Cultural adaptation of cognitive stimulation therapy (CST) for Chinese people with dementia: multicentre pilot study

OBJECTIVE: Ageing of the Chinese population will drive a continued surge in dementia prevalence. Empirically tested non‐pharmacological interventions developed in western cultures may be implemented in Chinese. Cognitive Stimulation Therapy (CST) that originated in the UK has proven benefits on cognition and quality of life in people with dementia. We investigated the feasibility and cultural appropriateness of CST in Hong Kong Chinese (CST‐HK). METHODS: Mixed methods research was conducted following the formative method for adapting psychotherapy. A culturally adapted CST‐HK, developed involving multidisciplinary stakeholders, was tested in a pilot multicentre study in people with mild dementia (n = 30) receiving community or residential care. Changes in cognition and quality of life were measured. Opinions from family caregivers and group facilitators (n = 25) were collected through focus groups and in‐depth interviews for understanding the appropriateness of CST‐HK. Feasibility was explored. RESULTS: After receiving CST‐HK, 54% of participants achieved outcome of no cognitive deterioration, and 23% showed clinically meaningful improvement. Family caregivers and group facilitators expressed good acceptance of CST, with a low attrition (13%) and high attendance rate of CST‐HK sessions (92%). Key cultural issues identified are (i) less active opinion sharing in group discussions due to conservatism/cautiousness and (ii) preference of practical activities with reward/recognition over pure discussion due to pragmatism. CONCLUSIONS: The CST‐HK is feasible and culturally appropriate in Hong Kong Chinese. Further amendments can be made to ensure language use and enjoyment, with potential implications on effectiveness. We have provided a systematically developed, culturally adapted protocol for larger‐scale implementation and research in Chinese populations

Psychotropic drugs and the risk of fractures in old age: a prospective population-based study

<p>Abstract</p> <p>Background</p> <p>There is evidence that the use of any psychotropic and the concomitant use of two or more benzodiazepines are related to an increased risk of fractures in old age. However, also controversial results exist. The aim was to describe associations between the use of a psychotropic drug, or the concomitant use of two or more of these drugs and the risk of fractures in a population aged 65 years or over.</p> <p>Methods</p> <p>This study was a part of a prospective longitudinal population-based study carried out in the municipality of Lieto, South-Western Finland. The objective was to describe gender-specific associations between the use of one psychotropic drug [benzodiazepine (BZD), antipsychotic (AP) or antidepressant (AD)] or the concomitant use of two or more psychotropic drugs and the risk of fractures in a population 65 years or over. Subjects were participants in the first wave of the Lieto study in 1990-1991, and they were followed up until the end of 1996. Information about fractures confirmed with radiology reports in 1,177 subjects (482 men and 695 women) during the follow-up was collected from medical records. Two follow-up periods (three and six years) were used, and previously found risk factors of fractures were adjusted as confounding factors separately for men and women. The Poisson regression model was used in the analyses.</p> <p>Results</p> <p>The concomitant use of two or more BZDs and the concomitant use of two or more APs were related to an increased risk of fractures during both follow-up periods after adjusting for confounding factors in men. No similar associations were found in women.</p> <p>Conclusions</p> <p>The concomitant use of several BZDs and that of several APs are associated with an increase in the risk of fractures in older men. Our findings show only risk relations. We cannot draw the conclusion that these drug combinations are causes of fractures.</p

The PDZ Domain as a Complex Adaptive System

Specific protein associations define the wiring of protein interaction networks and thus control the organization and functioning of the cell as a whole. Peptide recognition by PDZ and other protein interaction domains represents one of the best-studied classes of specific protein associations. However, a mechanistic understanding of the relationship between selectivity and promiscuity commonly observed in the interactions mediated by peptide recognition modules as well as its functional meaning remain elusive. To address these questions in a comprehensive manner, two large populations of artificial and natural peptide ligands of six archetypal PDZ domains from the synaptic proteins PSD95 and SAP97 were generated by target-assisted iterative screening (TAIS) of combinatorial peptide libraries and by synthesis of proteomic fragments, correspondingly. A comparative statistical analysis of affinity-ranked artificial and natural ligands yielded a comprehensive picture of known and novel PDZ ligand specificity determinants, revealing a hitherto unappreciated combination of specificity and adaptive plasticity inherent to PDZ domain recognition. We propose a reconceptualization of the PDZ domain in terms of a complex adaptive system representing a flexible compromise between the rigid order of exquisite specificity and the chaos of unselective promiscuity, which has evolved to mediate two mutually contradictory properties required of such higher order sub-cellular organizations as synapses, cell junctions, and others – organizational structure and organizational plasticity/adaptability. The generalization of this reconceptualization in regard to other protein interaction modules and specific protein associations is consistent with the image of the cell as a complex adaptive macromolecular system as opposed to clockwork

Topical use of MMC in the upper aerodigestive tract: a review on the side effects

Not much is known about the side effects of mitomycin C (MMC), an anti-fibrogenetic agent, in the upper aerodigestive tract. However, its use in ophthalmology is widely known and without quantitatively important side effects. A literature review was performed for side effects of MMC in the upper aerodigestive tract. Forty-six articles, describing the use of MMC to prevent scarring, were retracted from PubMed. Thirty-two are human studies. MMC is used in different concentrations (0.1–10 mg/ml) with different application times (2–5 min) and frequencies (up to 4 times). Five hundred and thirty-eight patients were included in those publications, of whom 19 developed side effects (3.53%). No side effects developed in studies, where post-application irrigation with saline was reported. The longest mean follow-up period is 75.5 months. Direct relations between the reported side effects and MMC seem absent in most studies. Serious complications seem to occur when MMC is used in high concentrations. Unfortunately, sometimes crucial information is lacking. One patient was described who supposedly developed laryngeal carcinoma after repeated treatment of hyperkeratosis and anterior commissure webbing. Animal studies show that excessive fibrin production can lead to acute airway obstruction. In conclusion, topical application of MMC on a wound with consecutive irrigation with saline can be performed safely to prevent scar formation in circular structures of the upper aerodigestive tract. Long-term yearly control of the application site seems advisable

Colour terms affect detection of colour and colour-associated objects suppressed from visual awareness

The idea that language can affect how we see the world continues to create controversy. A potentially important study in this field has shown that when an object is suppressed from visual awareness using continuous flash suppression (a form of binocular rivalry), detection of the object is differently affected by a preceding word prime depending on whether the prime matches or does not match the object. This may suggest that language can affect early stages of vision. We replicated this paradigm and further investigated whether colour terms likewise influence the detection of colours or colour-associated object images suppressed from visual awareness by continuous flash suppression. This method presents rapidly changing visual noise to one eye while the target stimulus is presented to the other. It has been shown to delay conscious perception of a target for up to several minutes. In Experiment 1 we presented greyscale photos of objects. They were either preceded by a congruent object label, an incongruent label, or white noise. Detection sensitivity (d’) and hit rates were significantly poorer for suppressed objects preceded by an incongruent label compared to a congruent label or noise. In Experiment 2, targets were coloured discs preceded by a colour term. Detection sensitivity was significantly worse for suppressed colour patches preceded by an incongruent colour term as compared to a congruent term or white noise. In Experiment 3 targets were suppressed greyscale object images preceded by an auditory presentation of a colour term. On congruent trials the colour term matched the object’s stereotypical colour and on incongruent trials the colour term mismatched. Detection sensitivity was significantly poorer on incongruent trials than congruent trials. Overall, these findings suggest that colour terms affect awareness of coloured stimuli and colour- associated objects, and provide new evidence for language-perception interaction in the brain

Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations : A transethnic genome-wide meta-analysis

Background Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. Methods & findings Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 x 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI0.55-0.74) of African American adults with T2Dto remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. Conclusions As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.Peer reviewe

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P &lt; 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.</p

Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences

Efficient processing of information by the central nervous system (CNS) represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly controlled and stable microenvironment. To provide such a milieu for neurons, extracellular fluids of the CNS are separated from the changeable environment of blood at three major interfaces: at the brain capillaries by the blood-brain barrier (BBB), which is localized at the level of the endothelial cells and separates brain interstitial fluid (ISF) from blood; at the epithelial layer of four choroid plexuses, the blood-cerebrospinal fluid (CSF) barrier (BCSFB), which separates CSF from the CP ISF, and at the arachnoid barrier. The two barriers that represent the largest interface between blood and brain extracellular fluids, the BBB and the BCSFB, prevent the free paracellular diffusion of polar molecules by complex morphological features, including tight junctions (TJs) that interconnect the endothelial and epithelial cells, respectively. The first part of this review focuses on the molecular biology of TJs and adherens junctions in the brain capillary endothelial cells and in the CP epithelial cells. However, normal function of the CNS depends on a constant supply of essential molecules, like glucose and amino acids from the blood, exchange of electrolytes between brain extracellular fluids and blood, as well as on efficient removal of metabolic waste products and excess neurotransmitters from the brain ISF. Therefore, a number of specific transport proteins are expressed in brain capillary endothelial cells and CP epithelial cells that provide transport of nutrients and ions into the CNS and removal of waste products and ions from the CSF. The second part of this review concentrates on the molecular biology of various solute carrier (SLC) transport proteins at those two barriers and underlines differences in their expression between the two barriers. Also, many blood-borne molecules and xenobiotics can diffuse into brain ISF and then into neuronal membranes due to their physicochemical properties. Entry of these compounds could be detrimental for neural transmission and signalling. Thus, BBB and BCSFB express transport proteins that actively restrict entry of lipophilic and amphipathic substances from blood and/or remove those molecules from the brain extracellular fluids. The third part of this review concentrates on the molecular biology of ATP-binding cassette (ABC)-transporters and those SLC transporters that are involved in efflux transport of xenobiotics, their expression at the BBB and BCSFB and differences in expression in the two major blood-brain interfaces. In addition, transport and diffusion of ions by the BBB and CP epithelium are involved in the formation of fluid, the ISF and CSF, respectively, so the last part of this review discusses molecular biology of ion transporters/exchangers and ion channels in the brain endothelial and CP epithelial cells

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10−8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution