Exploring the relationship between hemi-inattention and functional recovery in the first six months after stroke: a longitudinal study with a multilevel modelling approach to data analysis

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University LondonIn recent years, the functional outcomes of patients with right hemisphere stroke (RHS) received considerable attention due to their impact on disability, independent living, quality of life and economic burden. Hemi-inattention (HI) is a complex condition which often accompanies RHS. It is characterised by reduced alertness, attention and low spatial awareness levels. Past studies reported poor outcomes in patients with HI and inconsistent findings in regard to the relationship of HI with functional outcome. Literature review of 13 relevant studies highlighted poor research methodology which complicated interpretation of previous results. Aims: The aim of this study was to address the clinically important question “What is the relationship between early HI status (HI±) and functional change in the 1st six months after right hemisphere stroke?” by improving on research methodology from past studies. Methods: An all-inclusive stroke severity RHS sample (58 with and 35 without HI) were recruited from two stroke units and assessed on motor and cognitive factors with validated measurement tools on four occasions; baseline, hospital discharge, 6 weeks after discharge, and 6 months after stroke. A multi-level modelling approach was used to analyse change in functional progress over time with potential explanatory motor and cognitive factors. Results: HI status was only statistically significant when modelled alone. Its predictive importance greatly diminished when modelled with other factors e.g. stroke severity, time since stroke and age. Conclusion: On average, HI group membership at baseline is unrelated to functional recovery when other influential factors are also considered. The findings extend current knowledge in stroke recovery research and provide suggestions for optimal therapeutic and rehabilitation outcomes. In contrast with traditional methods of regression analysis, multi-level modelling techniques enabled important relationships to be studied in depth. This resulted in new insights into the data which can be used to inform patient management and future research in the field

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

What are the functional outcomes of right hemisphere stroke patients with or without hemi-inattention complications? A critical narrative review and suggestions for further research.

PURPOSE: There is widespread acceptance that patients demonstrating neglect/hemi-inattention (HI) following right hemisphere stroke (RHS) underachieve functionally compared to their counterparts without neglect. However, empirical evidence for this view needs examination. The purpose of this review is to critically appraise relevant studies that compared outcomes from RHS patients with/without hemi-attention and suggest more robust follow-up research. METHOD: Twelve studies published in 1995-2013 were critically reviewed. Two independent reviewers appraised design features including sample representation, assessment and data analysis methods. Strengths and limitations were highlighted. RESULTS: Results were largely inconsistent. Considerable heterogeneity within patient groups and across studies complicated interpretation. Evidence suggested average group disparity in scores between patients with and without HI at discharge but the cause of functional disparity could not be attributed specifically to HI from the data and modelling results available. CONCLUSION: The relationship between HI status and functional recovery warrants further investigation in studies with stronger methodology to ensure rigour and robustness in the results. Pending further research, HI status should not be regarded as a key predictor of functional recovery or rehabilitation potential in patients with RHSs. This group should continue to receive appropriate therapeutic intervention aimed at maximising their functional recovery post-stroke. Implications for Rehabilitation Findings from this review demonstrate a paucity of evidence to support the presence of hemi-inattention as a key predictor of functional recovery in patients with right hemisphere stroke; as such, practitioners should take this into consideration when planning rehabilitation programmes of their patients. In the initial months following right hemisphere stroke, there are wide-ranging differences in the rate and amount of functional recovery in patients, with and without hemi-inattention. Practitioners should not limit the aspirations of their patients based on the presence or absence of hemi-inattention. This review has identified a number of measurement limitations in commonly employed assessment tools for hemi-inattention and overall functional recovery. As such, practitioners should take the limitations of specific measures into account when interpreting the results contextually and with respect to their patients' situation