Cognitive training interventions for dementia and mild cognitive impairment in Parkinson's disease

Background Approximately 60% to 80% of people with Parkinson's disease (PD) experience cognitive impairment that impacts on their quality of life. Cognitive decline is a core feature of the disease and can often present before the onset of motor symptoms. Cognitive training may be a useful non‐pharmacological intervention that could help to maintain or improve cognition and quality of life for people with PD dementia (PDD) or PD‐related mild cognitive impairment (PD‐MCI). Objectives To determine whether cognitive training (targeting single or multiple domains) improves cognition in people with PDD and PD‐MCI or other clearly defined forms of cognitive impairment in people with PD. Search methods We searched the Cochrane Dementia and Cognitive Improvement Group Trials Register (8 August 2019), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, and PsycINFO. We searched reference lists and trial registers, searched relevant reviews in the area and conference proceedings. We also contacted experts for clarifications on data and ongoing trials. Selection criteria We included randomised controlled trials where the participants had PDD or PD‐MCI, and where the intervention was intended to train general or specific areas of cognitive function, targeting either a single domain or multiple domains of cognition, and was compared to a control condition. Multicomponent interventions that also included motor or other elements were considered eligible. Data collection and analysis Two review authors independently screened titles, abstracts, and full‐text articles for inclusion in the review. Two review authors also independently undertook extraction of data and assessment of methodological quality. We used GRADE methods to assess the overall quality of the evidence. Main results Seven studies with a total of 225 participants met the inclusion criteria for this review. All seven studies compared the effects of a cognitive training intervention to a control intervention at the end of treatment periods lasting four to eight weeks. Six studies included people with PD living in the community. These six studies recruited people with single‐domain (executive) or multiple‐domain mild cognitive impairment in PD. Four of these studies identified participants with MCI using established diagnostic criteria, and two included both people with PD‐MCI and people with PD who were not cognitively impaired. One study recruited people with a diagnosis of PD dementia who were living in long‐term care settings. The cognitive training intervention in three studies targeted a single cognitive domain, whilst in four studies multiple domains of cognitive function were targeted. The comparison groups either received no intervention or took part in recreational activities (sports, music, arts), speech or language exercises, computerised motor therapy, or motor rehabilitation combined with recreational activity. We found no clear evidence that cognitive training improved global cognition. Although cognitive training was associated with higher scores on global cognition at the end of treatment, the result was imprecise and not statistically significant (6 trials, 178 participants, standardised mean difference (SMD) 0.28, 95% confidence interval (CI) −0.03 to 0.59; low‐certainty evidence). There was no evidence of a difference at the end of treatment between cognitive training and control interventions on executive function (5 trials, 112 participants; SMD 0.10, 95% CI −0.28 to 0.48; low‐certainty evidence) or visual processing (3 trials, 64 participants; SMD 0.30, 95% CI −0.21 to 0.81; low‐certainty evidence). The evidence favoured the cognitive training group on attention (5 trials, 160 participants; SMD 0.36, 95% CI 0.03 to 0.68; low‐certainty evidence) and verbal memory (5 trials, 160 participants; SMD 0.37, 95% CI 0.04 to 0.69; low‐certainty evidence), but these effects were less certain in sensitivity analyses that excluded a study in which only a minority of the sample were cognitively impaired. There was no evidence of differences between treatment and control groups in activities of daily living (3 trials, 67 participants; SMD 0.03, 95% CI −0.47 to 0.53; low‐certainty evidence) or quality of life (5 trials, 147 participants; SMD −0.01, 95% CI −0.35 to 0.33; low‐certainty evidence). There was very little information on adverse events. We considered the certainty of the evidence for all outcomes to be low due to risk of bias in the included studies and imprecision of the results. We identified six ongoing trials recruiting participants with PD‐MCI, but no ongoing trials of cognitive training for people with PDD. Authors' conclusions This review found no evidence that people with PD‐MCI or PDD who receive cognitive training for four to eight weeks experience any important cognitive improvements at the end of training. However, this conclusion was based on a small number of studies with few participants, limitations of study design and execution, and imprecise results. There is a need for more robust, adequately powered studies of cognitive training before conclusions can be drawn about the effectiveness of cognitive training for people with PDD and PD‐MCI. Studies should use formal criteria to diagnose cognitive impairments, and there is a particular need for more studies testing the efficacy of cognitive training in people with PDD

The role of Gr‐1+ cells and tumour necrosis factor‐α signalling during Clostridium difficile colitis in mice

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110845/1/imm12425.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/110845/2/imm12425-sup-0001-FigS1-2.pd

A refined, controlled 16S rRNA gene sequencing approach reveals limited detection of cerebrospinal fluid microbiota in children with bacterial meningitis

Advances in both laboratory and computational components of high-throughput 16S amplicon sequencing (16S HTS) have markedly increased its sensitivity and specificity. Additionally, these refinements have better delineated the limits of sensitivity, and contributions of contamination to these limits, for 16S HTS that are particularly relevant for samples with low bacterial loads, such as human cerebrospinal fluid (CSF). The objectives of this work were to (i) optimize the performance of 16S HTS in CSF samples with low bacterial loads by defining and addressing potential sources of error, and (ii) perform refined 16S HTS on CSF samples from children diagnosed with bacterial meningitis and compare results with those from microbiological cultures. Several bench and computational approaches were taken to address potential sources of error for low bacterial load samples. We compared DNA yields and sequencing results after applying three different DNA extraction approaches to an artificially constructed mock-bacterial community. We also compared two postsequencing computational contaminant removal strategies, decontam R and full contaminant sequence removal. All three extraction techniques followed by decontam R yielded similar results for the mock community. We then applied these methods to 22 CSF samples from children diagnosed with meningitis, which has low bacterial loads relative to other clinical infection samples. The refined 16S HTS pipelines identified the cultured bacterial genus as the dominant organism for only 3 of these samples. We found that all three DNA extraction techniques followed by decontam R generated similar DNA yields for mock communities at the low bacterial loads representative of CSF samples. However, the limits of detection imposed by reagent contaminants and methodologic bias precluded the accurate detection of bacteria in CSF from children with culture-confirmed meningitis using these approaches, despite rigorous controls and sophisticated computational approaches. Although we did not find current DNA-based diagnostics to be useful for pediatric meningitis samples, the utility of these methods for CSF shunt infection remains undefined. Future advances in sample processing methods to minimize or eliminate contamination will be required to improve the sensitivity and specificity of these methods for pediatric meningitis

Towards refining WCRF/AICR cancer prevention recommendations for red and processed meat intake: Insights from Alberta\u27s Tomorrow Project cohort

Current cancer prevention recommendations advise limiting red meat intake to \u3c500g/week and avoiding consumption of processed meat, but do not differentiate the source of processed meat. We examined the associations of processed meat derived from red vs. non-red meats with cancer risk in a prospective cohort of 26,218 adults who reported dietary intake using the Canadian Diet History Questionnaire. Incidence of cancer was obtained through data linkage with Alberta Cancer Registry with median (IQR) follow-up of 13.3 (5.1) years. Multivariable Cox proportional hazards regression models were adjusted for covariates and stratified by age and gender. The median (IQR) consumption (g/week) of red meat, processed meat from red meat and processed meat from non-red meat were 267.9 (269.9), 53.6 (83.3), and 11.9 (31.8), respectively. High intakes (4th Quartile) of processed meat from red meat was associated with increased risk of gastro-intestinal cancer Adjusted Hazard Ratio (AHR) (95% CI): 1.68 (1.09-2.57) and colorectal cancers AHR (95% CI): 1.90 (1.12-3.22), respectively in women. No statistically significant associations were observed for intakes of red meat or processed meat from non-red meat. Results suggests that the carcinogenic effect associated with processed meat intake may be limited to processed meat derived from red meats. The findings provide preliminary evidence toward refining cancer prevention recommendations for red and processed meat intake

Molecular characterization of microbiota in cerebrospinal fluid from patients with CSF shunt infections using whole genome amplification followed by shotgun sequencing

Understanding the etiology of cerebrospinal fluid (CSF) shunt infections and reinfections requires detailed characterization of associated microorganisms. Traditionally, identification of bacteria present in the CSF has relied on culture methods, but recent studies have used high throughput sequencing of 16S rRNA genes. Here we evaluated the method of shotgun DNA sequencing for its potential to provide additional genomic information. CSF samples were collected from 3 patients near the beginning and end of each of 2 infection episodes. Extracted total DNA was sequenced by: (1) whole genome amplification followed by shotgun sequencing (WGA) and (2) high-throughput sequencing of the 16S rRNA V4 region (16S). Taxonomic assignments of sequences from WGA and 16S were compared with one another and with conventional microbiological cultures. While classification of bacteria was consistent among the 3 approaches, WGA provided additional insights into sample microbiological composition, such as showing relative abundances of microbial versus human DNA, identifying samples of questionable quality, and detecting significant viral load in some samples. One sample yielded sufficient non-human reads to allow assembly of a high-qualit

Isolated Disease of the Proximal Left Anterior Descending Artery Comparing the Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Surgery

ObjectivesThis study sought to systematically compare the effectiveness of percutaneous coronary intervention and coronary artery bypass surgery in patients with single-vessel disease of the proximal left anterior descending (LAD) coronary artery.BackgroundIt is uncertain whether percutaneous coronary interventions (PCI) or coronary artery bypass grafting (CABG) surgery provides better clinical outcomes among patients with single-vessel disease of the proximal LAD.MethodsWe searched relevant databases (MEDLINE, EMBASE, and Cochrane from 1966 to 2006) to identify randomized controlled trials that compared outcomes for patients with single-vessel proximal LAD assigned to either PCI or CABG.ResultsWe identified 9 randomized controlled trials that enrolled a total of 1,210 patients (633 received PCI and 577 received CABG). There were no differences in survival at 30 days, 1 year, or 5 years, nor were there differences in the rates of procedural strokes or myocardial infarctions, whereas the rate of repeat revascularization was significantly less after CABG than after PCI (at 1 year: 7.3% vs. 19.5%; at 5 years: 7.3% vs. 33.5%). Angina relief was significantly greater after CABG than after PCI (at 1 year: 95.5% vs. 84.6%; at 5 years: 84.2% vs. 75.6%). Patients undergoing CABG spent 3.2 more days in the hospital than those receiving PCI (95% confidence interval: 2.3 to 4.1 days, p < 0.0001), required more transfusions, and were more likely to have arrhythmias immediately post-procedure.ConclusionsIn patients with single-vessel, proximal LAD disease, survival was similar in CABG-assigned and PCI-assigned patients; CABG was significantly more effective in relieving angina and led to fewer repeat revascularizations

Novel approaches to analysis of the North Star Ambulatory Assessment (NSAA) in Duchenne muscular dystrophy (DMD): Observations from a phase 2 trial

Introduction: The North Star Ambulatory Assessment (NSAA) tool is a key instrument for measuring clinical outcomes in patients with Duchenne muscular dystrophy (DMD). To gain a better understanding of the longitudinal utility of the NSAA, we evaluated NSAA data from a phase II trial of 120 patients with DMD treated with domagrozumab or placebo. Methods: The NSAA exploratory analyses included assessment of individual skills gained/lost, total skills gained/lost, cumulative loss of function, and the impact of transient loss of function due to a temporary disability on NSAA total score (temporary zero score). Results: There was no significant difference in the total number of NSAA skills gained (mean 1.41 and 1.04, respectively; p = 0.3314) or lost (3.90 vs. 5.0; p = 0.0998) between domagrozumab- vs. placebo-treated patients at week 49. However, domagrozumab-treated patients were less likely to lose the ability to perform a NSAA item (hazard ratio 0.80, 95% confidence interval [CI]: 0.65–0.98, p = 0.029) over 48-weeks vs. placebo-treated patients. When temporary zero scores were changed to “not obtainable” (8 values from 7 patients), domagrozumab-treated patients scored higher on the NSAA total score versus placebo-treated patients (difference at week 49: 2.0, 95% CI: 0.1–3.9, p = 0.0359). Conclusions: These exploratory analyses reveal additional approaches to interpreting the NSAA data beyond just change in NSAA total score. These observations also highlight the importance of reporting items as “not obtainable” for a patient with a temporary/transient physical disability that impacts their ability to perform the NSAA test

Characterization of cerebrospinal fluid (CSF) microbiota at the time of initial surgical intervention for children with hydrocephalus

OBJECTIVE: To characterize the microbiota of the cerebrospinal fluid (CSF) from children with hydrocephalus at the time of initial surgical intervention. STUDY DESIGN: CSF was obtained at initial surgical intervention. One aliquot was stored in skim milk-tryptone-glucose-glycerol (STGG) medium and the second was unprocessed; both were then stored at -70°C. Bacterial growth for CSF samples stored in STGG were subsequently characterized using aerobic and anaerobic culture on blood agar and MALDI-TOF sequencing. All unprocessed CSF samples underwent 16S quantitative polymerase chain reaction (qPCR) sequencing, and a subset underwent standard clinical microbiological culture. CSF with culture growth (either after storage in STGG or standard clinical) were further analyzed using whole-genome amplification sequencing (WGAS). RESULTS: 11/66 (17%) samples stored in STGG and 1/36 (3%) that underwent standard clinical microbiological culture demonstrated bacterial growth. Of the organisms present, 8 were common skin flora and 4 were potential pathogens; only 1 was also qPCR positive. WGAS findings and STGG culture findings were concordant for only 1 sample, identifying Staphylococcus epidermidis. No significant difference in time to second surgical intervention was observed between the STGG culture-positive and negative groups. CONCLUSION(S): Using high sensitivity methods, we detected the presence of bacteria in a subset of CSF samples at the time of first surgery. Therefore, the true presence of bacteria in CSF of children with hydrocephalus cannot be ruled out, though our findings may suggest these bacteria are contaminants or false positives of the detection methods. Regardless of origin, the detection of microbiota in the CSF of these children may not have any clinical significance

The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development

Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD. We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme. To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation, repurposing, clinical trial design, manufacturing and ethics. Over the 5 years since its establishment TACT has amassed a body of experience that can be extrapolated to other groups of rare diseases to improve the community's chances of successfully bringing new rare disease drugs to registration and ultimately to marke