Improvement of Risk Prediction After Transcatheter Aortic Valve Replacement by Combining Frailty With Conventional Risk Scores

Objectives

This study sought to evaluate whether frailty improves mortality prediction in combination with the conventional scores.

Individual, household and community factors associated with HIV test refusal in rural Malawi

Objective To investigate individual, household and community factors associated with HIV test refusal in a counselling and testing programme offered at population level in rural Malawi. Methods HIV counselling and testing was offered to individuals aged 18–59 at their homes. Individual variables were collected by interviews and physical examinations. Household variables were determined as part of a previous census. Multivariate models allowing for household and community clustering were used to assess associations between HIV test refusal and explanatory variables. Results Of 2303 eligible adults, 2129 were found and 1443 agreed to HIV testing. Test refusal was less likely by those who were never married [adjusted odds ratio (aOR) 0.50 for men (95% CI 0.32; 0.80) and 0.44 (0.21; 0.91) for women] and by farmers [aOR 0.70 (0.52; 0.96) for men and 0.59 (0.40; 0.87) for women]. A 10% increase in cluster refusal rates increased the odds of refusal by 1.48 (1.32; 1.66) in men and 1.68 (1.32; 2.12) in women. Women counsellors increased the odds of refusal by 1.39 (1.00; 1.92) in men. Predictors of HIV test refusal in women were refusal of the husband as head of household [aOR 15.08 (9.39; 24.21)] and living close to the main road [aOR 6.07 (1.76; 20.98)]. Common reasons for refusal were fear of testing positive, previous HIV test, knowledge of HIV serostatus and the need for more time to think. Conclusion Successful VCT strategies need to encourage couples counselling and should involve participation of men and communities.     

Citicoline as Adjuvant Therapy in Parkinson's Disease: A Systematic Review

PurposeParkinson disease (PD) medications are not readily available in all countries. Citicoline increases dopamine synthesis and inhibits dopamine uptake. This systematic review aims to synthesize current existing evidence on the efficacy of citicoline adjunctive therapy in improving PD symptoms.MethodsAn extensive literature search of Scopus, Embase, PubMed, Cochrane Library, and Google Scholar was conducted for articles published on or before December 31, 2019. The studies were screened and selected by 2 independent reviewers. We included all studies that explored the efficacy of citicoline as an adjunct therapy in PD.FindingsA total of 7 studies (2 crossover, 3 randomized controlled, and 2 open prospective studies) were included. Despite the varied outcome tools, this review found that patients with PD who were taking citicoline had significant improvement in rigidity, akinesia, tremor, handwriting, and speech. Citicoline allowed effective reduction of levodopa by up to 50%. Significant improvement in cognitive status evaluation was also noted with citicoline adjunctive therapy.ImplicationsCiticoline adjuvant therapy has beneficial effects as an adjuvant therapy in patients with PD. However, due to the heterogeneity of the studies, there is a need for more high-quality studies.     

First-Hand Accounts of Interoceptive Difficulties in Autistic Adults

Journal of Autism and Developmental Disorders - Interoceptive awareness refers to one’s ability to detect, discriminate, and regulate internal bodily and mental processes. Interoceptive...     

A Novel Method for Reducing the Effect of Tonic Muscle Activity on the Gamma Band of the Scalp EEG

Neural oscillations in the gamma band are of increasing interest, but separating them from myogenic electrical activity has proved difficult. A novel algorithm has been developed to reduce the effect of tonic scalp and neck muscle activity on the gamma band of the EEG. This uses mathematical modelling to fit individual muscle spikes and then subtracts them from the data. The method was applied to the detection of motor associated gamma in two separate groups of eight subjects using different sampling rates. A reproducible increase in high gamma (65–85 Hz) magnitude occurred immediately after the motor action in the left central area (p = 0.02 and p = 0.0002 for the two cohorts with individually optimized algorithm parameters, compared to p = 0.03 and p = 0.16 before correction). Whilst the magnitude of this event-related gamma synchronisation was not reduced by the application of the EMG reduction algorithm, the baseline left central gamma magnitude was significantly reduced by an average of 23 % with a faster sampling rate (p < 0.05). In comparison, at left and right temporo-parietal locations the gamma amplitude was reduced by 60 and 54 % respectively (p < 0.05). The reduction of EMG contamination by fitting and subtraction of individual spikes shows promise as a method of improving the signal to noise ratio of high frequency neural oscillations in scalp EEG.     

α1β1 Integrin/Rac1-Dependent Mesangial Invasion of Glomerular Capillaries in Alport Syndrome

Alport syndrome, hereditary glomerulonephritis with hearing loss, results from mutations in type IV collagen COL4A3, COL4A4, or COL4A5 genes. The mechanism for delayed glomerular disease onset is unknown. Comparative analysis of Alport mice and CD151 knockout mice revealed progressive accumulation of laminin 211 in the glomerular basement membrane. We show mesangial processes invading the capillary loops of both models as well as in human Alport glomeruli, as the likely source of this laminin. l-NAME salt–induced hypertension accelerated mesangial cell process invasion. Cultured mesangial cells showed reduced migratory potential when treated with either integrin-linked kinase inhibitor or Rac1 inhibitor, or by deletion of integrin α1. Treatment of Alport mice with Rac1 inhibitor or deletion of integrin α1 reduced mesangial cell process invasion of the glomerular capillary tuft. Laminin α2–deficient Alport mice show reduced mesangial process invasion, and cultured laminin α2–null cells showed reduced migratory potential, indicating a functional role for mesangial laminins in progression of Alport glomerular pathogenesis. Collectively, these findings predict a role for biomechanical insult in the induction of integrin α1β1–dependent Rac1-mediated mesangial cell process invasion of the glomerular capillary tuft as an initiation mechanism of Alport glomerular pathology.Alport syndrome is characterized by delayed-onset progressive glomerulonephritis associated with sensorineural hearing loss and retinal flecks.¹ The most common form (80%) is X-linked and caused by mutations in the type IV collagen COL4A5 gene.² The two autosomal forms of the disease account for the remaining 20% of Alport patients, and result from mutations in the COL4A3 and COL4A4 genes.³ The α3(IV), α4(IV), and α5(IV) proteins form a heterotrimer that is assembled into a subepithelial network in the glomerular basement membrane (GBM) that is physically and biochemically distinct from a subendothelial type IV collagen network comprising α1(IV) and α2(IV) heterotrimers.⁴ Mutations in any one of the three type IV collagen genes that cause Alport syndrome result in the absence of all three proteins in the GBM due to an obligatory association to form functional heterotrimers.⁵ Thus, the net result for all genetic forms of Alport syndrome is the absence of the α3(IV) α4(IV) α5(IV) subepithelial collagen network, resulting in a GBM type IV collagen network comprising only α1(IV) and α2(IV) heterotrimers.This change in basement membrane composition does not result in immediate pathology. The GBM appears to function adequately for the first few years of life and sometimes past the first decade.⁶ This delayed onset predicts a triggering mechanism for glomerular disease initiation and a theoretical window for therapeutic intervention that may arrest or significantly ameliorate Alport renal disease in its earliest stages. The activation of genes encoding GBM matrix molecules, matrix metalloproteinases (MMPs), and proinflammatory cytokines have all been linked to the progression of Alport glomerular disease. These, however, are events that occur after the onset of proteinuria, and therefore, downstream of disease initiation events.^7–11 Consistent with this notion, experiments aimed at blocking these pathways have offered only limited therapeutic benefit in mouse models for Alport syndrome.^8–10,12 One of the earliest events we have documented is the appearance of an irregular deposition of laminin 211 in the GBM of Alport mice,⁸ an observation confirmed in both Alport dogs and human patients with the disease.¹³ This laminin is normally found only in the mesangium of the glomerulus, and is not expressed in the GBM at any stage of embryonic development.¹⁴ Indeed, several other mesangial matrix proteins appear in the GBM of Alport mice, including laminin 111 and fibronectin.^15,16In the Alport glomerulus, the podocytes are exposed to GBM that has an embryonic type IV collagen composition.^17,18 This could result in altered cell signaling that may trigger the onset of the disease. It has been proposed that this type of mechanism may account for the reactivation of laminin 111 expression in podocytes,¹⁹ because laminin 111 is found in the GBM during development.¹⁴ Because the α1(IV)/α2(IV) collagen network contains significantly fewer interchain disulfide crosslinks,²⁰ and the Alport GBM is thinner than normal,²¹ the Alport GBM is likely to be more elastic, resulting in elevated biomechanical strain on the glomerular cells at their points of contact with the GBM. Consistently, glomeruli from Alport mice have been shown to have elevated deformability relative to wild-type glomeruli,²² and salt-induced hypertension has been shown to accelerate glomerular disease progression in Alport mice.²³In this work, we show that the cellular origin of GBM laminin 211 in Alport glomeruli is mesangial cell process invasion, and that deletion of laminin 211 in Alport mice ameliorates the mesangial process invasion of the glomerular capillary loops in Alport mice. Salt-mediated hypertension exacerbates this mesangial process invasion. A knockout mouse for the integrin α3β1 coreceptor CD151 also develops mesangial process invasion of the capillary loops with GBM deposition of laminin 211, demonstrating the same phenotype for a completely unrelated component of the capillary structural barrier. The CD151 knockout mouse model also shows accelerated glomerular disease progression in response to hypertension.²⁴ We show that biomechanical stretching of cultured mesangial cells induces promigratory cytokines transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF), both known to be induced in Alport glomeruli.^7,12 Inhibitor studies indicate that mesangial cell migration is mediated by integrin α1β1 signaling through the Rho GTPases RAC1 and CDC42. Consistently, integrin α1 deletion in Alport mice was previously shown to ameliorate glomerular disease progression and slow the accumulation of laminin 211 in Alport GBM.⁸ Here, we show that mesangial process invasion of the capillary loops is ameliorated in integrin α1–null Alport mice. These data define a role for biomechanical strain-mediated induction of mesangial cell process invasion as a key aspect of Alport glomerular disease initiation, and set the stage for defining novel therapeutic targets aimed at blocking this process.     

Alternative Recruitment Strategies Influence Saliva Sample Return Rates in Community‐Based Genetic Association Studies

Collection of saliva for DNA extraction has created new opportunities to recruit participants from the community for genetic association studies. However, sample return rates are variable. No prior study has specifically addressed how study design impacts sample return. Using data from three large‐scale genetic association studies we compared recruitment strategy and sample return rates. We found highly significant differences in sample return rates between the studies. In studies that recruited retrospectively, overall returns were much lower from families with a self‐limiting condition who provided samples at a research centre or home visit, than adult elderly individuals with a chronic disease who provided samples by post (59% vs. 84%). Prospective recruitment was associated with high agreement to participate (72%), but subsequent low return of actual saliva samples (42%). A telephone call had marginal effect on recruitment in a retrospective family study, but significantly improved returns in a prospective family study. We found no effect upon DNA yield comparing observed versus unobserved sample collection, or between male and female adult participants. Overall, study design significantly impacts upon response rates for genetic association studies recruiting from the community. Our findings will help researchers in constructing and costing a recruitment protocol.     

Using Natural Language Processing on Electronic Health Records to Enhance Detection and Prediction of Psychosis Risk

BackgroundUsing novel data mining methods such as natural language processing (NLP) on electronic health records (EHRs) for screening and detecting individuals at risk for psychosis. MethodThe study included all patients receiving a first index diagnosis of nonorganic and nonpsychotic mental disorder within the South London and Maudsley (SLaM) NHS Foundation Trust between January 1, 2008, and July 28, 2018. Least Absolute Shrinkage and Selection Operator (LASSO)-regularized Cox regression was used to refine and externally validate a refined version of a five-item individualized, transdiagnostic, clinically based risk calculator previously developed (Harrell’s C = 0.79) and piloted for implementation. The refined version included 14 additional NLP-predictors: tearfulness, poor appetite, weight loss, insomnia, cannabis, cocaine, guilt, irritability, delusions, hopelessness, disturbed sleep, poor insight, agitation, and paranoia. ResultsA total of 92 151 patients with a first index diagnosis of nonorganic and nonpsychotic mental disorder within the SLaM Trust were included in the derivation (n = 28 297) or external validation (n = 63 854) data sets. Mean age was 33.6 years, 50.7% were women, and 67.0% were of white race/ethnicity. Mean follow-up was 1590 days. The overall 6-year risk of psychosis in secondary mental health care was 3.4 (95% CI, 3.3–3.6). External validation indicated strong performance on unseen data (Harrell’s C 0.85, 95% CI 0.84–0.86), an increase of 0.06 from the original model. ConclusionsUsing NLP on EHRs can considerably enhance the prognostic accuracy of psychosis risk calculators. This can help identify patients at risk of psychosis who require assessment and specialized care, facilitating earlier detection and potentially improving patient outcomes.