acute Regulatory Protein
Authors: Tetsuya Hayashi, Tatsuki Ogata, Shunsuke Kondo, Shota Matsumoto, Hideki Imano, Ryuji Kato, Yoshio Ijiri, Takehiro Yamaguchi, Yasukatsu Izumi, Minoru Yoshiyama, Michio Asahi
Journal: Circulation (2018)

Introduction: We have reported that factor Xa inhibition prevents hypoxia-induced cardiovascular remodeling via protease-activated receptor (PAR) signaling pathway. In patients with pulmonary arter...
Paucity of economic analyses of phase III clinical trials conducted by the cooperative oncology groups: A review of the evidence
Authors: K. Fitzner, J. McKoy, C. L. Bennett
Journal: Journal of Clinical Oncology (2007)

17052 Background: Cancer care is expensive, accounting for $72 billion in direct medical costs. New oncology drugs are frequently costly, and can be &gt; $100,000 per patient. Hence, assessments of the costs and cost-effectiveness of cancer pharmaceuticals alongside phase III clinical trials conducted by the NCI-sponsored cooperative oncology groups represents an important opportunity to generate relevant economic data. Methods: Review of published cost and cost-effectiveness analyses for cancer drugs conducted alongside phase III clinical trials conducted by the NCI-sponsored cooperative clinical trial groups. Results: See Table . Conclusions: Despite increasing concerns over the high costs of cancer pharmaceuticals and the need to evaluate the costs and cost-effectiveness of these agents, NCI sponsored phase III clinical trials rarely include economic assessments. Future phase III clinical trials with expensive new cancer agents conducted by cooperative clinical trials groups should include prospective economic assessments. [Table: see text] No significant financial relationships to disclose.
Abstract MP39: Incident Heart Failure Within Five Years of Delivery Among Women With Hypertensive Disorders of Pregnancy or Pre-pregnancy Hypertension in a Diverse Population
Authors: Angela M Malek, Dulaney Wilson, Tanya N Turan, Julio Mateus, Daniel T Lackland, Kelly J Hunt
Journal: Circulation (2020)

Introduction: Hypertensive disorders of pregnancy (HDP) and pre-pregnancy hypertension are associated with increased morbidity and mortality for the mother, with potential long-term implications. We investigated the relationships between HDP and pre-pregnancy hypertension with fatal and nonfatal incident maternal heart failure (HF) within five years of delivery, and examined racial/ethnic differences. Methods: A retrospective population-based study was conducted among 433,636 women aged 13-49 (58.7% non-Hispanic white [NHW], 31.8% non-Hispanic black [NHB], 9.5% Hispanic) with a live, singleton birth in South Carolina between 2004-2016. HDP were defined as pre-eclampsia, eclampsia, or gestational hypertension based on hospitalization/emergency department (ED) visit data, or HDP on birth certificates. Pre-pregnancy hypertension was based on hospitalization/ED visit data or birth certificates. Incident HF was defined by hospital/ED visit and death certificate data. Cox proportional hazards models adjusted for sociodemographic, behavioral, and clinical characteristics. Results: Eighteen percent of women were diagnosed with HDP in ≥1 pregnancy (n=78,317; 53.5% NHW, 40.8% NHB, 5.7% Hispanic). Of the 433,636 women, 2.3% had pre-pregnancy hypertension with superimposed HDP, 15.7% had no pre-pregnancy hypertension with HDP, 0.4% had pre-pregnancy hypertension without superimposed HDP and 81.6% had neither condition. Compared to those without pre-pregnancy hypertension or HDP, incident HF risk was increased for women with: no pre-pregnancy hypertension with HDP (HR=4.35; 95% CI: 4.01-4.71), pre-pregnancy hypertension without superimposed HDP (HR=5.07; 95% CI: 3.52-7.29), and pre-pregnancy hypertension with superimposed HDP (HR=6.66; 95% CI: 5.91-7.51). The table shows race/ethnic specific estimates of incident HF risk. Discussion: Women with HDP and pre-pregnancy hypertension were at higher risk for HF or HF death within five years of delivery and the risk varied across racial/ethnic groups.