tbuckley/cabot-search huggingface dataset:
Choosing Wisely in the UK: the Academy of Medical Royal Colleges' initiative to reduce the harms of too much medicine
Authors: A. Malhotra, D. Maughan, J. Ansell, R. Lehman, A. Henderson, M. Gray, T. Stephenson, S. Bailey
Journal: BMJ (2015)

A Malhotra and colleagues explain how and why a US initiative to get doctors to stop using interventions with no benefit is being brought to the UK
Denosumab in the treatment of bone metastases from advanced cancer or multiple myeloma (MM): Analyses from a phase III randomized trial.
Authors: S. Vadhan-Raj, D. H. Henry, R. von Moos, V. Hungria, F. Goldwasser, G. Scagliotti, J. Wang, S. Jun, R. D. Dansey, H. Yeh
Journal: Journal of Clinical Oncology (2010)

9042 Background: Bone metastases from solid tumors increase risk for skeletal-related events (SREs, defined as pathologic fractures, spinal cord compression, and radiation or surgery to bone) by stimulating osteoclast-mediated bone resorption. Denosumab is a fully human monoclonal antibody targeting RANKL, the primary effector of osteoclast activity. This phase III, randomized, double-blind, study compared denosumab and zoledronic acid (ZA) with respect to SREs in patients (pts) with metastatic disease. Previously, denosumab was non-inferior to ZA in time to first on- study SRE (HR = 0.84 [95% CI: 0.71, 0.98]; Henry D, et al. Eur J Cancer Suppl 2009;7:11). Here, we compare the time to first SRE, including HCM, time to first radiation to bone, number of on-study SREs, and acute phase reactions between treatment arms. Methods: Patients with advanced solid tumors (not including breast or prostate) or MM and no prior IV bisphosphonate use were randomized to denosumab 120 mg SC and placebo IV every 4 weeks (Q4W) or ZA 4 mg IV and placebo SC Q4W. Daily supplemental calcium ≥ 500 mg and vitamin D ≥ 400 IU were also advised. Results from time to event analyses are presented using a Cox proportional hazards model. Acute phase reactions occurring within 3 days of the first dose are based on 19 predefined terms. Results: Compared with pts receiving ZA (n = 890), time to first SRE or HCM was significantly longer in the denosumab group (n = 886) (KM median 19.0 months vs 14.4 months; HR = 0.83 [95% CI: 0.71, 0.97], p = 0.02) as was time to first radiation to bone (KM median not estimable; HR = 0.78 [95% CI: 0.63, 0.97], p = 0.03). Median time on study was 7.3 mos and 7.1 mos in the denosumab and ZA groups. At the primary cutoff date, 278 (31.4%) pts in the denosumab group had ≥ 1 on-study SRE vs. 323 (36.3%) in the ZA group. Overall adverse event rates were similar in both groups. Acute phase reactions by predefined terms within 3 days were lower in the denosumab group (n = 61 [6.9%]) vs. the ZA group (n = 127 [14.5%]). Conclusions: In this head-to-head study, pts receiving denosumab had longer time to first SRE or HCM and time to radiation to bone compared with ZA. A lower proportion of pts experienced an on-study SRE in the denosumab group compared with ZA. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Novartis, Ortho Biotech, Roche, Watson Pharmaceuticals Amgen Amgen, AstraZeneca, Lilly, Ortho Biotech, Roche, sanofi-aventis, Watson Pharmaceuticals Amgen, Ortho Biotech, Watson Pharmaceuticals
Healthcare Financing for the Under-Served: UK
Authors: John H James
Journal: Journal of the Royal Society of Medicine (2001)

The National Health Service (NHS), established in 1948, is mainly funded from taxation and largely free at the point of use. Anyone resident in the UK is entitled to use it.

The overall level of NHS spending is determined by the Government; and for most of its history, tight control has been exercised, resulting in spending that is lower relative to gross domestic product (GDP) than in most OECD countries. For many years NHS spending was within the range 5.5-6.2% of GDP. In March 1999 the Government committed itself to increase spending over the following five years to the average for the European Union. It is too early to assess what impact this will have on availability of healthcare, but the commitment has been accompanied by ambitious targets to reduce waiting times for treatment, to improve the responsiveness of services and to enhance the patient experience.

Most NHS spending has for the past thirty or so years been distributed by population-based allocations, adjusted for factors considered to affect the need for and costs of healthcare. The allocations are spent locally on the provision of services. Additional funding streams have been used either because Government has wanted to put its weight behind the development of a specific service (hospice funding at one stage fell into this category) or because the geographical distribution of a health problem was too skewed for any formula (AIDS treatment and care fell consistently into this category). Responsibility for spending both general and specific allocations has rested with local health authorities, which may loosely be seen as geographically specific health maintenance organizations.

In the current year the UK Government plans to spend some £44 billion (£1≏US$ 1.4) on health and healthcare on the 50 million population of England alone. About 1% of that total will be spent within an average-sized health authority.

There are three other important sources of funding. First, about 10 million people in the UK are covered by private insurance, either employer-based or privately purchased, most of them of working age together with their families. Collectively this equates to about 1% of GDP. It mainly purchases elective treatment. Secondly, older people requiring both clinical and social care support, whether in their own home or in a residential or nursing-home setting, may be required to meet the social care part of the costs from their own resources. Thirdly, some aspects of healthcare have been relatively successful in attracting capital, revenue or (unpaid) volunteer help. Palliative care and AIDS/HIV treatment come into this category.
Measurement of <i>S</i> -Nitrosylation Occupancy in the Myocardium With Cysteine-Reactive Tandem Mass Tags
Authors: Mark J. Kohr, Angel Aponte, Junhui Sun, Marjan Gucek, Charles Steenbergen, Elizabeth Murphy
Journal: Circulation Research (2012)

Rationale: S-nitrosylation (SNO) is a reversible, thiol-based protein modification that plays an important role in the myocardium by protecting critical cysteine residues from oxidation. However, little is known with regard to the percentage of a given protein that is modified by SNO (ie, SNO occupancy). Current methods allow for the relative quantification of SNO levels, but not for the determination of SNO occupancy. Objective: To develop a method for the measurement of SNO occupancy, and apply this methodology to determine SNO occupancy in the myocardium. Methods and Results: We developed a differential cysteinereactive tandem mass tag (cysTMT) labeling procedure for the measurement of SNO occupancy. To validate this cysTMT labeling method, we treated whole-heart homogenates with the S-nitrosylating agent S-nitrosoglutathione and determined maximal SNO occupancy. We also examined SNO occupancy under more physiological conditions and observed that SNO occupancy is low for most protein targets at baseline. Following ischemic preconditioning, SNO occupancy increased to an intermediate level compared to baseline and Snitrosoglutathione treatment, and this is consistent with the ability of SNO to protect against cysteine oxidation. Conclusions: This novel cysTMT labeling approach provides a method for examining SNO occupancy in the myocardium. Using this approach, we demonstrated that IPC-induced SNO occupancy levels are sufficient to protect against oxidation.
CD39/CD73 and the imbalance of Th17 and Tregs (regulatory T cells) in allergic asthma
Authors: Linlin Wang, Guochao Shi, Huanying Wan
Journal: European Respiratory Journal (2013)

Background  It has been demonstrated that CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) maintain self-tolerance and Th17 cells mediate inflammatory responses. CD39 was recently found expressed on a subset of human natural Tregs and CD39 + Treg cells play an important role in constraining pathogenic Th17 cells. More studies have shown that Tregs could differentiate into IL-17 + Foxp3 + T cells. Our previous results indicated there is imbalance of Th17 and Tregs in allergic asthma. However, the underlying mechanism remains poorly understood.   Methods  We investigate CD39 and CD73 mRNA by qPCR, and the proportions of IL-17 + Foxp3 + T cells, CD39 and CD73 expressed by CD4+T cells and Tregs in peripheral blood from all subjects by flow cytometry.   Results  Our data indicated that 1) there was an increase in frequency of CD4 + Foxp3 + IL-17 + T cells in moderate to severe asthmatics. 2) There was a deficiency both in CD39 mRNA and protein expressed by CD4 + T cells in asthmatics. 3) There was a deficiency in frequency of CD39 + Tregs and CD73 + Tregs in patients with asthmatics.   Conclusions  The plasticity of Tregs to transform to IL-17 + Foxp3 + CD4+T cells and the reduced frequency of CD39 + Tregs and less effective suppression of IL-17 production from residual CD39 + Tregs lead to the imbalance of Th17 and Tregs in asthmatics, it indicated that enhancing CD39 activity maybe can prevent the progress of asthma.
Variance over time of the obstructive sleep apnoea syndrome (OSAS) in patients with acute stroke
Authors: Anna Mola, Ana Mª Fortuna, Rosa Mª Miralda, Raquel Delgado, Joan Martí, Mercè Mayos
Journal: European Respiratory Journal (2011)

OSAS is a cardiovascular risk factor with a high prevalence in patients with acute stroke in whom could be related to a worse prognosis and an increased mortality. The aims are to evaluate the evolution and the prognostic role of OSAS in stroke patients. This is a prospective study in which a respiratory polygraphic (RP) evaluation was performed 7 days after stroke (acute phase) and was repeated on the third month (stable phase). 42 of 52 patients were included (age 69±12.5 years, 54.8% male, BMI 27±4 kg/m2, Epworth 7±3.6) and the RP was repeated on the 3rd month in 30 patients. The acute and stable phase studies showed a predominant hypopnoeas' pattern.

View this table:

Table 1. OSAS' prevalence by AHI





View this table:

Table 2. Acute & stable phase RP data





The results suggest that OSA' study in acute stroke can lead to an overestimation of the prevalence of severe OSA, because it significantly reduce its severity in the stable phase. This information may be important when taking the decision to start CPAP treatment in acute stroke. In accordance with previous studies, there wasn't found any relationship between OSA' presence and the stroke functional outcome on the 3rd month.
Full dose versus attenuated dose daunorubicin, cytosine arabinoside, and 6-thioguanine in the treatment of acute nonlymphocytic leukemia in the elderly.
Authors: S B Kahn, C B Begg, J J Mazza, J M Bennett, H Bonner, J H Glick
Journal: Journal of Clinical Oncology (1984)

Between July 1, 1981 and November 1, 1982, 45 patients with acute nonlymphocytic leukemia (age, greater than or equal to 70 years) were randomly assigned to receive induction chemotherapy using either daunorubicin, cytosine arabinoside, and 6-thioguanine in full dosage (F DAT) or an attenuated schedule of the same drugs (At DAT) as part of an Eastern Cooperative Oncology Group controlled trial. Forty patients were deemed evaluable, 20 on each arm. The overall complete remission (CR) rate for all patients in both arms was 28% (11/40). There was no significant difference in CR rates between the two arms. There were 12 early deaths (less than 60 days) in the F DAT arm compared with only five early deaths on the At DAT arm (P = .05). Due primarily to this early death rate, the median survival for the F DAT group was 29 days v 159 days for the At DAT groups (P = .02). The range of survival of the patients in CR for the At DAT group given either one or two cycles of induction therapy was 121 to 414 days, while the survival range for the F DAT CR patients was 121-186 + days. The median survival for those not achieving CR was 14 days for the F DAT group v 80 days for the At DAT (P less than .02). Fifty-nine percent of the At DAT patients spent greater than 100 days out of the hospital v 12% for the F DAT group. Attenuated chemotherapy with lower doses of DAT is the preferred induction regimen for elderly patients with acute nonlymphocytic leukemia since it causes fewer early deaths, allows a better quality of life, and yields survival times as durable as intensive therapy.
Six months outcomes from patients treated with lung volume reduction coils in a commercial setting: The RKK Stuttgart experience
Authors: Martin Hetzel, Tobias Merk, Andrea Philipp, Stefan Veitshans, Peter Willmes
Journal: European Respiratory Journal (2013)

Introduction: Since 2010, endoscopic lung volume reduction in patients with pulmonary emphysema using RePneu LVR-coils (LVRC) is an approved treatment approach in Germany. The method has been demonstrated to be safe and efficacious in European multi-center studies.  Objectives: LVRC has been considered part of the routine clinical care for selected emphysema patients at RKK Stuttgart since 2011. A validated analysis of patient outcomes is presented here.  Methods: Analysis was conducted on all bilaterally treated patients with at least one follow up visit (N=29, mean 165 days post baseline) after the second treatment (lung function tests, 6MWT, and complications). Selection criteria included patients with homogeneous or heterogeneous emphysema and RV >200% pred. Exclusion criteria included severe pulmonary hypertension, anticoagulant therapy, and bronchiectasis.  Results: The mean changes from baseline were: RV -1.39L, FEV1 +80.0mL, 6MWT +94.0m. Following 29 bilateral treatments (58 total procedures), we observed the following severe complications through the 6 month follow-up visit: COPD Exacerbation (6), Hemoptysis >5 mL (3), Pneumonia (1), Chest Pain (1), Aspiration (1), Embolus of lung artery (1). Additional data including follow-up at 9-months and 12-months will be collected and reported.  Conclusion: LVRC results in significant improvement of lung function and an increase in physical performance of treated patients. The procedure is well tolerated with an acceptable safety profile.
Efficacy of Nintedanib in Idiopathic Pulmonary Fibrosis across Prespecified Subgroups in INPULSIS
Authors: Ulrich Costabel, Yoshikazu Inoue, Luca Richeldi, Harold R. Collard, Inga Tschoepe, Susanne Stowasser, Arata Azuma
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

In the two replicate, placebo-controlled, 52-week, phase III INPULSIS trials, nintedanib 150 mg twice daily significantly reduced the annual rate of decline in FVC, the primary endpoint, in subjects with idiopathic pulmonary fibrosis (IPF). It is unknown if this effect was uniform across all subjects treated with nintedanib.To investigate the potential association of demographic and clinical variables with the effect of nintedanib in subjects with IPF.Subgroup analyses of pooled data from the INPULSIS trials were prespecified. Subgroups were analyzed by sex, age (<65, ≥65 yr), race (white, Asian), baseline FVC percentage predicted (≤70%, >70%), baseline St. George's Respiratory Questionnaire (SGRQ) total score (≤40, >40), smoking status (never, ex/current), systemic corticosteroid use (yes/no), and bronchodilator use (yes/no).A total of 1,061 subjects were treated (nintedanib n = 638, placebo n = 423). There was no statistically significant difference in the effect of nintedanib for the primary endpoint or the key secondary endpoints of change from baseline in SGRQ total score or time to first acute exacerbation in any subgroup. Treatment effects for the key secondary endpoints seemed more pronounced in subjects with baseline FVC ≤70% predicted, because the majority of acute exacerbations and a greater deterioration in SGRQ total score occurred in placebo-treated subjects in this subgroup.Pooled data from the INPULSIS trials support a consistent effect of nintedanib across a range of IPF phenotypes by slowing disease progression across a number of prespecified subgroups.
DEPRESSION OF ALANINE TRANSAMINASE ACTIVITY IN THE LIVER OF RATS BEARING WALKER CARCINOMA 256.
Authors: Homer R. Harding, Fred Rosen, Charles A. Nichol
Journal: Cancer Research (1964)

Summary  Alanine transaminase activity in the liver of adult rats (350–450 gm.) fell progressively from the 10th through the 30th day of growth of Walker carcinoma 256. The enzyme activity decreased to a level about 30 per cent of that found in comparable rats of the same age without tumors. Loss of enzyme activity occurred concurrently, with a gradual loss of carcass weight. Treatment with cortisol (4 mg/kg, administered during the first 10 days of tumor growth) increased the activity of alanine transaminase in liver 2.5-fold, but the same dose did not alter transaminase activity when the tumors were large (days 20 through 30). The activity of this transaminase could be raised to normal in the presence of large tumors by feeding a diet containing 75 per cent casein. When this high-protein diet was fed, treatment with cortisol (4 mg/kg) increased alanine transaminase activity fourfold. Tyrosine transaminase and tryptophan pyrrolase differed from alanine transaminase in that both of these enzymes were increased four- to fivefold by cortisol (10 mg/kg) in the livers of rats with established Walker tumors.
Elective ventilation of potential organ donors
Authors: P. G M Wallace
Journal: BMJ (1995)

Severe acute pancreatitis (AP) is responsible for significant human morbidity and mortality worldwide. Currently, no specific treatments for AP exist, primarily due to the lack of a mechanistic understanding of sterile inflammation and the resultant multisystem organ dysfunction, the pathologic response of AP linked to early death. In this study, we demonstrate that the class III major histocompatibility region III receptor for advanced glycation end products (RAGE) contributes to AP by modulating inflammasome activation in macrophages. RAGE mediated nucleosome-induced absent in melanoma 2 (but not NLRP3) inflammasome activation by modulating dsRNA-dependent protein kinase phosphorylation in macrophages. Pharmacological and genetic inhibition of the RAGE–dsRNA-dependent protein kinase pathway attenuated the release of inflammasome-dependent exosomal leaderless cytokines (e.g., IL-1β and high-mobility group box 1) in vitro. RAGE or absent in melanoma 2 depletion in mice limited tissue injury, reduced systemic inflammation, and protected against AP induced by l-arginine or cerulein in experimental animal models. These findings define a novel role for RAGE in the propagation of the innate immune response with activation of the nucleosome-mediated inflammasome and will help guide future development of therapeutic strategies to treat AP.
Extending Comprehensive Cancer Center Expertise in Clinical Cancer Genetics and Genomics to Diverse Communities: The Power of Partnership
Authors: Deborah J. MacDonald, Kathleen R. Blazer, Jeffrey N. Weitzel
Journal: Journal of the National Comprehensive Cancer Network (2010)

Rapidly evolving genetic and genomic technologies for genetic cancer risk assessment (GCRA) are revolutionizing the approach to targeted therapy and cancer screening and prevention, heralding the era of personalized medicine. Although many academic medical centers provide GCRA services, most people receive their medical care in the community setting. However, few community clinicians have the knowledge or time needed to adequately select, apply, and interpret genetic/genomic tests. This article describes alternative approaches to the delivery of GCRA services, profiling the City of Hope Cancer Screening &amp; Prevention Program Network (CSPPN) academic and community-based health center partnership as a model for the delivery of the highest-quality evidence-based GCRA services while promoting research participation in the community setting. Growth of the CSPPN was enabled by information technology, with videoconferencing for telemedicine and Web conferencing for remote participation in interdisciplinary genetics tumor boards. Grant support facilitated the establishment of an underserved minority outreach clinic in the regional County hospital. Innovative clinician education, technology, and collaboration are powerful tools to extend GCRA expertise from a National Cancer Institute–designated Comprehensive Cancer Center, enabling diffusion of evidenced-base genetic/genomic information and best practice into the community setting.
Iron deficiency in childhood
Authors: R J D Moy, A R Early
Journal: Journal of the Royal Society of Medicine (1999)

Iron deficiency is the commonest form of malnutrition worldwide, affecting 43% of the world's children, and is particularly common in Asia and Africa. In the UK, childhood iron deficiency anaemia has long been identified as an important issue in public health. The 1995 National Diet and Nutrition Survey indicated that 12% of children between 1 l and 2 1 years had a haemoglobin of less than 110 g/L; and in inner city areas with high levels of socioeconomic deprivation and large numbers of children from ethnic minority groups, the prevalence of childhood anaemia was much higher.
Caveolin-1 expression in airway smooth muscle cells is related to airway responsiveness magnitude in allergic asthma model
Authors: Fernando Gutierrez-Aguilar, Norma A. Bobadilla, Maria G. Campos, Ricardo Lascurain, Erasmo Martínez-Cordero, Mayra D. Alvarez-Santos, Patricia Ramos-Ramírez, Blanca Bazan-Perkins
Journal: European Respiratory Journal (2011)

Caveolin-1 (Cav-1) is an important signalling scaffold protein involved in smooth muscle contraction; however, the role of Cav-1 in airway responsiveness has not been elucidated so far. Our aim was to determine the relation of Cav-1 expression with airway hyperresponsiveness (AHR) in a guinea pig asthma model. To evaluate this relation, three inhaled antigenic challenges were applied every 10 days to antigen (ovalbumin; OVA) sensitized guinea pigs (n=9). Antigen-induced airway obstruction, AHR to histamine, and the expression of Cav-1 in lung and airway smooth muscle cells (ASMC), was evaluated at the third OVA challenge. The control group received saline solution instead of OVA (n=6). From the first challenge on, OVA induced a transient airway obstruction and the development of AHR at the third antigenic challenge. Cav-1 mRNA levels in lung (assessed by RT-PCR) significantly decreased in our asthma model compared with the control group (P
Flow-limitation and upper airways
Authors: S Kostianev, C Veriter, D Stanescu
Journal: European Respiratory Journal (1995)

<h3>Abstract</h3> Multiple myeloma (MM), a tumor of germinal center (GC)-experienced plasma cells, comprises distinct genetic subgroups, such as the t(11;14)/CCND1 and the t(4;14)/MMSET subtype. We have generated subgroup-specific MM models by the GC B cell-specific co-activation of Ccnd1 or MMSET with a constitutively active Ikk2 mutant, mimicking the secondary NFκB activation frequently seen in human MM. Ccnd1/Ikk2ca and MMSET/Ikk2ca mice developed a pronounced, clonally restricted plasma cell outgrowth with age, accompanied by serum M spikes, bone marrow insufficiency and bone lesions. The transgenic plasma cells could be propagated <i>in vivo</i> and showed transcriptional profiles resembling their human counterparts. Thus, we show that Ccnd1 and MMSET cooperate with NFκB in MM pathogenesis, considering for the first time the genetic heterogeneity of MM for the generation of preclinical models.