Applying GRADE Criteria to Clinical Inputs to Cost-Effectiveness Modeling Studies.

BACKGROUND: Concerns have been raised about the use of clinical data in cost-effectiveness models. The aim of this analysis was to evaluate the appropriate use of data on clinical effectiveness in cost-effectiveness modeling studies that were published between 2001 and 2015. METHODS: Assessors rated 72 modeling studies obtained from three therapeutic areas by applying criteria defined by the Grading of Recommendations Assessment, Development and Evaluation group for assessing the quality of clinical evidence: selection of clinical data (publication bias), imprecision, indirectness, inconsistency (i.e., heterogeneity), and study limitations (risk of bias). For all parameters included in the analyses, potential changes over time were assessed. RESULTS: Although three out of four modeling studies relied on randomized controlled trials, more than 60% of the modeling studies were based on clinical data with a high or unclear risk of bias, in more than 80%, a risk of publication bias was found, and in about 30%, evidence was based on indirect clinical evidence, having significantly increased over the years. Study limitations were inadequately described in more than one third of the studies. However, less than 10% of clinical studies showed inconsistency or imprecision in study results. CONCLUSION: Despite the fact that the majority of economic evaluations are based on precise and consistent randomized controlled trials, their results are often affected by limitations arising from methodological shortcomings in the underlying data on clinical efficacy. Modelers and assessors should be more aware of aspects surrounding the quality of clinical evidence as considered by the Grading of Recommendations Assessment, Development and Evaluation group.

The stomatal response to reduced relative humidity requires guard cell-autonomous ABA synthesis.

Stomata are pores on the leaf surface, bounded by two guard cells, which control the uptake of CO(2) for photosynthesis and the concomitant loss of water vapor. In 1898, Francis Darwin showed that stomata close in response to reduced atmospheric relative humidity (rh); however, our understanding of the signaling pathway responsible for coupling changes in rh to alterations in stomatal aperture is fragmentary. The results presented here highlight the primacy of abscisic acid (ABA) in the stomatal response to drying air. We show that guard cells possess the entire ABA biosynthesis pathway and that it appears upregulated by positive feedback by ABA. When wild-type Arabidopsis and the ABA-deficient mutant aba3-1 were exposed to reductions in rh, the aba3-1 mutant wilted, whereas the wild-type did not. However, when aba3-1 plants, in which ABA synthesis had been specifically rescued in guard cells, were challenged with dry air, they did not wilt. These data indicate that guard cell-autonomous ABA synthesis is required for and is sufficient for stomatal closure in response to low rh. Guard cell-autonomous ABA synthesis allows the plant to tailor leaf gas exchange exquisitely to suit the prevailing environmental conditions.

A novel role for Arabidopsis mitochondrial ABC transporter ATM3 in molybdenum cofactor biosynthesis.

The molybdenum cofactor (Moco) is a prosthetic group required by a number of enzymes, such as nitrate reductase, sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. Its biosynthesis in eukaryotes can be divided into four steps, of which the last three are proposed to occur in the cytosol. Here, we report that the mitochondrial ABC transporter ATM3, previously implicated in the maturation of extramitochondrial iron-sulfur proteins, has a crucial role also in Moco biosynthesis. In ATM3 insertion mutants of Arabidopsis thaliana, the activities of nitrate reductase and sulfite oxidase were decreased to approximately 50%, whereas the activities of xanthine dehydrogenase and aldehyde oxidase, whose activities also depend on iron-sulfur clusters, were virtually undetectable. Moreover, atm3 mutants accumulated cyclic pyranopterin monophosphate, the first intermediate of Moco biosynthesis, but showed decreased amounts of Moco. Specific antibodies against the Moco biosynthesis proteins CNX2 and CNX3 showed that the first step of Moco biosynthesis is localized in the mitochondrial matrix. Together with the observation that cyclic pyranopterin monophosphate accumulated in purified mitochondria, particularly in atm3 mutants, our data suggest that mitochondria and the ABC transporter ATM3 have a novel role in the biosynthesis of Moco.

Beating heart aortic valve replacement after previous coronary artery bypass surgery with a patent internal mammary artery graft.

Re-sternotomy for aortic valve replacement (AVR) in patients with a patent internal mammary artery (IMA) graft may present a challenging surgical problem. Thus, strategies to prevent IMA graft injury include avoiding its dissection and leaving the graft open. However, when aortic cross clamping and cardioplegia are required, this approach may be associated with cardioplegia washout, suboptimal myocardial protection, and anterior myocardial wall injury. We herein describe an alternative technique for AVR on the beating heart in 4 patients with patent IMA grafts. The IMA was left unclamped and continuous retrograde coronary sinus perfusion (RCSP) was administered. Additional simultaneous antegrade venous bypass graft perfusion was established according to the extent of native coronary artery disease as well as patency and level of aortic proximal anastomoses. Using additional coronary ostia backflow control, the aortic valve was successfully replaced on the beating heart in all four cases without perivalvular leak. Postoperatively, low creatine kinase-MB fraction levels and preserved or improved ventricular function suggested very good myocardial protection. No myocardial infarction occurred in any patient. In our experience, aortic valve replacement on the beating heart using simultaneous antegrade-retrograde blood perfusion is a safe and effective method in this challenging subset of patients to prevent myocardial injury and to minimize the risk of patent IMA injury.

Significant value of autopsy for quality management in cardiac surgery.

OBJECTIVE: With recent advances in diagnostic imaging, the value of autopsy has been called into question. The aim of our study was to assess the current impact of autopsy for early postoperative quality management in cardiac surgery. METHODS: Between 2000 and 2003, a total of 14,313 patients underwent cardiac surgery at our center. Of these, 898 patients (6.3%) died, and autopsy was performed in 468 cases (52.1%). Data from clinical and postmortem examination were prospectively analyzed regarding causes of death, postoperative complications, concomitant diseases, and surgery-associated pathologic findings. RESULTS: Mean age was 68.7 years. Mean survival was 13.9 postoperative days. On autopsy, causes of death were cardiac in 49.8% of cases (n = 233), respiratory in 8.3% (n = 39), cerebral in 6.4% (n = 30), abdominal in 4.7% (n = 22), multiorgan failure or sepsis in 14.9% (n = 70), pulmonary embolism in 6.6% (n = 31), procedure associated in 8.3% (n = 39), and others in 0.9% (n = 4). Discrepancies between clinical and postmortem determinations of cause of death were found in 108 cases (23.1%). These were acute myocardial infarction (n = 38), low cardiac output (n = 9), respiratory (n = 8), cerebral (n = 5), abdominal (n = 7), multiorgan failure or sepsis (n = 12), pulmonary embolism (n = 18), and procedure associated (11). Clinically unrecognized postoperative complications were found in 364 cases (77.8%). Unknown concomitant diseases were found in 464 cases (99.1%), with potential therapeutic relevance in 90 cases (19.2%). In 85 cases (18.2%), autopsy examination revealed 96 premortem unrecognized surgery-associated pathologic findings. CONCLUSION: A high overall discrepancy rate between premortem and autopsy diagnoses was recognized. Autopsy revealed clinically relevant information in a significant number of cases. Therefore autopsy remains essential for quality assessment in perioperative treatment.