text:
Figure 1. Receiver operating characteristic curve of significant logistic predictors (baseline Auditory Verbal Learning Test delayed recall, Logical Memory delayed, and left middle temporal lobe cortical thickness for mild cognitive impairment converter/nonconverter contrast). Note the"elbow" in the upper left portion of the graph, indicating reasonably high sensitivity over a range of specificities. The green line indicates the first variable to enter, Logical Memory delayed; the gray line the second variable, left middle temporal lobe cortical thickness; and the red line the last variable to enter, Auditory Verbal Learning Test delay. The area under the curve was 0.80.
Figure 2. Effect sizes derived from difference between baseline measure and 1- or 2-year measure for (A) Functional Assessment Questionnaire (FAQ) and cognitive markers and (B) biomarkers. ADAS indicates Alzheimer Disease Assessment Scale; AVLT, Auditory Verbal Learning Test; clock, Clock Drawing Test; L Ento, left entorhinal cortex; L HC, left hippocampus; mem, memory domain; nonmem, nonmemory domain; R Ento, right entorhinal cortex; R HC, right hippocampus; sem fluency, semantic fluency; Trails, Trail Making Tests; vent, ventricles; W brain, whole brain.
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Gomar JJ, Bobes-Bascaran MT, Conejero-Goldberg C, Davies P, Goldberg TE, Alzheimer's Disease Neuroimaging Initiative FT. Utility of Combinations of Biomarkers, Cognitive Markers, and Risk Factors to Predict Conversion From Mild Cognitive Impairment to Alzheimer Disease in Patients in the Alzheimer's Disease Neuroimaging Initiative. Arch Gen Psychiatry. 2011;68(9):961–969. doi:10.1001/archgenpsychiatry.2011.96
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Author Affiliations: Benito Menni Complex Assistencial en Salut Mental, Barcelona, Spain (Dr Gomar); Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) (Dr Gomar and Ms Bobes-Bascaran), Barcelona and Velencia, Spain; Litwin Zucker Alzheimer's Disease Center, Feinstein Institute for Medical Research, Manhasset, New York (Drs Gomar, Conejero-Goldberg, Davies, and Goldberg and Ms Bobes-Bascaran); Servicio de Psiquiatría, and Hospital Clínico Universitario, Valencia, Spain (Ms Bobes-Bascaran); and Albert Einstein College of Medicine, New York, New York (Drs Davies and Goldberg).
Context Biomarkers have become increasingly important in understanding neurodegenerative processes associated with Alzheimer disease. Markers include regional brain volumes, cerebrospinal fluid measures of pathological Aβ1-42 and total tau, cognitive measures, and individual risk factors.
Objective To determine the discriminative utility of different classes of biomarkers and cognitive markers by examining their ability to predict a change in diagnostic status from mild cognitive impairment to Alzheimer disease.
Design Longitudinal study.
Participants We analyzed the Alzheimer's Disease Neuroimaging Initiative database to study patients with mild cognitive impairment who converted to Alzheimer disease (n = 116) and those who did not convert (n = 204) within a 2-year period. We determined the predictive utility of 25 variables from all classes of markers, biomarkers, and risk factors in a series of logistic regression models and effect size analyses.
Setting The Alzheimer's Disease Neuroimaging Initiative public database.
Outcome Measures Primary outcome measures were odds ratios, pseudo- R2s, and effect sizes.
Results In comprehensive stepwise logistic regression models that thus included variables from all classes of markers, the following baseline variables predicted conversion within a 2-year period: 2 measures of delayed verbal memory and middle temporal lobe cortical thickness. In an effect size analysis that examined rates of decline, change scores for biomarkers were modest for 2 years, but a change in an everyday functional activities measure (Functional Assessment Questionnaire) was considerably larger. Decline in scores on the Functional Assessment Questionnaire and Trail Making Test, part B, accounted for approximately 50% of the predictive variance in conversion from mild cognitive impairment to Alzheimer disease.
Conclusions Cognitive markers at baseline were more robust predictors of conversion than most biomarkers. Longitudinal analyses suggested that conversion appeared to be driven less by changes in the neurobiologic trajectory of the disease than by a sharp decline in functional ability and, to a lesser extent, by declines in executive function.
Biomarkers have become increasingly important in understanding the neurodegenerative processes associated with Alzheimer disease (AD), their staging, and response to treatment. Such markers are directly or indirectly relevant to the histopathology of AD and disease stage. They include cerebrospinal fluid (CSF) measures of pathological Aβ1-42 and tau and regional brain volumes. Cognition, a behavioral marker that may be considered a surrogate for neural systems function, may also be related to regional pathologic characteristics and disease stage. Other individual risk factors, including susceptibility genes and some demographic variables (eg, age or educational level), may also influence disease vulnerability and progression. Especially pertinent for our study is the value of biomarkers and behavioral markers in predicting conversion from mild cognitive impairment (MCI) to AD. Such predictions have obvious utility for clinical decision making, understanding the nature of neurobiologic changes at a critical phase in the illness, and assessment of response to treatment.
Several comprehensive reviews of the area have emphasized the predictive power of biomarkers in identifying an individual's likelihood of converting to AD, as well as differences in biomarker values among cognitively healthy control subjects and MCI and AD individuals.1-5 Sensitivities and specificities have ranged as high as 0.95 and 0.83, respectively, although more recent large-scale studies that have involved multiple sites have found lower values, perhaps for technical reasons or case ascertainment differences.6,7 In an Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, total tau and Aβ1-42 were significant discriminators in logistic regression between controls and those with mild AD.8
Hippocampal atrophy is an important brain volume biomarker and is also a predictor of conversion from MCI to AD.9-11 In a large ADNI cohort, left hippocampal volume at baseline was the best single predictor among brain volume measures of conversion from MCI to AD in a 1-year period.12 Other regions of cortex (eg, posterior cingulate or temporal lobe) may also be predictive in this cohort.13
Studies have examined the role of cognitive markers in predicting conversion of MCI to AD; tests of episodic memory (including memory after a delay) were consistently robust predictors.14-19 Predictive accuracy for one such set of cognitive variables (composed of episodic memory and processing speed measures) has been found to be as high as 0.86 (sensitivity, 0.76; specificity, 0.90).20 Of genetic risk factors for late-onset AD, apolipoprotein E (APOE) is the strongest (with an odds ratio of approximately 3.8) and best replicated.22-24 Nevertheless, theε4 variant is not thought to be a strong predictor of conversion from MCI to AD.25 Of nongenetic risk factors, educational level may influence age of onset or progression of AD.26
Relatively few studies have combined these different classes of biomarkers, cognitive markers, and individual risk factors. One such study27 found that cognitive variables including verbal list learning, story recall, and composite cognition resulted in a predictive accuracy of 0.79. Magnetic resonance imaging (MRI) measures of hippocampal volume and ventricular volume, APOE genotype, and demographic variables did not appreciably improve on this. Other studies have found that cognitive markers remained significant predictors even when MRI structural measures were added to predictive accuracy in regression models.10,28
Thus, despite formidable evidence for the predictive validity of individual biomarkers and behavioral markers, they have rarely been examined in combined models. To our knowledge, our study is the first that has examined CSF biomarkers, brain volumes, and cognitive markers in combination to predict MCI to AD conversion. We chose to examine this issue using ADNI, a public data set very well suited for this task because of its large samples, breadth of cognitive markers and biomarkers, and prospective nature. Specifically, we included biomarkers directly related to the disease; behavioral markers (including cognitive measures), also directly subject to the impact of disease; individual genetic risk factors (ie, sex and APOE); and demographic risk factors (ie, age and educational level). We hypothesized that episodic memory variables would be strong predictors of conversion. The previously mentioned analyses used baseline variables. We also sought to determine whether magnitude of decline (from baseline to 1 or 2 years) was disproportionate in either cognitive markers, biomarkers, or everyday function. We believed that this analysis would have bearing on how to interpret the MCI-AD transition in this sample. Overall, we believe that our approach is relatively unbiased, comprehensive, and of possible clinical and economic utility.
Participants in this longitudinal study are part of a multisite observational project, ADNI (http://adni.loni.ucla.edu), created to seek an adequate explanation of the progression of MCI and early AD by using serial MRI, positron emission tomography, and CSF-derived biomarkers, as well as clinical and neurocognitive measures. A more detailed description of ADNI is in eMethods. Our sample comprised ADNI patients included in the public database as of August 3, 2009. Patients in the ADNI protocol who completed visits at 12 and 24 months and who had at least 1 follow-up examination were included in the present study.
Criteria for MCI were the same as defined by Petersen29: subjective or informed-by-partner memory complaints confirmed by impaired memory function (scoring below the education-adjusted cutoff on the Logical Memory II subscale of the Wechsler Memory Scale), a Folstein Mini-Mental State Examination score greater than 23, Clinical Dementia Rating equal to 0.5, absence of significant levels of impairment in other cognitive domains, and essentially preserved activities of daily living. Patients with MCI were subdivided into 2 groups: (1) MCI patients who had not converted to AD in the 2 years of follow-up (n = 204) (MCI diagnosed at baseline and at least 2 follow-up visits being MCI), and (2) MCI patients who had converted to AD during the 2 years of follow-up (n = 116). The cognitively healthy control group had no memory complaints aside from those common in other individuals of that age range with no abnormalities, a Mini-Mental State Examination score greater than 23, Clinical Dementia Rating equal to 0, and absence of significant levels of impairment in cognitive functions or activities of daily living. Only controls who were cognitively healthy at baseline and who remained healthy in at least 1 follow-up were included in the study (n = 197). Controls were not included in any of the conversion analyses. Patients with AD were used in the present study for descriptive purposes only. They had Mini-Mental State Examination scores from 20 to 26 and a Clinical Dementia Rating score of 0.5 or 1, and met criteria for probable AD as established by the National Institute of Neurological and Communicative Disorders and Stroke– Alzheimer's Disease and Related Disorders Association. In addition, they had memory complaint by subject or study partner that is verified by a study partner, and abnormal memory function documented by scoring below the education-adjusted cutoff on the Logical Memory II subscale (delayed recall) from the Wechsler Memory Scale–Revised.
Global indices of cognitive performance and global functional status were obtained using both the Mini-Mental State Examination and the Clinical Dementia Rating. The Functional Assessment Questionnaire (FAQ) measured functional activities of older adults using the patient's study partner as an informant. Certified professionals performed clinical and neuropsychologic assessments.
The neuropsychologic battery included measures of learning and memory, attention, visuospatial abilities, psychomotor speed, and executive function. Verbal episodic memory was assessed by the Alzheimer Disease Assessment Scale–Cognitive using a composite score for the memory tests (word recall test, delayed word recall, and word recognition). Other measures of verbal memory included were the Rey Auditory Verbal Learning Test (trial 5 and delayed recall, recognition at delay) and immediate and delayed memory from the Logical Memory Test of the Wechsler Memory Scale. Alzheimer Disease Assessment Scale–Cognitive"nonmemory" domains (language comprehension, constructional, ideational praxis, orientation, and attention) were included in a composite score. Attention and working memory were assessed by the digit span subtest (forward plus reverse) from the Wechsler Memory Scale–Revised. Semantic processing and speed were assessed using a category fluency test. Semantic knowledge and visuospatial processing were assessed by the Clock Drawing Test. Trail Making Test, parts A and B (hereafter Trails A and B), and the Wechsler Adult Intelligence Scale–Revised Digit Symbol Test were used to measure executive functions and speed of processing.
Samples of CSF were collected at baseline and at the 12-month visit through lumbar puncture. Samples were transferred into polypropylene transfer tubes followed by freezing on dry ice within 1 hour after collection; they were shipped overnight to the ADNI Biomarker Core laboratory at the University of Pennsylvania Medical Center on dry ice. The complete details can be found at http://www.adni-info.org. A standardized protocol was implemented to quantify biomarker concentrations (total tau and Aβ1-42) in each of the CSF ADNI baseline aliquots using a multiplex xMAP Luminex platform (Luminex Corp, Austin, Texas) with Innogenetics (INNO-BIA AlzBio3, Ghent, Belgium; reagents for research use only) immunoassay kit–based reagents. Because of nonnormal distributions, data were log transformed. The ratio of the log-transformed Aβ1-42 /total tau was also examined.
A blood sample for APOE genotyping was extracted at the screening. Genotyping was performed at the ADNI biomarker core laboratory.
All sites met all the requirements for the Alzheimer Disease Cooperative Study start-up and have completed the MRI certification for 1.5 T MRI. All the scans were reviewed for quality control by personnel in the ADNI MRI quality center at Mayo Clinic. For the present study, volumetric and cortical thickness data were downloaded from the ADNI database using the measures extracted by the Multimodal Imaging Laboratory of the University of California, San Diego ("Dale" methods), including entorhinal and lateral temporal cortical thicknesses and hippocampal, ventricular, and whole-brain volumes. Briefly, images were automatically corrected for spatial distortion due to gradient nonlinearity and B1 field inhomogeneity, registered, and averaged to improve signal-to-noise ratio. Volumetric segmentation methods based on FreeSurfer software, optimized for use on large, multisite data sets, were used (for details, see Walhovd et al30).
Comparisons between the groups on demographic and biomarker-related data were analyzed by means ofχ2 tests or analyses of variance followed by t tests for pairwise comparisons. The initial goal was to identify the baseline biomarkers and cognitive markers that predicted conversion anytime in the 2-year interval of the study using binary logistic regression models ("anytime" analyses). Our general analytic procedure was conducted in SAS (using PROC Logistic)31 and was sequenced in the following way: First, independent regression analyses were separately conducted using clusters of independent variables: (1) demographic and constitutional-related risk factors (APOEε 4 carrier or noncarrier), age, educational level, and sex; (2) cognitive markers (listed previously), (3) CSF biomarkers (listed previously), and (4) brain volumetric biomarkers (listed previously). Then, (as step 5) only the significant predictors (ie, the"winners") obtained in the clustered regression models were entered in the regression model to compare the magnitude of predictive power between clustered and composite approaches. Because this was our critical analysis, we subjected the model to a k-fold cross-validation procedure adapting SAS macros developed by Gonen31 to determine the robustness of our findings. We predicted that cognitive markers, including those related to episodic memory, would be significant predictors of conversion.
Relative predictive power of the logistic regression models was obtained through coefficient of determination of Nagelkerke expressed as a pseudo- R2. Predictive accuracy of the resulting models was calculated using receiver operating characteristic curve analysis. Entry was set at P < .05. In all regressions, lower cognitive performance, smaller brain volumes/thicknesses, and more abnormal CSF values were associated with greater risk of conversion (ie, were in a plausible neurobiologic relationship to conversion). Sample sizes for the regression models varied because of missing data and the number of variables initially included.
Significant predictors of time to conversion to AD from baseline status were obtained using time-dependent Cox regression models. The regression procedure followed the same set of steps as the logistic procedure. Patients with MCI who did not convert were censored. For MCI patients for whom a conversion to AD was reported, date of conversion was calculated as the midpoint between their last visit without AD and their first visit with AD. Four points of conversion were possible: 6, 12, 18, or 24 months. Results are reported in eResults and the eTable.
Finally, we sought to determine whether magnitude of decline (baseline to 1 or 2 years) was proportionate among CSF and brain-volume biomarkers, cognitive markers, and everyday function. We reasoned that a disproportionate decline in a biomarker might indicate a shift in the underlying neurobiologic characteristics of the disease that was associated with diagnosis of AD. If, on the other hand, a disproportionate decline was found in a measure of functional activities, this would suggest that diagnosis had to do with a"caseness call" independent of changes in neurobiologic trajectories. To implement this, we first computed the effect size of change scores between baseline and 12 or 24 months in CSF, cognitive, and brain morphometric measures, and functional activities. We then examined the predictive power of declines in these variables in identifying individuals who converted from MCI to AD in a logistic regression.
Table 1 represents the demographic and clinical features at baseline. No differences between groups were found in age, sex distribution, and years of education. The APOE genotype frequency differed among the groups. All staging variables (Clinical Dementia Rating and Mini-Mental State Examination) differed among the groups. Functional status (FAQ) differed among the groups (including MCI converters and nonconverters).
All groups significantly differed from each other on each cognitive measure with a single exception (Table 2). Compared with cognitively healthy controls, MCI patients demonstrated z score impairments in the −1.5 to −2.0 range in memory measures; for nonmemory measures, z score impairments were generally in the−0.6 to−1.0 range. These results suggested that a significant minority of MCI patients had impairments in multiple cognitive domains.
All groups significantly differed from each other on each of the CSF biomarker measures (Table 3). Aβ1-42 was decreased in the MCI and AD groups; tau was increased.
All groups significantly differed from each other on each of the regional morphometric biomarker measures (Table 4). Whole-brain volume and ventricular volume did not differ between the cognitively healthy controls and nonconverter MCI groups.
In the demographic and individual risk cluster, APOE was a significant predictor. Of the cognitive markers, Auditory Verbal Learning Test list recall at 30 minutes, logical memory delayed recall, Alzheimer Disease Assessment Scale memory, Clock Drawing Test, and Trails A were significant predictors of conversion during the 2-year duration of the study (Table 5). Of the CSF biomarkers, only Aβ1-42/total tau was a significant predictor. Among the brain volumetric biomarkers, left hippocampus and left middle temporal lobe cortical thickness were significant predictors.
When only the significant predictors of the clustered models were entered to predict conversion during the 2-year period, 3 variables entered as listed in Table 5: Logical Memory delayed, left middle temporal lobe cortical thickness, and Auditory Verbal Learning Test delayed recall. Pseudo- R2 was 0.34, with Logical Memory accounting for 0.18; middle temporal, 0.10; and Auditory Verbal Learning Test, 0.06. The receiver operating characteristic curve for this set of variables is shown in Figure 1. The area under the curve was 0.80, and the percentage of cases classified correctly was 71.9 at c = 0.50. Sensitivity was 0.56 and specificity was 0.82 at c = 0.50. The positive predictive value for the set of markers was 0.65; the negative predictive value was 0.75.
Because this was our key analysis, we conducted a k-fold cross validation to ascertain the robustness of the findings. In this analysis, the sample is broken into randomly chosen subgroups of more or less equal size. With k-fold (here 5), the analysis was repeated k times. The predictor variables used were those found to be significant in the previously mentioned winners model using the total sample of MCI patients. For each analysis in k-fold, one of the subsets is left out as the test set and the others are used as the training set. Parameter estimates are derived from the training set and applied to the test set. Predictive accuracies are then computed and averaged across the 5 separate test sets. Because we set k = 5, randomly generated subsets had samples ranging from 58 to 73. We used 5 because having 60 to 70 patients per test set is considered necessary for power but allowed for a reasonable number of validations.
The 3 independent variables from the previously mentioned analysis served as predictors (Auditory Verbal Learning Test list memory after a delay, story memory after a delay, and left middle temporal thickness), and conversion was the binary dependent measure. The area under the curve for the k-fold analysis was 0.78. Thus, cross-validation shrinkage was quite small and the model appeared to be robust.
We first examined difference scores for the risk factor FAQ, cognitive markers, and biomarkers between baseline and 12 months in MCI converters. When difference scores were converted to effect sizes to compare and contrast them in a common psychometric space, the FAQ difference score expressed in effect size units (Cohen d) was larger than any other variable. The effect size for select cognitive variables, all brain volumetric measures, and all CSF measures are illustrated in Figure 2.
Critically for our purposes, we also sought to determine whether the magnitude of the difference scores between baseline and 12 months for FAQ, various cognitive measures (verbal list learning delayed, Trails B, fluency), and CSF and brain volume biomarkers could predict conversion from MCI to AD in a single logistic regression model (24-month data for biomarkers were not available). Only 2 variables entered the model: FAQ difference score (P < .001) and Trails B difference score (P = .01). Remarkably, they accounted for nearly 50% of the predictive variance (pseudo- R2 = 0.47). The resulting receiver operating characteristic curve yielded an area under the curve of 0.85, a specificity of 0.93, and a sensitivity of 0.52 at c = 0.5.
In a systematic series of stepwise logistic regression analyses, we demonstrated that baseline brain morphometric and cognitive variables were the strongest predictors of conversion from MCI to AD. In the predictive model, verbal episodic memory measures and left middle temporal lobe cortical thickness entered significantly. Interestingly, the memory measures that were predictive generally involved a delay, suggesting the importance of consolidation factors. The APOE status and CSF levels of tau or Aβ1-42 did not add predictive value to this composite model.
One might argue that the use of cognitive markers in this context is a tautology because they are used in the diagnosis of AD itself. However, this may not be correct because the diagnosis of MCI already requires episodic memory impairment at a level consistent with AD itself. Irrespective of this line of argument, use of cognitive markers has certain advantages: clear and significant effect on odds ratios, objectivity in scoring, comparative economy in terms of expense and time, and reliability. From a pragmatic standpoint, using all available data to make an accurate prediction would appear optimal in clinical practice or to enrich samples in a clinical trial.
There are several possible reasons that CSF biomarkers were not more powerful predictors when used in combination with other biomarkers or cognitive markers. We do not think that colinearity was an issue, because when we tested for this in our models, all condition values (a measure of colinearity) were well below 30 (data not shown). On the other hand, these CSF measures may be more or less effective as a function of disease stage. Nevertheless, we note that it is not the case that these biomarkers were ineffective in ADNI samples (see our results when examining only brain volumes or CSF biomarkers in the clustered regressions, as well as prior work in smaller ADNI samples that examined CSF biomarkers, global measure of AD-related atrophy, and/or positron emission tomography with radiolabeled [18F]-2-fluoro-deoxy-D-glucose32,33), only that other types of biomarkers or cognitive markers were more robust predictors in our study. In addition, we note that different biomarkers and behavioral markers may have differentially predictive values at different times in disease progression. That is, biomarkers are dynamic and they will vary in their informativeness depending on when they are measuring, an important and heuristic point recently made by Jack and colleagues.34 They may be most informative in very early prodromal stages, a perspective that has been incorporated into proposed diagnostic criteria for preclinical AD.
Several recent studies are consistent with our results. In an ADNI sample, Fjell et al35 found that baseline morphometric volume measures were better predictors of Clinical Dementia Rating sum of boxes decline than CSF markers. The findings by Ewers et al,36 in a smaller ADNI cohort than our own and using different methods, were nevertheless broadly consistent with our own in that memory measures and Trails B were significant predictors of MCI conversion to AD. In a large meta-analysis that did not include ADNI data, baseline cognitive markers were better predictors of conversion than brain volumetric or CSF biomarkers.5
In addition to our study of baseline measures, we also examined decline in cognitive markers, biomarkers, and a measure of function. We found that the decline in functional competence was disproportionate to the decline in biomarkers and cognitive markers, based on 1- and 2-year change scores in both effect size analyses and logistic regression examining predictors of conversion. This suggested to us that diagnosis was not the result of a shift in the underlying neurobiologic characteristics of the disorder but rather was due to some combination of psychometrics of the FAQ, informant factors, and the tendency of a site neurologist to make a caseness call. We have argued elsewhere21 that it would be unlikely that if biomarkers, histopathology, and cognition were on a continuum from MCI to AD, functional impairment would be categorical (preserved or impaired). Reinforcing this view are the high rates of conversion from MCI to AD in this sample (approximately 40% within 2 years) and the fact that MCI patients had cognitive impairments in other domains. In the ADNI MCI group, Alzheimer Disease Assessment Scale–Cognitive nonmemory scores (a composite of language and praxic and gnosic abilities) were approximately−2.0. Trails B, a measure of executive function, had a z score of−1.5. Other scores (eg, fluency, Clock Drawing Test) were approximately−1.0. Given that z -score impairments of approximately−1.5 to−2.0 were present in multiple domains at the group level, at the level of individual cases approximately 35% to 45% of MCI patients demonstrate impairments of−2.0 or worse, ie, would meet cognitive criteria for AD based on a second domain beyond memory.
In effect, it appeared to us that many MCI patients may already have met cognitive criteria for AD, and the diagnostic trigger had little to do with a shift in the disease trajectory. In addition to this possibility, we suggest that a second smaller factor in conversion may reflect compromises in executive and cognitive control functions that reduce compensatory potential (because Trails B decline was a second, weaker predictor of conversion).
In summary, we believe that this study was comprehensive and systematic, in that we examined combinations of cognitive markers, brain volumetric biomarkers, and CSF biomarkers in predictive regression models. The sample that we used (from ADNI) was large, and the data were collected uniformly, rigorously, and prospectively. We demonstrated that cognitive markers were consistently significant and generally stronger predictors than biomarkers, and moreover, that conversion itself did not so much reflect a shift in the neurobiologic characteristics of the disease but rather a large functional decline.
Correspondence: Terry E. Goldberg, PhD, Litwin Zucker Alzheimer's Center/Zucker Hillside Hospital/A, 75-59 263rd St, Glen Oaks, NY 11004 (firstname.lastname@example.com).
Submitted for Publication: February 8, 2011; final revision received April 29, 2011; accepted May 1, 2011.
Financial Disclosure: Dr Goldberg reports that he has consulted for Merck and GlaxoSmithKline, receives royalties for use of a cognitive test battery (Brief Assessment of Cognition in Schizophrenia) in clinical trials, and has received an investigator-initiated grant from Eisai/Pfizer. Dr Davies reports that he has received research support from and served as a consultant to Applied Neurosolutions.
Funding/Support: This study was supported by grants from the Litwin-Zucker Alzheimer's Center (Drs Gomar, Conejero-Goldberg, Davies, and Goldberg and Ms Bobes-Bascaran), and by grant FI00322 from Instituto de Salud Carlos III (Dr Gomar).
Additional Information: Data used in the preparation of this article were obtained from the ADNI database (http://adni.loni.ucla.edu/.. As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this article. A complete listing of ADNI investigators is available at http://adni.loni.ucla.edu/. Data collection and sharing for this project was funded by ADNI (grant U01 AG024904 from the National Institutes of Health). The ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson& Johnson, Eli Lilly and Co, Medpace, Inc, Merck and Co, Inc, Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc, as well as nonprofit partners the Alzheimer's Association and Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. The ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. This research was also supported by grants P30 AG010129 and K01 AG030514 from the National Institutes of Health, and the Dana Foundation.
Additional Contributions: We thank Ted Huey, MD, for commenting on the manuscript.


text:
Apache HTTP Server Version 2.4
Directives in the configuration files may apply to the
entire server, or they may be restricted to apply only to particular
directories, files, hosts, or URLs. This document describes how to
use configuration section containers or
.htaccess files
to change the scope of other configuration directives.
|Related Modules
|Related Directives
There are two basic types of containers. Most containers are
evaluated for each request. The enclosed directives are applied only
for those requests that match the containers. The
<IfModule>, and
containers, on the other hand, are evaluated only at server startup
and restart. If their conditions are true at startup, then the
enclosed directives will apply to all requests. If the conditions are
not true, the enclosed directives will be ignored.
<IfDefine> directive
encloses directives that will only be applied if an appropriate
parameter is defined on the
httpd command line. For example,
with the following configuration, all requests will be redirected
to another site only if the server is started using
httpd -DClosedForNow:
<IfDefine ClosedForNow> Redirect "/" "http://otherserver.example.com/" </IfDefine>
directive is very similar, except it encloses directives that will
only be applied if a particular module is available in the server.
The module must either be statically compiled in the server, or it
must be dynamically compiled and its
LoadModule line must be earlier in the
configuration file. This directive should only be used if you need
your configuration file to work whether or not certain modules are
installed. It should not be used to enclose directives that you want
to work all the time, because it can suppress useful error messages
about missing modules.
In the following example, the
MimeMagicFile directive will be
applied only if
mod_mime_magic is available.
<IfModule mod_mime_magic.c> MimeMagicFile "conf/magic" </IfModule>
directive is very similar to
<IfDefine> and
<IfModule>, except it encloses directives that will
only be applied if a particular version of the server is executing. This
module is designed for the use in test suites and large networks which have to
deal with different httpd versions and different configurations.
<IfVersion >= 2.4> # this happens only in versions greater or # equal 2.4.0. </IfVersion>
<IfModule>, and the
can apply negative conditions by preceding their test with "!".
Also, these sections can be nested to achieve more complex
The most commonly used configuration section containers are the
ones that change the configuration of particular places in the
filesystem or webspace. First, it is important to understand the
difference between the two. The filesystem is the view of your disks
as seen by your operating system. For example, in a default install,
Apache httpd resides at
/usr/local/apache2 in the Unix
filesystem or
"c:/Program Files/Apache Group/Apache2" in
the Windows filesystem. (Note that forward slashes should always be
used as the path separator in Apache httpd configuration files, even for Windows.) In contrast,
the webspace is the view of your site as delivered by the web server
and seen by the client. So the path
/dir/ in the
webspace corresponds to the path
/usr/local/apache2/htdocs/dir/ in the filesystem of a
default Apache httpd install on Unix. The webspace need not map directly to
the filesystem, since webpages may be generated dynamically
from databases or other locations.
directives, along with their regex
counterparts, apply directives to
parts of the filesystem. Directives enclosed in a
<Directory> section apply to
the named filesystem directory and all subdirectories of that
directory (as well as the files in those directories).
The same effect can be obtained using .htaccess files. For example, in the
following configuration, directory indexes will be enabled for the
/var/web/dir1 directory and all subdirectories.
<Directory "/var/web/dir1"> Options +Indexes </Directory>
Directives enclosed in a
<Files> section apply to any file with
the specified name, regardless of what directory it lies in.
So for example, the following configuration directives will,
when placed in the main section of the configuration file,
deny access to any file named
private.html regardless
of where it is found.
<Files "private.html"> Require all denied </Files>
To address files found in a particular part of the filesystem, the
<Files> and
<Directory> sections
can be combined. For example, the following configuration will deny
access to
/var/web/dir1/subdir3/private.html, and any other instance
private.html found under the
<Directory "/var/web/dir1"> <Files "private.html"> Require all denied </Files> </Directory>
directive and its regex counterpart, on
the other hand, change the
configuration for content in the webspace. For example, the following
configuration prevents access to any URL-path that begins in /private.
In particular, it will apply to requests for
http://yoursite.example.com/private123, and
http://yoursite.example.com/private/dir/file.html as well
as any other requests starting with the
/private string.
<LocationMatch "^/private"> Require all denied </LocationMatch>
directive need not have anything to do with the filesystem.
For example, the following example shows how to map a particular
URL to an internal Apache HTTP Server handler provided by
No file called
server-status needs to exist in the
<Location "/server-status"> SetHandler server-status </Location>
In order to have two overlapping URLs one has to consider the order in which
certain sections or directives are evaluated. For
<Location> this would be:
<Location "/foo"> </Location> <Location "/foo/bar"> </Location>
<Alias>es on the other hand,
are mapped vice-versa:
Alias "/foo/bar" "/srv/www/uncommon/bar" Alias "/foo" "/srv/www/common/foo"
The same is true for the
ProxyPass "/special-area" "http://special.example.com" smax=5 max=10 ProxyPass "/" "balancer://mycluster/" stickysession=JSESSIONID|jsessionid nofailover=On
<Files>, and
directives can each use shell-style wildcard characters as in
fnmatch from the C standard library. The character "*"
matches any sequence of characters, "?" matches any single character,
and "[seq]" matches any character in seq. The "/"
character will not be matched by any wildcard; it must be specified
If even more flexible matching is required, each
container has a regular expression (regex) counterpart
<FilesMatch>, and
<LocationMatch> that allow
regular expressions
to be used in choosing the matches. But see the section below on
configuration merging to find out how using regex sections will change
how directives are applied.
A non-regex wildcard section that changes the configuration of all user directories could look as follows:
<Directory "/home/*/public_html"> Options Indexes </Directory>
Using regex sections, we can deny access to many types of image files at once:
<FilesMatch "\.(?i:gif|jpe?g|png)$"> Require all denied </FilesMatch>
Regular expressions containing named groups and
backreferences are added to the environment with the
corresponding name in uppercase. This allows elements of filename paths
and URLs to be referenced from within expressions
and modules like
<DirectoryMatch "^/var/www/combined/(?<SITENAME>[^/]+)"> require ldap-group "cn=%{env:MATCH_SITENAME},ou=combined,o=Example" </DirectoryMatch>
directive change the configuration depending on a condition which can be
expressed by a boolean expression. For example, the following configuration
denies access if the HTTP Referer header does not start with
<If "!(%{HTTP_REFERER} -strmatch 'http://www.example.com/*')"> Require all denied </If>
Choosing between filesystem containers and webspace containers is
actually quite easy. When applying directives to objects that reside
in the filesystem always use
<Directory> or
<Files>. When applying directives to objects
that do not reside in the filesystem (such as a webpage generated from
a database), use
It is important to never use
<Location> when trying to restrict
access to objects in the filesystem. This is because many
different webspace locations (URLs) could map to the same filesystem
location, allowing your restrictions to be circumvented.
For example, consider the following configuration:
<Location "/dir/"> Require all denied </Location>
This works fine if the request is for
http://yoursite.example.com/dir/. But what if you are on
a case-insensitive filesystem? Then your restriction could be easily
circumvented by requesting
http://yoursite.example.com/DIR/. The
<Directory> directive, in
contrast, will apply to any content served from that location,
regardless of how it is called. (An exception is filesystem links.
The same directory can be placed in more than one part of the
filesystem using symbolic links. The
<Directory> directive will follow the symbolic
link without resetting the pathname. Therefore, for the highest level
of security, symbolic links should be disabled with the appropriate
Options directive.)
If you are, perhaps, thinking that none of this applies to you
because you use a case-sensitive filesystem, remember that there are
many other ways to map multiple webspace locations to the same
filesystem location. Therefore you should always use the filesystem
containers when you can. There is, however, one exception to this
rule. Putting configuration restrictions in a
"/"> section is perfectly safe because this section will apply
to all requests regardless of the specific URL.
Some section types can be nested inside other section types. On the one
<Files> can be used
<Directory>. On
the other hand,
<If> can
be used inside
<Location>, and
<Files> sections. The regex
counterparts of the named section behave identically.
Nested sections are merged after non-nested sections of the same type.
container encloses directives that apply to specific hosts.
This is useful when serving multiple hosts from the same machine
with a different configuration for each. For more information,
see the Virtual Host Documentation.
containers apply enclosed configuration directives only
to sites accessed through
mod_proxy's proxy server
that match the specified URL. For example, the following configuration
will prevent the proxy server from being used to access the
www.example.com website.
<Proxy "http://www.example.com/*"> Require all granted </Proxy>
To find out what directives are allowed in what types of
configuration sections, check the Context of the directive.
Everything that is allowed in
sections is also syntactically allowed in
sections. There are some exceptions, however:
AllowOverride directive
works only in
FollowSymLinks and
Options work only in
<Directory> sections or
.htaccess files.
Options directive cannot
be used in
The configuration sections are applied in a very particular order. Since this can have important effects on how configuration directives are interpreted, it is important to understand how this works.
The order of merging is:
<Directory> (except regular expressions)
.htaccess done simultaneously (with
.htaccess, if allowed, overriding
<Directory "~">)
<Files> and
<FilesMatch> done
<LocationMatch> done simultaneously
Apart from
<Directory>, each group is processed in
the order that they appear in the configuration files.
<Directory> (group 1 above)
is processed in the order shortest directory component to longest.
So for example,
<Directory "/var/web/dir"> will
be processed before
"/var/web/dir/subdir">. If multiple
<Directory> sections apply
to the same directory they are processed in the configuration file
order. Configurations included via the
Include directive will be treated as if
they were inside the including file at the location of the
Include directive.
Sections inside
<VirtualHost> sections
are applied after the corresponding sections outside
the virtual host definition. This allows virtual hosts to
override the main server configuration.
When the request is served by
mod_proxy, the
container takes the place of the
<Directory> container in the processing
Later sections override earlier ones, however each module is responsible for interpreting what form this override takes. A later configuration section with directives from a given module might cause a conceptual "merge" of some directives, all directives, or a complete replacement of the modules configuration with the module defaults and directives explicitly listed in the later context.
sequence performed just before the name translation phase
Aliases and
are used to map URLs to filenames). The results of this
sequence are completely thrown away after the translation has
Below is an artificial example to show the order of merging. Assuming they all apply to the request, the directives in this example will be applied in the order A > B > C > D > E.
<Location "/"> E </Location> <Files "f.html"> D </Files> <VirtualHost *> <Directory "/a/b"> B </Directory> </VirtualHost> <DirectoryMatch "^.*b$"> C </DirectoryMatch> <Directory "/a/b"> A </Directory>
For a more concrete example, consider the following. Regardless of
any access restrictions placed in
<Directory> sections, the
<Location> section will be
evaluated last and will allow unrestricted access to the server. In
other words, order of merging is important, so be careful!
<Location "/"> Require all granted </Location> # Woops! This <Directory> section will have no effect <Directory "/"> <RequireAll> Require all granted Require not host badguy.example.com </RequireAll> </Directory>

subset: commoncrawl


text:
What is a Medicare Advantage Plan?
A Medicare Advantage Plan is a type of Medicare health plan offered by a private company that contracts with Medicare to provide you with all your Part A and Part B benefits.
Medicare Advantage Plans include Health Maintenance Organizations, Preferred Provider Organizations, Private Fee-for-Service Plans, Special Needs Plans, and Medicare Medical Savings Account Plans.
If you're enrolled in a Medicare Advantage Plan, Medicare services are covered through the plan and aren't paid for under Original Medicare.
Most Medicare Advantage Plans also offer prescription drug coverage.
What do Medicare Advantage Plans cover?
Medicare Advantage Plans must cover all of the services that Original Medicare covers except hospice care. Original Medicare covers hospice care even if you're in a Medicare Advantage Plan. In all types of Medicare Advantage Plans, you're always covered for emergency and urgently needed care.
Medicare Advantage Plans may offer extra coverage, like vision, hearing, dental, and/or health and wellness programs. Most include Medicare prescription drug coverage (Part D). In addition to your Part B premium, you usually pay a monthly premium for the Medicare Advantage Plan.
You can also ask the plan for a written advance coverage decision to make sure a service is medically necessary and will be covered. If the plan won't pay for a service you think you need, you'll have to pay all of the costs if you didn't ask for an advance coverage decision.
Contact us to learn more about the right Medicare Advantage plan for you.
We do not offer every plan available in your area. Any information we provide is limited to those plans we do offer in your area. Please contact Medicare.gov or 1-800-MEDICARE to get information on all your options.
(864) 757-8140
3675 Crestwood Pwky
Suite 400
Duluth, GA 30096
Click Here to Email Us


text:
I agree, that Facebook/Google transmitted automaticaly information to Web Administration S.L. and use this subsequent. In practiclar my profil-informations, especially my Basisdata.
I have read the data protection.
I can revoke these consent via Mail to firstname.lastname@example.com .
Telefon kullanıcısı canlı görüntüleri ücretsiz olarak alacaktır.
Privacy policy
1. Scope of application
This privacy policy clarifies the nature, scope and purpose of the collection and use of personal data on the website https://camworld.tv/ (hereinafter "website") by Web Administration S.L. (hereinafter "we" or "us"). We are the responsible party for all personal data collected on the website, unless this privacy policy contains different information.
2. Name and address of the controller
The controller within the meaning of the General Data Protection Regulation, other data protection laws in force in the Member States of the European Union, and other provisions of a data protection nature, is:
Web-Administration S.L.
La Mata 25
35629 Tuineje
Telephone: 0800 0000999
Email: firstname.lastname@example.com
3. Personal data
Personal data are any information relating to an identified or identifiable natural person. An identifiable person is a natural person who can be identified directly or indirectly, in particular by reference to an identifier such as a name, identification number, location data, online identifier or to one or more specific characteristics which are expressions of the physical, physiological, genetic, psychological, economic, cultural or social identity of that natural person.
4. Your rights
You have the right to obtain information about the personal data that has been stored about you free of charge on request (from the second provision within 12 months we may charge you a fee). In addition, you have the right to request the correction of incorrect data, the right to restrict the processing of excessively processed data and the right to delete any unlawfully processed personal data or any that has been stored too long (unless there is a statutory retention obligation and no other reasons prevent it pursuant to Article 17 para. 3 of the GDPR). Furthermore, you have the right of transfer of all data provided by you to us in a common file format (right to data portability).
Insofar as you have a right to object to the processing of individual proceedings, we inform regarding this in the description of the individual proceedings.
To exercise your rights, just send an email to firstname.lastname@example.com.
Additionally, you also have the right to complain to a data protection supervisory authority.
5. Voluntary nature of the provision of data
The provision of your personal data on this website is generally neither legally nor contractually required. You are not obligated to provide personal data on this website, unless we notify accordingly in individual cases in this privacy policy. However, the provision of the functions of this website and the processing of an order requires the processing of your personal data.
6. General notes about cookies
Cookies are small text files that are saved on your device by the browser used when you visit our website. In this way, individual services on a website can "recognise" you and "remember" which settings you have made. They help make websites more user friendly for the benefit of the user (e.g. storing login data). On the other hand, cookies are used to collect statistical data on website usage and to use the data obtained for analysis and advertising purposes.
Some cookies are automatically deleted from your device as soon as you leave the website (so called session cookies). Other cookies are stored for a period of time that does not exceed two years (persistent cookies). In addition, we also use so called third party cookies, which are managed by third parties to provide certain services.
You can influence the use of cookies. Most browsers have an option to allow the user to restrict or completely prevent cookies being saved. However, we must point out that the general use and in particular the user experience, may be restricted without cookies.
7. Automatic collection of access data/server log files
With each website access we automatically collect a set of technical data that is personally identifiable. These are:
The IP address of the user
Name of the retrieved website or file
Date and time of access
The amount of data transmitted.
Message about successful request
Browser type and version;
Operating system of the user
Device used by the user, including MAC address
Referrer URL code (the website previously visited)
These data shall not be merged with any other personally identifiable information you provide via the website.
The personal data in log files are processed on the basis of Article 6 para. 1 lit. f of the GDPR. This permission allows the processing of personal data in the context of the "legitimate interest" of the controller, unless your fundamental rights, freedoms or interests prevail. Our legitimate interest concerns easier administration and the ability to detect and track hacking. You can object to this data processing at any time if there are reasons that exist in your particular situation against the processing of data. All you need to do is send an email to the address shown above.
The server log files with the above data shall be automatically deleted after 30 days. We reserve the right to store the server log files longer, if there are facts that suggest the assumption of unauthorised access (such as the attempt of hacking or a so-called DOS attack).
8. What an IP address is
Each device (e.g. smartphone, tablet, PC) connected to the Internet is assigned an IP address. The IP address depends on which internet access your device is currently connected to the internet by. It can be the IP address assigned to you by your Internet service provider, for example, if you are connected to the Internet at home via your WiFi connection. It can also be an IP address assigned to you by your mobile service provider or the IP address of a provider of a public or private wireless network or other Internet access. In its current most frequently occurring form (IPv4), the IP address consists of four blocks of numbers separated by dots. In most cases, you as a private user will not use a static IP address, since you will only be assigned this temporarily by your provider (a so called "dynamic IP address"). In the case of a permanently assigned IP address (so-called "static IP address"), in principle a clear assignment of the user data via this feature is possible. Except for the purpose of pursuing unauthorised access to our Internet offer, we generally use these data without a personal assignment, but rather evaluate only on an anonymous basis, which of our websites are favoured, how many accesses are made daily and the like.
9. Registration
You have the possibility of registering yourself on the website of the controller by providing personal data. The type of personal data transferred to the controller is determined by the input mask used for registration. The personal data you enter shall be collected and stored solely for internal use by the controller and for its own purposes.
The IP address, date and time of registration given by the Internet service provider (ISP) of the data subject shall also be saved by registration on the website of the controller. The storage of these data is based on the fact that this is the only way to prevent misuse of our services and these data also enable us to investigate crimes and copyright infringements if necessary. In this respect, the storage of such data is necessary in order to safeguard the controller. In principle, these data shall not be passed on to third parties unless there is a legal obligation to do so, or the passing on serves the requirements of criminal or legal proceedings.
The data provided in the context of registration are processed based on Article 6 para. 1 and lit. f of the GDPR. The registration of the data subject, with the voluntary provision of personal data, serves for the controller to offer the data subject content or services which, due to the nature of the matter, can only be offered to registered users. Registered persons are free to modify the personal data given upon registration at any time, or to delete it completely from the database of the controller.
The controller shall provide you at any time upon request with information about which personal data concerning you are stored. Furthermore, the controller shall correct or delete personal data on request or notice from you, insofar as this does not conflict with any statutory storage requirements. All you need to do is send an email to the address shown above.
10. Newsletter
On the website, users are given the opportunity to subscribe to the newsletter of our company. The type of personal data transferred to the controller when you subscribe to the newsletter is determined by the input mask used for registration.
We inform our customers and business partners at regular intervals by means of a newsletter about the offers of the company. The newsletter of our company in principle can only be received by you if (1) you have a valid email address and (2) you register for the newsletter. For legal reasons, a confirmation email shall be sent to the email address entered by you using the double-opt-in procedure. This confirmation email is used to check whether the owner of the email address as the data subject authorised the receipt of the newsletter.
When subscribing to the newsletter, we also store the IP address of the computer system used by the data subject at the time of registration, as well as the date and time of registration, as assigned by the Internet Service Provider (ISP). The collection of these data is necessary in order to investigate the (possible) misuse of the email address of a data subject at a later date and therefore serves as a legal safeguard for the controller.
The personal data collected in the context of registering for the newsletter shall be used exclusively to send our newsletter. Subscribers to the newsletter may also be notified by email if this is necessary for the operation of the newsletter service or registration, as might be the case in the event of changes to the newsletter or technical changes. There shall be no transfer of the personal data collected as part of the newsletter service to third parties. Subscription to our newsletter may be terminated by you at any time. The consent to the storage of personal data that you have given us for the sending of the newsletter may be revoked at any time. For the purpose of revoking the consent, there is a corresponding link in each newsletter. Furthermore, it is also possible to inform the controller in a different way, such as by email.
11. Contact possibilities on the website
Due to legal regulations, our website contains information that enables the establishment of rapid electronic contact with our company as well as direct communication with us, which also includes a general address for what is known as electronic mail (email address). Insofar as you contact the controller by email, the personal data you provide shall be automatically saved. Such personal data transmitted to the controller by you on a voluntary basis shall be stored for the purpose of processing or contacting you. This personal data shall not be disclosed to third parties.
The data provided in the context of making contact are processed based on Article 6 para. 1 and lit. f of the GDPR. This permission allows the processing of personal data in the context of the "legitimate interest" of the controller, unless your fundamental rights, freedoms or interests prevail. Our justified interest lies in the processing of the contact established. You can object to this data processing at any time if there are reasons that exist in your particular situation against the processing of data. All you need to do is send an email to the address shown above.
The personal data stored in the context of establishing contact shall be deleted if the concerns associated with the contact have been completely clarified and it is also unlikely that the specific contact will become relevant again in the future.
12. Google Analytics
The controller has integrated Google Analytics (with the anonymisation function) into this website. Google Analytics is a web analytics service. Web analysis is the acquisition, collection and evaluation of data concerning the behaviour of the website visitors. Among other things, a web analysis service collects data about which website a data subject has accessed the current website from (so called referrer), which sub pages of the website were accessed or how often and for which length of time a sub page was viewed. Web analysis is mainly used to optimise a website and for carrying out a cost-benefit analysis of internet advertising.
The Google Analytics component is operated by Google Inc., 1600 Amphitheatre Pkwy, Mountain View, CA 94043-1351, USA.
For web analysis via Google Analytics, the controller uses the add-on "_gat. _anonymizeIp". By means of this add-on, the IP address of your internet connection is shortened and made anonymous by Google, if access to our websites is performed from a Member State of the European Union or another Contracting State to the Agreement on the European Economic Area.
The purpose of the Google Analytics component is to analyse visitor flows to our website. Among other things, Google uses the data and information obtained to evaluate the use of our website in order to compile online reports for us that show activities on our website and to provide other services related to the use of our website.
Google Analytics sets a cookie on your device. What cookies are, has already been explained above.
We base the processing of personal data by Google Analytics on Article 6 para. 1 lit. f of the GDPR. This permission allows the processing of personal data in the context of the "legitimate interest" of the controller, unless your fundamental rights, freedoms or interests prevail. Our legitimate interest lies in the analysis of the use of our website. You have the possibility to prevent the mentioned cookies from being stored on your computer. To do this, you must make a corresponding setting on your Internet browser. However, the possibility exists that then our website may be only partially usable for you. You can prevent Google from collecting, sending and processing your data and IP address. You can download and install a plugin for your internet browser. This plugin is available at the following link: Browser add-on to deactivate Google Analytics
You can prevent the collection of data by Google Analytics by clicking on the following link. An opt-out cookie will be set that will prevent the future collection of your data when you visit this website: disable Google Analytics
You can find further information regarding terms of use and data protection at: http://www.google.com/analytics/terms/gb.html and https://www.google.de/intl/gb/policies/.
13. Storage of personal data when registering as a webmaster, broadcaster or studio
The controller collects and processes the personal data for the purpose of completing the process when there is a registration as a webmaster, broadcaster or studio. For example, processing can be done by email or via the web form, and the data you provide shall be automatically transmitted to the controller. Such personal data transmitted to the controller by you on a voluntary basis shall be stored for the purpose of the processing. This personal data shall not be disclosed to third parties.
The processing of personal data in the context of applications is based on Article 6 para. 1 lit. b of the GDPR. Article 6 para. 1 S 1 lit. b of the GDPR allows data processing if this is necessary for the initiation and execution of a contract.
14. Duration of storage of data
We store personal information only as long as necessary to perform the services you desire or to which you have given your consent, unless otherwise required by law. Retention requirements, which obligate us to store data, result from accounting regulations (§ 257 of the German commercial code) and from tax regulations (§ 147 of the Tax code as well as § 14b of the Sales tax law). According to these regulations, business communications, closed contracts and accounting documents must be kept for up to 10 years. Insofar as we no longer need these data to carry out the services for you, the data shall be blocked. This means that the data may then only be used for accounting purposes and for tax purposes.
15. Registration and Login over Single-Sign-On- Services
Different parts of this service require you to register. For registration, we provide various options. You can either immediately create a user account with us, or you can use an existing account with another provider, e.g. Register Facebook, Google or Twitter.
If you log in as a logged in user, the following features will be saved and linked to your user account for the duration of your registration.
- Current timestamp
- Your current IP-Adress
This is for your safety, because the IP address ensures that nobody can hack into your session (so-called "session hijacking").
You can also sign up using an existing single sign-on account ("SSO") .So SSO accounts allow you to sign up for a different service and platform with a once-created account. We offer you the opportunity to register for the use of the registered services using SSO services, which is currently available with the services of Facebook, Google and Twitter.
Facebook is a social network of Facebook Ireland Limited (Hanover Reach, 5-7 Hanover Quay, Dublin 2 Ireland). To register for and use Facebook, the privacy and use conditions of the social network apply, which you can see here and here.
Twitter is a microblogging service provided by the American company Twitter, Inc. (795 Folsom St., Suite 600, San Francisco, CA 94107). To register for and use Twitter, the privacy and usage policies of the social network apply, which you can view here and here.
The SSO-service from Google is provided by Google Inc. ("Google"), Amphitheatre Parkway, Mountain View, CA 94043, USA, angeboten. To register for and use google, the privacy and usage policies of the social network apply, which you can view here.
To register via one of the SSO providers listed above requires that you already be registered with the SSO provider or create such an account as part of the registration, provided this option is offered by the respective provider. Please note that the registration and use of SSO services are subject to the privacy and usage conditions of the respective provider.
A) Login to the SSO-provider
If you decide to register with your SSO account, you will be redirected to your SSO provider in a first step. There you will be asked by the SSO provider to provide your access data and to register or register with the SSO service. If you are already logged into the SSO service at this moment, this query will be skipped for login. Your credentials to the SSO service will not be communicated to us and will remain with your SSO provider.
B) Connection to the SSO service
In a second step you connect your profile with your SSO provider with us. Which of your information from your SSO profile can be queried by us, you'll learn in this step as well. In the case of Facebook, for example, this includes your so-called "public information" and those that you make publicly available or release, such as your name, profile and cover image, gender, username and user ID (eg Facebook Finally, to register with us, we'll need the email address stored in your SSO profile, so that if you decide to break the link between your SSO profile and your profile with us in the future would like to be able to continue using your profile.
If you agree that we may use your above-mentioned data for the purposes of use, you will establish in the SSO service the connection between your SSO profile and us and will then be redirected for further registration.
We then took over the information you provided during registration from your SSO provider and used it to create a profile for us. In future, you can always log in to us via the corresponding login button for the SSO provider you use (for example, in the case of Facebook: "Login with Facebook").
C) Data collection and storage by us
In this context, we receive access to a small amount of data from your SSO provider. However, we only use this option in relation to the email, name and profile picture we use to create your profile for you.
D) Data collection and storage by the SSO provider
If you want to register with us with your SSO credentials, the SSO provider will know that you want to register with us by clicking on the button marked with the respective SSO provider logo.
As a rule, the SSO provider also sets a cookie in your browser when you click on the button provided with the respective SSO provider logo. Using this text file, the SSO provider can collect more information about you and your browsing habits. The information generated by the cookie is transmitted to the servers of the SSO provider. It is possible that these are outside Germany, for example in the USA. There they are stored and possibly merged with other profile data that the SSO provider has stored about you. In this way, your SSO provider may create user profiles that go beyond what you yourself have disclosed to information.
What data your SSO provider collects in detail and for what purposes this data is collected or used, you will find in the privacy policy of your respective provider. There you will also find more information about your rights to data collection and processing.
E) Further information
Once you have completed this form of registration, we will store the information that you have registered with us through your SSO provider. This information is stored in the form of a key. Your access data to the respective SSO service, however, are never stored by us.
If you change your details in the SSO service profile that was sent to us in connection with the registration, you must also make these changes in your account with us. We do not automatically receive your updated data from your SSO account and will not send any information to your SSO provider unless you agree.
F) Cancellation of the connection
If you want to use us regardless of your SSO account, you can. In this case, please request a new password from us via the "Forgotten password" function.
If you would like to disconnect from us to your SSO account, please sign in to your SSO provider and make the required changes to your profile, if available from your SSO provider. That way, you can deprive us of permission to use information from your SSO profile. In this case, you can only continue to use your account with us if you request your own password via the "Forgot your password" function.
Deleting your account with us automatically removes the connection to your SSO provider. The account with your SSO provider is not affected.


text:
Many people abhor traveling for business, while some only hate it when they are consistently on the road as a road warrior. They frequently miss home, having their own familiar place to stay, and home cooking. Still, there are a number of tips for the business traveler that can make the best of traveling for business.
Free Fun Travel
Traveling for business can also help increase traveling for pleasure. While flying, staying at hotels, and renting cars one can be collecting loyalty points for future use. This means that one can be traveling for fun with the rewards of their business travel. It is a liberating feeling to walk to an airline counter and cash in some points for a trip to anywhere in the world- Vegas for the weekend or take someone special to Paris.
Travel Perks
Being a frequent traveler with the loyalty programs will have you an established elite traveler in no time. Pay attention to the requirements and do what you can to get elite status as soon as you can. The perks are tremendous with free and sometimes unexpected upgrades. Preference in the check-in lines will make a huge difference when you are pressed for time or dog tired at the end of the day. Preference in check-in/check-out times will be a perk you will use often.
Be In The Now
Every major town will have its unique flavor and will have some tourist must sees. See them when you have down time. When you are constantly on the road it will seem enticing to stay in a hotel room and relax to some TV, but when you do this day after day, town after town no wonder burn-out settles in. Get out and explore, get to know the town, it will undoubtedly help your business in that town to know more about it. Try the specialty foods of the area, stay away from national chains. And if you do find that you travel the same cities consistently, then make it your town. Find some favorite places to eat and entertain yourself, then you can actually look forward to visiting again.
Being able to travel for business is a wonderful opportunity and should not be seen as a burden. Changing of the attitude may be as simple as looking to the pluses and not focusing on the negatives of frequent travel.


text:
Zack Greinke (2-1, 4.80) vs. Tim Hudson (4-4, 4.80)*
Tim Hudson once filled Adam LaRoche's glove with human shit. (Deadspin)
I repeat: Tim Hudson once filled Adam LaRoche's glove with human shit. Does that sound like someone who should get to win a ballgame? No, I think not. (The baseball gods may agree with me, since he hasn't won a game since May 5th.)
On the other hand, the Dodgers' season to this point has been the equivalent of a glove full of human shit. Just when they thought they were out of the basement, the Padres shoved them back down the stairs. I want to say that this series against the Braves can't be worse than the last one, where the Dodgers were swept in three games (after holding leads in each), but now it's a four-game series. OF COURSE IT CAN BE WORSE.
I'll be at tonight's game, but up in the fancypants suites, as DelinO was recently. I promise to give the proletariat a wave or two.
*Hooray for identically mediocre ERAs!


text:
About exchanging Cash AMD to USD Coin TRC20
All exchangers specified in the list provide the service of exchanging Cash AMD to USD Coin TRC20 automatically. You can use our instructions in the FAQ section if you have never exchanged electronic money at our site before and you come across any difficulties with the exchange process.
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Turk is a Hindu Jat gotra (clan or lineage) found in India. There are different opinions as to the origin of the Jats, but most seem to recognize them to be from Indo-Aryan tribes native to the Punjab region that straddles modern Pakistan and India. There is a theory suggesting that they may be the predecessors of Gypsies. They probably reached Egypt with the Muslim conquerors, lived in Afghanistan before the Muslims, and invaded China with the Mongol Army. They also proved to be a threat to Tamarlane in Persia and Uzbekistan in the 1400s.
There are very few records concerning Jats prior to the 1600s. They rose to prominence following the 1669 Jat uprising against Mughal rule, and they ruled various princely states throughout the 18th century. For centuries the Jat lifestyle was designed to foster a martial spirit. Whenever they lost their kingdoms, Jat people became landlords who were ready to defend their land against any invaders.
After 1858, under the British Raj, the Jats were known for their service in the Indian Army, being categorized as a "martial race" by the British. For a couple hundred years Jats were a force that could not be ignored by South Asians or British imperialists.
The largest concentration of Hindu Jats is in the Indian states of Punjab and Haryana where one-fourth of the people are Jats.
Turk Jats have a very good self-image. "Men may come and men may go, but I go on forever," is a well-known Jat proverb. They are brave, hardworking people who possess both the desire and ability to rule. It has been said that no Jat wants to be ruled. Rather, he desires to have power over a group if not over an area. They take great pride in their ancestry. In fact, all the Jats in a particular village consider themselves to be the descendants of the man whom they believe founded it by the power of the sword.
Conservative by nature, the Jats rarely marry people from other people groups. From about 1650 AD onwards marrying within same clan became more common. The modern-day litmus test that Jat people use in marriage is if the girl and boy must not have the same great-great-grandparents (not related for four generations). If they are from the same clan but are not directly related for four generations then it is considered acceptable for them to marry.
Physically, the Jats are usually taller and heavier than most of their neighbors. Because of their larger build, their reputation for violence, and the fact that they control much of the land and village income, they are generally feared by other communities.
Most of the Jats live in rural areas, and they are usually landowners. A small percentage are traders and laborers. Today, the Jats are well read, and some occupy high positions in academic and technical arenas. The Jat peoples are one of the most prosperous groups in India on a per-capita basis (Punjab, Haryana, and Gujarat are the wealthiest of Indian states). Haryana has the largest number of rural crorepatis (similar to "millionaires") in India, all of whom are Jats. Ironically, because they value thriftiness and diligence, the Jats are often regarded as miserly.
Hindu Jats adhere to traditional practices as well as a wide variety of additional beliefs. They might worship one god, many gods, or none at all depending on what they believe will benefit them most. They are very pragmatic in their spiritual practices. Regardless of their religious affiliation, Jats observe many ceremonies, especially rites of passage. Like many other Indian communities of good standing, the Jats have a negative view of Christianity. The only Indians they see embracing Christ come from low caste groups.
Many Jat communities need clean drinking water and proper health care facilities. Christian medical teams and humanitarian aid workers are needed to work among them and show them God's love in practical ways.
Missionaries, Christian broadcasts, and evangelistic literature are needed to effectively reach the Jats with the light of the gospel. Most importantly, they need people who will begin to intercede for them, tearing down the strongholds that are keeping them in spiritual bondage. Only then will their hearts be prepared to receive the good news as it is presented to them.
Ask the Lord to send out additional laborers to work among the Hindu Turk Jats.
Pray that Christian doctors, nurses, and humanitarian aid workers will have opportunities to share the love of Jesus with the Jats.
Ask God to save key Turk Jat leaders who will boldly proclaim the gospel to their own people.
Pray that churches and mission organizations will accept the challenge of adopting and reaching the Turk Jats.
Ask God to raise up teams of intercessors who will faithfully stand in the gap for the Jats.
Pray for a disciple making movement to emerge among every Jat clan and community.
Scripture Prayers for the Jat Turk in India.
|Profile Source: Keith Carey
|People Name General
|Jat Turk
|People Name in Country
|Jat Turk
|Natural Name
|Turk Jat
|terk jot
|Alternate Names
|जाट, तुर्क
|Population this Country
|Population all Countries
|Total Countries
|Progress Scale
|1 ●
|Frontier People Group
|Pioneer Workers Needed
|People ID
|ROP3 Code
|ROP25 Code
|ROP25 Name
|Asia, South
|10/40 Window
|National Bible Society
|Persecution Rank
|11 (Open Doors top 50 rank, 1 = highest persecution ranking)
|Interactive map, listing and data download
|Specialized Website
|South Asia Peoples
|Asia, South
|10/40 Window
|National Bible Society
|Persecution Rank
|11 (Open Doors top 50 rank, 1 = highest persecution ranking)
|Total States
|Haryana 40,000
|South Asia Peoples
|Primary Religion:
|Major Religion ▲
|Percent *
0.00 %
|Christianity (Evangelical 0.00 %)
0.00 %
|Ethnic Religions
0.00 %
100.00 %
0.00 %
0.00 %
|Other / Small
0.00 %
0.00 %
* From latest India census data.
Current Christian values may substantially differ.
|Primary Language
|Hindi (26,000 speakers)
|Language Code
|hin Ethnologue Listing
|Language Written
|Yes ScriptSource Listing
|Total Languages
|Secondary Languages
|Primary Language
|Hindi (26,000 speakers)
|Language Code
|hin Ethnologue Listing
|Total Languages
|Secondary Languages
|Punjabi, Eastern 5,800
|Haryanvi 1,600
|Braj Bhasha 200
|People Groups
|Speaking Hindi
Primary Language: Hindi
|Bible Translation ▲
|Status (Years)
|Yes (1806-1962)
|Bible-New Testament
|Yes (1811-1998)
|Yes (1818-2022)
|FCBH NT (www.bible.is)
|YouVersion NT (www.bible.com)
|Possible Print Bibles
|World Bibles
|Forum Bible Agencies
|National Bible Societies
|World Bible Finder
|Virtual Storehouse
|Resource Type ▲
|Resource Name
|Audio Recordings
|Audio Bible teaching
|Global Recordings Network
|Audio Recordings
|DAVAR Partners recording, Old Testament
|DAVAR Partners International
|Audio Recordings
|Online Audio Scripture
|Talking Bibles
|Audio Recordings
|Oral Bible stories
|One Story
|Audio Recordings
|Story of Jesus audio
|Jesus Film Project
|Film / Video
|Following Jesus video
|Jesus Film Project
|Film / Video
|God's Story video
|God's Story
|Film / Video
|Indigitube.tv Video / Animation
|Create International
|Film / Video
|Jesus Film: view in Hindi
|Jesus Film Project
|Film / Video
|Love letter to you from scripture
|Father's Love Letter
|Film / Video
|LUMO film of Gospels
|Bible Media Group/LUMO
|Film / Video
|Magdalena video
|Jesus Film Project
|Film / Video
|My Last Day video, anime
|Jesus Film Project
|Film / Video
|Rivka video
|Jesus Film Project
|Film / Video
|Story of Jesus for Children
|Jesus Film Project
|Film / Video
|The Hope Video
|Mars Hill Media
|Film / Video
|World Christian Videos
|World Christian Videos
|Bible for Children
|Bible for Children
|Bible for Children
|Bible for Children
|Biblical answers to your questions
|Got Questions Ministry
|Faith Comes By Hearing - Bible in text or audio or video
|Faith Comes by Hearing
|Faith Comes By Hearing - Bible in text or audio or video
|Faith Comes by Hearing
|Faith Comes By Hearing - Bible in text or audio or video
|Faith Comes by Hearing
|Faith Comes By Hearing - Bible in text or audio or video
|Faith Comes by Hearing
|Faith Comes By Hearing - Bible in text or audio or video
|Faith Comes by Hearing
|Map Source
|People Group data: Omid. Map geography: UNESCO / GMI. Map Design: Joshua Project
|Profile Source
|Keith Carey
|Data Sources
|Data is compiled from various sources. Learn more.


text:
Do I Have Sleep Apnea Forest Hills, NY
If you feel as though you have no energy and are too tired to keep up with your friends and family, you should visit our dental office to talk about sleep apnea. This may be what is causing your issues, and a simple non-invasive treatment may be just what you need to feel like yourself again. To schedule an appointment with our dental office, call (718) 924-2387. We will be happy to discuss your treatment and then make a recommendation for how you should proceed.
What is sleep apnea?
Sleep apnea is a condition that makes it difficult for your body to receive the oxygen you need to properly function. Without enough oxygen, you will feel drained and sluggish, but since the condition manifests itself at night, most people have no idea that they have it.
How does sleep apnea impact a person's health?
There are many health problems that can arise from untreated sleep apnea. They can include a stroke, high blood pressure, headaches, diabetes, depression, mood swings, heart failure, ADHD that becomes worse, and an overall lack of well being.
How does sleep apnea negatively impact a person's life?
With enough oxygen, your body will have a difficult time functioning. Beyond the health effects, this can translate to not having enough energy to stay awake past dinner, enjoy your kid's birthday parties, go for a bike ride, or even drive your car. In fact, when you are tired, the basic and often mundane activities of life can put you to sleep. This can make it dangerous to get behind the wheel and could compromise your work performance. Essentially, your quality of life can be greatly diminished, making it critical that you visit a Forest Hills dentist to have your sleep apnea treated.
What is the difference between sleep apnea and a sleep disorder?
Sleep apnea is a physical condition that makes it impossible to breathe clearly while you are sleeping. As a result, your body will not get enough oxygen to function at an optimal level. A sleep disorder can be one of the following:
- Insomnia. When it comes to sleep disorders, insomnia can be long-term or temporary. Often brought on by external factors like stress, insomnia can be treated with an oral medication.
- Narcolepsy. As a sleep disorder, narcolepsy is by far the worst. It can impact you throughout your entire life, making you feel so exhausted that you are forced to suddenly fall asleep, regardless of where you are or what you are doing. Narcolepsy is a true life disrupter.
- Restless leg syndrome. Commonly impacting pregnant women, restless leg syndrome can force your legs to move all throughout the night. Giving you a feeling of constant tingles or a burning and itching sensation, RLS can be highly distracting and impact anyone at any time. It helps to go for a walk or exercise during the day, since those who are sedentary tend to experience RLS more frequently.
- Jet lag. While most people view jet lag as a part of long-distance travel, it is a real sleep disorder, and if your body does not adjust well to the changes in time zones, jet lag could impact you for days or even weeks if you continue to travel from place to place. This disruption in your sleep patterns can make it difficult to get caught up on the rest you need, and may leave you feeling worn down to the point of potentially getting sick. Fortunately, this condition will eventually rectify itself when you get back home and stop traveling.
- Snoring. If you snore too loudly, you could wake up your Forest Hills neighbors, your spouse, or just yourself. Many people cannot get a good night's sleep because they snore too loudly, and this condition is often brought on by sleep apnea.
Check out what others are saying about our sleep apnea support services on Yelp: Do I Have Sleep Apnea?
What are the two main types of sleep apnea?
- Obstructive Sleep Apnea (OSA). When you have obstructive sleep apnea, your lower jawbone muscles will be too weak to hold your jaw in place as you sleep. As a result, it can fall backward and your tongue with it. Your tongue will then block your airway, making it impossible to breathe clearly while sleeping. This is why people with OSA will typically snore or sound like they are choking in their sleep. This is one of the signs that the body is trying to move the tongue in order to breathe. Another cause of OSA is having too much fatty tissue in the back of your throat. This is one reason obesity is a risk factor for OSA.
- Central Sleep Apnea. In this condition, the brain is responsible for the sleep apnea. By not sending signals to the muscles in charge of breathing, your body fails to respond as it should. This is not something that can be treated by a dentist, but instead, you will need to see a specialist.
How is sleep apnea treated?
At Gentle Touch Dental Care, we recommend that patients explore all non-invasive treatment options first. This is why we will often suggest that our Forest Hills, NY patients wear a removable oral appliance. An oral appliance is a convenient treatment option because it does not make any noise and is incredibly discrete. Some patients also require the use of a CPAP machine to provide them with additional oxygen. The challenge with a CPAP is that it can be loud and uncomfortable to wear. The third treatment option for OSA is to have surgery to remove the extra fatty tissue blocking your airway.
How does an oral appliance work?
Wearing an oral appliance is incredibly easy. It is customized for your mouth specifically so it fits snugly and securely. As a result, you can simply slip it into place when you go to sleep. It remains in place inside of your mouth and does an excellent job of holding your lower jaw in the forward position. This prevents your tongue from falling backward and keeps your airway clear. Some people receive all of the benefit they need by wearing an oral appliance, while those with severe sleep apnea may also require the use of a CPAP machine at the same time. In this case, most patients report that their CPAP is far more comfortable than when they were using it as a standalone treatment option.
To learn more about sleep apnea or discuss your oral health in general, call 718-924-2387 and schedule an appointment with our Forest Hills dental office. At Gentle Touch Dental Care, we are happy to discuss your health challenges and make recommendations, even if we have to refer you to a specialist for treatment.
Questions Answered on This Page
Q. Is sleep apnea a sleep disorder?
Q. What are the treatment options for sleep apnea?
People Also Ask
Q. What do I need to know when searching for a dentist?
Definition of Dental Terminology
- Cosmetic Dentistry
- Cosmetic dentistry is generally used to refer to any dental work that improves the appearance (though not necessarily the function) of a person's teeth, gums and/or bite.
- Decay
- Tooth decay is when the enamel of the tooth begins to decay and cause erosion from plaque and tartar on the teeth.
- Dental Caries
- Dental caries are also known as cavities and result from a lack of proper oral hygiene leaving plaque that forms tiny holes in the teeth.
- Dental Checkup
- A dental checkup is an appointment that involves cleaning the teeth, identifying any signs of infection and removing said signs of infection at least once every six months in the office.
- Dental Filling
- A dental filling involves restoring the structure of the tooth by using metal, alloy, porcelain or plastic to fill the tooth.
- Dental Prophylaxis
- A dental prophylaxis is a professional and detailed cleaning that involves the removal of plaque, calculus and stains from the teeth.
- Dental Sealants
- Dental sealants contain a resinous material that we apply to the chewing surfaces of the posterior teeth to prevent dental caries.
- Dentist
- A dentist, also known as a dental surgeon, is a doctor who specializes in the diagnosis, prevention, and treatment of diseases and conditions of the oral cavity.
- Gingivitis
- Gingivitis is the inflammation of gum tissue that results from plaque, other infections in the mouth and poor oral hygiene.
- Preventive Dentistry
- Preventive dentistry is the dentistry that focuses on maintaining oral health in order to prevent the spread of plaque, the formation of tartar and infections in the mouth.
- Tartar
- Tartar forms when plaque builds up on the surface of the teeth and calcifies into a hard surface that is much more difficult to remove and will require professional treatment.
- Tooth Enamel
- Tooth enamel is the protective visible outer surface of a tooth that contains the dentin and dental pulp.
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text:
Tsarina Jewels
Weight: 1.35 ct
Treatment: Untreated
Origin: Russia
Measurements(L*W*H):6.46 X 6.46 X 3.42
Certificate: ICL
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