Cross-Cultural Applicability of the Montreal Cognitive Assessment (MoCA): A Systematic Review

The Montreal Cognitive Assessment (MoCA) is widely used to screen for mild cognitive impairment (MCI). While there are many available versions, the cross-cultural validity of the assessment has not been explored sufficiently. We aimed to interrogate the validity of the MoCA in a cross-cultural context: in differentiating MCI from normal controls (NC); and identifying cut-offs and adjustments for age and education where possible. This review sourced a wide range of studies including case-control studies. In addition, we report findings for differentiating dementias from NC and MCI from dementias, however, these were not considered to be an appropriate use of the MoCA. The subject of the review assumes heterogeneity and therefore meta-analyses was not conducted. Quality ratings, forest plots of validated studies (sensitivity and specificity) with covariates (suggested cut-offs, age, education and country), and summary receiver operating characteristic curve are presented. The results showed a wide range in suggested cutoffs for MCI cross-culturally, with variability in levels of sensitivity and specificity ranging from low to high. Poor methodological rigor appears to have affected reported accuracy and validity of the MoCA. The review highlights the necessity for cross-cultural considerations when using the MoCA, and recognizing it as a screen and not a diagnostic tool. Appropriate cutoffs and point adjustments for education are suggested

Cyclodextrin-siRNA conjugates as versatile gene silencing agents

Functional siRNAs (luciferase and PLK1) have been conjugated to β-cyclodextrin and the ability of the conjugates to retain gene knockdown activity has been assessed by delivery to cancer cell lines using various formulations. Initially two formulations used complexation with polycations, namely Lipofectamine 2000 and an amphiphilic polycationic cyclodextrin. Gene knockdown results for human glioblastoma cells (U87) and prostate cancer cells (PC3, DU145) showed that conjugation to the cyclodextrin did not reduce gene silencing by the RNA. A third mode of delivery involved formation of targeted nanoparticles in which the conjugate was first complexed with adamantyl-PEG-ligands (targeting ligand RVG peptide or dianisamide) by adamantyl inclusion in the cyclodextrin cavities of the conjugates, followed by charge neutralisation with the cationic polymer chitosan. Enhanced knockdown was achieved by these ligand-targeted formulations. In summary, while this study illustrated the gene silencing efficacy of a simple cyclodextrin-siRNA conjugate it is envisaged that future studies will explore the use of conjugates with a modified cyclodextrin which would be self-delivering. Detailed data such as stability, lysosomal escape etc. will then be reported for each conjugate, since this will be appropriate for conjugates which are intended to exploit, rather than merely demonstrate, the concept. The present paper was intended to demonstrate the viability and generality of this novel concept

Continuous cardiac autonomic and haemodynamic responses to isometric exercise in females

Purpose: Hypertension is associated with impaired haemodynamic control mechanisms and autonomic dysfunction. Isometric exercise (IE) interventions have been shown to improve autonomic modulation and reduce blood pressure (BP) in predominantly male participants. The physiological responses to IE are under explored in female populations; therefore, this study investigated the continuous cardiac autonomic and haemodynamic response to a single bout of IE in a large female population. Methods: Forty physically inactive females performed a single, individually prescribed isometric wall squat training session. Total power spectral density of heart rate variability (HRV) and associated low frequency (LF) and high-frequency (HF) power spectral components, were recorded in absolute (ms2) and normalised units (nu) pre, during and post an IE session. Heart rate (HR) was recorded via electrocardiography and baroreceptor reflex sensitivity (BRS) via the sequence method. Continuous blood pressure was recorded via the vascular unloading technique and stroke volume via impedance cardiography. Total peripheral resistance (TPR) was calculated according to Ohm’s Law. Results: During IE, there were significant reductions in HRV (p<0.001) and BRS (p<0.001), and significant increases in heart rate (p<0.001), systolic, mean and diastolic BP (p<0.001 for all). In recovery following the IE session, cardiac autonomic parameters returned to baseline (p=0.974); however, total peripheral vascular resistance significantly reduced below baseline (p<0.001). This peripheral vascular response was associated with significant reductions in systolic (-17.3±16.5 mmHg, p<0.001), mean (-18.8±17.4 mmHg, p<0.001) and diastolic BP (-17.3±16.2 mmHg, p<0.001), below baseline. Conclusion: A single IE session is associated with improved haemodynamic cardiovascular responses in females. Cardiac autonomic responses return to baseline values, which suggests alternative mechanisms are responsible for the post exercise haemodynamic improvements in females. Future mechanistic research is required to investigate the acute and chronic effects of IE in female populations with different resting BP profiles

Increased complexity of Tmem16a/Anoctamin 1 transcript alternative splicing

<p>Abstract</p> <p>Background</p> <p>TMEM16A (Anoctamin 1; ANO1) is an eight transmembrane protein that functions as a calcium-activated chloride channel. <it>TMEM16A </it>in human exhibits alternatively spliced exons (6b, 13 and 15), which confer important roles in the regulation of channel function. Mouse <it>Tmem16a </it>is reported to consist of 25 exons that code for a 956 amino acid protein. In this study our aim was to provide details of mouse <it>Tmem16a </it>genomic structure and to investigate if <it>Tmem16a </it>transcript undergoes alternative splicing to generate channel diversity.</p> <p>Results</p> <p>We identified <it>Tmem16a </it>transcript variants consisting of alternative exons 6b, 10, 13, 14, 15 and 18. Our findings indicate that many of these exons are expressed in various combinations and that these splicing events are mostly conserved between mouse and human. In addition, we confirmed the expression of these exon variants in other mouse tissues. Additional splicing events were identified including a novel conserved exon 13b, tandem splice sites of exon 1 and 21 and two intron retention events.</p> <p>Conclusion</p> <p>Our results suggest that <it>Tmem16a </it>gene is significantly more complex than previously described. The complexity is especially evident in the region spanning exons 6 through 16 where a number of the alternative splicing events are thought to affect calcium sensitivity, voltage dependence and the kinetics of activation and deactivation of this calcium-activated chloride channel. The identification of multiple <it>Tmem16a </it>splice variants suggests that alternative splicing is an exquisite mechanism that operates to diversify TMEM16A channel function in both physiological and pathophysiological conditions.</p

HOw patients view extended half‐life products: impressions from real‐world experience (The HOPE study)

Introduction Extended half‐life (EHL) clotting factors have been shown to offer people with haemophilia (PwH) protection from bleeding with fewer infusions, which might reduce treatment burden. Aim The HOw Patients view Extended half‐life products (HOPE) study aimed to explore, understand and describe patient expectations around the prophylactic use of EHL products and to establish whether these expectations were met through individual follow‐up analysis. Methods The HOPE study was a prospective, qualitative cohort study conducted among PwH who had switched to Fc fusion protein EHL products in routine clinical care and who had not been recruited to clinical trials of these products. Semi‐structured audio‐recorded interviews were undertaken over two time points; transcripts were analysed to systematically generate theory from data that contains both inductive and deductive thinking. Results Forty‐three interviews were conducted with 25 participants. Most participants were positive about EHL treatment and intended to continue using them. Reduced frequency of infusions meant lives were less disrupted or dominated by haemophilia, and there was less perceived stress on overused veins. For those PwH who did not reduce infusion frequency, there were other perceived benefits from EHLs with respect to greater protection with higher trough levels and fewer bleeds. Conclusion Patients switching to EHL treatments believe these products will result in fewer infusions and less disruption of everyday life, leaving them feeling more protected with fewer bleeds and increased activity levels, as well as enhanced well‐being and mental health. Understanding patient expectation and experience around using products adds real‐world data to clinical trial experience

Profiles and trajectories of mental health service utilisation during early intervention in psychosis

Background: Early intervention in psychosis services (EIS) support individuals experiencing a first episode of psychosis. Support required will vary in response to the remittance and reoccurrence of symptoms, including relapses. Characterising individuals who will need more intensive support can inform care planning. This study explores service utilisation profiles and their trajectories of service use in a sample of individuals referred to EIS. Method: We analysed service utilisation during the 3 years following referral to EIS (n = 2363) in West London between 2011 and 2020. Mental health service utilisation data were submitted to model-based clustering. Latent growth models were then estimated for identified profiles. Profiles were compared regarding clinical and demographic characteristics and onward pathways of care. Results: Analyses revealed 5 profiles of individuals attending EIS based on their service utilisation over 3 years. 55.5% of the sample were members of a low utilisation and less clinically severe profile. The distinct service use patterns of these profiles were associated with Health of the Nations Outcome Scale scores at treatment initiation (at total, subscale, and individual item level), along with age and gender. These patterns of use were also associated with onward care and ethnicity. Conclusions: Profiles and trajectories of service utilisation call for development of integrated care pathways and use of more personalised interventions. Services should consider patient symptoms and characteristics when making clinical decisions informing the provision of care. The profiles represent typical patterns of service use, and identifying factors associated with these subgroups might help optimise EIS support

Reviews

Reviews of Incomes policy in New Zealand : 1968-1984, Economics: a workers' education manual, Lost managers: Supervisors In Industry and society, The closed shop in British industry

Can non-viral technologies knockdown the barriers to siRNA delivery and achieve the next generation of cancer therapeutics?

Cancer is one of the most wide-spread diseases of modern times, with an estimated increase in the number of patients diagnosed worldwide, from 11.3 million in 2007 to 15.5 million in 2030 (www.who.int). In many cases, due to the delay in diagnosis and high increase of relapse, survival rates are low. Current therapies, including surgery, radiation and chemotherapy, have made significant progress, but they have many limitations and are far from ideal. Although immunotherapy has recently offered great promise as a new approach in cancer treatment, it is still very much in its infancy and more information on this approach is required before it can be widely applied. For these reasons effective, safe and patient-acceptable cancer therapy is still largely an unmet clinical need. Recent knowledge of the genetic basis of the disease opens up the potential for cancer gene therapeutics based on siRNA. However, the future of such gene-based therapeutics is dependent on achieving successful delivery. Extensive research is ongoing regarding the design and assessment of non-viral delivery technologies for siRNA to treat a wide range of cancers. Preliminary results on the first human Phase I trial for solid tumours, using a targeted non-viral vector, illustrate the enormous therapeutic benefits once the issue of delivery is resolved. In this review the genes regulating cancer will be discussed and potential therapeutic targets will be identified. The physiological and biochemical changes caused by tumours, and the potential to exploit this knowledge to produce bio-responsive ‘smart’ delivery systems, will be evaluated. This review will also provide a critical and comprehensive overview of the different non-viral formulation strategies under investigation for siRNA delivery, with particular emphasis on those designed to exploit the physiological environment of the disease site. In addition, a section of the review will be dedicated to pre-clinical animal models used to evaluate the stability, safety and efficacy of the delivery systems