This study (n = 161) related morphometric MR imaging, FDG-PET and APOE
genotype to memory scores in normal controls (NC), mild cognitive impairment
(MCI) and Alzheimer’s disease (AD). Stepwise regression analyses focused
on morphometric and metabolic characteristics of the episodic memory network:
hippocampus, entorhinal, parahippocampal, retrosplenial, posterior cingulate,
precuneus, inferior parietal, and lateral orbitofrontal cortices. In NC,
hippocampal metabolism predicted learning; entorhinal metabolism predicted
recognition; and hippocampal metabolism predicted recall. In MCI, thickness of
the entorhinal and precuneus cortices predicted learning, while parahippocampal
metabolism predicted recognition. In AD, posterior cingulate cortical thickness
predicted learning, while APOE genotype predicted recognition. In the total
sample, hippocampal volume and metabolism, cortical thickness of the precuneus,
and inferior parietal metabolism predicted learning; hippocampal volume and
metabolism, parahippocampal thickness and APOE genotype predicted recognition.
Imaging methods appear complementary and differentially sensitive to memory in
health and disease. Medial temporal and parietal metabolism and morphometry best
explained memory variance. Medial temporal characteristics were related to
learning, recall and recognition, while parietal structures only predicted
MCI; AD; PET; MR morphometry; APOE; episodic memory
We evaluated factors associated with physicians’ intentions to perform Pap smears in human papillomavirus-vaccinated women.
Physicians were mailed a survey asking about intentions to change cervical cancer screening based on patients’ human papillomavirus vaccination status.
A national sample of 1,738 Family Physicians, Internal Medicine physicians, Pediatricians, and Obstetricians and Gynecologists was selected from the American Medical Association Physician Masterfile. Completed surveys were received from 1,118 physicians, of which 791 were included in the analyses.
Main Outcome Measures
Bivariate analyses compared physician, practice, and patient characteristics by intention change screening frequency. Significant variables were included in a multivariable logistic regression model.
Overall, 81.8% (n = 647) physicians reported not planning to change Pap smear frequency for vaccinated women. Internal Medicine physicians were significantly more likely than Obstetrician/Gynecologists to report intentions to change frequency for vaccinated patients. Other factors significantly associated with the intention to change frequency were self-identification as a late adopter of new vaccines, a solo practice, and practicing primarily in a clinic or hospital-based setting.
Although it appears most clinicians understand that human papillomavirus vaccination should not alter current screening practices, there is a need to develop and evaluate interventions for physicians who are likely to change their screening pattern based on human papillomavirus vaccination receipt.
human papillomavirus; HPV vaccines; Papanicolaou test; physicians
To determine whether age-standardized brain morphometric and cognitive profiles differ in young-old (aged 60–75 years) and very-old (aged 80–91 years) patients with Alzheimer disease (AD).
Using a case-control retrospective design, we compared hippocampal volume and cortical gray matter thickness in areas known to be affected by AD in 105 patients with AD and 125 healthy control (HC) participants divided into young-old and very-old subgroups. Brain morphometric and cognitive scores of the AD groups were standardized to their respective age-appropriate HC subgroup and then compared.
Several cognitive domains (executive function, immediate memory, and attention/processing speed) were less abnormal in the very old with AD than in the young old with AD. Similarly, the very old with AD showed less severe cortical thinning than the young old with AD in the left posterior cingulate cortex, right lateral temporal cortex, and bilateral parietal cortex and in overall cortical thickness. This effect is partially explained by an age-related decrease in cortical thickness in these brain regions in the HC participants.
The typical pattern of AD-related cognitive and morphometric changes seen in the young old appear to be less salient in the very old. Thus, mild cases of AD in the very old may go undetected if one expects to see the prototypical pattern and severity of cognitive or brain changes that occur in the young old with AD. These results underscore the importance of interpreting neuropsychological test performance and morphometric brain measures in reference to the individual's age. Neurology® 2011;77:713–721
To evaluate whether ratings on Clinical Dementia Rating (CDR) items related to instrumental activities of daily living (IADL) are associated with cognitive or brain morphometric characteristics of participants with mild cognitive impairment (MCI) and global CDR scores of 0.5.
Baseline cognitive and morphometric data were analyzed for 283 individuals with MCI who were divided into 2 groups (impaired and intact) based on their scores on the 3 CDR categories assessing IADL. Rates of progression to Alzheimer disease (AD) over 2 years were also compared in the 2 groups.
The impaired IADL MCI group showed a more widespread pattern of gray matter loss involving frontal and parietal regions, worse episodic memory and executive functions, and a higher percentage of individuals progressing to AD than the relatively intact IADL MCI group.
The results demonstrate the importance of considering functional information captured by the CDR when evaluating individuals with MCI, even though it is not given equal weight in the assignment of the global CDR score. Worse impairment on IADL items was associated with greater involvement of brain regions beyond the mesial temporal lobe. The conventional practice of relying on the global CDR score as currently computed underutilizes valuable IADL information available in the scale, and may delay identification of an important subset of individuals with MCI who are at higher risk of clinical decline.
A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia.
An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD.
General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods.
A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.
The population pharmacokinetic parameters of zidovudine (AZT), lamivudine (3TC), and their active intracellular metabolites in 75 naïve HIV-infected patients receiving an oral combination of AZT and 3TC twice daily as part of their multitherapy treatment in the COPHAR2-ANRS 111 trial are described. Four blood samples per patient were taken after 2 weeks of treatment to measure drug concentrations at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients, and among those, 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between the mean plasma and intracellular concentrations of each drug. A one-compartment model with first-order absorption and elimination best described the plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero-order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. The half-lives of AZT and 3TC were 0.81 h (94.8%) and 2.97 h (39.2%), respectively, whereas the intracellular half-lives of AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent bioavailability of AZT, as well as on the mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma drug and intracellular metabolite concentrations were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once- versus twice-daily regimens suggested that a daily dosing regimen with double doses could be appropriate.
Diabetes is a risk factor for MCI and dementia. However, the association between high normal fasting blood glucose (FBG) and dementia has not been studied.
Polytomous logistic regression was used to assess the association of dementia and MCI with FBG in an age- and sex-matched sample of 32 dementia patients, 27 amnestic MCI (aMCI) patients and 31 normal controls (NC). Analyses were repeated for those with normal FBG. Correlations between FBG and cognitive test scores were obtained.
Controlling for age, sex, education, body mass index, Hachinski Ischemic Score, MRI stroke, and normalized brain, hippocampal and white matter hyperintensity MRI volumes; higher FBG was associated with dementia vs. aMCI status (OR= 3.13; 95% CI:1.28–7.69). This association remained (OR= 7.75; 95% CI:1.10–55.56) when analyses were restricted to subjects with normal FBG. When dementia patients were compared with NC adjusting for age, sex and education a significant association with FBG also was seen (OR=1.83; 95%CI:1.09–3.08), but the association was lost when vascular covariates were added to the model. FBG was not associated with aMCI status vs. NC. Higher FBG was correlated with poorer performance on the Trailmaking Test Part B (p=0.003). The percentage of dementia patients with high normal FBG (90%) was significantly higher than that of aMCI patients with high normal FBG (32.9%) (χ2=13.9, p<0.001).
Higher FBG was associated with dementia (vs. aMCI) independent of vascular risk factors and MRI indicators of vascular disease, and remained a significant risk factor when analyses were restricted to subjects with normal FBG. The results of this cross-sectional study suggest that a high normal level of FBG may be a risk factor for dementia.
dementia; Alzheimer’s disease; mild cognitive impairment; fasting blood glucose; diabetes; hippocampal volume; white matter hyperintensity; magnetic resonance imaging; cognitive performance; vascular risk
We examined the improvement in statistical power that could be obtained in therapeutic trials for early (pre-dementia) Alzheimer’s disease (AD) by constraining enrollment to individuals with amnestic mild cognitive impairment (MCI) and an atrophy pattern on a screening MRI previously found to be predictive of clinical decline, or to individuals with MCI and the apolipoprotein E ε4 genetic risk factor for AD. Treatable effects were defined as absolute change versus change relative to healthy controls (HC). Data from 168 HC and 299 MCI participants were analyzed to determine sample sizes required to detect 25% slowing in mean rate of decline using global function, cognitive function, and structural measures as outcome variables. Reductions in estimated sample sizes of 10-43%, were observed using the genetic enrichment strategy; reductions of 43-60% were observed with the neuroimaging enrichment strategy. Sample sizes needed to detect slowing in rate of atrophy in MCI relative to HC were dramatically larger than those needed to detect absolute change in atrophy rates. Constraining enrollment to MCI subjects with predictive atrophy on a screening MRI could improve the efficiency of clinical trials. Failure to take into account normal age-related changes risks under-powering trials designed to test disease-modifying properties of potential treatments.
mild cognitive impairment; magnetic resonance imaging; atrophy; Clinical trials Methodology/study design; apolipoprotein E ε4
We sought cognitive event-related potential (ERP) biomarkers of disease progression and subsequent conversion to dementia in mild cognitive impairment (MCI).
Two ERP components, the P600 and N400, are sensitive to abnormal episodic/declarative memory and semantic processing. When congruous category-exemplars are repeated, smaller P600s (relative to initial presentation) are normally elicited. Repetitions of semantically incongruous words yield smaller N400 amplitude. In mild Alzheimer disease (AD), abnormalities of both the N400 and P600 repetition effects are present, suggesting a wide-spread failure of synaptic plasticity.
Patients with amnestic MCI (n = 32) were longitudinally studied annually with an ERP paradigm in which semantically congruous (50%) and incongruous target words are repeated 10 to 140 seconds after initial presentation. ERP data were analyzed to contrast MCI-to-AD converters (within 3 years) vs nonconverters, using split-plot analyses of variance.
A statistically significant P600 congruous word repetition effect was found only in the nonconverter group (F = 9.9, p = 0.005 vs MCI converters). This effect correlated with verbal memory measures. Repetition of incongruous words produced a significant N400 amplitude attenuation (across right-hemisphere sites) in nonconverters, but not in converters. Patients with MCI with abnormal/reduced N400 or P600 word repetition effects had an 87 to 88% likelihood of dementia within 3 years while those with normal/spared N400 and P600 repetition effects had only an 11 to 27% likelihood.
Abnormalities of the P600 or N400 in mild cognitive impairment are associated with an increased risk of subsequent conversion to Alzheimer disease (AD). These event-related potential components may offer useful biomarkers for the detection and staging of very early AD.
Recent research suggests that pulse pressure (PP), a putative marker of vascular integrity, may be associated with brain microvascular damage and age-related cognitive decline. Thus, the present study examined the relationship between PP and cognition in a sample of healthy nondemented older adults. One hundred nine participants were administered neurological and neuropsychological evaluations and determined to be nondemented. Regression analyses were used to examine the relationships among pulse pressure (PP) [systolic blood pressure (SBP) – diastolic blood pressure (DBP)], age, and cognition. PP and related measures were inversely correlated with global cognitive functioning and scores on a composite measure of language function, even after adjusting for age, education, and relevant vascular risk factors. Results indicate that increases in the pulsatile component of blood pressure may convey added risk of global cognitive decline and specific impairment in language abilities.
Blood pressure; Hypertension; Aging; Cognition; Stroke; Arterial stiffness
The retrogenesis model of Alzheimer's disease (AD) posits that white matter (WM) degeneration follows a pattern that is the reverse of myelogenesis. Using diffusion tensor imaging (DTI) to test this model, we predicted greater loss of microstructural integrity in late-myelinating WM fiber pathways in AD patients than in healthy older adults, whereas differences in early-myelinating WM fiber pathways were not expected. We compared 16 AD patients and 14 demographically-matched healthy older adults with a whole-brain approach via tract-based spatial statistics (TBSS), and a region of interest (ROI) approach targeting early-myelinating (posterior limb of internal capsule, cerebral peduncles) and late-myelinating (inferior longitudinal fasciculus [ILF], superior longitudinal fasciculus [SLF]) fiber pathways. Permutation-based voxelwise analysis supported the retrogenesis model. There was significantly lower fractional anisotropy (FA) in AD patients compared to healthy older adults in late-myelinating but not early-myelinating pathways. These group differences appeared to be driven by loss of myelin integrity based on our finding of greater radial diffusion in AD than in healthy elderly. ROI analyses were generally in agreement with whole-brain findings, with significantly lower FA and increased radial diffusion in the ILF in the AD group. Consistent with the retrogenesis model, AD patients showed demonstrable changes in late-myelinating WM fiber pathways. Given greater change in the ILF than the SLF, wallerian degeneration secondary to cortical atrophy may also be a contributing mechanism. Knowledge of the pattern of WM microstructural changes in AD and its underlying mechanisms may contribute to earlier detection and intervention in at-risk groups.
Objectives: Illegal drug use is common in emergency department (ED) patients, but previous prevalence studies have relied upon approaches that may underestimate the true extent of the problem. The aim of this study was to examine illegal drug use in a typical adult ED.
Methods: We employed an independent researcher to prospectively and anonymously interview patients attending an inner city adult ED throughout all 168 hours of a typical week. Additional information collected from the treating clinician indicated whether each presentation was directly or indirectly related to illegal drug use.
Results: We found that 6.9% of all patient attendances were directly or indirectly related to illegal drug use, and hospital admission was required in nearly half of these. The majority of drug related problems were acute injuries, overdose, and the medical complications of drug use.
Conclusions: This suggests that the emergency healthcare burden related to illegal drug use is substantial, and higher than previously reported.
Background: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown.
Objectives: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a cortical dementia (Alzheimer's disease).
Design: Survey of cognitive features.
Setting: General community in Rogaland county, Norway, and a university dementia and movement disorder research centre in the USA.
Patients: 60 patients with DLB, 35 with PDD, 49 with progressive supranuclear palsy, and 29 with Alzheimer's disease, diagnosed by either standardised clinical procedures and criteria (all PDD and Alzheimer cases and 76% of cases of progressive supranuclear palsy), or necropsy (all DLB cases and 24% of cases of progressive supranuclear palsy). Level of dementia severity was matched using the total score on the dementia rating scale adjusted for age and education.
Main outcome measures: Dementia rating scale subscores corrected for age.
Results: No significant differences between the dementia rating scale subscores in the PDD and DLB groups were found in the severely demented patients; in patients with mild to moderate dementia the conceptualisation subscore was higher in PDD than in DLB (p = 0.03). Compared with Alzheimer's disease, PDD and DLB had higher memory subscores (p < 0.001) but lower initiation and perseveration (p = 0.008 and p=0.021) and construction subscores (p = 0.009 and p = 0.001). DLB patients had a lower conceptualisation subscore (p = 0.004). Compared with progressive supranuclear palsy, PDD and DLB patients had lower memory subscores (p < 0.001).
Conclusions: The cognitive profiles of patients with DLB and PDD were similar, but they differed from those of patients with Alzheimer's disease and progressive supranuclear palsy. The cognitive pattern in DLB and PDD probably reflects the superimposition of subcortical deficits upon deficits typically associated with Alzheimer's disease.
Background: It has been reported that patients with amnesia have a reduced effect of word repetition upon the late positive component of the event related potential (ERP), which peaks at around 600 ms after word onset.
Objective: To study a word repetition ERP paradigm in subjects with mild cognitive impairment.
Subjects: 14 patients with mild cognitive impairment (mean mini-mental state examination score = 27); 14 normal elderly controls.
Methods: Auditory category statements were each followed by a single visual target word (50% "congruous" category exemplars, 50% "incongruous") while ERPs were recorded. N400 (an ERP component elicited by semantically "incongruous" words) and LPC amplitude data were submitted to analysis of variance.
Results: The latency of the N400 was slower in mild cognitive impairment. In normal controls, the ERPs to "congruous" targets showed a late positive component to new words, which was greatly diminished with repetition. This repetition effect in normal subjects started before 300 ms at right frontal sites, and peaked at ∼600 ms post-stimulus over posterior sites. In contrast, the group with mild cognitive impairment had a reduced repetition effect (p < 0.02), which started around 500 ms, with a more central distribution. Further comparisons within the cognitive impairment group showed no appreciable congruous word repetition effect among seven individuals who subsequently converted to probable Alzheimer's disease. The congruous word repetition effect in the group with mild cognitive impairment was almost entirely accounted for by the non-converters. The amplitude of the congruous late positive component word repetition effect was significantly correlated (0.38 ≤ r ≤ 0.73) with several verbal memory measures.
Conclusions: The congruous word repetition ERP effect appears sensitive to the memory impairment in mild cognitive impairment and could have value in predicting incipient Alzheimer's disease.
All jurisdictions in the US require proof of vaccination for school entrance. Most states permit non-medical exemptions. Public health officials must balance the rights of individuals to choose whether or not to vaccinate their children with the individual and societal risks associated with choosing not to vaccinate (i.e., claiming an exemption). To assist the public health community in optimally reaching this balance, this analysis examines the constitutional basis of non-medical exemptions and examines policies governing conscientious objection to conscription as a possible model. The jurisprudence that the US Supreme Court has developed in cases in which religious beliefs conflict with public or state interests suggests that mandatory immunization against dangerous diseases does not violate the First Amendment right to free exercise of religion. Accordingly, states do not have a constitutional obligation to enact religious exemptions. Applying the model of conscientious objectors to conscription suggests that if states choose to offer nonmedical exemptions, they may be able to optimally balance individual freedoms with public good by considering the sincerity of beliefs and requiring parents considering exemptions to attend individual educational counseling.
We report a rare case of ergotism related to a single dose of ergotamine tartrate in a man with AIDS being treated with ritonavir. He was treated with a prostacyclin analogue and made a complete recovery.
Keywords: ergotism; ergotamine tartrate; AIDS; ritonavir; adverse drug reaction; HIV infection
We investigated the in vivo antimalarial activities of pefloxacin and ciprofloxacin in Swiss albino mice infected intravenously with 5 x 10(6) Plasmodium yoelii N67 parasites 1 h before treatment. Groups of 20 mice received a subcutaneous injection of 40, 80, or 160 mg of ciprofloxacin or pefloxacin per kg of body weight every 8 h for 3 days. Parasitologic activity was assessed on day 4, and survival was assessed on day 21. Control mice had a fulminant course with a parasitemia of 61.3% +/- 12.1% on day 4, and 90% of the mice were dead on day 21. The lower dosages of pefloxacin and ciprofloxacin (40 and 80 mg/kg) were not efficient. With 160 mg/kg, ciprofloxacin achieved an 85.8% reduction in parasitemia and 17 of 20 mice survived. Pefloxacin achieved a 92.8% reduction in parasitemia, and all mice survived. All treated, noninfected control mice survived. With ciprofloxacin, the antimalarial activity was similar with injections of 240 mg/kg every 12 h but was strongly diminished with injections of 160 mg/kg every 12 h. With pefloxacin, similar activities were observed with injections of 160 mg/kg every 8 h or injections of 160 or 240 mg/kg every 12 h. With both drugs, this activity was highly reduced when the treatment was delayed by 24 h. This underlines the need to provide treatment within the first hours after infection to achieve an optimal effect in this rapidly lethal experimental model of malaria. Pefloxacin and, to a lesser extent, ciprofloxacin are potent antimalarial drugs which might prove useful in the treatment of less rapidly aggressive human malaria.
A controlled prospective study compared the performance of 14 patients with dementia of Alzheimer type (DAT) and 14 patients with Huntington's Disease (HD), who were matched for overall level of dementia, on a battery of semantic and episodic memory tests. The DAT patients were significantly more impaired on measures of delayed verbal and figural episodic memory, and in addition showed a more rapid rate of decline on tests which depend upon the integrity of semantic knowledge (naming, number information, similarities and category fluency). In contrast, the HD patients were significantly worse, and showed a more rapid decline on the letter fluency test, a task especially sensitive to deficiencies in retrieval. The HD patients were also more impaired than DAT patients on a vocabulary test and on copying geometric figures. The observed double dissociations offer compelling evidence that aetiologically distinct forms of dementing illness result in different patterns of cognitive impairment.
In this study, we examined the potential interactions between antimalarial (chloroquine, quinine, and mefloquine) and oxidant reagents. The data indicate that their effects enhance those of one another in vitro. The viability of Plasmodium falciparum in culture was assessed by [3H]hypoxanthine incorporation during 24 h of incubation in the presence of lactoperoxidase, glucose-glucose oxidase, hydrogen peroxide, chloroquine, quinine, and mefloquine, either alone or in combination. At subinhibitory concentrations, a significant inhibition was produced by the following combinations: lactoperoxidase plus hydrogen peroxide, lactoperoxidase plus glucose-glucose oxidase, lactoperoxidase plus hydrogen peroxide or glucose-glucose oxidase plus chloroquine or quinine but not with mefloquine. Deletion of any component from the system markedly decreased the toxic effect on P. falciparum. This toxic effect was not inhibited by catalase. These results indicate that the peroxidase-hydrogen peroxide system and antimalarial drugs can potentiate each other to inhibit the growth of P. falciparum.
The viability of Plasmodium falciparum in culture was assessed by [3H]hypoxanthine incorporation during 24 h of incubation with lactoperoxidase, glucose-glucose oxidase, hydrogen peroxide, halides, or thiocyanate, alone or in combination. Synergistic inhibition was produced by the following combinations: lactoperoxidase plus hydrogen peroxide, lactoperoxidase plus glucose-glucose oxidase, and lactoperoxidase plus hydrogen peroxide plus halides or thiocyanate. These inhibitory effects were reversed by catalase and glutathione. The presence of plasmodial crisis forms inside the erythrocytes suggests that the oxygen-dependent microbicidal system of phagocytes has a killing effect.
Generalization of four retarded children's object naming responses to stimuli in the natural environment was assessed after training with either objects or pictures of the objects. Generalization was typically greater after training with objects. In a second experiment, half of the stimuli that showed little generalization were retrained by alternating the original training object with an object that belonged to the same stimulus class as the training stimulus. The other half were simply retrained using the object. The alternating procedure resulted in substantial increases in generalization to untrained objects.
Interaction between human neutrophils (polymorphonuclear leukocytes [PMN]) and Plasmodium falciparum in the natural defense of the host remains to be elucidated. In patients with acute malaria, oxygen consumption (QO2) of PMN at rest and after stimulation by zymosan was significantly increased compared with that in the controls. With 10% immune serum, both QO2 and chemiluminescence of normal PMN were significantly increased after stimulation by a P. falciparum erythrocyte culture. This activation was not observed with a nonparasitized erythrocyte culture and was correlated with parasitemia. Immune serum and complement were required to trigger this metabolic activation of normal PMN. With normal serum or heat-inactivated immune serum, a parasitized erythrocyte culture did not significantly stimulate QO2 or chemiluminescence of normal PMN. The classical complement pathway was essential for this stimulation, whereas the alternate pathway was less involved. Hyperimmune sera from subjects residing in endemic areas were more able to trigger the metabolic burst than were immune sera from subjects from other sources. The use of synchronous cultures showed that PMN were more stimulated by cultures rich in merozoites than by the same cultures which contained only intraerythrocytic forms. Giemsa staining showed granules of hemozoin and occasional merozoites or parasitized erythrocytes within PMN. This increase in production of activated oxygen radicals could damage intra-or extraphagocytic parasitic forms. As P. falciparum is sensitive to oxidant stress and PMN is the phagocyte with the most intense metabolic burst, the role of PMN in defense against malaria should be considered.