bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Bayesian approach for unplanned sample sizes in phase II cancer clinical trials
Authors: Li Yimei , Mick Rosemarie , Heitjan Daniel F 
Published: April 2012

Background Phase II cancer clinical trials commonly employ two-stage designs that incorporate a single interim analysis for lack of efficacy and are designed to achieve specified frequentist properties. The requirement to examine the outcome at a prespecified sample size (SS) can be problematic, because the attained SS often differs from the planned SS. Purpose We propose to address unplanned SSs achieved at either stage by means of a Bayesian approach that approximately preserves the original design’s properties. Methods Our approach translates the rejection rule of the original frequentist design into equivalent statements about the posterior distribution of the response rate and applies this Bayesian criterion to the analysis with any realized SS. Results The results demonstrate that our approach approximately maintains operating characteristics of the original frequentist design including type I and type II error rates, probability of early termination, and expected SS under the null hypothesis. Limitations Designs attained under this approach may not satisfy target limits for type I error rate and power. Conclusions Our method offers a coherent analysis plan when the attained SS at either stage deviates from that specified in the original design. The price of its flexibility, in terms of erosion of the desired frequentist properties, is modest.
Education as part of wider health policy and improvement strategies
Authors: Ellis Benjamin , Johnson Martin , Taylor Ann 
Published: April 2012

Summary points 1. The majority of people living with persistent pain will receive treatment for the pain from non-specialists in pain management who may not have received the necessary training to deliver high-quality care. 2. There is now a wide range of learning platforms and packages available, but these may struggle to reach beyond those with a specialist interest. Addressing this will require action at both local and national levels to prioritise training in pain management. 3. Although education may improve knowledge, changing behaviour will require a wider change in clinical culture, including changing public and clinical attitudes and ensuring that the NHS recognises, prioritises and rewards high-quality pain management.
Altitude illness is related to low hypoxic chemoresponse and low oxygenation during sleep
Authors: Nespoulet Hugo , Wuyam Bernard , Tamisier Renaud , Saunier Carole , Monneret Denis , Remy Judith , Chabre Olivier , Pépin Jean-Louis , Lévy Patrick 
Published: April 2012

Altitude illness remains a major cause of mortality. Reduced chemosensitivity, irregular breathing leading to central apnoeas/hypopnoeas, and exaggerated pulmonary vasoconstriction may compromise oxygenation. All factors could enhance susceptibility to acute mountain sickness (AMS).We compared 12 AMS-susceptible individuals with recurrent and severe symptoms (AMS+) with 12 “AMS-nonsusceptible” subjects (AMS-), assessing sleep-breathing disorders in simulated altitude as well as chemoresponsive and pulmonary vasoconstrictive responses to hypoxia.During exposure to simulated altitude, mean blood oxygen saturation during sleep was lower in AMS+ subjects (81.6±2.6versus86.0±2.4%, p<0.01), associated with a lower central apnoea/hypopnoea index (18.2±18.1versus33.4±24.8 events·h−1in AMS+ and AMS- subjects, respectively; p=0.038). A lower hypoxic (isocapnic) chemoresponsiveness was observed in AMS+ subjects (0.40±0.49versus0.97±0.46 L·min−1·%; p<0.001). This represented the only significant and independent predictive factor for altitude intolerance, despite a higher increase in pulmonary artery systolic pressure in response to hypoxia, a lower lung diffusing capacity and a higher endothelin-1 level at baseline in AMS+ subjects (p<0.05). AMS+ subjects were more hypoxaemic whilst exhibiting fewer respiratory events during sleep owing to lower hypoxic (isocapnic) chemoresponsiveness.In conclusion, the reduction in peripheral hypoxic chemosensitivity appears to be a major causative factor for altitude intolerance.
At 68 years, unrecognised sleep apnoea is associated with elevated ambulatory blood pressure
Authors: Roche Frédéric , Pépin Jean-Louis , Achour-Crawford Emilie , Tamisier Renaud , Pichot Vincent , Celle Sébastien , Maudoux Delphine , Chouchou Florian , Ntougou-Assoumou Hourfil G. , Lévy Patrick , Barthélémy Jean Claude 
Published: April 2012

After the age of 65 yrs the specific impact of unrecognised sleep-related breathing disorders (SRBD) on 24-h blood pressure (BP) levels remains under debate. We tested the cross-sectional relationship between the severity of obstructive sleep apnoea/hypopnoea (OSAH) and the increase of BP using ambulatory BP monitoring (ABPM) in the PROOF (PROgnostic indicator OF cardiovascular and cerebrovascular events study)-SYNAPSE (Autonomic Nervous System Activity, Aging and Sleep Apnea/Hypopnea study) cohort.470 subjects (aged 68 yrs) neither treated for hypertension nor diagnosed for SRBD were included. All subjects underwent ABPM, and unattended at-home polygraphic studies. OSAH was defined by an apnoea/hypopnoea index (AHI) >15·h−1. The severity of the sleep apnoea was also quantified as the index of dips in oxyhaemoglobin saturation >3% (ODI). Results are expressed in per protocol analysis.Severe OSAH (AHI >30·h−1, 17% of subjects) was associated with a significant 5 mmHg increase in both diurnal and nocturnal systolic BP (SBP), and with a nocturnal 3 mmHg increase in diastolic BP (DBP). Systolic (mean SBP >135 mmHg) or diastolic (mean DBP >80 mmHg) hypertension were more frequently encountered in subjects suffering from moderate (AHI 15–30) or severe OSAH. After adjustment, the independent association between severe OSAH and 24-h systolic hypertension remained significant (OR 2.42, 95% CI 1.1–5.4). The relationship was further reinforced when SRBD severity was expressed using ODI >10·h−1.The impact of unrecognised SRBD on BP levels also exists at the age of 68 yrs. The hypoxaemic load appears to be the pathophysiological cornerstone for such a relationship.
Clinical and inflammatory determinants of bronchial hyperresponsiveness in COPD
Authors: van den Berge Maarten , Vonk Judith M. , Gosman Margot , Lapperre Thérèse S. , Snoeck-Stroband Jiska B. , Sterk Peter J. , Kunz Lisette I.Z. , Hiemstra Pieter S. , Timens Wim , ten Hacken Nick H.T. , Kerstjens Huib A.M. , Postma Dirkje S. 
Published: April 2012

Bronchial hyperresponsiveness (BHR) is regarded as a hallmark of asthma, yet it is also present in a considerable number of chronic obstructive pulmonary disease (COPD) patients. Epidemiological studies have shown that BHR provides complementary information to forced expiratory volume in 1 s (FEV1) for development and progression of COPD. We hypothesised that the severity of BHR and its longitudinal changes associate with both clinical and airway inflammation measures in COPD.Our hypothesis was tested in 114 COPD patients (median age 62.9 years, smoking exposure 45.9 pack-yrs) participating in the GLUCOLD (Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease) study, which previously showed an improvement in BHR with fluticasone and fluticasone/salmeterol. At baseline, and 6 and 30 months after treatment, we investigated lung function, including body plethysmography, provocative concentration of methacholine causing a 20% fall in FEV1, sputum induction, and bronchial biopsies.By performing both cross-sectional and longitudinal analyses, we show that BHR in COPD is predominantly associated with residual volume/total lung capacity (a measure of air trapping) and airway inflammation reflected by the number of neutrophils, macrophages and lymphocytes in sputum and bronchial biopsies.Our findings indicate that BHR is an independent trait in COPD and provides important information on phenotype heterogeneity and disease activity.
The role of mannose-binding lectin in pneumococcal infection
Authors: García-Laorden M. Isabel , Rodríguez de Castro Felipe , Solé-Violán Jordi , Payeras Antoni , Briones M. Luisa , Borderías Luis , Aspa Javier , Blanquer José , Rajas Olga , Marcos-Ramos J. Alberto , Herrera-Ramos Estefanía , García-Bello Miguel A. , Noda Judith , Ferrer José M. , Rello Jordi , Rodríguez-Gallego Carlos 
Published: April 2012

The role of mannose-binding lectin (MBL) deficiency (MBL2;XA/OandO/Ogenotypes) in host defences remains controversial. The surfactant proteins (SP)-A1, -A2 and -D, other collectins whose genes are located nearMBL2, are part of the first-line lung defence against infection. We analysed the role of MBL on susceptibility to pneumococcal infection and the existence of linkage disequilibrium (LD) among the four genes.We studied 348 patients with pneumococcal community-acquired pneumonia (P-CAP) and 2,110 controls. A meta-analysis ofMBL2genotypes in susceptibility to P-CAP and to invasive pneumococcal disease (IPD) was also performed. The extent of LD ofMBL2withSFTPA1,SFTPA2andSFTPDwas analysed.MBL2genotypes did not associate with either P-CAP or bacteraemic P-CAP in the case–control study. The MBL-deficientO/Ogenotype was significantly associated with higher risk of IPD in a meta-analysis, whereas the other MBL-deficient genotype (XA/O) showed a trend towards a protective role. We showed the existence of LD betweenMBL2and SP genes.The data do not support a role of MBL deficiency on susceptibility to P-CAP or to IPD. LD amongMBL2and SP genes must be considered in studies on the role of MBL in infectious diseases.
Acetazolamide and chronic hypoxia: effects on haemorheology and pulmonary haemodynamics
Authors: Pichon Aurélien , Connes Philippe , Quidu Patricia , Marchant Dominique , Brunet Julien , Levy Bernard I. , Vilar José , Safeukui Innocent , Cymbalista Florence , Maignan Maxime , Richalet Jean-Paul , Favret Fabrice 
Published: April 2012

We tested the effect of acetazolamide on blood mechanical properties and pulmonary vascular resistance (PVR) during chronic hypoxia.Six groups of rats were either treated or not treated with acetazolamide (curative: treated after 10 days of hypoxic exposure; preventive: treated before hypoxic exposure with 40 mg·kg−1·day−1) and either exposed or not exposed to 3 weeks of hypoxia (at altitude >5,500 m). They were then used to assess the role of acetazolamide on pulmonary artery pressure, cardiac output, blood volume, haematological and haemorheological parameters.Chronic hypoxia increased haematocrit, blood viscosity and PVR, and decreased cardiac output. Acetazolamide treatment in hypoxic rats decreased haematocrit (curative by -10% and preventive by -11%), PVR (curative by -36% and preventive by -49%) and right ventricular hypertrophy (preventive -20%), and increased cardiac output (curative by +60% and preventive by +115%). Blood viscosity was significantly decreased after curative acetazolamide treatment (-16%) and was correlated with PVR (r=0.87, p<0.05), suggesting that blood viscosity could influence pulmonary haemodynamics. The fall in pulmonary vascular hindrance (curative by -27% and preventive by -45%) after treatment suggests that acetazolamide could decrease pulmonary vessels remodelling under chronic hypoxia.The effect of acetazolamide is multifactorial by acting on erythropoiesis, pulmonary circulation, haemorheological properties and cardiac output, and could represent a pertinent treatment of chronic mountain sickness.
Effectiveness of an inspiratory pressure-limited approach to mechanical ventilation in septic patients
Authors: Martin-Loeches Ignacio , de Haro Candelaria , Dellinger R. Phillip , Ferrer Ricard , Phillips Gary S. , Levy Mitchell M. , Artigas Antonio 
Published: April 2012

Severe sepsis is one of the most common causes of acute lung injury (ALI) and is associated with high mortality. The aim of the study was to see whether a protective strategy based approach with a plateau pressure <30 cmH2O was associated with lower mortality in septic patients with ALI in the Surviving Sepsis Campaign international database.A retrospective analysis of an international multicentric database of 15,022 septic patients from 165 intensive care units was used.Septic patients with ALI and mechanical ventilation (n=1,738) had more accompanying organ dysfunction and a higher mortality rate (48.3%versus33.0%, p<0.001) than septic patients without ALI (n=13,284). In patients with ALI and mechanical ventilation, the use of inspiratory plateau pressures maintained at <30 cmH2O was associated with lower mortality by Chi-squared test (46.4%versus55.1%, p<0.001) and by Kaplan–Meier and log-rank test (p<0.001). In a multivariable random-effects Cox regression, plateau pressure <30 cmH2O was significantly associated with lower mortality (hazard ratio 0.84, 95% CI 0.72–0.99; p=0.038).ALI in sepsis was associated with higher mortality, especially when an inspiratory pressure-limited mechanical ventilation approach was not implemented.
Vitamin K1 enhances sorafenib-induced growth inhibition and apoptosis of human malignant glioma cells by blocking the Raf/MEK/ERK pathway
Authors: Du Wei , Zhou Jing-ru , Wang Dong-liang , Gong Kai , Zhang Qing-jun 
Published: April 2012

Abstract

Background
The combined effects of anticancer drugs with nutritional factors against tumor cells have been reported previously. This study characterized the efficacy and possible mechanisms of the combination of sorafenib and vitamin K1 (VK1) on glioma cell lines.

Methods
We examined the effects of sorafenib, VK1 or their combination on the proliferation and apoptosis of human malignant glioma cell lines (BT325 and U251) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, flow cytometry and 4′,6-diamidino-2-phenylindole (DAPI) assay. The signaling pathway changes were detected by western blotting.

Results
Sorafenib, as a single agent, showed antitumor activity in a dose-dependent manner in glioma cells, but the effects were more pronounced when used in combination with VK1 treatment. Sorafenib in combination with VK1 treatment produced marked potentiation of growth inhibition and apoptosis, and reduced expression of phospho-mitogen-activated protein kinase kinase (MEK) and phospho-extracellular signal-regulated kinase (ERK). Furthermore, the expression levels of antiapoptotic proteins Bcl-2 and Mcl-1 were significantly reduced.

Conclusions
Our findings indicated that VK1 enhanced the cytotoxicity effect of sorafenib through inhibiting the Raf/MEK/ERK signaling pathway in glioma cells, and suggested that sorafenib in combination with VK1 maybe a new therapeutic option for patients with gliomas.
Insecticide resistance in Culex quinquefasciatus from Zanzibar: implications for vector control programmes
Authors: Jones Christopher M , Machin Camille , Mohammed Khalfan , Majambere Silas , Ali Abdullah S , Khatib Bakari O , Mcha Juma , Ranson Hilary , Kelly-Hope Louise A 
Published: April 2012

AbstractBackgroundZanzibar has a long history of lymphatic filariasis (LF) caused by the filarial parasiteWuchereria bancrofti, and transmitted by the mosquitoCulex quinquefasciatusSay. The LF Programme in Zanzibar has successfully implemented mass drug administration (MDA) to interrupt transmission, and is now in the elimination phase. Monitoring infections in mosquitoes, and assessing the potential role of interventions such as vector control, is important in case the disease re-emerges as a public health problem. Here, we examineCulexmosquito species from the two main islands to detectW. bancroftiinfection and to determine levels of susceptibility to the insecticides used for vector control.MethodsCulexmosquitoes collected during routine catches in Vitongoji, Pemba Island, and Makadara, Unguja Island were tested forW. bancroftiinfection using PCR. Insecticide bioassays onCulexmosquitoes were performed to determine susceptibility to permethrin, deltamethrin, lambda-cyhalothrin, DDT and bendiocarb. Additional synergism assays with piperonyl butoxide (PBO) were used for lambda-cyhalothrin. Pyrosequencing was used to determine thekdrgenotype and sequencing of the mitochondrial cytochrome oxidase I (mtCOI) subunit performed to identify ambiguousCulexspecies.ResultsNone of the wild-caughtCulexmosquitoes analysed were found to be positive forW. bancrofti. High frequencies of resistance to all insecticides were found in Wete, Pemba Island, whereasCulexfrom the nearby site of Tibirinzi (Pemba) and in Kilimani, Unguja Island remained relatively susceptible. Species identification confirmed that mosquitoes from Wete wereCulex quinquefasciatus. The majority of theCulexcollected from Tibirinzi and all from Kilimani could not be identified to species by molecular assays. Two alternativekdralleles, both resulting in a L1014F substitution were detected inCx. quinquefasciatusfrom Wete with no homozygote susceptible detected. Metabolic resistance to pyrethroids was also implicated by PBO synergism assays.ConclusionsResults from the xenomonitoring are encouraging for the LF programme in Zanzibar. However, the high levels of pyrethroid resistance found in the principle LF vector in Pemba Island will need to be taken into consideration if vector control is to be implemented as part of the elimination programme.
Management of isolated non-traumatic renal artery dissection: report of four cases
Authors: Abdel-Kerim Amr , Cassagnes Lucie , Alfidja Agaicha , Gageanu Cristian , Favrolt Gregory , Dumousset Eric , Ravel Anne , Boyer Louis , Chabrot Pascal 
Published: April 2012

BackgroundIsolated non-traumatic renal artery dissection (RAD) is a rare disorder with uncertain natural history. The management may be surgical reconstruction, endovascular repair, or conservative medical treatment, yet no official consensus had been established.PurposeTo report the management of four cases of isolated non-traumatic RAD, emphasizing the beneficial role of conservative medical treatment.Material and MethodsFrom the year 2000 till 2011, four male patients with mean age of 42.5 years (range 34–48 years) presented with isolated non-traumatic RAD and were initially treated with medical therapy. Transcatheter in situ thrombolysis was performed in a case with thrombotic occlusion.ResultsIsolated non-traumatic RAD in four patients involving at least seven branches progressed to thrombotic occlusion in two branches, luminal narrowing in five, dual lumens in two, and aneurysmal dilatation in three. Medical treatment was efficacious in three patients, who showed persistent preserved renal function, controlled blood pressure, and favorable arterial remodeling. After failure of medical therapy, the fourth patient was referred to surgery. Thrombolysis was successful to dissolute an occluding thrombotic dissection.ConclusionConservative therapy is safe and effective when the renal artery is patent and blood pressure is controlled: we propose it as the first line of treatment, reserving interventional management for refractory cases.
Advances in First-Line Treatment for Patients with HER-2+ Metastatic Breast Cancer
Authors: De Mattos-Arruda Leticia , Cortes Javier 
Published: April 2012

AbstractLearning Objectives:After completing this course, the reader will be able to: Discuss the optimal strategies to treat HER-2+ metastatic breast cancer patients in the first-line setting and after recurrence with adjuvant trastuzumab.Identify the current first-line therapeutic options for HER-2+ metastatic breast cancer, including HER-2/hormone receptor copositive tumors.Discuss the most important advances for HER-2+ metastatic breast cancer and the potential of novel anti-HER-2 therapies.CME This article is available for continuing medical education credit at CME.TheOncologist.comBackground.The prognosis for breast cancer patients overexpressing human epidermal growth factor receptor (HER)-2 has changed with anti–HER-2–targeted therapy. Although anti–HER-2 therapy with trastuzumab and chemotherapy is the standard first-line treatment, the best therapeutic regimen has yet to be defined, and new strategies are evolving.Methods.A literature review of well-established and recently published trials, reviews, and ongoing clinical trials addressing first-line treatment for HER-2+ metastatic breast cancer patients was performed.Results.Taxanes are the agents most commonly used in combination with trastuzumab, but other chemotherapy drugs, such as anthracyclines, vinorelbine, and gemcitabine and triple-combination therapies including platinum compounds, capecitabine, and taxanes have been studied. The combination of aromatase inhibitors with anti–HER-2 therapies is a new therapeutic option for some patients who coexpress HER-2 and hormone receptors, although its activity observed in randomized clinical trials seems to be inferior to that of chemotherapy plus anti–HER-2 therapies. In addition, new anti–HER-2 therapies have shown activity in HER-2+ tumors, both alone and in combination with trastuzumab.Conclusions.Trastuzumab plus chemotherapy is the current standard of care for the upfront treatment of HER-2+ breast cancer patients, though other anti–HER-2–targeting agents may appear as new standards in the upcoming years.
Bone Mineral Density and Fracture Risk in Older Individuals with CKD
Authors: Yenchek Robert H. , Ix Joachim H. , Shlipak Michael G. , Bauer Douglas C. , Rianon Nahid J. , Kritchevsky Stephen B. , Harris Tamara B. , Newman Anne B. , Cauley Jane A. , Fried Linda F. 
Published: April 2012

Summary

Background and objectives
Kidney Disease Improving Global Outcomes guidelines recommend against bone mineral density (BMD) screening in CKD patients with mineral bone disease, due to a lack of association of BMD with fractures in cross-sectional studies in CKD. We assessed whether BMD is associated with fractures in participants with and without CKD in the Health, Aging, and Body Composition study, a prospective study of well functioning older individuals.

Design, setting, participants, & measurements
Hip BMD was measured by dual-energy x-ray absorptiometry. Osteoporosis was defined as a femoral neck BMD (FNBMD) T score below −2.5 and CKD as an estimated GFR <60 ml/min per 1.73 m2. The association of BMD with incident nonspine, fragility fractures to study year 11 was analyzed using Cox proportional hazards analyses, adjusting for age, race, sex, body mass index, hyperparathyroidism, low vitamin D level, and CKD. Interaction terms were used to assess whether the association of BMD with fracture differed in those with and without CKD.

Results
There were 384 incident fractures in 2754 individuals (mean age 73.6 years). Lower FNBMD was associated with greater fracture, regardless of CKD status. After adjustment, the hazard ratios (95% confidence intervals) were 2.74 (1.99, 3.77) and 2.15 (1.80, 2.57) per lower SD FNBMD for those with and without CKD, respectively (interaction P=0.68), and 2.10 (1.23, 3.59) and 1.63 (1.18, 2.23) among those with osteoporosis in patients with and without CKD, respectively (interaction P=0.75).

Conclusions
BMD provides information on risk for fracture in older individuals with or without moderate CKD.