Why do so many drugs for Alzheimer's disease fail in development? Time for new methods and new practices?
ABSTRACT: Alzheimer's disease (AD) drug developments and clinical trials (CT) remain vulnerable to problems that undermine research validity. Investigations of CT methods reveal how numerous factors decrease active drug-placebo group differences and increase variance, thereby reducing power to reach statistical significance for outcome measure differences in AD CTs. Such factors include, amongst many, inaccuracy, imprecision, bias, failures to follow or lack of operational protocols for applying CT methods, inter-site variance, and lack of homogeneous sampling using disorder criteria. After a review of the literature and survey of a sample of AD and Mild Cognitive Impairment (MCI) CTs, the authors question whether problems of human error preclude AD researchers from continuing their dependence on rated outcome measures for CTs. The authors propose that the realities of AD, especially a probable irreversible progression of neuropathology prior to onset of clinical symptoms or signs capable of differentiating persons at risk for AD from normal aged, require AD investigators and clinicians to privilege biomarkers and encourage their development as surrogate targets for preventive AD treatment developments, testing, and use in clinical practice.
Project description:The authors describe algorithms to control dynamic attenuators in CT and compare their performance using simulated scans. Dynamic attenuators are prepatient beam shaping filters that modulate the distribution of x-ray fluence incident on the patient on a view-by-view basis. These attenuators can reduce dose while improving key image quality metrics such as peak or mean variance. In each view, the attenuator presents several degrees of freedom which may be individually adjusted. The total number of degrees of freedom across all views is very large, making many optimization techniques impractical. The authors develop a theory for optimally controlling these attenuators. Special attention is paid to a theoretically perfect attenuator which controls the fluence for each ray individually, but the authors also investigate and compare three other, practical attenuator designs which have been previously proposed: the piecewise-linear attenuator, the translating attenuator, and the double wedge attenuator.The authors pose and solve the optimization problems of minimizing the mean and peak variance subject to a fixed dose limit. For a perfect attenuator and mean variance minimization, this problem can be solved in simple, closed form. For other attenuator designs, the problem can be decomposed into separate problems for each view to greatly reduce the computational complexity. Peak variance minimization can be approximately solved using iterated, weighted mean variance (WMV) minimization. Also, the authors develop heuristics for the perfect and piecewise-linear attenuators which do not require a priori knowledge of the patient anatomy. The authors compare these control algorithms on different types of dynamic attenuators using simulated raw data from forward projected DICOM files of a thorax and an abdomen.The translating and double wedge attenuators reduce dose by an average of 30% relative to current techniques (bowtie filter with tube current modulation) without increasing peak variance. The 15-element piecewise-linear dynamic attenuator reduces dose by an average of 42%, and the perfect attenuator reduces dose by an average of 50%. Improvements in peak variance are several times larger than improvements in mean variance. Heuristic control eliminates the need for a prescan. For the piecewise-linear attenuator, the cost of heuristic control is an increase in dose of 9%. The proposed iterated WMV minimization produces results that are within a few percent of the true solution.Dynamic attenuators show potential for significant dose reduction. A wide class of dynamic attenuators can be accurately controlled using the described methods.
Project description:BACKGROUND:Chest computed tomography (CT) in children with cystic fibrosis (CF) is sensitive in detecting early airways disease. The pressure-controlled CT-protocol combines a total lung capacity scan (TLC PC-CT) with a near functional residual capacity scan (FRC PC-CT) under general anesthesia, while another CT-protocol is acquired during free breathing (FB-CT) near functional residual capacity. The aim of this study was to evaluate the sensitivity in detecting airways disease of both protocols in two cohorts. METHODS:Routine PC-CTs (Princess Margaret Children's Hospital) and FB-CTs (Erasmus MC-Sophia Children's Hospital) were retrospectively collected from CF children aged 2 to 6 years. Total airways disease (%disease), bronchiectasis (%Bx), and low attenuation regions (%LAR) were scored on CTs using the Perth-Rotterdam annotated grid morphometric analysis-CF method. The Wilcoxon signed-rank test was used for differences between TLC and FRC PC-CTs and the Wilcoxon rank-sum test for differences between FRC PC-CTs and FB-CTs. RESULTS:Fifty patients with PC-CTs (21 male, aged 2.5-5.5 years) and 42 patients with FB-CTs (26 male, aged 2.3-6.8 years) were included. %Disease was higher on TLC PC-CTs compared with FRC PC-CTs (median 4.51 vs 2.49; P?<?.001). %Disease and %Bx were not significantly different between TLC PC-CTs and FB-CTs (median 4.51% vs 3.75%; P?=?.143 and 0.52% vs 0.57%; P?=?.849). %Disease, %Bx, and %LAR were not significantly different between FRC PC-CTs and FB-CTs (median 2.49% vs 3.75%; P?=?.055, 0.54% vs 0.57%; P?=?.797, and 2.49% vs 1.53%; P?=?.448). CONCLUSIONS:Our data suggest that FRC PC-CTs are less sensitive than TLC PC-CTs and that FB-CTs have similar sensitivity to PC-CTs in detecting lung disease. FB-CTs seem to be a viable alternative for PC-CTs to track CF lung disease in young patients with CF.
Project description:Although condensed tannins (CTs) are known to reduce forage intake by mammalian herbivores in controlled experiments, few studies have tested these effects in the field. Thus the role of CTs on foraging ecology of free-ranging herbivores is inadequately understood. To investigate the effects of CTs under natural savanna conditions, we pre-dosed groups of goats with polyethylene glycol (PEG, a CT-neutralising chemical), CT powder or water before observing their foraging behaviour. While accounting for the effects of season and time of the day, we tested the hypothesis that herbivores forage in ways that reduce the intake rate (g DM per minute) of CTs. We expected pre-dosing goats with CTs to reduce CT intake rates by (1) consuming diets low in CTs, (2) reducing bite rates, (3) increasing the number of foraging bouts, or (4) reducing the length of foraging bouts. Lastly, (5) expected CT to have no influence the number of dietary forage species. In both wet and dry seasons, pre-dosing goats with CTs resulted in lower CT consumption rates compared to PEG goats which seemed relieved from the stress associated with CT consumption. During dry season, the number of dietary forage species was similar across treatments, although goats that were dosed with PEG significantly increased this number in the wet season. Dosing goats with PEG increased the number and length of browsing bouts compared to goats from the other treatments. Pre-loading goats with PEG also tended to increase bite rates on browse forages, which contributed to increased consumption rates of CTs. Based on the behavioural adjustments made by goats in this study and within the constraints imposed by chemical complexity in savanna systems, we concluded that herbivores under natural conditions foraged in ways that minimised CTs consumption. More research should further elucidate the mechanism through which CTs regulated feeding behaviour.
Project description:To use Cone Beam CT scans obtained just prior to treatments of head and neck cancer patients to measure the setup error and cumulative dose uncertainty of the cochlea.Data from 10 head and neck patients with 10 planning CTs and 52 Cone Beam CTs taken at time of treatment were used in this study. Patients were treated with conventional fractionation using an IMRT dose painting technique, most with 33 fractions. Weekly radiographic imaging was used to correct the patient setup. The authors used rigid registration of the planning CT and Cone Beam CT scans to find the translational and rotational setup errors, and the spatial setup errors of the cochlea. The planning CT was rotated and translated such that the cochlea positions match those seen in the cone beam scans, cochlea doses were recalculated and fractional doses accumulated. Uncertainties in the positions and cumulative doses of the cochlea were calculated with and without setup adjustments from radiographic imaging.The mean setup error of the cochlea was 0.04 ± 0.33 or 0.06 ± 0.43 cm for RL, 0.09 ± 0.27 or 0.07 ± 0.48 cm for AP, and 0.00 ± 0.21 or -0.24 ± 0.45 cm for SI with and without radiographic imaging, respectively. Setup with radiographic imaging reduced the standard deviation of the setup error by roughly 1-2 mm. The uncertainty of the cochlea dose depends on the treatment plan and the relative positions of the cochlea and target volumes. Combining results for the left and right cochlea, the authors found the accumulated uncertainty of the cochlea dose per fraction was 4.82 (0.39-16.8) cGy, or 10.1 (0.8-32.4) cGy, with and without radiographic imaging, respectively; the percentage uncertainties relative to the planned doses were 4.32% (0.28%-9.06%) and 10.2% (0.7%-63.6%), respectively.Patient setup error introduces uncertainty in the position of the cochlea during radiation treatment. With the assistance of radiographic imaging during setup, the standard deviation of setup error reduced by 31%, 42%, and 54% in RL, AP, and SI direction, respectively, and consequently, the uncertainty of the mean dose to cochlea reduced more than 50%. The authors estimate that the effects of these uncertainties on the probability of hearing loss for an individual patient could be as large as 10%.
Project description:OBJECTIVES:Although computerized decision support for imaging is often recommended for optimizing computed tomography (CT) use, no studies have evaluated emergency physicians' (EPs') preferences regarding computerized decision support in the emergency department (ED). In this needs assessment, the authors sought to determine if EPs view overutilization as a problem, if they want decision support, and if so, the kinds of support they prefer. METHODS:A 42-item, Web-based survey of EPs was developed and used to measure EPs' attitudes, preferences, and knowledge. Key contacts at local EDs sent letters describing the study to their physicians. Exploratory principal components analysis (PCA) was used to determine the underlying factor structure of multi-item scales, Cronbach's alpha was used to measure internal consistency of items on a scale, Spearman correlations were used to describe bivariate associations, and multivariable linear regression analysis was used to identify variables independently associated with physician interest in decision support. RESULTS:Of 235 surveys sent, 155 (66%) EPs responded. Five factors emerged from the PCA. EPs felt that: 1) CT overutilization is a problem in the ED (? = 0.75); 2) a patient's cumulative CT study count affects decisions of whether and what type of imaging study to order only some of the time (? = 0.75); 3) knowledge that a patient has had prior CT imaging for the same indication makes EPs less likely to order a CT (? = 0.42); 4) concerns about malpractice, patient satisfaction, or insistence on CTs affect CT ordering decisions (? = 0.62); and 5) EPs want decision support before ordering CTs (? = 0.85). Performance on knowledge questions was poor, with only 18% to 39% correctly responding to each of the three multiple-choice items about effective radiation doses of chest radiograph and single-pass abdominopelvic CT, as well as estimated increased risk of cancer from a 10-mSv exposure. Although EPs wanted information on patients' cumulative exposures, they feel inadequately familiar with this information to make use of it clinically. If provided with patients' cumulative radiation exposures from CT, 87% of EPs said that they would use this information to discuss imaging options with their patients. In the multiple regression model, which included all variables associated with interest in decision support at p < 0.10 in bivariate tests, items independently associated with EPs' greater interest in all types of decision support proposed included lower total knowledge scores, greater frequency that cumulative CT study count affects EP's decision to order CTs, and greater agreement that overutilization of CT is a problem and that awareness of multiple prior CTs for a given indication affects CT ordering decisions. CONCLUSIONS:Emergency physicians view overutilization of CT scans as a problem with potential for improvement in the ED and would like to have more information to discuss risks with their patients. EPs are interested in all types of imaging decision support proposed to help optimize imaging ordering in the ED and to reduce radiation to their patients. Findings reveal several opportunities that could potentially affect CT utilization.
Project description:National guidelines recommend that fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) is performed in all patients being considered for radical treatment of oesophageal or oesophago-gastric cancer without computerised tomography scan (CTS) evidence of metastasis. Guidance also mandates that all patients with cancer have treatment decisions made within the context of a multi-disciplinary team (MDT) meeting. Little is known, however, about the influence of PET-CT on decision making within MDTs. The aim of this study was to assess the role of PET-CT in oesophago-gastric cancer on MDT decision making.A retrospective analysis of a prospectively held database of all patients with biopsy-proven oesophageal or oesophago-gastric cancer discussed by a specialist MDT was interrogated. Patients selected for radical treatment without CTS evidence of M1 disease were identified. The influence of PET-CT on MDT decision making was examined by establishing whether the PET-CT confirmed CTS findings of M0 disease (and did not change the patient staging pathway) or whether the PET-CT changed the pathway by showing unsuspected M1 disease, refuting CTS suspicious metastases, or identifying another lesion (needing further investigation).In 102 MDT meetings, 418 patients were discussed, of whom 240 were initially considered for radical treatment and 238 undergoing PET-CT. The PET-CT confirmed CTS findings for 147 (61.8%) and changed MDT recommendations in 91 patients (38.2%) by (i) identifying M1 disease (n=43), (ii) refuting CTS suspicions of M1 disease (n=25), and (iii) identifying new lesions required for investigations (n=23).The addition of PET-CT to standard staging for oesophageal cancer led to changes in MDT recommendations in 93 (38.2%) patients, improving patient selection for radical treatment. The validity of the proposed methods for evaluating PET-CT on MDT decision making requires more work in other centres and teams.
Project description:The cytotoxic properties of cytotoxins (CTs) from snake venom are mediated by their interaction with the cell membrane. The hydrophobic pattern containing the tips of loops I-III and flanked by polar residues is known to be a membrane-binding motif of CTs. However, this is not enough to explain the difference in activity among various CTs which are similar in sequence and in 3D structure. The mechanism of further CT-membrane interaction leading to pore formation and cell death still remains unknown. Published experimental data on the specific interaction between CT and low molecular weight anionic components (sulphatide) of the bilayer point to the existence of corresponding ligand binding sites on the surface of toxin molecules. In this work we study the membrane-lytic properties of CT I, CT II (Naja oxiana), and Ct 4 (Naja kaouthia), which belong to different structural and functional types (P- and S-type) of CTs, by measuring the intensity of a fluorescent dye, calcein released from liposomes containing a phosphatidylserine (PS) lipid as an anionic component. Using molecular docking simulations, we find and characterize three sites in CT molecules that can potentially bind the PS polar head. Based on the data obtained, we suggest a hypothesis that CTs can specifically interact with one or more of the anionic lipids (in particular, with PS) contained in the membrane, thus facilitating the interaction between CTs and the lipid bilayer of a cell membrane.
Project description:The frequency of positive findings on computed tomography (CT) of the head in critically ill patients who develop neurologic dysfunction is not known.Cohort study of head CTs for patients admitted to 3 intensive care units from 2005 to 2010. We documented the frequency of acute changes for all head CTs and for the subgroup of patients with altered mental status (AMS). We also examined associations between patient characteristics or medications administered before head CT and the odds of an acute change on head CT using multivariate logistic regression.During 11 338 intensive care unit admissions, there were 901 eligible head CTs on 706 patients (6% of patients). Among head CTs, 155 (17.2%) assessed concern of new focal deficit, 99 (11.0%) concern for a seizure, and 635 (70.5%) for AMS. Acute changes were found on 109 (12.1%; 95% confidence interval [CI], 10.0%-14.2%) of all head CTs, and 30% (22.4%-36.9%) of patients with focal deficits, 16.2% (8.8%-23.5%) of patients with seizures but only 7.4% (5.4%-9.4%) for patients with AMS. A diagnosis of sepsis was associated with a decreased odds of an acute change on head CT for all head CTs (odds ratio 0.61; 95% CI, 0.40-0.95; P = .028) but was not significantly associated with a decreased risk among the cohort of head CTs for AMS (odds ratio 0.82; 95% CI, 0.41-1.62; P = .56). No other factors were associated with an altered risk of acute change on head CT for all patients in our cohort or for those with AMS.Acute changes on head CTs performed for concern regarding new focal neurologic deficit or seizures are frequent compared with those performed for AMS with a nonfocal examination. No specific patient characteristics or medications were associated with a large change in the likelihood of finding an acute change for patients with AMS.
Project description:Green-synthesized silver nanoparticles (SNPs) have great potential for biomedical applications, due to their distinctive optical, chemical, and catalytic properties. In this study, we aimed to develop green-synthesized SNPs from extracts of Cudrania tricuspidata (CT) roots (CTR), stems (CTS), leaves (CTL), and fruit (CTF) and to evaluate their physicochemical, photocatalytic, and biological properties. CTR, CTS, CTL, and CTF extracts were evaluated and compared for their total phenol and flavonoid content, reducing capacity, and antioxidant activity. The results revealed that CTR, CTS, CTL, and CTF extracts have high phenol and flavonoid content, as well as a powerful antioxidant and reducing capacity. CTR and CTS extracts showed the strongest effects. The results from UV-Vis spectra analysis, dynamic light scattering, high-resolution transmission electron microscopy, energy dispersive spectroscopy, X-ray diffraction, and Fourier-transform infrared spectroscopy showed the successful formation of CT-SNPs with surface morphology, crystallinity, reduction capacity, capsulation, and stabilization. Synthesized CT-SNPs successfully photocatalyzed methylene blue, methyl orange, rhodamine B, and Reactive Black 5 within 20 min. The CTR- and CTS-SNPs showed better antibacterial properties against different pathogenic microbes (Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Salmonella enteritidis) than the CTL- and CTF-SNPs. CTS- and CTR-SNPs showed the most effective cytotoxicity and antiapoptosis properties in human hepatocellular carcinoma cells (HepG2 and SK-Hep-1). CT-SNPs also seemed to be more biologically active than the CT extracts. The results of this study provide evidence of the establishment of CT extract SNPs and their physicochemical, photocatalytic, and biological properties.
Project description:BACKGROUND:Constitutional thinness (CT), a non-malnourished underweight state with no eating disorders, is characterized by weight gain resistance to high fat diet. Data issued from muscle biopsies suggested blunted anabolic mechanisms in free-living state. Weight and metabolic responses to protein caloric supplementation has not been yet explored in CT. METHODS:A 2 week overfeeding (additional 600 kcal, 30 g protein, 72 g carbohydrate, and 21 g fat) was performed to compare two groups of CTs (12 women and 11 men) to normal-weight controls (12 women and 10 men). Bodyweight, food intake, energy expenditure, body composition, nitrogen balance, appetite hormones profiles, and urine metabolome were monitored before and after overfeeding. RESULTS:Before overfeeding, positive energy gap was found in both CT genders (309 ± 370 kcal in CT-F and 332 ± 709 kcal in CT-M) associated with higher relative protein intake per kilo (1.74 ± 0.32 g/kg/day in CT-F vs. 1.16 ± 0.23 in C-F, P < 0.0001; 1.56 ± 0.36 in CT-M vs. 1.22 ± 0.32 in C-M, P = 0.03), lower nitrogen (7.26 ± 2.36 g/day in CT-F vs. 11.41 ± 3.64 in C-F, P = 0.003; 9.70 ± 3.85 in CT-M vs. 14.14 ± 4.19 in C-M, P = 0.02), but higher essential amino acids urinary excretion (CT/C fold change of 1.13 for leucine and 1.14 for arginine) in free-living conditions. After overfeeding, CTs presented an accentuated positive energy gap, still higher than in controls (675 ± 540 in CTs vs. 379 ± 427 in C, P = 0.04). Increase in lean mass was induced in both controls genders but not in CTs (a trend was noticed in CT women), despite a similar nitrogen balance after overfeeding (5.06 ± 4.33 g/day in CTs vs. 4.28 ± 3.15 in controls, P = 0.49). Higher anorectic gut hormones' tone, glucagon-like peptide 1 and peptide tyrosine tyrosine, during test meal and higher snacking frequency were noticed before and after overfeeding in CTs. CONCLUSIONS:The blunted muscle energy mechanism, previously described in CTs in free-living state, is associated with basal saturated protein turn over suggested by the concordance of positive nitrogen balance and an increased urine excretion of several essential amino acids. This saturation cannot be overpassed by increasing this spontaneous high-protein intake suggesting a resistance to lean mass gain in CT phenotype.