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Alzheimer's Research & Therapy
The association of antidiabetic medications and Mini-Mental State Examination scores in patients with diabetes and dementia
Juraj Secnik ORCID: orcid.org/0000-0002-1532-39671,2,
Hong Xu1,3,
Emilia Schwertner1,
Niklas Hammar4,
Michael Alvarsson5,
Bengt Winblad6,7,
Maria Eriksdotter1,7,
Sara Garcia-Ptacek1,7 &
Dorota Religa1,7
Alzheimer's Research & Therapy volume 13, Article number: 197 (2021) Cite this article
The effect of antidiabetic medication on cognitive function is unclear. We analyzed the association between five antidiabetic drugs and change in Mini-Mental State Examination (MMSE) scores in patients with diabetes and dementia.
Using the Swedish Dementia Registry and four supplementary Swedish registers/databases, we identified 1873 patients (4732 observations) with diagnosis of type 2 diabetes (diabetes) and Alzheimer's disease or mixed-pathology dementia who were followed up at least once after dementia diagnosis. Use of metformin, insulin, sulfonylurea, thiazolidinediones (TZD), and dipeptidyl-peptidase-4 inhibitors (DPP-4i) was identified at baseline. Prevalent-user, incident-user, and drug-drug cohorts were sampled, and propensity-score matching was used to analyze comparable subjects. Beta coefficients with 95% confidence intervals (CI) from the random intercept and slope linear mixed-effects models determined the association between the use of antidiabetic medications and decline in MMSE score points between the follow-ups. Inverse-probability weighting was used to account for patient dropout.
Compared to non-users, prevalent users of metformin (beta 0.89, 95% CI 0.44; 1.33) and DPP-4i (0.72, 0.06; 1.37) experienced a slower cognitive decline with time. Secondly, compared to DPP-4i, the use of insulin (−1.00, −1.95; −0.04) and sulfonylureas (−1.19; −2.33; −0.04) was associated with larger point-wise decrements in MMSE with annual intervals.
In this large cohort of patients with diabetes and dementia, the use of metformin and DPP-4i was associated with a slower decline in MMSE scores. Further examination of the cognitive effects of metformin and incretin-based medications is warranted.
Diabetes is a complex risk factor for cognitive deterioration and a common comorbidity in dementia [1, 2]. In addition, multiple antidiabetic drugs have been evaluated in randomized and observational settings for putative cognitive properties. Specifically, metformin has been associated with protection against overall dementia risk and memory decline [3, 4]; however, some studies suggest an even opposite relationship [5], possibly due to vitamin B12 deficiency in long-term users [6] contributing to neurodegeneration.
Moreover, the role of cerebral insulin gained recognition in the last decade [7]; however, neither intranasal nor systemic insulin administration has significantly improved cognitive functioning [8, 9]. Similarly, the studies on sulfonylurea derivates have found either no association [10] or higher relative risk of dementia compared to metformin [11]. On the other hand, both sulfonylurea and systemic insulin treatment are associated with the risk of hypoglycemia [12], which may contribute to dementia incidence [13]. Moreover, manifest dementia is an independent predictor of severe hypoglycemia [14], as cognitive health is a prerequisite for proper diabetes self-management [15].
Thiazolidinediones (TZD) have not exhibited cognitive benefit in a randomized controlled setting [16]; moreover, faster memory decline was observed in TZD users among patients with Alzheimer's disease (AD) [4].
Among the drugs affecting the incretin system, the glucagon-like peptide-1 analogues (GLP-1a) increased cerebral glucose metabolism in a small randomized controlled trial [17], while multiple neuroprotective mechanisms have been suggested in animal models of AD [18]. Second, the use of dipeptidyl-peptidase-4 inhibitors (DPP-4i) was cognitively protective in observational [4, 19] but not in interventional studies [20].
The potential recommendations for cognitive performance are further complicated by the applications of specific antidiabetic drugs in the course of diabetes (diabetes control, complications, application method, patient preference, etc.).
In summary, despite robust relationships between diabetes and dementia, it is unclear whether some antidiabetic medications provide cognitive benefit compared to others. Moreover, studies evaluating the rate of cognitive decline in patients with established dementia are scarce. Due to the absence of disease-modifying dementia treatment, good management of comorbidities can play a major role in preserving residual cognitive functioning in dementia patients.
The aim of this study was to compare the change in Mini-Mental State Examination (MMSE) scores among users of five antidiabetic drug groups in a large cohort of patients with diabetes and AD or mixed-pathology dementia (MixDem).
This was a prospective open-cohort study with data originating from five Swedish registries/databases. Swedish personal identification number (personnummer) was used to merge information across data sources, with the National Board of Health and Welfare and Statistics Sweden performing the merge and data anonymization. Registers and data are described below.
Swedish Dementia Registry (SveDem)
SveDem was established in 2007 with the aim to register all patients with dementia in Sweden at the time of diagnosis [21, 22]. SveDem comprises information on clinical determinants (e.g., MMSE), demography (e.g., age and living arrangements), community support (e.g., daycare), and common pharmacological treatment [21]. Dementia diagnoses are coded using ICD-10 and comprise AD, MixDem (both AD and vascular pathology present), vascular dementia, Lewy body dementias, frontotemporal dementia, unspecified, and other dementia types. Patients are followed up on an annual basis with clinical examination including cognitive assessment using MMSE.
Out of the 80,004 patients registered in SveDem between May 1, 2007, and October 16, 2018, we included only patients with a diagnosis of AD or MixDem who were also diagnosed with diabetes (diabetes sections below) and had been followed up at least once. SveDem provided data on demography (age, sex), type of dementia, cohabitation, and baseline and follow-up dates with MMSE scores (the outcome). After applying sample restrictions, the final cohort consisted of 1873 patients with 4732 observations (baseline and follow-ups; supplementary figure 1). This population was then used to sample propensity-score exposure-matched pairs for the analyses.
Swedish National Patient Register (Patient Register)
The Patient Register provided records on inpatient diagnoses since 1998 and specialized outpatient visits since 2001 [23] until December 31, 2017. Diagnoses were coded according to the 10th version of the International Classification of Diseases (ICD-10) [24].
Diagnosis of diabetes was determined when the ICD-10 codes E10–E14 occurred in the Patient Register or antidiabetic drug dispensation (Anatomical Therapeutic and Chemical [ATC] classification code A10) was observed in the Swedish Prescribed Drug Register (Drug Register) prior to and including the date of dementia diagnosis. Subsequently, diabetes was grouped into three types—type 1 diabetes, type 2 diabetes, and other/unspecified diabetes (for details on extraction and coding, see supplementary algorithm 1). Only patients with type 2 diabetes and other/unspecified types were included for the analyses.
Baseline diabetes duration was based on the difference between the date of dementia diagnosis and the date of the earliest record of diabetes—either in the Patient Register where the diagnosis of diabetes occurred or the earliest dispensation date of ATC code A10 from the Drug Register, whichever came first.
To adjust for the effect of additional chronic diseases, we created a baseline comorbidity index as described by Charlson et al. [25], using the algorithm described by Quan et al. [26] as a weighted sum of diagnosed chronic disorders up to and including the date of dementia diagnosis. Renal disease was not included in the index and was extracted as a separate variable. Diabetes and dementia variables were omitted from the index.
Longitudinal integrated database for health insurance and labour market studies (LISA)
LISA is an administrative database covering the adult Swedish population since 1990 and provides high-quality information on major socioeconomic characteristics (sick leave, disability, pensions, etc.) [27].
To take baseline socioeconomic position into account, disposable income at the time of dementia diagnosis inflated on the 2019 value of Consumer Price Index was extracted from LISA and categorized into low-, middle-, and high-income groups with 33rd and 66th percentiles used as cut-offs.
Swedish Prescribed Drug Register
The Drug Register was established in 2005 and stores information on all dispensed drug prescriptions at Swedish pharmacies using ATC coding [28]. Medication dispensation data (=prescription fills) were extracted from the start of the register until December 31, 2018.
ATC codes A10 (drugs used in diabetes), A10A (insulins), and A10B (blood glucose-lowering drugs excluding insulin) before and after dementia diagnosis extracted from the Drug Register were used in combination with the Patient Register to identify overall diabetes prevalence and duration and to classify diabetes types (see supplementary algorithm 1).
Antidiabetic medications
Data on antidiabetic drug classes was extracted from the Drug Register according to the following ATC codes—insulin (A10A), metformin (A10BA02), sulfonylurea derivates (SU; A10BB), thiazolidinediones (A10BG), dipeptidyl-peptidase-4 inhibitors (A10BH), glucagon-like peptide-1 analogues (A10BJ), and sodium-glucose co-transporter-2 inhibitors (SGLT-2i; A10BK). Dispensations of the individual medication classes were extracted on a yearly basis prior to the date of dementia diagnosis date. GLP-1a and SGLT-2i could not be directly analyzed due to too few users; however, their use was matched on in the propensity-score matching. Two frameworks for exposure were created.
First, patients were grouped into baseline users and non-users of individual medications according to the incident and prevalent exposure design. A subject was an incident user if a dispensation of medication was observed in the 1-year period prior to and including the date of dementia diagnosis, without a record of medication dispensation prior to the 1-year period. Complementary incident non-user was a subject without a dispensation in neither the 1-year period nor at any time before the diagnosis of dementia. Prevalent use was based on the presence/absence of at least one medication dispensation prior to the diagnosis of dementia.
Second, we compared non-metformin antidiabetic medications directly. For example, to compare baseline insulin vs baseline sulfonylurea, patients exposed to insulin treatment at least once prior to diagnosis of dementia while never having sulfonylurea prior to diagnosis of dementia constituted one group, while subjects who had sulfonylurea and never had insulin constituted the comparison group. Due to the low number of possible pairs, we could only analyze prevalent users (see the section "Statistical analysis"). Metformin was not compared directly to other medications due to its specific position as first-line therapy and very frequent use in the cohort, thus lacking a sufficient number of patients in the never-metformin control group.
Subsequently, propensity-score matching on baseline exposure assignment was performed to produce comparable user/non-user and user/other-user pairs. Afterwards, the associations between antidiabetic drug usage and the change in post-dementia MMSE scores were assessed in intention-to-treat analyses.
Supplementary medication
Dispensations of antihypertensive (ATC codes C02, C07, C08, and C09), hypolipidemic (statins, C10AA), antithrombotic (B01), antipsychotic (N05A), antidepressant drugs (N06A), and cholinesterase inhibitors (N06DA) were extracted up to 3 years prior to and including the date of dementia diagnosis as recorded by the Drug Register.
Swedish Cause of Death Register (Death Register)
The records in the Death Register begin from the year 1952 and are the basis for official statistics on causes of death in Sweden [29]. The register's purpose is to describe the development of national all-cause and specific-cause mortality.
We extracted the information from the Death Register since its initiation until October 16, 2018—the end of the study follow-up. Overall mortality was considered if a valid record (patient death dated after the date of dementia diagnosis) was present. The information on mortality was used to determine censoring and to account for patient dropout.
Study sample selection
The original cohort consisted of 80,004 patients diagnosed with dementia and registered to SveDem until October 16, 2018. SveDem data were linked with other data sources and several selection criteria were applied, mainly excluding incorrect or missing baseline information. Afterwards, 12,396 patients who had diagnosis of diabetes and dementia at baseline were identified. After including only patients with at least one follow-up, exclusions of other dementia types than AD or MixDem, patients with diabetes type 1 and baseline severe dementia (MMSE < 10; to avoid floor effects), the final cohort consisted of 1873 patients and 4732 observations (supplementary figure 1).
Propensity-score matching
From the whole cohort of 1873 subjects with diabetes and dementia, we sampled PS-matched comparable pairs of users/non-users and users/other-users of antidiabetic medications as per the framework described above. The 1:1 and 1:4 nearest-neighbor matching with 0.1 caliper of the logit of the propensity score was used. Baseline characteristics used to generate PS included age at dementia diagnosis; sex; cohabitation; dementia type; Charlson comorbidity score; renal disease; diabetes type and duration; income category; use of statins; antihypertensive, antithrombotic, antipsychotic, and antidepressant drugs; cholinesterase inhibitors; use of other glucose-lowering drugs apart from insulin (as a summary measure user/non-user); and use of insulin (omitted in insulin analyses) prior to dementia diagnosis. Matching was less extensive in situations with few available exposed subjects (to uphold the 10 subjects per predictor rule), and matching priority was given to prognostic characteristics. Matching ratio 1:4 was used in the prevalent-user analyses of DPP-4i and TZD, all incident-user analyses, and comparisons of insulin vs DPP-4i, insulin vs TZD, sulfonylurea vs TZD, and sulfonylurea vs DPP-4i. Other cohorts were matched using a 1:1 ratio.
For the incident-user analyses, we identified the following user/non-user cohorts: 101 metformin users vs 277 non-users, 66 insulin users vs 263 non-users, and 37 sulfonylurea users vs 147 non-users. Prevalent-user analyses were based on 514 metformin user/non-user pairs, 543 insulin pairs, 640 sulfonylurea pairs, 67 TZD users vs 260 non-users, and 103 DPP-4i users vs 389 non-users (Table 1).
Table 1 Balance in baseline characteristics among prevalent users versus non-users of antidiabetic medications—propensity-score-matched cohorts
In the non-metformin antidiabetic drug comparisons, 259 pairs of insulin vs sulfonylurea users were generated, 138 insulin vs 35 TZD users, 199 insulin vs 51 DPP-4i users, 111 sulfonylurea vs 31 TZD users, 141 sulfonylurea vs 38 DPP-4i users, and 45 DPP-4i vs TZD pairs. The baseline differences between matched cohorts as well as the number eligible for individual matchings from the original cohort are summarized in Table 1 and supplementary tables 1 and 3.
Patient dropout—inverse-probability weighting
Patient dropout was determined, if the patient had neither died nor did the study end occur in the year following the last observed MMSE. The last observed MMSE was defined as the last observed MMSE measurement, provided the time difference between the last observed MMSE examination and previous MMSE examination was more than 9 months to reflect the yearly schedule of follow-ups. If the difference was less than 9 months, the 1-year period for dropout was assessed from the previous date of MMSE measurement. Using this definition, the overall dropout rate was high (1382 patients [73.8%]; supplementary table 2); thus, we weighted the analyses using inverse probability of remaining in the study based on the MMSE scores in the previous observation and time since baseline. We used the same process as described by Handels and colleagues [30]: first computing the probability of dropout in the next observation, then defining cumulative probabilities of remaining in the study, and finally producing an inverse of the cumulative probabilities—inverse-probability weights of remaining in the study. The weights were unstabilized and truncated at 100 if the weight was above the 99th percentile of the weight distribution to avoid the models being dominated by few large weights.
Differences in baseline characteristics between the matched pairs of users and non-users of antidiabetic medications were assessed using chi-square, independent samples t-test, and their non-parametric equivalents. Standardized mean differences (SMDs) were used to assess balance in the propensity-score-matched cohorts.
MMSE change—mixed-effects models
In the PS-matched cohorts, random-slope linear mixed-effects models were used to determine the beta coefficients with 95% confidence intervals of the associations between the use of antidiabetic medications and change in MMSE scores with time in years. Fixed effects in the model included only the interaction between the users/non-users or users/other users of antidiabetic medication with time. Random effects were included for subjects and time (intercept and slope). Three mixed-effects models were designed in the propensity-score-matched cohorts—unweighted analysis, inverse-probability-weighted analysis, and weighted analysis in the imputed dataset. Residual baseline differences between the matched cohorts were adjusted for and kept in the models if both the association with MMSE and 10% change in the main exposure were significant. Subjects with missing information in matching or weighting variables were excluded prior to analysis (see supplementary figure 1).
Data were analyzed using Stata v16 (Stata Statistical Software: Release 16. StataCorp LLC, College Station, TX) and R version 4.0.0 [31] with package "MatchIt."
Sensitivity analysis—imputed dataset
To model the ideal scenario with yearly follow-ups, we have imputed MMSE scores based on the slope between the observed MMSE measurements and time from baseline. Missing scores were imputed using multivariate multiple imputation with chained equations. Imputations were done only in observations with missing yearly follow-ups between observed MMSE (e.g., observed baseline and year 3) and not performed beyond observed MMSE. Afterwards, the inverse-probability-weighted mixed-effects models were performed in the imputed dataset.
Baseline differences
The differences between the matched cohorts are summarized in Table 1 (prevalent use) and supplementary table 1 (incident use) and 3 (drug vs drug comparisons).
The PS matching provided balanced exposure groups, except for few differences. DPP-4i users were more frequently exposed to statins in all cohorts (88.3% vs 70.2% in prevalent users; 90.2% vs 75.9% in DPP-4i vs insulin; 97.4% vs 75.2% DPP-4i vs sulfonylurea). Incident insulin users were less commonly treated with antidepressants (15.2% vs 34.6%). Finally, incident metformin users had significantly shorter diabetes duration (0.8 vs 3.5 years). All residual differences were adjusted for in the mixed models.
MMSE and antidiabetic medications
The results from the random-slope linear mixed-effects models are summarized in Tables 2 and 3. In the weighted user vs non-user analyses, the use of metformin was associated with a slower annual decline in MMSE compared to non-users, specifically 0.89 points slower in prevalent users vs non-users (β 0.89, 95% CI 0.44; 1.33), however not in incident-user weighted analysis (0.70, −0.16; 1.56). Similar association was observed in the unweighted (0.67, 0.35; 0.99) and imputed analyses (0.88, 0.44; 1.32). The prevalent use of DPP-4i was associated with a slower annual MMSE decline compared to non-users in the weighted (0.72, 0.06; 1.37) and imputed (0.70, 0.03; 1.37) analyses, but not statistically significantly in the unweighted analysis (0.53, −0.02; 1.09; p = 0.06).
Table 2 Annual point change in post-dementia Mini-Mental State Examination scores associated with the use of antidiabetic medications
Table 3 Comparisons between non-metformin antidiabetic drugs and annual point change in Mini-Mental State Examination scores
Figure 1 visualizes the main observed trends over time in the annual MMSE decline in users of metformin, DPP-4i, and comparisons between insulin and sulfonylurea and insulin and DPP-4i based on the weighted analyses.
Linear changes in MMSE scores associated with the use of metformin, DPP-4i, insulin, and sulfonylurea exposure among patients with dementia and diabetes. Figures are based on weighted prevalent-user analyses; DPP-4i, dipeptidyl-peptidase-4 inhibitors; CI, confidence interval; MMSE, Mini-Mental State Examination; year represents time after baseline; thin lines represent MMSE change in individual subjects (circles) in time, and thick lines represent estimated MMSE change derived from the mixed models
In the head-to-head comparisons of the non-metformin antidiabetic medications, the use of sulfonylureas was associated with an accelerated MMSE decline compared to DPP-4i users (−1.10, −2.12; −0.08; weighted analyses), with similar findings in the unweighted (−1.07; −2.10; −0.05) and imputed models (−1.07, −2.12; −0.02). Similarly, insulin users experienced an accelerated cognitive decline compared to DPP-4i users (−1.00, −1.95; −0.04) when weighted for dropout.
In this large cohort of patients with diabetes and dementia, the use of metformin and DPP-4i was associated with a slower decline in MMSE scores in time compared to non-users. Moreover, patients with dementia using DPP-4i experienced a slower decline in MMSE scores compared to sulfonylurea and insulin users.
The overall (prevalent) use of metformin was associated with a slower decline in MMSE compared to non-users, suggesting either a well-managed diabetes in metformin users or a direct neuroprotective effect of metformin. While lower dementia risk was observed in metformin users in multiple studies [11, 32, 33], MMSE was unaffected in a 2018 meta-analysis [3]. On the other hand, metformin was recently associated with protection against memory decline, however only in patients with normal cognition and without ApoE-ε4 burden [4]. While we could not stratify on ApoE genotype, we analyzed metformin initiation, which failed to provide significant benefit to users, despite the shorter diabetes duration. Metformin's role in the AD pathological process is uncertain, with both neuroprotective [34,35,36] and pathology-accelerating properties [37, 38] reported in non-human studies. Recently, Wu and colleagues suggested that metformin's putative neuroprotection may be limited to preclinical AD stages, whereas its later use may contribute to AD pathology [4]. In our cohort, we conclude metformin's cognitive effect as neutral to positive; however, we lacked a comparable number of never-exposed to metformin for prevalent users, and this analysis drove the protective association. Moreover, the comparison group of metformin non-users comprised a non-negligible number of subjects without any medication for diabetes, which likely affected the association even after thorough matching; however, it is not clear in which direction. Possibly, metformin's molecular changes may not be directly reflected on a robust point-based MMSE score; however, if metformin would exhibit serious cognitive harm, this would likely be noticed between the follow-ups. Overall, a life-course approach combined with the evaluation of individual cognitive domains would be valuable to deconstruct metformin's neuronal properties.
Importantly, the prevalent users of DPP-4i experienced a significantly slower decline in MMSE scores compared to non-users. Among incretin-based therapies, DPP-4i are frequently used in Swedish patients with dementia [39], possibly due to the oral application and neutral weight effects. In observational studies, DPP-4i were associated with a lower risk of dementia [10, 40] and improvements in immediate and delayed memory in patients with established AD [4]. On the other hand, a recent randomized trial of linagliptin failed to show cognitive benefit in high-risk albeit dementia-free type 2 diabetes patients [20].
In our cohort, DPP-4i exhibited a 0.7-point slower MMSE decline in users vs non-users, corroborating the findings by Isik and colleagues [19]. Similarly, Rizzo and colleagues concluded higher MMSE among DPP-4i-metformin therapy compared to sulfonylurea-metformin after 2 years [41]; however, patients with dementia were excluded making the comparison difficult. Moreover, the addition of DPP-4i vildagliptin to metformin was associated with higher MMSE at 6 months compared to metformin alone, but the study was underpowered for multivariate analyses [42].
DPP-4i users specifically experienced a slower MMSE decline compared to sulfonylurea and insulin users. Conceptually, patients using sulfonylureas and insulin may have been at greater risk of hypoglycemia (DPP-4i have negligible hypoglycemia risk) [12]; unfortunately, we could not test such hypothesis. On the other hand, Cukierman-Yaffe and colleagues have recently contested the connection between severe hypoglycemia and cognitive decline; however, it is unclear whether this extends to dementia patients [43].
DPP-4i exhibit their antidiabetic effect in a glucose-dependent manner by increasing the endogenous GLP-1 through inhibition of its breakdown [12]; however, their potency is lower compared to GLP-1a [44]. Interestingly, the preclinical studies on GLP-1's role in cerebral metabolism concluded amelioration of oxidative stress, growth factor, and insulin signaling in AD pathology [18]. DPP-4i could possibly provide direct neuronal benefit; however, enhancing cerebral signaling through increasing the pool of GLP-1 is more likely [45] as the DPP-4i transfer through the blood-brain barrier is limited in comparison to GLP-1a [46].
Unfortunately, our study lacked the power to analyze GLP-1a users, which would strengthen the argument for the incretin-based therapies if a similar association was observed.
In general, the available evidence suggests that the protection associated with incretin therapies may be limited to later phases of neurodegeneration.
Despite the encouraging results for metformin and DPP-4i, the inter-follow-up MMSE change was rather modest (approximately 1 point) and the minimal clinically important decline in MMSE was recently estimated at around 2–3 points [47]. If accurate, the difference in DPP-4i and metformin users vs non-users should be observable approximately at the third-year follow-up. On the other hand, any preservation of cognitive functioning associated with the use of established antidiabetic drugs should be considered valuable, especially in the absence of disease-modifying therapy.
Neither sulfonylurea nor insulin was associated with a significant change in MMSE scores compared to non-users, while a similar decline was observed when directly comparing the two drugs or compared to TZD.
Sulfonylurea's neurophysiological properties are not entirely clear, as some evidence suggests a higher risk of dementia in comparison to metformin [11, 32], or no association [10, 48]. In cognitive functioning, sulfonylureas have not modified either delayed or immediate memory [4], while a larger, albeit inconsistent global cognitive change was observed in sulfonylurea users in a pooled meta-analysis [48]. We provide robust evidence that sulfonylurea use does not affect global cognition in patients with AD or MixDem.
On the other hand, insulin treatment has a specific position in the treatment of type 2 diabetes in Sweden, where its use is prioritized in the guidelines [49] and common even in patients with dementia [39]. While insulin use was associated with a higher risk of all-cause dementia and a modestly larger decline in global cognition [48], the association was not found in other studies [9, 10]. In line with our findings, Cukierman-Yaffe and colleagues reported no effect of basal insulin on MMSE scores; however, the population was younger and cognitively unimpaired at baseline [9]. Thus, insulin indeed may be cognitively neutral; however, further research is needed to clarify if hypoglycemia may balance out some cognitive protection, especially in a region with frequent insulin usage.
We have not observed any substantial effect on global cognition in patients using TZD, corroborating the randomized controlled trials on rosiglitazone [16] and pioglitazone [50]. While TZD may accelerate memory decline in ApoE-ε4 non-carriers with AD and diabetes [4], we did not have access to such data. Currently, the only approved TZD in Europe is pioglitazone; however, a careful patient selection is necessary prior to drug initiation due to a higher risk of edema, heart failure, and fractures [12]. Overall, the use of TZD in elderly patients with dementia exhibited neither cognitive protection nor harm in our cohort.
In conclusion, metformin and DPP-4i had a positive effect on global cognition measured by MMSE in patients with diabetes and dementia. Further research should focus on the putative neurocognitive properties of incretin and biguanide therapy.
One of the main limitations is the observational nature of the study, precluding us from concluding causal relationships. Second, SveDem is a real-world database and thus suffers from significant patient dropout, which cannot be controlled for in the data collection phase. Conversely, we have addressed this issue of selective dropouts by weighting on the inverse probability of remaining in the study, which produced reasonable estimates and was previously used in the SveDem setting [30]. MMSE has known ceiling and floor effects; however, the median baseline MMSE score was 21 points (18 and 24 being the 25th and 75th percentile) and patients with baseline MMSE below 10 points were excluded. Most patients had been living with diabetes for several years; thus, there were insufficient incident-users for more recent medications and for head-to-head drug comparisons. While we had a plethora of data on confounding, information on two principal confounders was lacking—glycemic markers (such as HbA1c) and the ApoE genotype. The absence of HbA1c likely skewed some of the results in favor of metformin—being the first-line therapy and representing a group of patients with an overall shorter course of diabetes and fewer complications. On the other hand, the insufficient data on hypoglycemic episodes may have confounded the results of insulin and sulfonylureas. Secondly, the ApoE genotype information was lacking; thus, associations pertinent only to patients carrying ε4 genotype could have been diluted. Lastly, we had no information on the reason for medication dispensation and no access to further blood or CSF biochemistry that would supplement the matching strategy; thus, residual confounding or confounding by indication cannot be ruled out.
The study's main strength comprises the large cohort of patients with diabetes and established dementia, a typically understudied multimorbid population. Moreover, high-quality data were available on medication dispensations allowing multiple exposure models and overall good coverage in the data sources [21, 23, 27,28,29]. In addition, the breadth of variables allowed extensive PS matching possibilities, decreasing the variability between matched subjects. This was observed even when matching was restricted and the differences in most unmatched variables were balanced as well. Importantly, the inclusion of incident-user and prevalent-user analyses, drug vs drug comparisons, and inverse-probability weighting provided comprehensive information about the use of antidiabetics and their association to a well-established global cognitive screening test—MMSE.
In conclusion, there are significant differences between the common antidiabetic medications and their association with changes in MMSE scores. Specifically, metformin and the incretin-based medications should be further evaluated for possible cognitive properties.
No data are available. The entities responsible for the original data and the Swedish law do not allow for sharing of the data from the Swedish national or quality-of-care registers.
Anatomical Therapeutic and Chemical
DPP-4i:
Dipeptidyl-peptidase-4 inhibitors
GLP-1a:
Glucagon-like peptide-1 analogues
Longitudinal integrated database for health insurance and labour market studies
MMSE:
Mini-Mental State Examination
MixDem:
Mixed-pathology dementia
GLD:
Glucose-lowering drugs
SGLT-2i:
Sodium-glucose co-transporter-2 inhibitors
SMDs:
Standardized mean differences
SveDem:
Swedish Dementia Registry
Patient Register:
Swedish National Patient Register
Death Register:
Swedish Cause of Death Register
TZD:
Thiazolidinediones
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Wettermark B, Hammar N, Fored CM, Leimanis A, Otterblad Olausson P, Bergman U, et al. The new Swedish Prescribed Drug Register--opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol Drug Saf. 2007;16(7):726–35.
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We would like to thank all patients, care providers, and staff for providing the information to the Swedish Dementia Registry.
Open access funding provided by Karolinska Institute. This study has been supported by the Swedish Brain Power, Swedish Research Council (grant numbers 2012-2291, 2016-02317, 2018-02843), Alzheimerfonden, Stockholm County Council (ALF project), the Swedish Associations of Local Authorities and Regions, the Swedish Order of Saint John/Johanniterorden, Swedish Society for Medical Research, FORTE (the Swedish Council for Health, Working Life and Welfare, dnr: 2017-01646), the Swedish Stroke Association, Margaretha af Ugglas foundation, and the Stiftelsen för Gamla Tjänarinnor. The supporting bodies played no role in the design, analysis, or interpretation of the data.
Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo, Blickagången 16, 14152, Huddinge, Sweden
Juraj Secnik, Hong Xu, Emilia Schwertner, Maria Eriksdotter, Sara Garcia-Ptacek & Dorota Religa
Department of Neurology, Second Faculty of Medicine, Charles University, Motol University Hospital, Prague, Czech Republic
Juraj Secnik
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Hong Xu
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Niklas Hammar
Growth and Metabolism, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Michael Alvarsson
Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
Bengt Winblad
Theme Aging, Karolinska University Hospital, Huddinge, Sweden
Bengt Winblad, Maria Eriksdotter, Sara Garcia-Ptacek & Dorota Religa
Emilia Schwertner
Maria Eriksdotter
Sara Garcia-Ptacek
Dorota Religa
H.X. participated on data preparation and sensitivity analyses. E.S. co-designed the study. N.H. suggested the statistical methods and contributed to the discussion. D.H. advised on methodology. M.A. and B.W. contributed to the introduction and discussion. M.E. interpreted the data and contributed to the discussion. S.G-P. obtained the data. D.R. supervised and co-designed the study. J.S. designed the study, analyzed the data and wrote the manuscript. All authors have revised and contributed to the manuscript's content and approved of its final version.
Correspondence to Juraj Secnik.
The researchers were provided only with anonymized data linkages, and no link could be made to an individual. Analyses were performed only on a group level. The study complies with the Declaration of Helsinki and was approved by the regional ethical committee in Stockholm, Sweden (number of the ethical approval: 2017/501-31). Patients were informed about the registration to SveDem, and they have the option to have their data removed from the register. The Swedish law does not require informed consent for registry-based research; however, the regional ethical committees may require informed consent on patients' behalf for any study—no such request was made for this particular study.
Additional file 1: Supplementary Algorithm 1.
Diabetes types assessed from the Patient and Drug Register data.
Additional file 2: Supplementary Figure 1.
Study sample selection. DPP-4i, dipeptidyl-peptidase-4 inhibitors; IPW, inverse-probability weighting; MMSE, Mini-Mental State Examination; SveDem, Swedish Dementia Registry; TZD, thiazolidinediones.
Additional file 3: Supplementary Table 1.
Balance in baseline characteristics among incident users versus non-users of antidiabetic medications – propensity-score matched cohorts. ChEI, cholinesterase inhibitors; DPP-4i, dipeptidyl-peptidase-4 inhibitors; MMSE, Mini-Mental State Examination; GLDs, glucose-lowering drugs apart from insulin; SMD, standardized mean differences; Comparisons per baseline incident exposure assignment – exposure assessed at one-year period prior to dementia diagnosis in subjects without history of exposure before the one-year period; p-values refer to the exposure "Yes" vs exposure "No" comparisons; Age is described as mean (SD); Charlson comorbidity index, Diabetes duration and MMSE are described as median (IQR); all other variables are described as n (%); SMDs were calculated for the matching variables; All cohorts matched using 1:4 ratio; "Total eligible" expresses the number of eligible subjects for propensity-score matching from the original cohort, with % retained after PS matching.
Dropout rate and number of follow-ups in observed and imputed data by users of antidiabetic medications. DPP-4i, dipeptidyl-peptidase-4 inhibitors; TZD, thiazolidinediones; Dropout was counted when the patient had neither died nor did the study end occur in the year following the last observed MMSE; Number of follow-ups are expressed in number of follow-ups in total per drug user, and percentage from baseline number of users; Imputed follow-ups were based on the slope of change between observed MMSE measurements and time from baseline.
Baseline differences in the propensity-score matched comparison pairs of the non-metformin antidiabetic drug users. AD, Alzheimer's disease; ChEI, cholinesterase inhibitors; DPP-4i, dipeptidyl-peptidase-4 inhibitors; MixDem, mixed-pathology dementia; MMSE, Mini-Mental State Examination; GLDs, glucose-lowering drugs apart from insulin; SMD, standardized mean differences; SMDs were calculated for the matching variables; Matching was restricted by number of available users; Insulin vs sulfonylurea analysis was matched using 1:1 ratio, otherwise 1:4 ratio was used; "Total eligible" expresses the number of eligible subjects for propensity-score matching from the original cohort, with % retained after PS matching.
Secnik, J., Xu, H., Schwertner, E. et al. The association of antidiabetic medications and Mini-Mental State Examination scores in patients with diabetes and dementia. Alz Res Therapy 13, 197 (2021). https://doi.org/10.1186/s13195-021-00934-0
Antidiabetics
DPP-4i
MMSE
Submission enquiries: rheamae.sombilon@springernature.com


First responders are expected to save lives. In one wrongful death case, however, the city of Columbus settled a lawsuit against a firefighter who drove a fire truck through an intersection and caused the death of an 86-year-old driver back in November of 2013.
The firefighter was assigned to Columbus station 32 and dispatched to drive the fire truck to a blaze. According to his affidavit, he turned on an electronic siren before leaving the station but did not activate the apparatus' mechanical siren.
His vehicle approached an intersection without sirens or lights being activated. He pulled an air horn in short bursts to warn drivers as he approached heavy traffic in the intersection, according to his affidavit.
Despite a red traffic light, the firefighter drove the truck through the intersection because he though it could proceed unimpeded.
His truck crashed into the decedent's car at 35 mph and without stopping. She died a week later from injuries she suffered in the accident.
At the time, the firefighter claimed that he could have driven safely through the intersection. The rules of his fire division, however, dictate that fire trucks must stop at red lights. These vehicles can only drive through them if it is done safely.
The firefighter, now retired, admitted that he did not safely enter the intersection. He believes, with the benefit of hindsight, that there would have been no accident if he brought the fire truck to a full stop at the intersection.
After the lawsuit was filed by the deceased driver's son, the 10th District Court of Appeals ruled that the City of Columbus could not be sued because it had governmental immunity. However, the court found that the firefighter driver was not entitled to this immunity. The City of Columbus City Council voted on November 5th to settle the wrongful death lawsuit. It agreed to pay $410,000 to the victim's family.


We are excited to introduce a program specially for children and teens that are obese, overweight or just trying to learn how to live a healthy lifestyle.
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Bodega Phuket is a 4-star hostel accommodation for tourists, located in Patong beach in the Phuket province region. Bodega Phuket is the perfect accommodation for youngsters willing to experience a fun, relaxed atmosphere in a hostel setting. The hostel provides dorm rooms of different types that the guests can choose from. Known as a slumber party hostel, this is the ideal spot for those who love to party and socialize. A backpackers haven, through Bodega one, can go for the Phuket pub crawl arranged by the hostel by the night, after checking out the best tourist attractions during the day. To make the experience as convenient and comfortable as possible, guests are provided with free access to wifi at the hostel. Situated close to Bangla road, famous for its bars and clubs, and a 5-minute walk from Patong beach, this hostel is everything a young traveler could ask for.
All the rooms at Bodega Hostel Phuket are provided with free access to wifi. Each room is equipped with bunk beds. There are mixed dormitories featuring 4-bed, 6-bed, 8-bed, and 10-bed arrangements. All dormitories come with a shared bathroom for the guests. The bathrooms are clean and tidy and ensure a comfortable stay to all the guests at the hotel. All the rooms are fully air-conditioned. The bunk-beds come with fluffy pillows and duvets to promise a comfy good nights sleep to all the guests at the hostel.
Bodega Phuket offers all the essential facilities and services a guest could ask for. The hostel ensures a good experience for all the guests with their comfortable bunk beds having fluffy duvets and pillows. The hostel features an extremely helpful and warm staff to cater to the needs of all the guests. All rooms are provided with access to free wifi to ensure a great experience to all the guests. Guests are also provided with free lockers in each dorm. Apart from that, the staff is available round the clock and the hostel remains under CCTV surveillance throughout the day. The slumber party hostel as it is known also arranges for drinking games and activities for the guests.
Bodega Phuket features a cafe and kitchen to cater to the guests. One can grab a cup of coffee here or opt for their famous English breakfast. The kitchen ensures a fulfilling and delectable dining experience to the guests at the hostel. Guests can get to taste the authentic flavors of Thai cuisine with the dishes offered by the hostel kitchen. One can also opt for the Western food options on their menu. There is a bar at the hostel as well, where drinking games and parties are frequently hosted.
If one is looking for a completely different experience in this beautiful land of beaches, Bodega is the perfect option. A paradise for backpackers, this hostel offers the ideal atmosphere and facilities for the true adventure seekers and travelers who want to socialize. The hostel ensures a promising experience for the guests with their superb facilities and arrangements. The dorm rooms are clean and comfortable for staying and security is promised to all the guests.
How far is Bodega Phuket from Phuket International airport?
The hostel is at a 24-kilometer distance from Phuket International airport.
What are the check-in and check-out timings at the hostel?
The guests can check in at 14:00 hours and they must ensure checking out by 12:00 hours.
Does the hostel provide access to wifi?
What are the security provisions provided by the hostel?
The hostel provides free lockers in every dorm and the staff is available round the clock to cater to all the needs of the guests. The property is fitted with CCTV cameras to ensure safety of all the guests.
What are the dining options in and around the hostel?
The hostel has its own kitchen and cafe which offers Thai and western delicacies to all the guests. The hostel also offers great coffee and a delectable English breakfast. Guests can head to First Seafood restaurant number 5 as well, which is merely a few meters away from the hostel.
If your purpose of visiting Bangkok is to enjoy the vibrant nightlife and party all night long, then this hostel is the perfect place to stay. The staff ensures you are well-entertained in the evening with fun games, lively ambience and good food. The hostel has clean rooms with comfortable beds.
Bodega Phuket offers the perfect stay for the adventure seekers. A hostel-type accommodation, this property offers the perfect atmosphere for those who love to socialize and interact with new people. The Slumber Party Hostel as it is referred to, hosts drinking games and arranges pub crawls for those who wish to explore the pub culture of Phuket. A 10-minute walk from the famous Patong beach, the hostel is situated at a very ideal location. The hostel features a cafe and kitchen to cater to the guests as well. Guests can grab a cup of coffee or their delectable English breakfast here. Guests can also go for the authentic, local Thai delicacies that the hostel kitchen offers. Apart from that, the guests can also try their western dishes on the a la carte menu. The hostel is equipped with CCTV cameras and the staff is on the watch throughout the day for the safety and security of guests. Ideal for youngsters, this hostel is a backpackers haven and can make for a truly adventurous experience. Those who wish to go beyond the conventional hotel options and explore something new, Bodega makes for the perfect option.


I currently offer two free training courses.
One is for fiction writers, and one is for business writers.
Both will teach you valuable techniques.
You simply register with your email address, and twice a week, I will send you a focused mini-lesson on one aspect of the writing craft.


WORXSAFE Pedestrian Barrier 2.4 m is used for temporary fencing in construction sites/events.
Our Pedestrian Barrier is made of galvanized steel and has interchangeable feet to simplify maintenance/repair.
Alternative flat foot, which is rotatable 90degrees for easy packing in stackable box.
Comes complete with Alu plate with reflective label mounted, which is riveted in the frame.


text:
Home News & Press Haier partners wi...
Haier partners with Unimoni Asia Cup 2018 in UAE
Haier partners with Unimoni Asia Cup 2018 as Official Global Partner & Associate Gold Sponsor
Announces consumer contest for 50 lucky winners to stand a chance to travel to UAE and watch an Asia Cup match live
New Delhi, August 31st, 2018: Haier, the global leader in Home Appliances & Consumer Electronics and World's Number 1 brand in Major Appliances for 9 Consecutive Years* today announced partnership with the Unimoni Asia Cup 2018 as one of the official sponsors. Haier will be the official Global Partner and Associate Gold Sponsor of the 2018 series which is scheduled from 15th SeptembeR to 28th September' 2018.
Haier has always believed in innovation, teamwork, dedication and values that resonate well with cricket and its sportsmanship. This partnership with Unimoni Asia Cup 2018 strengthens the perfect synergy of core values of both partner brands which are committed to bring cricket to a larger Indian audience.
As part of the partnership, Haier will gain significant brand exposure on the grounds in form of in-stadium promotional methods such as perimeter electronic board branding, stadium electronic board branding etc., for visitors to see and have a top of mind brand recall. In order to celebrate this association and engage with its fans and consumers across India, Haier will be running an exciting consumer contest. The contest will be live from 1st September to 18th September, 2018 and will be promoted across offline and online mediums.
In order to participate, consumers will have to buy any Haier product worth 15,000 INR or above. The participants will have to fill up an interesting quiz from their Facebook profile and submit required information in the Haier Facebook App called #AsiaCupWithHaier. Fifty lucky winners of the contest will stand a chance to travel to UAE and watch an Asia Cup match live.
On partnering with Unimoni Asia Cup, Mr. Eric Braganza, President, Haier Appliances Pvt Ltd. Said, "We are delighted to associate with the Unimoni Asia Cup and are proud to be their official Global Partners and Associate Gold Sponsors. This association is a significant initiative by the company to expand horizons and build a closer connect with the consumers across Asian markets and enjoy the spirit of cricket together. Our passion and commitment continues to strengthen for a fascinating sport like cricket which demands its players and fans to be active, bold, dynamic and tenacious. This will further help us in building a momentous recall for the brand and its products amongst Asian consumers. "
Held in every two years, the Asia Cup was founded in 1983 by the Asian Cricket Council in order to encourage goodwill between the Asian nationals. It is a multi-national limited overs International tournament between Asian countries. The 2018 Unimoni Asia Cup will take place in UAE from 15th September to 30th September and will be the 14th edition of this tournament since its inception.
ABOUT HAIER INDIA
Initiated in January 2004, Haier Appliances (India) P. Ltd is a 100 per cent subsidiary of Haier Group. Headquartered in New Delhi, Haier India has 33 operations spread from Bombay, Bangalore, Chennai to Calcutta and a complete distribution network throughout the country as well as a manufacturing facility in Pune. Products offerings of Haier India range from refrigerators, air conditioners, washing machines, TVs, water heaters, freezers to microwave ovens, with a special focus on local needs. For example, washing machines that work at nearly Zero Water Pressure help solve the biggest challenge that Indian consumers face in their daily lives, while Haier BMR refrigerators have also been well received by Indian consumers due to its large refrigeration capacity which caters to local people's dietary habits. A larger refrigeration capacity means consumers can store more vegetables while the refrigerator also makes people's lives easier by placing the refrigerating chamber at the top of the machine.
ABOUT HAIER GROUP
Haier Group today is the world's leading brand of major household appliances which is now transforming from a traditional manufacturer to an open entrepreneurship platform. In the era of the Internet and post e-commerce, Haier will extend its ecosystem to social networks and community economies while enhancing the user value of Haier products and services and instilling integrity as a core competency throughout the Group. Haier aims to become a global leader in the era of the Internet of Things. Revenue generated by the traditional economy: Haier Group's global revenue in 2017 was US$ 37.2 billion, with year-on-year growth of 20%; total pre-tax profits exceeded US$ 4.62 billion, profits achieved a year-on-year growth of 12.8%. Currently, the Group's brands include Haier, Casarte, GE Appliances, AQUA, Fisher & Paykel, Leader, RRS, DCS, and Monogram. Each brand has its own unique market positioning and provides outstanding user experiences for end users. Haier is now further deploying and demonstrating the effectiveness of the Rendanheyi management model and will internationalize Rendanheyi through its unique cultural integration system.
*According to the Euromonitor ranking 2017
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redpajama_set_name: RedPajamaCommonCrawl


We were planning on hitting Vegas next Sunday. After looking at my bank account I decided it would be best to avoid such a large expense.
We would pay for one of the two nights for a hotel, $60 for a rental car, $100 a day average in gambling (per person), and Kelli would have to pay $135 for a pet sitter. Ouch. I could dig into savings, but we are going on a cruise next month. Makes more sense to save money for that.....will be gambling on the boat as well.
Instead we are going to Los Angeles for two days. Kelli mentioned hitting Sacramento. Flights to both are open (for the first time ever a flight from Sacramento is wickedly open....less than 30 people on board!). We could head out separately. I want to hit the Los Angeles Auto Show. This will be my fifth auto show this year. I hit Detroit, New York, Dallas, Tokyo and maybe Los Angeles. We went to the Chicago Auto Show last year. All I have left would be Miami.....that's about it for the "big" shows. Miami really isn't that big. Eh. For Los Angeles we are using Starwood points for a night at a Four Points by Sheraton. I love the Starwood Preferred membership program.
Under the Starwood Preferred program I can get a hotel for as low as 2000 points. More commonly is 3-4000 points. With our previous Holiday Inn program we needed 25,000 points. By and large the Starwood hotels are all nicer than Holiday Inn. We both have Starwood American Express cards. We used Starwood points for our hotel in Denver and Tokyo. Painless. Awesome.
So free hotel in Los Angeles. I found a Hertz coupon for $26 all in (taxes, fees and BS) for a midsize car for two days.
Beyond that I get to work in the Kitchen today. Kelli decided to cook last night. Kelli is an incredibly intelligent person...but the kitchen is not her domain.
She peeled four good sized potatoes. No problem. But she put all the peels down the garbage disposal.....without any water running....or the disposal turned on. Clog. Bad. No water is getting through. I bought some professional strength drain cleaner from Home Depot. Nada. I am going to have to get some PPE (Personal Protective Equipment) and manually drain out all of the drain cleaner/water and take off the disposal and likely elbow down below. At least it's my day off.
Passed 13,000 miles on my car yesterday. Only 12,200 are really mine. It came with 800 on it. Still averaging 642 miles a month.
Back in 1995 I went to a Target in Lubbock, Texas and bought a copy of Netscape. What is Netscape? Well Netscape was an Internet browser (like Internet Explorer or Firefox). Back then there were very few "browsers". I paid $30 a month for a dial up Internet account. I remember the ISP (Internet Service Provider) having to really work with me to get my account. Very few private individuals had dial up Internet accounts. Mostly businesses and well....that's about it. Netscape was slow to load, but ran great. I never used Internet Explorer until Eric told me about Internet Explorer 4.0 and how great it was. This was at least 1997. Eh....Netscape is long gone.
I've got a secret. Fatsecret.com. A Weight Watchers like site that's FREE. Has a free application for my G1. I can scan the bar codes of food with my phone and it stores it in the phone and online. It counts calories, fat, carbs, fiber...everything. Very easy to use. Even calculates Weight Watchers points.
When I worked in an office I did very well on Weight Watchers because I could put my food into the website as I ate since I worked on a computer. Being mobile it was hard...thus I didn't do it. With this new application I have no excuse. It has a huge database of fast food and restaurants as well. I am more than happy with the quality of the program and website.
Wow 642 miles a month, I'm averaging about 2000/month 45miles 1way to work that's 90miles per day. And some extra driving taking gianna to school and picking her up. about 100miles per day.


text:
She was 97 and had been retired from Hollywood for more than half a century, having devoted the second half of her life to animal welfare causes. She was also nominated for a Best Actress Oscar in 1959 for her role in Pillow Talk, and was given a Lifetime Achievement Golden Globe Award in 1989.
"I've always said that age is just a number and I have never paid much attention to birthdays", Day said in a statement to The Hollywood Reporter.
BREAKING: Doris Day, whose wholesome screen presence stood for a time of innocence in '60s films, has died, her foundation says. She left the band a few years later to go solo, and went on to cut more than 650 songs over a 20-year period from 1947 to 1967. Everyone knows her megahit, "Que Sera, Sera", a sort of anthem about going whichever way the wind takes you, the ideal song to sing to a child who, in the way children are, is eager for all the answers. She took singing lessons and began appearing on local radio.
Day's movie debut, "Romance on the High Seas" in 1948, was a hit. She expanded her range again in Alfred Hitchcock's remake of his own "The Man Who Knew Too Much", which co-starred Jimmy Stewart.
"Since the '70s, Day had focused her energies on the Doris Day Animal Foundation".
Her most famous songs, meanwhile, surely include the 1956 release of Que Sera, Sera (Whatever Will Be, Will Be).
Day received the the Presidential Medal of Freedom in 2004. "She had a heart of gold and was a very amusing lady who I shared many laughs with".
Two for Tea: A personal favorite of mine as it's all my grandparents used to sing, this song is from Day's film of the same name.
At 17, Day married Al Jorden, a trombone player who she later claimed beat her.
"With Six You Get Eggroll" was her last film in 1968.
The Doris Day Show: According to Justwatch.com, this sitcom originally broadcast on the CBS network from September 1968 until March 1973. Check out a great scene from Pillow Talk below. Melcher was the adoptive father of her only child - son Terry Melcher, who died of cancer in 2004.
Day did not learn until after Melcher's death that he had committed her to do the show and she was initially reluctant to do it.
Melcher famously worked with The Beach Boys and turned down aspiring musician Charles Manson.
Our thoughts are with her family and friends during this hard time.
Day married a fourth time at age 52, to businessman Barry Comden in 1976.
Sweden to reopen rape case against WikiLeaks' Assange
Supreme Court rules against Apple, allowing lawsuit targeting App Store to proceed
Kevin Durant to miss at least remainder of series against Rockets
Gerrard admits Rangers are unlikely to sign Rennes defender Mexer
Korea Launches Missiles, US Seizes Ship for Violating Sanctions
Lewis Hamilton insists Valtteri Bottas's success is down to his former mechanic
House Chairman Issues Subpoenas To Treasury And IRS For Trump Tax Returns
Ghost Recon Breakpoint Leaked Ahead Of Livestream
British Green Party launches European election campaign
Roger Federer loses cool in flawed victory
Google introduces new emojis, these smartphones will get them
Pope Francis Issues Church Law Governing Sex Abuse Reporting And Investigation
Fortnite Season 9 Takes You To The Future With Improved Switch Performance
Felicity Huffman will formally enter a guilty plea for her role in the college admissions scam on Monday. During the hearing on Monday, prosecutors said they would recommend four months in prison for Huffman.
Rain and storms continue through mid-week
As the rain continues to fall, the severe weather risk will transition to a flash flooding risk into the early afternoon hours. Large hail, high winds and heavy rain appear to be the primary threats across the region Monday afternoon into Tuesday.
Here's what Joel Embiid told Drake after 76ers lost to Raptors
The margin of victory was a clear indication at just how well the Raptors played and how the 76ers failed to rise to the occasion. Whereas Toronto's supporting cast has gotten better as the series has progressed, Philadelphia's has gotten worse.
Denver becomes the first United States city to decriminalize 'magic mushrooms'
Venezuelan Justice Arrests Opposition Legislator Edgar Zambrano
Bruins Hold Historical Advantage After Game 1 Win Over Hurricanes
Madrid Open: Rafael Nadal through to third round
Production Companies Pledge Boycott of Georgia over 'Heartbeat' Abortion Law


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text:
package admin.bean;

import java.util.List;

import org.aries.common.PersonName;

import admin.User;
import admin.UserCriteria;

public interface UserManager {

	public void initialize();

	public void clearContext();

	public List<User> getAllUserRecords();

	public User getUserRecordById(Long id);

	public User getUserRecordByUserName(String userName);

	//public List<User> getUserRecordsByName(PersonName name);

	public List<User> getUserRecordsByPersonName(PersonName personName);

	public List<User> getUserRecordsByPage(int pageIndex, int pageSize);

	public List<User> getUserRecordsByCriteria(UserCriteria userCriteria);

	public Long addUserRecord(User user);

	public void saveUserRecord(User user);

	public void removeAllUserRecords();

	public void removeUserRecord(User user);

	public void removeUserRecord(Long id);

	public void removeUserRecords(UserCriteria userCriteria);

	public void importUserRecords();

}

redpajama_set_name: RedPajamaGithub


I wanted to look at degree programs related to education and TESOL but slightly different.
This Vanderbilt PhD has a strong focus on literacy but also works with oral communication and ESL.
UMBC Masters in Intercultural Communication – 2 year program with or without thesis that offers no assistance for native English speakers.
The university of Florida has one but their website offers relatively little information. You can see how the 34 credits required break down by checking out the pdf.
Hawaii has an MA in Communication with specializations like global communication, organizationa & intercultural communication, etc.
UMass has a program that leads to an EdD in International Education – specifically improving it in developing countries.
I also searched for Intercultural Studies but many results were for religious things and I gave up on that one.
This George Mason PhD in cultural studies sounds interesting.


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The Student Action Plan for 2013 was presented at a meeting on Tuesday, 21 May at Loxley House.
It has been produced by Nottingham City Council in collaboration with Street Cleansing, Waste Management, Community Protection and Sustainability & Climate Change. The purpose of the plan is to deliver a co-ordinated response to the environmental issues arising in areas with a high percentage of student-occupied properties, particularly towards the end of the academic year.


Shop (verb): to visit places (or websites) where goods (or services) are sold to look at and buy things. Overshop (verb): to visit places (or websites) where goods (or services) are sold to look at and buy things in the face of adverse consequences (long term detriment of finances, relationships and self-esteem).
Whenever we engage in any spending behaviors, we are acting from a set of beliefs and attitudes that we learned when we were young. Generally, we are not even conscious of the underlying money scripts motivating our actions. We are robot shoppers, spending automatically, carrying out instructions from a program installed years ago.
There is more to overspending than a broad psychological perspective on our behaviors. We may have had things happen to us in our past that never lead to overshopping. Instead, there is something that triggers us to spend beyond our means and ultimately hurt our long term financial health.
That's an overview on overspending, its psychological impact and its long-term effects on our health. It's important to note: there is no quick fix. Because many of our spending habits are psychological in nature, simply creating a budget and trying to stick to it is like putting a band-aid on a torn ACL. It's going to take more than a budget to solve the problem. However, being aware of your finances is a great first step in the right direction! Feel free to use this article to recognize your own spending habits and the emotions around them. Print it out and circle or star the items that ring true to you. Come back to it in the coming months and see how your spending has evolved.


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Cell migration: is there another personality inside you?
Perhaps you believe that your body and mind are yours alone. In fact, you are a fusion of many organisms – possibly including another person, says BBC Future.
Once upon a time there was a very simple description for human origins: a man and a woman met, had fun, and then – relatively quickly – a tiny fertilized egg turned into a screaming newborn baby.
Everything was very clear: the man was half father, half mother, but 100% owned by himself.
However, this simple story has become quite complicated over the past decades. As it turned out, in addition to the genes passed on to us by our parents, we are home to an extensive set of viruses, bacteria and even, possibly, other personalities.
Moreover, if you have a twin, particles of it are likely to be present in your body (including your brain). And they are not just present, but, possibly, capable of influencing your behavior.
A monster named toxoplasma
"People are not individuals, but superorganisms," says Peter Kramer of the University of Padua. "A huge variety of organisms are constantly fighting for power over our body."
Co-authored with Paola Bressan, Dr. Kramer recently published an article in the scientific journal Perspectives in Psychological Science that urges psychologists and psychiatrists to consider the possible impact of this factor on human behavior.
For some, this will be alarming news, but scientists have long known that the human body is a jumble of different organisms.
Gut microbes are capable of producing neurotransmitters that alter our mood ; some researchers even speculate that microbes can influence a person's appetite, forcing us to consume their preferred food.
And infection with a parasite called Toxoplasma gondii can kill you in some cases. By infecting a rat or mouse, this microbe changes the consciousness of the host in such a way that he ceases to be afraid of cats and even reaches out to their habitats – for reproduction, Toxoplasma certainly needs to get into the cat's body.
However, Toxoplasma can also infect a person in the same way, as a result of gaining control over human behavior: some of those infected become prone to unnecessary risks, while others are more likely to develop schizophrenia or suicidal depression.
Meanwhile, despite the potentially dangerous consequences of infection for humans, about a third of all meat sold in Britain is infected with this parasite . "We need to end this," says Kramer.
Twins are closer together than they might seem
Thus, it becomes clear that we are not necessarily entirely responsible for our own behavior.
This alone is enough to make a person doubt the usual perception of their own identity, but the thought that our brain is inhabited not only by tiny microbes, but also by other human beings, becomes really uncomfortable.
Siamese twins, who share a common brain for two bodies, are the most graphic illustration of this, Kramer says. However, even ordinary, non-fused twins may have common organs that they are not even aware of.
During early embryonic development, cells of twins or triplets are able to migrate from one embryo to another.
Previously, scientists believed that this happens very rarely, but it turned out that such a scenario is very common. So, about 8% of non-identical twins and 21% of non-identical triplets have one, but two blood groups: the blood of one group is produced by their own cells, and the blood of the other is produced by cells migrated from the twins.
In other words, they are "chimeric" or hybrid organisms. Moreover, the matter is not limited to blood – a similar situation is observed with cells of various organs, including the brain.
This hybridity in relation to the brain can have very serious consequences.
For example, it is known that the relative position of different parts of the brain is very important for its normal functioning.
The presence of foreign tissue in the brain, for the development of which foreign genes are responsible, can disrupt its architecture.
This can explain, for example, the fact that twins are very often left-handed – it is believed that the distribution of motor functions between the right and left sides of the body depends precisely on the organization of the right and left hemispheres of the brain. Perhaps it is hybridity that upsets this balance.
Even if you have never had a twin in your life, it is possible that your body still contains cells from another human being.
It so happens that two embryos fuse into a single whole at the stage of early development. As a result, the cells of one embryo enter the tissues of another and, at first glance, develop without deviations. However, they carry the genetic information of another person.
"You may feel like you are one, while there are foreign cells in your body – so there were two of you since birth," says Kramer.
There was even a case when a genetic study found that a woman is not the biological mother of her two children.
The opposite also happens – the cells of the older child remain in the mother's body and, after the conception of the younger child, move into the embryo.
Whichever way this happens, it's entirely possible that another person's cells can cause the brain to develop in completely unexpected ways, says Lee Nelson of the University of Washington. She is studying the possibility of the mother's cells entering the baby's brain.
"Depending on the number and type of cells, as well as in what period of embryo growth they migrate, there are different scenarios for the deviation of the child's brain from normal development," says Nelson.
As it turned out, even adults are not immune to the penetration of other people's cells into their body.
A man is in a woman
Several years ago, Nelson and William Chen of the University of Alberta, Canada, decoded genomes taken from female brain slices. They looked for signs of a male Y chromosome.
In about 63% of the samples studied, the researchers found male cells. "We didn't just find male DNA in the female medulla – it was present in several parts of the brain at once," says Chen.
In other words, women's brains were stuffed with male cells. According to scientists, the stem cells of a male child somehow overcome the placenta barrier and enter the mother's brain.
Interestingly, according to some reports, the presence of male cells in the brain of women reduces the likelihood of developing Alzheimer's disease in the latter – although exactly why this happens remains a mystery.
Some researchers are even starting to wonder if the baby's cells may affect the mother's mood during pregnancy.
Our knowledge of the human "superorganism" is still very fragmentary, and many of the implications of such a symbiosis are now discussed only in the form of theoretical calculations.
The purpose of Cramer and Bressan's paper was not to provide clear answers to the questions at hand, but to educate other psychologists and psychiatrists about the many organisms that make us who we are.
"We are not able to fully understand human behavior, considering a person as only one individual, – notes Kramer. "It is necessary to consider it as a collection of organisms in order to understand why we behave in one way or another."
For example, scientists often use the study of twins to get closer to understanding human behavior.
However, the fact that even non-identical twins could exchange fragments of brain tissue at the stage of early development casts doubt on the purity of such experiments.
Caution must be exercised when using the findings of twin studies to study diseases such as schizophrenia, which can be caused by inappropriate brain architecture, warn Bressan and Kramer.
However, do not worry about foreign organisms in our own. After all, it is they who make us who we are.
"For better or worse, we're going to have to share the body with these 'immigrants,'" Nelson says. "And I think the pros of this cohabitation outweigh the cons."
By David Robson
Source BBC com
PS: The phenomenon of subpersonalities has long been studied in the psychological literature. Now classical science has come close to this question.
In this article:personalities, toxoplasma


Robert Pattinson may have walked the Golden Globes red carpet alone, but the actor still managed to bag himself a date for one the after-parties – in the form of girlfriend Kristen Stewart.
HAVE ROBERT PATTINSON AND KRISTEN STEWART SPLIT?
According to insiders, Robert Pattinson hit a swanky bash, thrown by Globes hosts Tina Fey and Amy Pohler, straight after the event, while Kristen Stewart joined him later.
Guests at the private party, held at Soho House in West Hollywood, included Jonn Hamm, Jennifer Westfeldt, Zooey Deschanel and Kristen Wiig.
Onlookers say Kristen Stewart arrived at the party at 1am, and 'ran over' to Robert Pattinson, as soon as she was inside.
'They hung out and stayed close for over an hour,' the insider added.
While Rob was still looking super-smart in his dapper Gucci suit, Kristen, who had touched down in La earlier in the day arrived in a laid-back ensemble, with a cap backwards on her head.
The couple made a beeline for British pals Tom Sturridge, Sienna Miller and Eddie Redmayne, before heading to another party with friends.
Earlier this month, Robert Pattinson and Kristen Stewart were spied in London enjoying a romantic dinner date.
According to onlookers, the pair enjoyed a cosy evening at Mexican restaurant Mestizo with a group of friends, staying close and holding hands during the evening.
Hollywoodlife reports Rob and Kristen arrived at the trendy London hangout with a group of pals, and tucked into the restaurant's £100-a-head New Year menu.
'They held hands as they left and Rob was seen smoking an e-cig at one point,' the source added.
This comes just days after it was rumoured Robert Pattinson and Kristen Stewart could even be shopping for a more permanent home in London.
'Ever since Kristen's affair last year, Rob has realised just how much his friends and family in the UK mean to him. After spending more time here in recent months, Rob's decided he wants to split his time more between London and Los Angeles,' an insider reveals.


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text:
City of Design inspiring new projects in 2019
A visit to Europe by Mayor Bruce Harwood has provided major inspiration and opened up a range of possibilities for Geelong, as the city looks to make the most of its UNESCO City of Design status.
The Mayor and City of Greater Geelong Manager of Economic Development and Events, Tim Ellis attended the UNESCO Creative Cities Annual General Meeting in Poland during June 2018, alongside 180 leading cities from around the world.
We are Geelong: Tim Ellis, Manager Economic Development and Events, City of Greater Geelong presenting at the UNESCO Annual General Meeting, June 2018
Mayor Bruce Harwood presenting Geelong's story at the UNESCO AGM
AGM Day 1 – pictured left to right is President of Design Kortrijk Dominiek Callewier with Mayor Bruce Harwood and Tim Ellis
Following the AGM, the pair embarked on a tour of fellow design cities Dundee, Scotland and Turin, Italy, getting a first-hand look at how others have benefited from the City of Design designation.
Mayor Harwood said the chance to promote Geelong on the world stage, and to learn from other UNESCO Creative Cities, was incredibly valuable.
"It's amazing – you bring 100-plus nations into one room, and there's nothing but positivity," Mayor Harwood said.
The main reasons for selecting these cities to visit, is the similarities to Geelong. All three cities have transitioned from a traditional manufacturing background, and all are located close to other capital / major cities – Melbourne, Edinburgh and Milan. As these major cities grow so does Geelong, Dundee and Turin and this has to be planned for.
The impacts on transport, employment, connectivity all become challenges for the municipalities to manage. Geelong can learn from the experiences and examples of how Turin and Dundee have handled these challenges and how they have embedded design thinking into their growth planning.
Mr Ellis said taking part in the UNESCO conference would be vital as Geelong works towards its vision of being an internationally recognised clever and creative city-region.
"We went for some really core reasons," Mr Ellis said.
"We went as part of our obligation as Secretariat, and to learn from others – to see how they're structured, what projects they do and how long it's taken them.
"We also went to make contacts that will help Geelong and the people of Geelong, and to share Geelong's success stories.
"We achieved all of those goals without a shadow of a doubt, and we're now in the phase of taking those learnings, sharing them, and planning where we focus our efforts and which projects we would like to implement.
"Our immediate aim is to raise awareness of our City of Design designation and to work on how all interested parties can contribute."
While a number of ideas picked up from other cities of design are being considered, Mr Ellis said some opportunities immediately stood out.
One is the chance for local creatives and designers to showcase their work by attending overseas design weeks, such as the major event run by the City of Shenzhen in China.
"They have sections for professional designers, for youth, and a whole range of other categories, and if you're selected, there's prize money," Mr Ellis said.
"And that's not open to everybody – it's only open to Geelong and the other 30 Cities of Design.
"So it's a big opportunity for our local designers."
Another key concept, used effectively in both Kobe, Japan and Helsinki, Finland, is factoring in design thinking as a central part of planning for city services, new buildings and engaging youth in the design process.
Mayor Harwood said this type of approach could have a significant impact on upcoming major construction projects – such as the new City of Greater Geelong office building and the long-awaited conference and convention centre.
"It's an opportunity not just to build a convention centre, but something that has that 'wow' factor," the mayor said.
"It's about thinking differently to what we may have thought we might build."
In addition, Mr Ellis said promoting the Greater Geelong region to leaders from 180 different international cities would have major economic and tourism impacts.
"We had the opportunity to showcase Geelong to a group of international cities, many that had never even heard of us," he said.
"There are a number of other cities around Australia that are now looking at Geelong and would love to be a City of Design."
"Now they've not only heard about us, they're amazed by the natural beauty of the region and impressed by Geelong's transition and what we're achieving as a clever and creative city."
Geelong is Australia's only UNESCO City of Design, and the only regional Australian city in the UNESCO Creative Cities network.
Other cities of design include world famous destinations such as Berlin, Montreal, Dubai, Shanghai, Singapore and Mexico City.
"The designation alone has been a massive coup for the city," Mayor Harwood said.
To learn more about the Creative Cities Network and the key learnings from the AGM, click HERE.
The Design Subnetwork table at the UNESCO AGM
Mayor Bruce Harwood at UCCN AGM June 2018
Tim Ellis and Mayor Bruce Harwood with Stewart Murdoch and Annie Day from Creative Dundee


This post is my old way of setting up AdSense with DFP. I no longer recommend this approach because I figured out a way around the old limitation of styling and adding AdSense Custom channels to the build in AdSense option of DFP. You can follow this guide if you want but the new method is easier. Read: How to set up Google AdSense using DFP Small Business build in AdSense option. You only need to follow this approach if you want to run Split Tests for specific Ad Units.
Create a new Order and name it like "YourWebsite – Google AdSense". Now click on Company > Add a new company. As Name use 'Google AdSense' and as Type select 'Ad Network' and click save.
Now create a Line Item for each Ad Unit you have on your website. Here it is important to create a separate Line Item for each Ad Unit which serves an AdSense Ad Unit that has its own unique channel. Check your AdSense Ad Units to see which Line Items you need to create.
Name the Line Item to describe the placement on your website and define the Inventory Size for this Line Item like we did in the example.
For Type select 'Network', for Start Time select 'immediately' and for End Time select 'Unlimited'.
For Rotate creatives select 'Evenly' and leave the rest of the settings as they are.
Now select the Ad Unit you want this Line Item to be served on and click save.
Repeat this step for each of your AdSense Ad Units that you track with a separate channel so that you have a separate Line Item for each AdSense Ad Unit.
Switch to your AdSense Account and get the Code for the AdSense Ad Unit that you want to display in this Line Item and past the code into the Code snippet box. DFP will recognize AdSense code.
Give it a descriptive Name and click Save.
it will not be delivered until you do. Approve it by clicking on the 'Approve" Button.
Repeat the above step of adding your AdSense Code to each Line Item you just created until all Line Items have their AdSense Code as Creative assigned to them.
After you added a new Creative to a Line Item the status of the creative says 'Ready'. It can take up to 60 Minutes before a creative starts to be delivered. Once it starts the Status will change to 'Delivering'.
Now your AdSense Ads are delivered on your websites via DFP Small Business.
How do I make it so that I can have up to three different ad sizes each load up on one ad unit slot for each visit? For example, a page loads and medium rectangle is shown, then next time the page is loaded, skyscraper is shown, on that same spot. please help.
Thanks for the info, admin. I actually thought it was possible due to your posts on "split test." I thought that was what you meant, and spent five hours looking up how to do it.
You can try the method I described in the Split Test article however I never tried it with a skyscraper in a rectangle space.