Estimated research and development costs of rotavirus vaccines

Diseases like rotavirus afflict both upper- and lower-income countries, but most serious illnesses and deaths occur among the latter. It is a vital public health issue that vaccines for these types of global diseases can recover research and development (R&D) costs from high-priced markets quickly so that manufacturers can offer affordable prices to lower-income nations. Cost recovery depends on how high R&D costs are, and this study attempts to replace high, unverified estimates with lower, more verifiable estimates for two new vaccines, RotaTeq (Merck) and Rotarix (GlaxoSmithKline or GSK), based on detailed searches of public information and follow-up interviews with senior informants. We also offer a new perspective on “cost of capital” as a claim for recovery from public bodies. Our estimates suggest that companies can recover all fixed costs quickly from affluent markets and thus can offer these vaccines to lower-income countries at prices they can afford. Better vaccines are a shared project between companies and public health agencies; greater transparency and consistency in reporting of R&D costs is needed so that fair prices can be established.     

Simultaneous versus sequential optimal design for pharmacokinetic-pharmacodynamic models with FO and FOCE considerations

We consider nested multiple response models which are used extensively in the area of pharmacometrics. Given the conditional nature of such models, differences in predicted responses are a consequence of different assumptions about how the models interact. As such, sequential versus simultaneous and First Order (FO) versus First Order Conditional Estimation (FOCE) techniques have been explored in the literature where it was found that the sequential and FO approaches can produce biased results. It is therefore of interest to determine any design consequences between the various methods and approximations. As optimal design for nonlinear mixed effects models is dependent upon initial parameter estimates and an approximation to the expected Fisher information matrix, it is necessary to incorporate any influence of nonlinearity (or parameter-effects curvature) into our exploration. Hence, sequential versus simultaneous design with FO and FOCE considerations are compared under low, typical and high degrees of nonlinearity. Additionally, predicted standard errors of parameters are also compared to empirical estimates formed via a simulation/estimation study in NONMEM. Initially, design theory for nested multiple response models is developed and approaches mentioned above are investigated by considering a pharmacokinetic–pharmacodynamic model found in the literature. We consider design for situations where all responses are continuous and extend this methodology to the case where a response may be a discrete random variable. In particular, for a binary response pharmacodynamic model, it is conjectured that such responses will offer little information about all parameters and hence a sequential optimization, in the form of product design optimality, may yield near optimal designs.     

Perugia urodynamic method of analysis (PUMA): a new advanced method of urodynamic analysis applied clinically and compared with other advanced methods.

AIMS: The aim of this study is to compare PUMA curves with different pathologic conditions causing bladder dysfunction in 158 men and 83 women. METHODS: PUMA results in terms of bladder outlet obstruction and detrusor contractility were compared in 92 men with benign prostatic hypertrophy (BPH) and p(ves) congruent with p(det) (i.e., p(abd) congruent with 0) with the results of the urodynamics operator's opinion, the provisional International Continence Society method, Abrams and Griffith's diagram, urethral resistence factor (URA), Sch?fer's diagram, and Watt factor. PUMA curves correlated reliably with different pathologic conditions such as obstructive BPH, orthotopic bladder, cystocele, the neurological bladder, and bladder diverticulum. Statistical analysis indicated excellent agreement between PUMA and URA; agreement with other methods was good in cases of obstruction and nonobstruction. In doubtful cases, as diagnosed by standard methods, PUMA agreed only with the Abrams and Griffith's diagram. PUMA and Wmax were in good agreement on detrusor con traction force. Agreement between PUMA and Sch?fer's diagram was excellent for patients with detrusor hypercontractility and good for patients with detrusor hypocontractility and normocontractility. PUMA is the only method applicable to women. It is easy to perform. When integrated with other diagnostic tests, it provides realistic data for diagnosis, medical or surgical therapy, and outcome.     

Lung function development in the first 2 yr of life is independent of allergic diseases by 2 yr

The aim of the study was to assess if lung function at birth predicts lung function at 2 yr and secondly, if lung function development was influenced by the common phenotypes of recurrent bronchial obstruction (rBO) or atopic eczema (AE) by 2 yr. Lung function was assessed at birth (n = 802) and at 2 yr within the prospective birth cohort study 'the Environment and Childhood Asthma Study' in Oslo. The 135 children with lung function measured at birth by tidal flow volume (TFV) loops and passive respiratory mechanics, who were included in a nested case-control study were reinvestigated at 2 yr with clinical examination, TFV loops (n = 90) (mean age 26.6 (3.7 s.d.) months), skin prick test and parental interview. Children were categorized into quartiles (lower, middle two, upper) according to time to peak tidal expiratory flow/total expiratory time (t(PTEF)/t(E)) at birth as well as clinical phenotype based on the presence of rBO and/or AE (ever) by 2 yr. The observed reduction in mean t(PTEF)/t(E) from birth to 2 yr within the quartiles, were not significantly different after controlling for 'regression to the mean'. t(PTEF)/t(E) at birth correlated significantly with t(PTEF)/t(E) at 2 yr, (r = 0.475, p < 0.001). Children with both rBO and AE by 2 yr had significantly lower t(PTEF)/t(E) at 2 yr (p = 0.002) and at birth (p = 0.027), compared with children with no rBO or AE. Clinical phenotype at 2 yr did not influence the change in t(PTEF)/t(E) from birth to 2 yr. This study demonstrates a clear tracking of lung function from birth, not influenced by rBO or AE by 2 yr.     

Fat and water separation in balanced steady-state free precession using the Dixon method.

In this work the feasibility of separating fat and water signals using the balanced steady-state free precession (SSFP) technique is demonstrated. The technique is based on the observation (Scheffler and Hennig, Magnetic Resonance in Medicine 2003;49:395-397) that at the nominal values of TE = TR/2 in SSFP imaging, phase coherence can be achieved at essentially only two orientations (0 degrees and 180 degrees ) relative to the RF pulses in the rotating frame, under the assumption of TR < T2, and independently of the SSFP angle. This property allows in-phase and out-of-phase SSFP images to be obtained by proper choices of the center frequency offset, and thus allows the Dixon subtraction method to be utilized for effective fat-water separation. The TR and frequency offset for optimal fat-water separation are derived from theories. Experimental results from healthy subjects, using a 3.0 Tesla system, show that nearly complete fat suppression can be accomplished.     

中风毒邪论与神经保护治疗的研究

中风毒邪论是一种与传统中医中风病理有所不同的理论 ,在中风毒邪论指导下形成解毒通络方是较为理想的神经保护剂 ,可解决目前神经保护治疗的主要障碍 ,有望成为提高中医治疗中风急性期疗效的关键     

葛根素对血管性痴呆患者认知功能和事件相关电位P300的影响

目的观察葛根素对血管性痴呆（VaD）患者认知功能和听觉事件相关电位P300的影响。方法将70例VaD患者随机分成两组各35例，葛根素治疗组和对照组。应用简易精神状态检查量表（MMSE）评定两组患者治疗前后认知功能状况，并进行治疗前后P300检查。同时记录药物不良反应。结果两组各35例进入结果分析。治疗前两组MMSE评分、P300的潜伏期及波幅差异无显著性（均P〉0．05）。治疗14d、30d时，两组MMSE评分显著提高（均P〈0．01），P300潜伏期均有缩短，波幅均有提高（葛根素组P〈0．01，对照组P〈0．05）；治疗后14d时认知功能改善葛根素组明显优于对照组（总有效率分别为91．4％，71．4％）（P〈0．05）。两组治疗期间无严重不良反应。结论葛根素能够改善VaD患者的认知功能，这可能与葛根素的扩血管、脑保护作用有关。     

Flavocoxid is as effective as naproxen for managing the signs and symptoms of osteoarthritis of the knee in humans: a short-term randomized,double-blind pilot study

Flavocoxid (Limbrel), a proprietary mixture of flavonoid molecules (baicalin and catechin), was tested against a traditional nonsteroidal anti-inflammatory drug, naproxen, for the management of the signs and symptoms of moderate osteoarthritis (OA) in humans. Discomfort and global disease activity were used as the primary end points, and safety assessments were also taken for both treatments as a secondary endpoint. In this double-blind study, 103 subjects were randomly assigned to receive either flavocoxid [500 mg twice daily (BID)] or naproxen (500 mg BID) in a 1-month onset of action trial. Outcome measures included the short Western Ontario and McMaster University Osteoarthritis Index, subject Visual Analogue Scale for discomfort and global response, and investigator Visual Analogue Scale for global response and fecal occult blood. Both flavocoxid and naproxen showed significant reduction in the signs and symptoms of knee OA (P ≤ .001). There were no statistically detectable differences between the flavocoxid and naproxen groups with respect to any of the outcome variables. Similarly, there were no statistically detectable differences between the groups with respect to any adverse event, although there was a trend toward a higher incidence of edema and nonspecific musculoskeletal discomfort in the naproxen group. In this short-term pilot study, flavocoxid was as effective as naproxen in controlling the signs and symptoms of OA of the knee and would present a safe and effective option for those individuals on traditional nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors. A low incidence of adverse events was reported for both groups.