Conducting indirect-treatment-comparison and network-meta-analysis studies: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 2.

Evidence-based health care decision making requires comparison of all relevant competing interventions. In the absence of randomized controlled trials involving a direct comparison of all treatments of interest, indirect treatment comparisons and network meta-analysis provide useful evidence for judiciously selecting the best treatment(s). Mixed treatment comparisons, a special case of network meta-analysis, combine direct evidence and indirect evidence for particular pairwise comparisons, thereby synthesizing a greater share of the available evidence than traditional meta-analysis.

Mechanistic logic underlying the axonal transport of cytosolic proteins.

Proteins vital to presynaptic function are synthesized in the neuronal perikarya and delivered into synapses via two modes of axonal transport. While membrane-anchoring proteins are conveyed in fast axonal transport via motor-driven vesicles, cytosolic proteins travel in slow axonal transport via mechanisms that are poorly understood. We found that in cultured axons, populations of cytosolic proteins tagged to photoactivatable GFP (PAGFP) move with a slow motor-dependent anterograde bias distinct from both vesicular trafficking and diffusion of untagged PAGFP.

Preexisting cognitive impairment and mild cognitive impairment in subjects presenting for total hip joint replacement.

Background: The prevalence of preexisting cognitive impairment (PreCI) is documented before cardiac surgery, but there is less information before noncardiac surgery. In addition, the prevalence of mild cognitive impairment, defined by different cognitive criteria and subjective complaints, and which may progress to Alzheimer disease, is unknown in these subjects. Because anesthesia and surgery have been implicated in Alzheimer disease pathology, we prospectively measured PreCI and mild cognitive impairment in subjects scheduled for total hip joint replacement surgery in an observational study.

In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors.

Synthesis and biological evaluation of a series of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors was reported. Biochemical screening, followed by profile optimization, resulted in JAK2 inhibitors exhibiting good kinase selectivity, pharmacokinetic properties, physical properties and pharmacodynamic effects.

Postoperative cognitive dysfunction is independent of type of surgery and anesthetic.

Background: Postoperative cognitive dysfunction (POCD) has been documented after cardiac and noncardiac surgery. The type of surgery and anesthetic has been assumed to be associated with the incidence but there are few prospective data comparing the incidence after different procedures. In this study, we sought to determine the association of the type of surgical procedure and anesthesia on the incidence of POCD after procedures involving light sedation, general anesthesia for noncardiac surgery, and general anesthesia for cardiac surgery involving cardiopulmonary bypass.

3-amido-4-anilinocinnolines as a novel class of CSF-1R inhibitor.

3-Amido-4-anilinocinnolines have been identified as potent and highly selective inhibitors of CSF-1R. The synthesis and SAR of these compounds is reported, along with some physical property, pharmacokinetic and kinase selectivity data.

Deletion of genes encoding cytochrome oxidases and quinol monooxygenase blocks the aerobic-anaerobic shift in Escherichia coli K-12 MG1655.

The constitutive activation of the anoxic redox control transcriptional regulator (ArcA) in Escherichia coli during aerobic growth, with the consequent production of a strain that exhibits anaerobic physiology even in the presence of air, is reported in this work. Removal of three terminal cytochrome oxidase genes (cydAB, cyoABCD, and cbdAB) and a quinol monooxygenase gene (ygiN) from the E. coli K-12 MG1655 genome resulted in the activation of ArcA aerobically.

Diabetes-related molecular signatures in infrared spectra of human saliva.

Background: There is an ongoing need for improvements in non-invasive, point-of-care tools for the diagnosis and prognosis of diabetes mellitus. Ideally, such technologies would allow for community screening.

Methods: In this study, we employed infrared spectroscopy as a novel diagnostic tool in the prediction of diabetic status by analyzing the molecular and sub-molecular spectral signatures of saliva collected from subjects with diabetes (n = 39) and healthy controls (n = 22).

Reimbursement and value-based pricing: stratified cost-effectiveness analysis may not be the last word.

During recent discussions, it has been argued that stratified cost-effectiveness analysis has a key role in reimbursement decision-making and value-based pricing (VBP). It has previously been shown that when manufacturers are price-takers, reimbursement decisions made in reference to stratified cost-effectiveness analysis lead to a more efficient allocation of resources than decisions based on whole-population cost-effectiveness analysis. However, we demonstrate that when manufacturers are price setters, reimbursement or VBP based on stratified cost-effectiveness analysis may not be optimal.

A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration.

Several neurodegenerative diseases are typified by intraneuronal alpha-synuclein deposits, synaptic dysfunction, and dementia. While even modest alpha-synuclein elevations can be pathologic, the precise cascade of events induced by excessive alpha-synuclein and eventually culminating in synaptotoxicity is unclear. To elucidate this, we developed a quantitative model system to evaluate evolving alpha-synuclein-induced pathologic events with high spatial and temporal resolution, using cultured neurons from brains of transgenic mice overexpressing fluorescent-human-alpha-synuclein.

Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: a tutorial.

Background: Data on survival endpoints are usually summarised using either hazard ratio, cumulative number of events, or median survival statistics. Network meta-analysis, an extension of traditional pairwise meta-analysis, is typically based on a single statistic. In this case, studies which do not report the chosen statistic are excluded from the analysis which may introduce bias.

Tobacco upregulates P. gingivalis fimbrial proteins which induce TLR2 hyposensitivity.

Background: Tobacco smokers are more susceptible to periodontitis than non-smokers but exhibit reduced signs of clinical inflammation. The underlying mechanisms are unknown. We have previously shown that cigarette smoke extract (CSE) represents an environmental stress to which P.

Phosphoproteome dynamics reveal heat-shock protein complexes specific to the Leishmania donovani infectious stage.

Leishmania is exposed to a sudden increase in environmental temperature during the infectious cycle that triggers stage differentiation and adapts the parasite phenotype to intracellular survival in the mammalian host. The absence of classical promoter-dependent mechanisms of gene regulation and constitutive expression of most of the heat-shock proteins (HSPs) in these human pathogens raise important unresolved questions as to regulation of the heat-shock response and stage-specific functions of Leishmania HSPs. Here we used a gel-based quantitative approach to assess the Leishmania donovani phosphoproteome and revealed that 38% of the proteins showed significant stage-specific differences, with a strong focus of amastigote-specific phosphoproteins on chaperone function.

Relapsing and remitting scapular winging in a pediatric patient.

Scapular winging (scapula alata) is a condition in which the scapula is rotated or displaced away from the body. The nature of this rotation or displacement can vary depending on the origin. There are many different causes of scapular winging including neurogenic, structural, muscular, and bursal (Frontera, Silver, Essentials of Physical Medicine and Rehabilitation.

Postoperative cognitive dysfunction and aortic atheroma.

Background: The relationship of aortic atheroma to postoperative cognitive dysfunction (POCD), a common complication of coronary artery bypass graft surgery, has not been resolved. We undertook assessment of aortic atheroma using intraoperative ultrasonography and related the degree of aortic atheroma to POCD.

Methods: Aortic atheroma was assessed using intraoperative transesophageal and epiaortic echocardiography in 311 patients who underwent coronary artery bypass graft surgery.

Cost-effectiveness analysis: discount the placebo at your peril.

Introduction: The authors consider alternative mechanisms that might explain placebo responses and their implications for cost-effectiveness modeling. Three alternative placebo mechanisms are examined: a ''regression to the mean'' effect arising from natural variation and the preferential selection of patients with acutely severe disease into clinical trials, a patient expectancy effect specific to the clinical trial setting (Hawthorne effect), and a patient expectancy effect generalizable to routine clinical practice (true placebo effect).

Methods: To estimate cost-effectiveness, the authors needed to generalize from trial data to estimate responses to treatment that they would see in routine clinical practice.

Plasma amyloid beta42 and amyloid beta40 levels are associated with early cognitive dysfunction after cardiac surgery.

Background: Decreased cognitive function associated with coronary artery bypass graft surgery is common. These deficits may be similar to the cognitive dysfunction seen in the spectrum of mild cognitive impairment to Alzheimer's disease, which are believed to result from the accumulation of amyloid beta (Abeta) peptide in the brain. We measured cognition both before and after coronary artery bypass graft surgery and assayed Abeta levels to investigate whether the cognitive dysfunction of cardiac surgery was associated with Abeta levels.

Direct evidence of 1,900 years of indigenous silver production in the Lake Titicaca Basin of Southern Peru.

Archaeological excavations at a U-shaped pyramid in the northern Lake Titicaca Basin of Peru have documented a continuous 5-m-deep stratigraphic sequence of metalworking remains. The sequence begins in the first millennium AD and ends in the Spanish Colonial period ca. AD 1600.

Salivary antioxidants in patients with type 1 or 2 diabetes and inflammatory periodontal disease: a case-control study.

Background: The purpose of this study was to evaluate and compare salivary concentrations of reduced, oxidized glutathione, uric acid, ascorbic acid, and total antioxidant capacity in subjects with diabetes and systemically healthy subjects with inflammatory periodontal disease.

Methods: Sixteen patients with type 1 diabetes mellitus (DM), 25 patients with type 2 DM, and 24 systemically healthy patients, all with inflammatory periodontal disease, were recruited. Whole-saliva samples were obtained, and full-mouth clinical periodontal measurements, including plaque index, probing depth, gingival recession, clinical attachment level, and bleeding on probing, were recorded at six sites per tooth.

How far do you go? Efficient searching for indirect evidence.

Background: Indirect evidence is particularly valuable in health care decision making when direct trial evidence comparing relevant treatments is absent or limited. Current approaches using a predetermined set of comparators in the search query may fail to identify all relevant indirect evidence.

Purpose: To present a framework for the efficient design of search strategies for identifying clinical trials providing indirect evidence for a treatment comparison.

No study left behind: a network meta-analysis in non-small-cell lung cancer demonstrating the importance of considering all relevant data.

Objective: To demonstrate the importance of considering all relevant indirect data in a network meta-analysis of treatments for non-small-cell lung cancer (NSCLC).

Methods: A recent National Institute for Health and Clinical Excellence appraisal focussed on the indirect comparison of docetaxel with erlotinib in second-line treatment of NSCLC based on trials including a common comparator. We compared the results of this analysis to a network meta-analysis including other trials that formed a network of evidence.

Methylene tetrahydrofolate dehydrogenase/cyclohydrolase and the synthesis of 10-CHO-THF are essential in Leishmania major.

10-Formyl tetrahydrofolate (10-CHO-THF) is a key metabolite in C1 carbon metabolism, arising through the action of formate-tetrahydrofolate ligase (FTL) and/or 5,10-methenyltetrahydrofolate cyclohydrolase/5,10-methylene tetrahydrofolate dehydrogenase (DHCH). Leishmania major possesses single DHCH1 and FTL genes encoding exclusively cytosolic proteins, unlike other organisms where isoforms occur in the mitochondrion as well. Recombinant DHCH1 showed typical NADP(+)-dependent methylene tetrahydrofolate DH and 5,10-methenyltetrahydrofolate CH activities, and the DH activity was potently inhibited by a substrate analogue 5,10-CO-THF (K(i) 105 nM), as was Leishmania growth (EC(50) 1.

Tobacco-induced alterations to Porphyromonas gingivalis-host interactions.

Smokers are more susceptible than non-smokers to persistent infection by Porphyromonas gingivalis, a causative agent of periodontitis. Patients who smoke exhibit increased susceptibility to periodontitis and are more likely to display severe disease and be refractory to treatment. Paradoxically, smokers demonstrate reduced clinical inflammation.