The importance of engaging in physical activity in older adulthood for transitions between cognitive status categories and death: A coordinated analysis of 14 longitudinal studies

Background: Given increasing incidence of cognitive impairment and dementia, further understanding of modifiable factors contributing to increased healthspan is crucial. Extensive literature provides evidence that physical activity (PA) delays the onset of cognitive impairment; however, it is unclear whether engaging in PA in older adulthood is sufficient to influence progression through cognitive status categories. Method: Applying a coordinated analysis approach, this project independently analyzed 14 longitudinal studies (NTotal = 52 039; mean baseline age across studies = 69.9-81.73) from North America and Europe using multistate survival models to estimate the impact of engaging in PA on cognitive status transitions (nonimpaired, mildly impaired, severely impaired) and death. Multinomial regression models were fit to estimate life expectancy (LE) based on American PA recommendations. Meta-analyses provided the pooled effect sizes for the role of PA on each transition and estimated LEs. Results: Controlling for baseline age, sex, education, and chronic conditions, analyses revealed that more PA is significantly associated with decreased risk of transitioning from nonimpaired to mildly impaired cognitive functioning and death, as well as substantially longer LE. Results also provided evidence for a protective effect of PA after onset of cognitive impairment (eg, decreased risk of transitioning from mild-to-severe cognitive impairment; increased likelihood of transitioning backward from severe-to-mild cognitive impairment), though between-study heterogeneity suggests a less robust association. Conclusions: These results yield evidence for the importance of engaging in PA in older adulthood for cognitive health, and a rationale for motivating older adults to engage consistently in PA

An evaluation of alcohol attendances to an inner city emergency department before and after the introduction of the UK Licensing Act 2003

Background: The Licensing Act 2003 (The Act) was implemented on the 24th November 2005 across England and Wales. The Act allowed more flexible and longer opening hours for licensed premises. We investigated the effect of The Act on alcohol related attendances to an inner city emergency department in Birmingham, UK. \ud \ud Methods: We compared the proportion and time of alcohol related emergency department attendances in one week periods in January 2005 and 2006, before and after the implementation of The Licensing Act 2003. An alcohol related attendance was defined as any attendance where there was any documentation of the patient having consumed alcohol before presenting to the emergency department, if they appeared intoxicated on examination, or if alcohol attributed to their final diagnosis. \ud \ud Results: The total weekly attendances increased slightly from 1,912 in 2005 to 2,146 in 2006. There was non-significant reduction in the proportion of alcohol related attendances between 2005 (3.6%) and 2006 (2.9%). A significantly greater proportion of attendances occurred at the weekend between 18.00 and 23.59 in 2005 (61.4%) than in 2006 (17.2%). There was a corresponding significant increase in the weekend proportion of attendances occurring between 03.00 to 05.59 in 2006. \ud \ud Conclusion: Our findings show that there was a change in the pattern of alcohol related attendances to the emergency department around the time of implementation of the Licensing Act 2003, which has implications for delivery of emergency department services

Fast 3D shape screening of large chemical databases through alignment-recycling

<p>Abstract</p> <p>Background</p> <p>Large chemical databases require fast, efficient, and simple ways of looking for similar structures. Although such tasks are now fairly well resolved for graph-based similarity queries, they remain an issue for 3D approaches, particularly for those based on 3D shape overlays. Inspired by a recent technique developed to compare molecular shapes, we designed a hybrid methodology, alignment-recycling, that enables efficient retrieval and alignment of structures with similar 3D shapes.</p> <p>Results</p> <p>Using a dataset of more than one million PubChem compounds of limited size (< 28 heavy atoms) and flexibility (< 6 rotatable bonds), we obtained a set of a few thousand diverse structures covering entirely the 3D shape space of the conformers of the dataset. Transformation matrices gathered from the overlays between these diverse structures and the 3D conformer dataset allowed us to drastically (100-fold) reduce the CPU time required for shape overlay. The alignment-recycling heuristic produces results consistent with <it>de novo </it>alignment calculation, with better than 80% hit list overlap on average.</p> <p>Conclusion</p> <p>Overlay-based 3D methods are computationally demanding when searching large databases. Alignment-recycling reduces the CPU time to perform shape similarity searches by breaking the alignment problem into three steps: selection of diverse shapes to describe the database shape-space; overlay of the database conformers to the diverse shapes; and non-optimized overlay of query and database conformers using common reference shapes. The precomputation, required by the first two steps, is a significant cost of the method; however, once performed, querying is two orders of magnitude faster. Extensions and variations of this methodology, for example, to handle more flexible and larger small-molecules are discussed.</p

Relative effects of sensory modalities and importance of fatty acid sensitivity on fat perception in a real food model

Fat can be perceived through mouthfeel, odour and taste, but the influence of these modalities on fat perception remains undefined. Fatty acids are stimuli. Individual’s sensitivity to fatty acids varies. Studies show association between fatty acid sensitivity, dietary intake and BMI, but results are conflicting. Therefore, this study examined this association, and the effects of modalities on fat perception. Two sub-studies conducted. In Study 1 (n=46), fat intensity was assessed by milk/cream mixtures varying by five fat levels. Fat intensity was rated under four conditions: mouthfeel-odour masked, mouthfeel masked, odour masking and no masking. Mouthfeel masking was achieved using thickener and paraffin, odour masking using nose-clips. Fatty acid sensitivity was measured by 3-AFC-staircase method using milk containing oleic acid (0.31-31.4mM). In Study 2 (n=51), more fat levels were added in fat intensity rating. A 2-AFC discrimination test was used to confirm whether fat levels could be distinguished. In the sensitivity test, a wider range of oleic acid was included. Fat intensity was rated higher without nose-clips (p<0.0001), implying that odour increased fat perception. Samples with mouthfeel-masked were rated higher, showing that increased viscosity and lubricity enhanced fat perception (p<0.0001). Participants could distinguish fat levels based on “taste” in rating tests and 2-AFC-tests. Participants were divided into high/medium/low-sensitivity groups. No significant difference found in fat intensity between groups, however, high-sensitivity group discriminated more fat levels. No association between sensitivity groups, nutrient intake or BMI found

Long-Term Quality of Life Improvement in Subjects with Healed Erosive Esophagitis: Treatment with Lansoprazole

Gastroesophageal reflux disease (GERD) is a chronic symptomatic condition and may be associated with erosive esophagitis (EE). Considerable data on the long-term maintenance of healing of EE are available, but data on long-term GERD symptom prevention and patient quality of life (QOL) are limited. To investigate QOL in subjects with healed EE who received 12 months of double-blind maintenance treatment with lansoprazole or ranitidine, followed by long-term open-label lansoprazole therapy to prevent recurrence of EE. Subjects with healed EE received 12 months of double-blind maintenance treatment with lansoprazole 15 mg once daily or ranitidine 150 mg twice daily, followed by dose-titrated, open-label lansoprazole therapy for up to 82 months. During double-blind treatment (n = 206), lansoprazole-treated patients showed significantly (P ≤ 0.05) greater improvements than ranitidine-treated patients in the frequency, severity, and ‘bothersomeness’ of heartburn, the symptom index, problems of activity limitation, eating and drinking problems, symptom problems, health distress, and social functioning. During dose-titrated, open-label treatment (n = 195), all disease-specific QOL scales except sleep improved significantly (P &lt; 0.001) from open-label baseline at each time-point. Maintenance treatment with lansoprazole for 12 months in healed EE subjects produced significantly greater improvements in QOL indicators than ranitidine. These improvements were sustained during dose-titrated, open-label lansoprazole treatment

Spatial chemical distance based on atomic property fields

Similarity of compound chemical structures often leads to close pharmacological profiles, including binding to the same protein targets. The opposite, however, is not always true, as distinct chemical scaffolds can exhibit similar pharmacology as well. Therefore, relying on chemical similarity to known binders in search for novel chemicals targeting the same protein artificially narrows down the results and makes lead hopping impossible. In this study we attempt to design a compound similarity/distance measure that better captures structural aspects of their pharmacology and molecular interactions. The measure is based on our recently published method for compound spatial alignment with atomic property fields as a generalized 3D pharmacophoric potential. We optimized contributions of different atomic properties for better discrimination of compound pairs with the same pharmacology from those with different pharmacology using Partial Least Squares regression. Our proposed similarity measure was then tested for its ability to discriminate pharmacologically similar pairs from decoys on a large diverse dataset of 115 protein–ligand complexes. Compared to 2D Tanimoto and Shape Tanimoto approaches, our new approach led to improvement in the area under the receiver operating characteristic curve values in 66 and 58% of domains respectively. The improvement was particularly high for the previously problematic cases (weak performance of the 2D Tanimoto and Shape Tanimoto measures) with original AUC values below 0.8. In fact for these cases we obtained improvement in 86% of domains compare to 2D Tanimoto measure and 85% compare to Shape Tanimoto measure. The proposed spatial chemical distance measure can be used in virtual ligand screening

The self-reported Montgomery-Åsberg depression rating scale is a useful evaluative tool in major depressive disorder

Abstract Background The use of Patient-reported Outcomes (PROs) as secondary endpoints in the development of new antidepressants has grown in recent years. The objective of this study was to assess the psychometric properties of the 9-item, patient-administered version of the Montgomery-Åsberg Depression Rating Scale (MADRS-S). Methods Data from a multicentre, double-blind, 8-week, randomised controlled trial of 278 outpatients diagnosed with Major Depressive Disorder were used to evaluate the validity, reliability and sensitivity to change of the MADRS-S using psychometric methods. A Receiver Operating Characteristic (ROC) curve was plotted to identify the most appropriate threshold to define perceived remission. Results No missing values were found at the item level, indicating good acceptability of the scale. The construct validity was satisfactory: all items contributed to a common underlying concept, as expected. The correlation between MADRS-S and physicians' MADRS was moderate (r = 0.54, p Conclusion Taking account of patient's perceptions of the severity of their own symptoms along with the psychometric properties of the MADRS-S enable its use for evaluative purposes in the development of new antidepressant drugs.</p

Antisense-Mediated Knockdown of NaV1.8, but Not NaV1.9, Generates Inhibitory Effects on Complete Freund's Adjuvant-Induced Inflammatory Pain in Rat

Tetrodotoxin-resistant (TTX-R) sodium channels NaV1.8 and NaV1.9 in sensory neurons were known as key pain modulators. Comparing with the widely reported NaV1.8, roles of NaV1.9 on inflammatory pain are poorly studied by antisense-induced specific gene knockdown. Here, we used molecular, electrophysiological and behavioral methods to examine the effects of antisense oligodeoxynucleotide (AS ODN) targeting NaV1.8 and NaV1.9 on inflammatory pain. Following complete Freund's adjuvant (CFA) inflammation treatment, NaV1.8 and NaV1.9 in rat dorsal root ganglion (DRG) up-regulated mRNA and protein expressions and increased sodium current densities. Immunohistochemical data demonstrated that NaV1.8 mainly localized in medium and small-sized DRG neurons, whereas NaV1.9 only expressed in small-sized DRG neurons. Intrathecal (i.t.) delivery of AS ODN was used to down-regulate NaV1.8 or NaV1.9 expressions confirmed by immunohistochemistry and western blot. Unexpectedly, behavioral tests showed that only NaV1.8 AS ODN, but not NaV1.9 AS ODN could reverse CFA-induced heat and mechanical hypersensitivity. Our data indicated that TTX-R sodium channels NaV1.8 and NaV1.9 in primary sensory neurons played distinct roles in CFA-induced inflammatory pain and suggested that antisense oligodeoxynucleotide-mediated blocking of key pain modulator might point toward a potential treatment strategy against certain types of inflammatory pain

Comparative efficacy of the Cognitive Behavioral Analysis System of Psychotherapy versus Supportive Psychotherapy for early onset chronic depression: design and rationale of a multisite randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Effective treatment strategies for chronic depression are urgently needed since it is not only a common and particularly disabling disorder, but is also considered treatment resistant by most clinicians. There are only a few studies on chronic depression indicating that traditional psycho- and pharmacological interventions are not as effective as in acute, episodic depression. Current medications are no more effective than those introduced 50 years ago whereas the only psychotherapy developed specifically for the subgroup of chronic depression, the Cognitive Behavioral Analysis System of Psychotherapy (CBASP), faired well in one large trial. However, CBASP has never been directly compared to a non-specific control treatment.</p> <p>Methods/Design</p> <p>The present article describes the study protocol of a multisite parallel-group randomized controlled trial in Germany. The purpose of the study is to estimate the efficacy of CBASP compared to supportive psychotherapy in 268 non-medicated early-onset chronically depressed outpatients. The intervention includes 20 weeks of acute treatment with 24 individual sessions followed by 28 weeks of continuation treatment with another 8 sessions. Depressive symptoms are evaluated 20 weeks after randomisation by means of the 24-item Hamilton Rating Scale of Depression (HRSD). Secondary endpoints are depressive symptoms after 12 and 48 weeks, and remission after 12, 20, and 48 weeks. Primary outcome will be analysed using analysis of covariance (ANCOVA) controlled for pre-treatment scores and site. Analyses of continuous secondary variables will be performed using linear mixed models. For remission rates, chi-squared tests and logistic regression will be applied.</p> <p>Discussion</p> <p>The study evaluates the comparative effects of a disorder-specific psychotherapy and a well designed non-specific psychological approach in the acute and continuation treatment phase in a large sample of early-onset chronically depressed patients.</p> <p>Trial registration</p> <p>ClinicalTrials.gov (<a href="http://www.clinicaltrials.gov/ct2/show/NCT00970437">NCT00970437</a>).</p