Abstract
Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and ...diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5–15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer’s disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI.
A 2019 review concluded that spinal manipulative therapy (SMT) results in similar benefit compared to other interventions for chronic low back pain (LBP). Compared to traditional aggregate analyses ...individual participant data (IPD) meta-analyses allows for a more precise estimate of the treatment effect.
To assess the effect of SMT on pain and function for chronic LBP in a IPD meta-analysis.
Electronic databases from 2000 until April 2016, and reference lists of eligible trials and related reviews.
Randomized controlled trials (RCT) examining the effect of SMT in adults with chronic LBP compared to any comparator.
We contacted authors from eligible trials. Two review authors independently conducted the study selection and risk of bias. We used GRADE to assess the quality of the evidence. A one-stage mixed model analysis was conducted. Negative point estimates of the mean difference (MD) or standardized mean difference (SMD) favors SMT.
Of the 42 RCTs fulfilling the inclusion criteria, we obtained IPD from 21 (n=4223). Most trials (s=12, n=2249) compared SMT to recommended interventions. There is moderate quality evidence that SMT vs recommended interventions resulted in similar outcomes on pain (MD −3.0, 95%CI: −6.9 to 0.9, 10 trials, 1922 participants) and functional status at one month (SMD: −0.2, 95% CI −0.4 to 0.0, 10 trials, 1939 participants). Effects at other follow-up measurements were similar. Results for other comparisons (SMT vs non-recommended interventions; SMT as adjuvant therapy; mobilization vs manipulation) showed similar findings. SMT vs sham SMT analysis was not performed, because we only had data from one study. Sensitivity analyses confirmed these findings.
Only 50% of the eligible trials were included.
Sufficient evidence suggest that SMT provides similar outcomes to recommended interventions, for pain relief and improvement of functional status. SMT would appear to be a good option for the treatment of chronic LBP.
Systematic Review Registration Number PROSPERO CRD42015025714
Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the ...results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10⁻⁶ (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 ...non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR95%CI=0.860.76-0.96, P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
ECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in individuals without cardiac disease. Slow conduction may promote re-entrant arrhythmias.
We performed a ...genome-wide association study to identify genomic markers of QRS duration in 5272 individuals without cardiac disease selected from electronic medical record algorithms at 5 sites in the Electronic Medical Records and Genomics (eMERGE) network. The most significant loci were evaluated within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium QRS genome-wide association study meta-analysis. Twenty-three single-nucleotide polymorphisms in 5 loci, previously described by CHARGE, were replicated in the eMERGE samples; 18 single-nucleotide polymorphisms were in the chromosome 3 SCN5A and SCN10A loci, where the most significant single-nucleotide polymorphisms were rs1805126 in SCN5A with P=1.2×10(-8) (eMERGE) and P=2.5×10(-20) (CHARGE) and rs6795970 in SCN10A with P=6×10(-6) (eMERGE) and P=5×10(-27) (CHARGE). The other loci were in NFIA, near CDKN1A, and near C6orf204. We then performed phenome-wide association studies on variants in these 5 loci in 13859 European Americans to search for diagnoses associated with these markers. Phenome-wide association study identified atrial fibrillation and cardiac arrhythmias as the most common associated diagnoses with SCN10A and SCN5A variants. SCN10A variants were also associated with subsequent development of atrial fibrillation and arrhythmia in the original 5272 "heart-healthy" study population.
We conclude that DNA biobanks coupled to electronic medical records not only provide a platform for genome-wide association study but also may allow broad interrogation of the longitudinal incidence of disease associated with genetic variants. The phenome-wide association study approach implicated sodium channel variants modulating QRS duration in subjects without cardiac disease as predictors of subsequent arrhythmias.
Background and aim: Normal articulation before school start is a main objective in cleft palate treatment. The aim was to investigate if differences exist in consonant proficiency at age 5 years ...between children with unilateral cleft lip and palate (UCLP) randomised to different surgical protocols for primary palatal repair. A secondary aim was to estimate burden of care in terms of received additional secondary surgeries and speech therapy.
Design: Three parallel group, randomised clinical trials were undertaken as an international multicentre study by 10 cleft teams in five countries: Denmark, Finland, Norway, Sweden, and the UK.
Methods: Three different surgical protocols for primary palatal repair were tested against a common procedure in the total cohort of 448 children born with non-syndromic UCLP. Speech audio- and video-recordings of 391 children (136 girls and 255 boys) were available and transcribed phonetically. The main outcome measure was Percent Consonants Correct (PCC) from blinded assessments.
Results: In Trial 1, arm A showed statistically significant higher PCC scores (82%) than arm B (78%) (p = .045). No significant differences were found between prevalences in Trial 2, A: 79%, C: 82%; or Trial 3, A: 80%, D: 85%. Across all trials, girls achieved better PCC scores, excluding s-errors, than boys (91.0% and 87.5%, respectively) (p = .01).
Conclusions: PCC scores were higher in arm A than B in Trial 1, whereas no differences were found between arms in Trials 2 or 3. The burden of care in terms of secondary pharyngeal surgeries, number of fistulae, and speech therapy visits differed.
Trial registration: ISRCTN29932826.
Background and aim: Adequate velopharyngeal function and speech are main goals in the treatment of cleft palate. The objective was to investigate if there were differences in velopharyngeal ...competency (VPC) and hypernasality at age 5 years in children with unilateral cleft lip and palate (UCLP) operated on with different surgical methods for primary palatal repair. A secondary aim was to estimate burden of care in terms of received additional secondary surgeries and speech therapy.
Design: Three parallel group, randomised clinical trials were undertaken as an international multicentre study by 10 cleft teams in five countries: Denmark, Finland, Sweden, Norway, and the UK.
Methods: Three different surgical protocols for primary palatal repair were tested against a common procedure in the total cohort of 448 children born with a non-syndromic UCLP. Speech audio and video recordings of 391 children (136 girls, 255 boys) were available and perceptually analysed. The main outcome measures were VPC and hypernasality from blinded assessments.
Results: There were no statistically significant differences between the prevalences in the arms in any of the trials. VPC: Trial 1, A: 58%, B: 61%; Trial 2, A: 57%, C: 54%; Trial 3, A: 35%, D: 51%. No hypernasality: Trial 1, A: 54%, B: 44%; Trial 2, A: 47%, C: 51%; Trial 3, A: 34%, D: 49%.
Conclusions: No differences were found regarding VPC and hypernasality at age 5 years after different methods for primary palatal repair. The burden of care in terms of secondary pharyngeal surgeries, number of fistulae, and speech therapy visits differed.
Trial registration: ISRCTN29932826.
Abstract
Objective. Anxiety disorders are frequently under-diagnosed conditions in primary care, although they can be managed effectively by general practitioners. Methods. This paper is a short and ...practical summary of the World Federation of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) for the treatment in primary care. The recommendations were developed by a task force of 30 international experts in the field and are based on randomized controlled studies. Results. First-line pharmacological treatments for these disorders are selective serotonin reuptake inhibitors (for all disorders), serotonin-norepinephrine reuptake inhibitors (for some) and pregabalin (for generalized anxiety disorder only). A combination of medication and cognitive behavior/exposure therapy was shown to be a clinically desired treatment strategy. Conclusions. This short version of an evidence-based guideline may improve treatment of anxiety disorders, OCD, and PTSD in primary care.
Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on ...protein expression, and whether such proteins are altered in disease, is unknown.
We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.
We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).
We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.
Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
Healthy Cities Phase V evaluation de Leeuw, Evelyne; Green, Geoff; Tsouros, Agis ...
Health promotion international,
06/2015, Letnik:
30, Številka:
suppl 1
Journal Article
Recenzirano
Odprti dostop
In this article we reflect on the quality of a realist synthesis paradigm applied to the evaluation of Phase V of the WHO European Healthy Cities Network. The programmatic application of this ...approach has led to very high response rates and a wealth of important data. All articles in this Supplement report that cities in the network move from small-scale, time-limited projects predominantly focused on health lifestyles to the significant inclusion of policies and programmes on systems and values for good health governance. The evaluation team felt that, due to time and resource limitations, it was unable to fully exploit the potential of realist synthesis. In particular, the synthetic integration of different strategic foci of Phase V designation areas did not come to full fruition. We recommend better and more sustained integration of realist synthesis in the practice of Healthy Cities in future Phases.
PDF
