tbuckley/cabot-search huggingface dataset:
Current and future trends in antibiotic therapy of acute bacterial skin and skin-structure infections
Authors: A Russo, E Concia, F Cristini, F G De Rosa, S Esposito, F Menichetti, N Petrosillo, M Tumbarello, M Venditti, P Viale, C Viscoli, M Bassetti
Journal: Clinical Microbiology and Infection (2016)

In 2013 the US Food and Drug Administration (FDA) issued recommendations and guidance on developing drugs for treatment of skin infection using a new definition of acute bacterial skin and skin-structure infection (ABSSSI). The new classification includes cellulitis, erysipelas, major skin abscesses and wound infection with a considerable extension of skin involvement, clearly referring to a severe subset of skin infections. The main goal of the FDA was to better identify specific infections where the advantages of a new antibiotic could be precisely estimated through quantifiable parameters, such as improvement of the lesion size and of systemic signs of infection. Before the spread and diffusion of methicillin-resistant Staphylococcus aureus (MRSA) in skin infections, antibiotic therapy was relatively straightforward. Using an empiric approach, a β-lactam was the preferred therapy and cultures from patients were rarely obtained. With the emergence of MRSA in the community setting, initial ABSSSI management has been changed and readdressed. Dalbavancin, oritavancin and tedizolid are new drugs, approved or in development for ABSSSI treatment, that also proved to be efficient against MRSA. Dalbavancin and oritavancin have a long half-life and can be dosed less frequently. This in turn makes it possible to treat patients with ABSSSI in an outpatient setting, avoiding hospitalization or potentially allowing earlier discharge, without compromising efficacy. In conclusion, characteristics of long-acting antibiotics could represent an opportunity for the management of ABSSSI and could profoundly modify the management of these infections by reducing or in some cases eliminating both costs and risks of hospitalization.
Arsenical Encephalopathy
Authors: B. Singh
Journal: BMJ (1948)

The administration of calciferol in the form of high-potency ostelin tablets resulted in dramatic improvement of the skin lesions.The main improvement occurred during a threeweeks period of severe toxic effects unrelated to the level of serum calcium.The relationship of sarcoidosis to tuberculosis is discussed.It may be that they are the same disease.The response of the skin lesions of sarcoidosis to treatment with calciferol resembles that of lupus vulgaris, this being another point in favour of a close relationship.In view of the risks of "flaring up " a sarcoid lesion elsewhere and of causing sudden extension and ulceration of the skin lesions, calciferol should not be used in the treatment of sarcoidosis unless the skin lesions are extensive and disfiguring.A delayed positive tuberculin reaction is described in sarcoidosis.
Website of the Week: Diets and obesity
Authors: Vittal Katikireddi
Journal: BMJ (2004)

The BBC Horizon programme reviewed in this week's BMJ again raised questions about the ever popular Atkins diet. Does it work? If so, how does it work? And what are the risks?

The website of Atkins Nutritionals (http://atkins.com/) offers an overview of the science behind the diet—with summaries of articles from peer reviewed journals taken from PubMed—as well as providing many controlled carb recipes. There is also a carbohydrate gram counter, to help dieters find the net carbs in many of their “favourite everyday foods.”

An opposite viewpoint comes from the Physicians Committee for Responsible Medicine, a US based advocate for preventive medicine, especially good nutrition. The committee's Atkins Diet Alert (www.atkinsdietalert.org) provides information “for physicians and laypeople with questions and concerns about high-protein Atkins-type diets.” There is a wealth of information here—some of it targeted at doctors—including brief reviews, expert opinions, and even some “Survivor Stories” and tales of those who were not so lucky, such as 16 year old Rachel Huskey who died after following a high protein, low carbohydrate diet.

Most of us may want to stick to tried and tested approaches to the management of obesity. The UK's National Obesity Forum (www.nationalobesityforum.org.uk) was “established in May 2000 to raise awareness of the growing impact of obesity and overweight on our patients and our National Health Service.” Site features include useful management guidelines and links to educational materials. The site of the US National Center for Chronic Disease Prevention and Health Prevention (www.cdc.gov/nccdphp/dnpa/obesity/) offers more in-depth information about overweight and obesity, with sections on definitions, research, statistics, contributing factors, consequences, recommendations, and resources.

Those wanting to know more about current research on obesity and weight loss programmes, or even to participate in trials, should visit the US ClinicalTrials.gov website (http://clinicaltrials.gov/ct/gui/action/FindCondition?ui=D009765&recruiting=tree). Forthcoming studies include one that will compare the Atkins diet with Brownell's LEARN programme, a high carbohydrate, low fat diet (http://clinicaltrials.gov/ct/show/{type:clinical-trial,attrs:{text:NC6193,term_id:NC6193}}NC6193?order=42).
NCO-10INTELLECTUAL OUTCOME IN MOLECULAR SUBGROUPS OF MEDULLOBLASTOMA
Authors: Iska Moxon-Emre, Michael D. Taylor, Eric Bouffet, Kristina Hardy, Cynthia Campen, David Malkin, Cynthia Hawkins, Normand Laperriere, Vijay Ramaswamy, Nadia Scantlebury, Brenda Spiegler, Laura Janzen, Nicole M. Law, Karin S. Walsh, Donald J. Mabbott
Journal: Neuro-Oncology (2015)

BACKGROUND: Medulloblastoma subgroups have distinct demographic, genetic and clinical features, yet their respective intellectual outcomes are unknown. With the advent of subgroup-specific therapy de-escalation strategies, it is critical to characterize intellectual functioning in each subgroup according to treatment intensity. METHODS: One hundred and twenty one patients with medulloblastoma (51 Group 4; 25 Group 3; 28 SHH; 17 WNT), treated between 1991 and 2013 at the Hospital for Sick Children (Toronto, Canada), Children's National Medical Center (Washington, DC) or the Lucile Packard Children's Hospital (Palo Alto, CA), had longitudinal intellectual functioning evaluations. First, we compared IQ measures between subgroups, controlling for relevant clinical and demographic variables. Next, we evaluated the effect of: a) radiation intensity (i.e. reduced-dose radiation with a focal tumor bed boost vs. treatments with higher radiation doses and/or larger boost volumes), and b) mutism, on full scale IQ (FSIQ) in each subgroup. Growth curve analysis was used to determine stability or change in IQ scores over time. RESULTS: Subgroups declined comparably in all IQ measures except processing speed (PS). SHH had lower baseline PS, and declined less, than Groups 3 and 4 (all P   0.05). Although FSIQ decline did not differ according to mutism status for any subgroup (all P > 0.05), Group 3 patients with mutism had lower baseline FSIQ (P = 0.014). CONCLUSION: Therapy de-escalation appears to be a suitable way to achieve optimal intellectual functioning in patients with WNT and Group 4 medulloblastoma.
TCTAP A-128 Short-Term Efficacy and Safety of Clopidogrel Versus Ticagrelor in Acute Myocardial Infarction Patients in a Series of Asian Population
Authors: Seung-Woon Rha, Jae Joong Lee, Byoung Geol Choi, Se Yeon Choi, Jae Kyeong Byun, Min Shim, Sung Hun Park, Eun Jin Park, Jah Yeon Choi, Sunki Lee, Li Hu, Jin Oh Na, Cheolung Choi, Hong Euy Lim, Jin Won Kim, Eung Ju Kim, Chang Gyu Park, Hong Seog Seo, Dong Joo Oh
Journal: Journal of the American College of Cardiology (2016)
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Authors: Matias E Valsecchi
Journal: New England Journal of Medicine (2015)

BACKGROUNDNivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma.In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. METHODSWe assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone.Progression-free survival and overall survival were coprimary end points.Results regarding progression-free survival are presented here. RESULTSThe median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001).In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]).Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONSAmong previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone.In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone.
The PI3K/ERK Dual Inhibitor AEZS-136 Induces ROS-Dependent Necroptotic Cell Death and Exerts Potent Antitumor Effects In NOD/SCID Mice With Hodgkin Lymphoma Cell Line Xenografts
Authors: Silvia L Locatelli, Giuliano G Stirparo, Silvia Tartari, Elena Saba, Luca Rubino, Ercole Brusamolino, Luca Castagna, Armando Santoro, Carmelo Carlo-Stella
Journal: Blood (2013)
NHS Update Freeman Hospital: the will to survive
Authors: S Kingman
Journal: BMJ (1994)

The future looks uncertain for the Freeman Hospital trust in Newcastle upon Tyne. There are plans to rationalise the health service in Newcastle by shifting resources from secondary to primary care, and by providing more services locally for people who live in the region but outside Newcastle. These could reduce the level of contracts that purchasers place with the trust in the future. Staff at the trust say the service they provide is good value for money, but purchasers do not seem to take this into account. Instead of choosing from a "shopping list" of priced procedures, purchasers are forcing the trust to dovetail its prices to meet their budgets. There is also concern at the potential impact on the trust's financial situation of reduced working hours for junior doctors and the Calman proposals on training.
Epigenetic assimilation in the aging human brain
Authors: Gabriel Oh, Sasha Ebrahimi, Sun-Chong Wang, Rene Cortese, Zachary A. Kaminsky, Irving I. Gottesman, James R. Burke, Brenda L. Plassman, Art Petronis
Journal: Genome biology (2016)

Epigenetic drift progressively increases variation in DNA modification profiles of aging cells, but the finale of such divergence remains elusive. In this study, we explored the dynamics of DNA modification and transcription in the later stages of human life. We find that brain tissues of older individuals (>75 years) become more similar to each other, both epigenetically and transcriptionally, compared with younger individuals. Inter-individual epigenetic assimilation is concurrent with increasing similarity between the cerebral cortex and the cerebellum, which points to potential brain cell dedifferentiation. DNA modification analysis of twins affected with Alzheimer's disease reveals a potential for accelerated epigenetic assimilation in neurodegenerative disease. We also observe loss of boundaries and merging of neighboring DNA modification and transcriptomic domains over time. Age-dependent epigenetic divergence, paradoxically, changes to convergence in the later stages of life. The newly described phenomena of epigenetic assimilation and tissue dedifferentiation may help us better understand the molecular mechanisms of aging and the origins of diseases for which age is a risk factor.
Value of PET scan in treatment decision making for nodal metastases in SCHNC-single institutional update
Authors: R. Roy, Y. Lebowicz, M. Anne, S. Nissel-Horowitz, A. Caramalis, J. Marsh, B. Mehrotra
Journal: Journal of Clinical Oncology (2008)

6043 Background: Management of nodal neck disease in patients with SCHNC (squamous cell carcinoma of the head and neck) treated with CRT (chemoradiotherapy) remains controversial. We retrospectively evaluated the utility of PET scans in monitoring response to therapy and in determining the role of neck dissections (ND) in patients presenting with SCHNC stages N2b or higher, treated with combined CRT. Methods: A retrospective review of medical records of all patients treated at our institution with HNC Tx N2b, N2c or N3 between the years 2002–2007 was undertaken. IRB approval was obtained for this study. To be eligible for this analysis, patients must have had baseline and follow up PET scans at the end of CRT and prior to ND. Data regarding age, gender, primary tumor site, stage, baseline and follow up PET scan results, operative pathology of ND when performed, and local control were recorded. Results: Thirty-six eligible patients were identified. Median age was 56 (range: 37–84) years; M:F ratio: 30–6. Primary site of tumor was: Lip and oral cavity (n=4); Pharynx: n=28 (Tonsil: n=18; hypopharynx: n=2; BOT: n=5; oropharynx: n=3); Larynx: n=3. Stage distribution: IVa: n=32; IVb: n=4; Nodal stage: N2b: n=25; N2c: n=8; N3: n=3. At the first post CRT assessment: PET scan was negative at primary and nodal sites: n=25 (69%); positive at primary and nodal sites: n=11 (31%); primary site only: n=2; nodal site only: n=7; both primary and nodal site uptake: n=2. Twenty three of twenty five patients (92%) that were PET negative post CRT, remain in complete remission at a median follow up of 19 months. ND data are available in 9 of 11 patients that had a positive PET scan post CRT. Six of nine patients with positive post CRT PET had SCC noted in post CRT ND. Three of nine patients with positive PET had no disease found on ND, however, two of these three patients had a PET scan post CRT performed <8 weeks post completion of treatment. Conclusions: Post CRT PET scan negativity predicts for an extremely favorable outcome. To reduce false positive rates, follow up PET scans should be performed no sooner than 8 weeks post CRT. PET scan positivity after 8 weeks post CRT, either at the primary or nodal site, predicts high probability of persistent nodal disease detected during ND. No significant financial relationships to disclose.
Targeted treatment of idiopathic pulmonary fibrosis: one step at a time
Authors: Luca Richeldi
Journal: European Respiratory Journal (2016)

On October 21, 1999, physicians involved in the care of patients affected by idiopathic pulmonary fibrosis (IPF) read with enthusiastic surprise in the pages of the New England Journal of Medicine that this deadly disease could not only be stopped, but in fact be reverted by injecting interferon gamma-1b subcutaneously three times a week [1]. In an attempt to provide a mechanistic substrate to the impressive clinical results, this trial focused on two specific molecules, transforming growth factor-β1 and connective tissue growth factor (CTGF), as the relevant therapeutic molecular targets, responsible for the functional improvement observed. In fact, the transcription levels of these two genes were significantly reduced in transbronchial biopsies obtained from some of the trial patients after 6 months of interferon gamma-1b treatment [1]. At the time of publication of this study, we didn't know (and we still do not know) if at least some of these 18 patients were representing a specific IPF subgroup (or endotype). As in the words of Niels Bohr, winner of the Nobel Prize in Physics in 1922, “prediction is very difficult, especially if it's about the future”. Thus, we had to wait for two large placebo-controlled trials to be completed, involving several hundreds of patients being randomised [2, 3], before knowing that the hopes for the possibility of reverting IPF with this drug had vanished; interferon gamma-1b is no longer considered an option for IPF patients. Nonetheless, the question of whether the original 1999 study identified a specific subgroup of “responders” still remains without a definitive answer. Targeting CTGF in a selected group of IPF patients: a further step towards personalised treatments in IPF <http://ow.ly/YMtEP>
ATR-101 phase 1 clinical study for adrenocortical carcinoma.
Authors: Aung Naing, Siqing Fu, Mouhammed Amir Habra, Rashmi Chugh, Electron Kebebew, Jeffrey Russell, Dawn Welshans, Martin Fassnacht, Matthias Kroiss, Maria-Elisabeth Goebeler, Marian Ijzerman, Marianne R Plaunt, Pharis Mohideen, Martin Phillips, David C. Smith
Journal: Journal of Clinical Oncology (2015)

TPS4585 Background: ATR-101 (Atterocor, Inc., Ann Arbor, MI, USA) is a selective inhibitor of ACAT1 (acyl coenzyme A:cholesterol acyltransferase) in clinical development for the treatment of adrenocortical carcinoma (ACC). ACAT1 catalyzes cholesterol ester formation from cholesterol and long-chain fatty acyl-CoA and, in the adrenals, is particularly important in creating a reservoir of substrate for steroid biosynthesis. ATR-101 selectively distributes to the adrenals, inhibits steroidogenesis and causes apoptosis of cells of the adrenal cortex, as well as in H295R ACC cells. ACC is an ultra-rare malignancy, occurring in about 2 per million population annually. ACC is frequently discovered in Stage 4 and the overall disease survival is approximately 17 months. Tumors often overproduce steroids normally produced in the adrenal cortex and cause therapy-resistant Cushing’s syndrome. Current therapies are toxic, difficult to administer, and poorly effective. Methods: ATR-101-001 is a phase 1 study being conducted at four centers in the United States and one in Germany. It is a “3+3” design: 3 subjects with advanced ACC who have failed or declined existing therapies are enrolled at each dose level for 28 days. If no Dose Limiting Toxicity is observed, three additional subjects are enrolled at a higher dose. An expansion cohort of 20 subjects will be enrolled after the MTD has been determined. Subjects who appear to be deriving benefit may stay on ATR-101 indefinitely. ATR-101 is taken by mouth. The primary objective is to determine the safety and tolerability of ATR-101 in subjects with advanced ACC. Secondary objectives include efficacy by RECIST, measurement of production of steroid hormones and intermediates, determination of pharmacokinetics, the Maximum Tolerated Dose and the recommended phase 2 dose. The study is open to patients age 18 and over with advanced ACC. Patient’s mitotane level must be 5 µg/ml or less; the QTcF 470 ms or less; and if present, CNS metastases must be treated and inactive. Full study information is available on ClinicalTrials.gov, Identifier NCT01898715. Clinical trial information: NCT01898715.
Modafinil/armodafinil in obstructive sleep apnoea: a systematic review and meta-analysis
Authors: Julia L. Chapman, Andrew Vakulin, Jan Hedner, Brendon J. Yee, Nathaniel S. Marshall
Journal: European Respiratory Journal (2016)

Modafinil is used internationally to treat residual sleepiness despite continuous positive airway pressure in obstructive sleep apnoea (res-OSA). In 2011, the European Medicines Agency removed the indication based on an unfavourable risk–benefit profile in two trials for efficacy and all accumulated safety data. We performed a meta-analysis of all randomised controlled trials of modafinil (or armodafinil) in res-OSA to quantify efficacy and safety. We systematically searched and assessed studies from major databases, conferences and trials registries to find randomised, placebo-controlled trials of modafinil/armodafinil for ≥2 weeks in adult res-OSA treating sleepiness. We analysed 10 of the 232 articles identified that met inclusion criteria (1466 patients). Modafinil/armodafinil improved the Epworth Sleepiness Scale score (2.2 points, 95% CI 1.5–2.9) and the Maintenance of Wakefulness Test over placebo (3 min, 95% CI 2.1–3.8 min). Modafinil/armodafinil tripled adverse events and doubled adverse events leading to withdrawal but did not increase serious adverse events (hospitalisations or death). Modafinil and armodafinil improve subjective and objective daytime sleepiness in res-OSA. We believe our analysis is a fairer analysis of the risk–benefit profile of this indication. Clinicians may want to use this data to balance the risks and benefits on a case-by-case basis with their patients.
The Cell Cycle Regulator CDC25A Is a Target for JAK2V617F Oncogene
Authors: Emilie-Fleur Gautier, Christian Recher, Camille Laurent, Caroline Marty, Jean-Luc Villeval, Cécile Demur, Francois Delhommeau, Elizabeth Hexner, Stephane Giraudier, Nicolas Bonnevialle, Bernard Ducommun, Guy Laurent, Stéphane Manenti, Véronique Mansat- De Mas
Journal: Blood (2011)