Network analysis of neuropsychiatric, cognitive, and functional complications of stroke: implications for novel treatment targets.

AIM: Recovery from stroke is adversely affected by neuropsychiatric complications, cognitive impairment, and functional disability. Better knowledge of their mutual relationships is required to inform effective interventions. Network theory enables the conceptualization of symptoms and impairments as dynamic and mutually interacting systems. We aimed to identify interactions of poststroke complications using network analysis in diverse stroke samples. METHODS: Data from 2185 patients were sourced from member studies of STROKOG (Stroke and Cognition Consortium), an international collaboration of stroke studies. Networks were generated for each cohort, whereby nodes represented neuropsychiatric symptoms, cognitive deficits, and disabilities on activities of daily living. Edges characterized associations between them. Centrality measures were used to identify hub items. RESULTS: Across cohorts, a single network of interrelated poststroke complications emerged. Networks exhibited dissociable depression, apathy, fatigue, cognitive impairment, and functional disability modules. Worry was the most central symptom across cohorts, irrespective of the depression scale used. Items relating to activities of daily living were also highly central nodes. Follow-up analysis in two studies revealed that individuals who worried had more densely connected networks than those free of worry (CASPER [Cognition and Affect after Stroke: Prospective Evaluation of Risks] study: S = 9.72, P = 0.038; SSS [Sydney Stroke Study]: S = 13.56, P = 0.069). CONCLUSION: Neuropsychiatric symptoms are highly interconnected with cognitive deficits and functional disabilities resulting from stroke. Given their central position and high level of connectedness, worry and activities of daily living have the potential to drive multimorbidity and mutual reinforcement between domains of poststroke complications. Targeting these factors early after stroke may have benefits that extend to other complications, leading to better stroke outcomes.

Predicting incident dementia in cerebral small vessel disease: comparison of machine learning and traditional statistical models.

Background: Cerebral small vessel disease (SVD) contributes to 45% of dementia cases worldwide, yet we lack a reliable model for predicting dementia in SVD. Past attempts largely relied on traditional statistical approaches. Here, we investigated whether machine learning (ML) methods improved prediction of incident dementia in SVD from baseline SVD-related features over traditional statistical methods. Methods: We included three cohorts with varying SVD severity (RUN DMC, n = 503; SCANS, n = 121; HARMONISATION, n = 265). Baseline demographics, vascular risk factors, cognitive scores, and magnetic resonance imaging (MRI) features of SVD were used for prediction. We conducted both survival analysis and classification analysis predicting 3-year dementia risk. For each analysis, several ML methods were evaluated against standard Cox or logistic regression. Finally, we compared the feature importance ranked by different models. Results: We included 789 participants without missing data in the survival analysis, amongst whom 108 (13.7%) developed dementia during a median follow-up of 5.4 years. Excluding those censored before three years, we included 750 participants in the classification analysis, amongst whom 48 (6.4%) developed dementia by year 3. Comparing statistical and ML models, only regularised Cox/logistic regression outperformed their statistical counterparts overall, but not significantly so in survival analysis. Baseline cognition was highly predictive, and global cognition was the most important feature. Conclusions: When using baseline SVD-related features to predict dementia in SVD, the ML survival or classification models we evaluated brought little improvement over traditional statistical approaches. The benefits of ML should be evaluated with caution, especially given limited sample size and features.

Short-term Trajectories of Poststroke Cognitive Function: A STROKOG Collaboration Study.

BACKGROUND AND OBJECTIVES: Past studies on poststroke cognitive function have focused on the average performance or change over time, but few have investigated patterns of cognitive trajectories after stroke. This project used latent class growth analysis (LCGA) to identify clusters of patients with similar patterns of cognition scores over the first-year poststroke and the extent to which long-term cognitive outcome is predicted by the clusters ("trajectory groups"). METHODS: Data were sought from the Stroke and Cognition consortium. LCGA was used to identify clusters of trajectories based on standardized global cognition scores at baseline (T1) and at the 1-year follow-up (T2). One-step individual participant data meta-analysis was used to examine risk factors for trajectory groups and association of trajectory groups with cognition at the long-term follow-up (T3). RESULTS: Nine hospital-based stroke cohorts with 1,149 patients (63% male; mean age 66.4 years [SD 11.0]) were included. The median time assessed at T1 was 3.6 months poststroke, 1.0 year at T2, and 3.2 years at T3. LCGA identified 3 trajectory groups, which were characterized by different mean levels of cognition scores at T1 (low-performance, -3.27 SD [0.94], 17%; medium-performance, -1.23 SD [0.68], 48%; and high-performance, 0.71 SD [0.77], 35%). There was significant improvement in cognition for the high-performance group (0.22 SD per year, 95% CI 0.07-0.36), but changes for the low-performance and medium-performance groups were not significant (-0.10 SD per year, 95% CI -0.33 to 0.13; 0.11 SD per year, 95% CI -0.08 to 0.24, respectively). Factors associated with the low- (vs high-) performance group include age (relative risk ratio [RRR] 1.18, 95% CI 1.14-1.23), years of education (RRR 0.61, 95% CI 0.56-0.67), diabetes (RRR 3.78, 95% CI 2.08-6.88), large artery vs small vessel strokes (RRR 2.77, 95% CI 1.32-5.83), and moderate/severe strokes (RRR 3.17, 95% CI 1.42-7.08). Trajectory groups were predictive of global cognition at T3, but its predictive power was comparable with scores at T1. DISCUSSION: The trajectory of cognitive function over the first-year poststroke is heterogenous. Baseline cognitive function ∼3.6 months poststroke is a good predictor of long-term cognitive outcome. Older age, lower levels of education, diabetes, large artery strokes, and greater stroke severity are risk factors for lower cognitive performance over the first year.

Cognition, function, and prevalent dementia in centenarians and near-centenarians: An individual participant data (IPD) meta-analysis of 18 studies.

INTRODUCTION: There are limited data on prevalence of dementia in centenarians and near-centenarians (C/NC), its determinants, and whether the risk of dementia continues to rise beyond 100. METHODS: Participant-level data were obtained from 18 community-based studies (N = 4427) in 11 countries that included individuals ≥95 years. A harmonization protocol was applied to cognitive and functional impairments, and a meta-analysis was performed. RESULTS: The mean age was 98.3 years (SD = 2.67); 79% were women. After adjusting for age, sex, and education, dementia prevalence was 53.2% in women and 45.5% in men, with risk continuing to increase with age. Education (OR 0.95;0.92-0.98) was protective, as was hypertension (odds ratio [OR] 0.51;0.35-0.74) in five studies. Dementia was not associated with diabetes, vision and hearing impairments, smoking, and body mass index (BMI). DISCUSSION: Among the exceptional old, dementia prevalence remains higher in the older participants. Education was protective against dementia, but other factors for dementia-free survival in C/NC remain to be understood.

Texture Features of Magnetic Resonance Images Predict Poststroke Cognitive Impairment: Validation in a Multicenter Study.

BACKGROUND: Imaging features derived from T1-weighted (T1w) images texture analysis were shown to be potential markers of poststroke cognitive impairment, with better sensitivity than atrophy measurement. However, in magnetic resonance images, the signal distribution is subject to variations and can limit transferability of the method between centers. This study examined the reliability of texture features against imaging settings using data from different centers. METHODS: Data were collected from 327 patients within the Stroke and Cognition Consortium from centers in France, Germany, Australia, and the United Kingdom. T1w images were preprocessed to normalize the signal intensities and then texture features, including first- and second-order statistics, were measured in the hippocampus and the entorhinal cortex. Differences between the data led to the use of 2 methods of analysis. First, a machine learning modeling, using random forest, was used to build a poststroke cognitive impairment prediction model using one dataset and this was validated on another dataset as external unseen data. Second, the predictive ability of the texture features was examined in the 2 remaining datasets by ANCOVA with false discovery rate correction for multiple comparisons. RESULTS: The prediction model had a mean accuracy of 90% for individual classification of patients in the learning base while for the validation base it was ≈ 77%. ANCOVA showed significant differences, in all datasets, for the kurtosis and inverse difference moment texture features when measured in patients with cognitive impairment and those without. CONCLUSIONS: These results suggest that texture features obtained from routine clinical MR images are robust early predictors of poststroke cognitive impairment and can be combined with other demographic and clinical predictors to build an accurate prediction model.

Is hospitalization a risk factor for cognitive decline in older age adults?

OBJECTIVES: Many studies document cognitive decline following specific types of acute illness hospitalizations (AIH) such as surgery, critical care, or those complicated by delirium. However, cognitive decline may be a complication following all types of AIH. This systematic review will summarize longitudinal observational studies documenting cognitive changes following AIH in the majority admitted population and conduct meta-analysis (MA) to assess the quantitative effect of AIH on post-hospitalization cognitive decline (PHCD). METHODS: We followed Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Selection criteria were defined to identify studies of older age adults exposed to AIH with cognitive measures. 6566 titles were screened. 46 reports were reviewed qualitatively, of which seven contributed data to the MA. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: The qualitative review suggested increased cognitive decline following AIH, but several reports were particularly vulnerable to bias. Domain-specific outcomes following AIH included declines in memory and processing speed. Increasing age and the severity of illness were the most consistent risk factors for PHCD. PHCD was supported by MA of seven eligible studies with 41,453 participants (Cohen's d = -0.25, 95% CI [-0.02, -0.49] I2 35%). CONCLUSIONS: There is preliminary evidence that AIH exposure accelerates or triggers cognitive decline in the elderly patient. PHCD reported in specific contexts could be subsets of a larger phenomenon and caused by overlapping mechanisms. Future research must clarify the trajectory, clinical significance, and etiology of PHCD: a priority in the face of an aging population with increasing rates of both cognitive impairment and hospitalization.

Long-Term Cognitive Decline After Stroke: An Individual Participant Data Meta-Analysis.

BACKGROUND: Poststroke cognitive impairment is common, but the trajectory and magnitude of cognitive decline after stroke is unclear. We examined the course and determinants of cognitive change after stroke using individual participant data from the Stroke and Cognition Consortium. METHODS: Nine longitudinal hospital-based cohorts from 7 countries were included. Neuropsychological test scores and normative data were used to calculate standardized scores for global cognition and 5 cognitive domains. One-step individual participant data meta-analysis was used to examine the rate of change in cognitive function and risk factors for cognitive decline after stroke. Stroke-free controls were included to examine rate differences. Based on the literature and our own data that showed short-term improvement in cognitive function after stroke, key analyses were restricted to the period beginning 1-year poststroke to focus on its long-term effects. RESULTS: A total of 1488 patients (mean age, 66.3 years; SD, 11.1; 98% ischemic stroke) were followed for a median of 2.68 years (25th-75th percentile: 1.21-4.14 years). After an initial period of improvement through up to 1-year poststroke, decline was seen in global cognition and all domains except executive function after adjusting for age, sex, education, vascular risk factors, and stroke characteristics (-0.053 SD/year [95% CI, -0.073 to -0.033]; P<0.001 for global cognition). Recurrent stroke and older age were associated with faster decline. Decline was significantly faster in patients with stroke compared with controls (difference=-0.078 SD/year [95% CI, -0.11 to -0.045]; P<0.001 for global cognition in a subgroup analysis). CONCLUSIONS: Patients with stroke experience cognitive decline that is faster than that of stroke-free controls from 1 to 3 years after onset. An increased rate of decline is associated with older age and recurrent stroke.

Resveratrol: A "miracle" drug in neuropsychiatry or a cognitive enhancer for mice only? A systematic review and meta-analysis.

BACKGROUND: Over the last decade resveratrol has been trialled for the prevention and treatment of cognitive decline; however, the results have shown a conflict between human studies compared with animal studies, especially on cognition, blood pressure, neuroimaging, and mood. METHODS: Human clinical trials and animal studies published prior to January 2020, were identified searching across major electronic databases. PRISMA guidelines were used for data extraction, which was independently performed by two authors. Pooled standard mean difference (SMD, random effect model) and odds ratios (ORs) were calculated. RESULTS: Most publications on animal models reported positive outcomes on cognition and brain function following exposure to resveratrol or grape seed extracts. By contrast, 11 meta-analyses of data from human placebo vs resveratrol, grape or wine treatment trials identified no statistically significant effect on a variety of measures, including cognitive and mood assessments, grey matter volume and blood pressure. CONCLUSIONS: Based on currently available data, the promising effects of resveratrol in animal models is not replicated in human clinical trials. The effects, if any, of resveratrol on human cognition are likely to be small. This work may be useful for the design and implementation of future pre-clinical and clinical studies using resveratrol in a neurological setting.

Assessing the Predictive Validity of Simple Dementia Risk Models in Harmonized Stroke Cohorts.

BACKGROUND AND PURPOSE: Stroke is associated with an increased risk of dementia. To assist in the early identification of individuals at high risk of future dementia, numerous prediction models have been developed for use in the general population. However, it is not known whether such models also provide accurate predictions among stroke patients. Therefore, the aim of this study was to determine whether existing dementia risk prediction models that were developed for use in the general population can also be applied to individuals with a history of stroke to predict poststroke dementia with equivalent predictive validity. METHODS: Data were harmonized from 4 stroke studies (follow-up range, ≈12-18 months poststroke) from Hong Kong, the United States, the Netherlands, and France. Regression analysis was used to test 3 risk prediction models: the Cardiovascular Risk Factors, Aging and Dementia score, the Australian National University Alzheimer Disease Risk Index, and the Brief Dementia Screening Indicator. Model performance or discrimination accuracy was assessed using the C statistic or area under the curve. Calibration was tested using the Grønnesby and Borgan and the goodness-of-fit tests. RESULTS: The predictive accuracy of the models varied but was generally low compared with the original development cohorts, with the Australian National University Alzheimer Disease Risk Index (C-statistic, 0.66) and the Brief Dementia Screening Indicator (C-statistic, 0.61) both performing better than the Cardiovascular Risk Factors, Aging and Dementia score (area under the curve, 0.53). CONCLUSIONS: Dementia risk prediction models developed for the general population do not perform well in individuals with stroke. Their poor performance could have been due to the need for additional or different predictors related to stroke and vascular risk factors or methodological differences across studies (eg, length of follow-up, age distribution). Future work is needed to develop simple and cost-effective risk prediction models specific to poststroke dementia.

APOE ε4 and the Influence of Sex, Age, Vascular Risk Factors, and Ethnicity on Cognitive Decline.

We aimed to examine the relationship between Apolipoprotein E ε4 (APOE*4) carriage on cognitive decline, and whether these associations were moderated by sex, baseline age, ethnicity, and vascular risk factors. Participants were 19,225 individuals aged 54-103 years from 15 longitudinal cohort studies with a mean follow-up duration ranging between 1.2 and 10.7 years. Two-step individual participant data meta-analysis was used to pool results of study-wise analyses predicting memory and general cognitive decline from carriage of one or two APOE*4 alleles, and moderation of these associations by age, sex, vascular risk factors, and ethnicity. Separate pooled estimates were calculated in both men and women who were younger (ie, 62 years) and older (ie, 80 years) at baseline. Results showed that APOE*4 carriage was related to faster general cognitive decline in women, and faster memory decline in men. A stronger dose-dependent effect was observed in older men, with faster general cognitive and memory decline in those carrying two versus one APOE*4 allele. Vascular risk factors were related to an increased effect of APOE*4 on memory decline in younger women, but a weaker effect of APOE*4 on general cognitive decline in older men. The relationship between APOE*4 carriage and memory decline was larger in older-aged Asians than Whites. In sum, APOE*4 is related to cognitive decline in men and women, although these effects are enhanced by age and carriage of two APOE*4 alleles in men, a higher numbers of vascular risk factors during the early stages of late adulthood in women, and Asian ethnicity.

Association of Prediabetes and Type 2 Diabetes With Cognitive Function After Stroke: A STROKOG Collaboration Study.

Background and Purpose- Type 2 diabetes mellitus (T2D) is associated with cognitive impairment and an increased risk of dementia, but the association between prediabetes and cognitive impairment is less clear, particularly in a setting of major cerebrovascular events. This article examines the impact of impaired fasting glucose and T2D on cognitive performance in a stroke population. Methods- Seven international observational studies from the STROKOG (Stroke and Cognition) consortium (n=1601; mean age, 66.0 years; 70% Asian, 26% white, and 2.6% African American) were included. Fasting glucose level (FGL) during hospitalization was used to define 3 groups, T2D (FGL ≥7.0 mmol/L), impaired fasting glucose (FGL 6.1-6.9 mmol/L), and normal (FGL <6.1 mmol/L), and a history of diabetes mellitus and the use of a diabetes mellitus medication were also used to support a diagnosis of T2D. Domain and global cognition Z scores were derived from standardized neuropsychological test scores. The cross-sectional association between glucose status and cognitive performance at 3 to 6 months poststroke was examined using linear mixed models, adjusting for age, sex, education, stroke type, ethnicity, and vascular risk factors. Results- Patients with T2D had significantly poorer performance in global cognition (SD, -0.59 [95% CI, -0.82 to -0.36]; P<0.001) and in all domains compared with patients with normal FGL. There was no significant difference between impaired fasting glucose patients and those with normal FGL in global cognition (SD, -0.10 [95% CI, -0.45 to 0.24]; P=0.55) or in any cognitive domain. Conclusions- Diabetes mellitus, but not prediabetes, is associated with poorer cognitive performance in patients 3 to 6 months after stroke.

Profile of and risk factors for poststroke cognitive impairment in diverse ethnoregional groups.

OBJECTIVE: To address the variability in prevalence estimates and inconsistencies in potential risk factors for poststroke cognitive impairment (PSCI) using a standardized approach and individual participant data (IPD) from international cohorts in the Stroke and Cognition Consortium (STROKOG) consortium. METHODS: We harmonized data from 13 studies based in 8 countries. Neuropsychological test scores 2 to 6 months after stroke or TIA and appropriate normative data were used to calculate standardized cognitive domain scores. Domain-specific impairment was based on percentile cutoffs from normative groups, and associations between domain scores and risk factors were examined with 1-stage IPD meta-analysis. RESULTS: In a combined sample of 3,146 participants admitted to hospital for stroke (97%) or TIA (3%), 44% were impaired in global cognition and 30% to 35% were impaired in individual domains 2 to 6 months after the index event. Diabetes mellitus and a history of stroke were strongly associated with poorer cognitive function after covariate adjustments; hypertension, smoking, and atrial fibrillation had weaker domain-specific associations. While there were no significant differences in domain impairment among ethnoracial groups, some interethnic differences were found in the effects of risk factors on cognition. CONCLUSIONS: This study confirms the high prevalence of PSCI in diverse populations, highlights common risk factors, in particular diabetes mellitus, and points to ethnoracial differences that warrant attention in the development of prevention strategies.

Postnatal dexamethasone, respiratory and neurodevelopmental outcomes at two years in babies born extremely preterm.

IMPORTANCE: Postnatal dexamethasone is associated with reduction in bronchopulmonary dysplasia. There remains, however, concern that its short-term benefits are accompanied by long-term adverse effects e.g. poorer neurodevelopmental outcomes. OBJECTIVE: Our aim was to determine the effects of administration of postnatal dexamethasone on respiratory and neurodevelopmental outcome at two years of age after adjusting for neonatal and infant risk factors. MATERIALS AND METHODS: The study included 412 infants born at 23-28 weeks of gestation, 29% had received postnatal dexamethasone. Two outcomes were examined, respiratory hospital admissions in the past 12 months and neurodevelopmental impairment. Logistic regression, adjusted for sex, birthweight z-score, gestation, maternal smoking, oxygen dependency at 36 weeks, airleak, patent ductus arteriosus, pulmonary haemorrhage, major ultrasound abnormality, mode of ventilation and age at assessment, was undertaken. RESULTS: After adjustment, postnatal dexamethasone was associated with significantly increased proportions of both respiratory hospital readmission: (0.35 vs 0.15, difference = 0.20; 95% CI: 0.08, 0.31) and neurodevelopmental impairment (0.59 vs 0.45, difference = 0.14; 95% CI: 0.02, 0.26). CONCLUSIONS: Postnatal dexamethasone use in extremely preterm infants is associated with increased risks of respiratory hospital admissions and neurodevelopmental impairment. These associations were not explained by excess neonatal morbidities.

STROKOG (stroke and cognition consortium): An international consortium to examine the epidemiology, diagnosis, and treatment of neurocognitive disorders in relation to cerebrovascular disease.

INTRODUCTION: The Stroke and Cognition consortium (STROKOG) aims to facilitate a better understanding of the determinants of vascular contributions to cognitive disorders and help improve the diagnosis and treatment of vascular cognitive disorders (VCD). METHODS: Longitudinal studies with ≥75 participants who had suffered or were at risk of stroke or TIA and which evaluated cognitive function were invited to join STROKOG. The consortium will facilitate projects investigating rates and patterns of cognitive decline, risk factors for VCD, and biomarkers of vascular dementia. RESULTS: Currently, STROKOG includes 25 (21 published) studies, with 12,092 participants from five continents. The duration of follow-up ranges from 3 months to 21 years. DISCUSSION: Although data harmonization will be a key challenge, STROKOG is in a unique position to reuse and combine international cohort data and fully explore patient level characteristics and outcomes. STROKOG could potentially transform our understanding of VCD and have a worldwide impact on promoting better vascular cognitive outcomes.

A phase III, multi-centre, double-masked randomised controlled trial of adjunctive intraocular and peri-ocular steroid (triamcinolone acetonide) versus standard treatment in eyes undergoing vitreoretinal surgery for open globe trauma (ASCOT): statistical analysis plan.

BACKGROUND: Open globe ocular trauma complicated by intraocular scarring (proliferative vitreoretinopathy) is a relatively rare, blinding, but potentially treatable condition for which, at present, surgery is often unsatisfactory and visual results frequently poor. To date, no pharmacological adjuncts to surgery have been proven to be effective. The aim of the Adjunctive Steroid Combination in Ocular Trauma (ASCOT) randomised controlled trial is to determine whether adjunctive steroid (triamcinolone acetonide), given at the time of surgery, can improve the outcome of vitreoretinal surgery in patients with open globe ocular trauma. This article presents the statistical analysis plan for the main publication as approved and signed off by the Trial Steering Committee prior to the first data extraction for the Data Monitoring Committee meeting report. METHODS/DESIGN: ASCOT is a pragmatic, multi-centre, parallel-group, double-masked randomised controlled trial. The aim of the study is to recruit from 20-25 centres in the United Kingdom and randomise 300 eyes (from 300 patients) into two treatment arms. Both groups will receive standard surgical treatment and care; the intervention arm will additionally receive a pre-operative steroid combination (triamcinolone acetonide) into the vitreous cavity consisting of 4 mg/0.1 ml and 40 mg/1 ml sub-Tenon's. Participants will be followed for 6 months post-surgery. The primary outcome is the proportion of patients achieving a clinically meaning improvement in visual acuity in the study eye at 6 months after initial surgery, defined as a 10 letter score improvement in the ETDRS (the standard scale to test visual acuity). TRIAL REGISTRATION: ISRCTN30012492 . Registered on 5 September 2014. EudraCT2014-002193-37 . Registered on 5 September 2014.

Adjunctive intraocular and peri-ocular steroid (triamcinolone acetonide) versus standard treatment in eyes undergoing vitreoretinal surgery for open globe trauma (ASCOT): study protocol for a phase III, multi-centre, double-masked randomised controlled trial.

BACKGROUND: Eyes sustaining open globe trauma are at high risk of severe visual impairment. Ocular injuries which result in visual loss invariably affect the posterior segment of the eye, and prevention of visual loss involves posterior segment (vitreoretinal) surgery. Despite improvements in vitreoretinal surgical techniques, outcomes in these patients remain unsatisfactory, and development of the intraocular scarring response proliferative vitreoretinopathy is the leading cause. Proliferative vitreoretinopathy is the most common cause of recurrent retinal detachment in these eyes; it is reported to occur in up to 45 % of cases. METHODS/DESIGN: The Adjunctive Steroid Combination in Ocular Trauma (ASCOT) trial is a multi-centre, double-masked, parallel-arm randomised controlled trial with an internal pilot designed to investigate the effectiveness and cost-effectiveness of using intravitreal and sub-Tenon's triamcinolone acetonide peri-operatively in patients undergoing vitrectomy following open globe trauma. In total, 300 eyes of 300 patients will be recruited and randomly allocated to one of two treatment groups. Both groups will receive standard surgical treatment and routine pre-operative and post-operative treatment and care. The treatment group will receive an adjunctive peri-operative steroid combination (triamcinolone acetonide) consisting of 4 mg/0.1 ml into the vitreous cavity and 40 mg/1 ml into the sub-Tenon's space. The trial incorporates a two-stage internal pilot to examine projected recruitment and retention rates. Progression criteria from the internal pilot study will enable us to determine whether to undertake the main trial. Patients and primary outcome assessors will be masked to treatment allocation. The primary outcome will be an improvement from baseline to 6 months of at least 10 on the corrected visual acuity as measured by ETDRS letter score. Secondary outcomes will be development of scarring, retinal detachment, intraocular pressure abnormalities, quality of life and public sector service use. DISCUSSION: This is the first powered, controlled clinical trial to investigate the use of adjunctive triamcinolone in patients undergoing vitrectomy following open globe trauma. TRIAL REGISTRATION: EudraCT2014-002193-37 . Registered on 5 September 2014. ISRCTN30012492 . Registered on 5 September 2014.

The prevalence and impact of undiagnosed cognitive impairment in older vascular surgical patients.

OBJECTIVE: The objectives of this observational cohort study were to investigate the prevalence of undiagnosed cognitive impairment in older patients presenting for vascular surgery, to examine its association with adverse postoperative outcomes, and to test the feasibility of a preoperative cognitive assessment tool. METHODS: Patients aged 60 years or older were recruited by consent on admission to the vascular surgical ward of an inner-city teaching hospital with a large tertiary referral practice for proposed elective or emergency aortic or lower limb arterial intervention. Cognition was assessed preoperatively by the Montreal Cognitive Assessment (MoCA), and a score below 24/30 indicated cognitive impairment or dementia. The mean length of time taken to complete the assessment was recorded. Baseline characteristics (medical multimorbidity, frailty, and laboratory tests), hospital length of stay (LOS), and postoperative complications were documented. RESULTS: Preoperative MoCA was completed in 114 patients with a mean age of 76.3 years (standard deviation, 7.36 years); 67.5% were men, and 55.3% of procedures were elective. The MoCA was completed in 100% of patients and was quick and acceptable to patients in this setting. Cognitive impairment or dementia was found in 68% of patients (77 of 114) and was previously unrecognized in 88.3% of patients (68 of 77). Therefore, 60.5% of patients (68 of 114) aged 60 years or older presenting for vascular surgery had previously undiagnosed cognitive impairment. MoCA <24 was univariately associated with pre-existing frailty (Edmonton Frail Scale [EFS] score ≥6.5) and longer LOS (≥12 days). In logistic regression modeling, MoCA <24 was strongly independently associated with frailty EFS score ≥6.5 (odds ratio, 12.55; P < .001). By use of the area under the receiver operating characteristic curve (AUC), MoCA <24 was predictive of longer LOS of ≥12 days (AUC, 0.621; P = .049). The strength of predictive power increased with the addition of frailty (EFS score ≥6.5) to the models (AUC, 0.695; P = .002). CONCLUSIONS: The prevalence of cognitive impairment among older patients presenting for vascular surgery is high and frequently undiagnosed before admission. It is feasible to use the MoCA to identify cognitive impairment in this high-risk surgical group preoperatively. The combined assessment of frailty and cognition is predictive of adverse postoperative outcomes and longer LOS.

Late outcomes of a randomized trial of high-frequency oscillation in neonates.

BACKGROUND: Results from an observational study involving neonates suggested that high-frequency oscillatory ventilation (HFOV), as compared with conventional ventilation, was associated with superior small-airway function at follow-up. Data from randomized trials are needed to confirm this finding. METHODS: We studied 319 adolescents who had been born before 29 weeks of gestation and had been enrolled in a multicenter, randomized trial that compared HFOV with conventional ventilation immediately after birth. The trial involved 797 neonates, of whom 592 survived to hospital discharge. We compared follow-up data from adolescents who had been randomly assigned to HFOV with follow-up data from those who had been randomly assigned to conventional ventilation, with respect to lung function and respiratory health, health-related quality of life, and functional status, as assessed with the use of questionnaires completed when the participants were 11 to 14 years of age. The primary outcome was forced expiratory flow at 75% of the expired vital capacity (FEF75). RESULTS: The HFOV group had superior results on a test of small-airway function (z score for FEF75, -0.97 with HFOV vs. -1.19 with conventional therapy; adjusted difference, 0.23 [95% confidence interval, 0.02 to 0.45]). There were significant differences in favor of HFOV in several other measures of respiratory function, including forced expiratory volume in 1 second, forced vital capacity, peak expiratory flow, diffusing capacity, and impulse-oscillometric findings. As compared with the conventional-therapy group, the HFOV group had significantly higher ratings from teachers in three of eight school subjects assessed, but there were no other significant differences in functional outcomes. CONCLUSIONS: In a randomized trial involving children who had been born extremely prematurely, those who had undergone HFOV, as compared with those who had received conventional ventilation, had superior lung function at 11 to 14 years of age, with no evidence of poorer functional outcomes. (Funded by the National Institute for Health Research Health Technology Assessment Programme and others.).

Respiratory morbidity at follow-up of small-for-gestational-age infants born very prematurely.

BACKGROUND: The aim of this study was to determine whether small-for-gestational-age (SGA) infants born very prematurely had increased respiratory morbidity in the neonatal period and at follow-up. METHODS: Data were examined from infants recruited into the United Kingdom Oscillation Study (UKOS). Of the 797 infants who were born at <29 wk of gestational age, 174 infants were SGA. Overall, 92% were exposed to antenatal corticosteroids and 97% received surfactant; follow-up data at 22-28 mo were available for 367 infants. RESULTS: After adjustment for gestational age and sex, SGA infants had higher rates of supplementary oxygen dependency at 36 wk postmenstrual age (odds ratio (OR): 3.23; 95% confidence interval: 2.03, 5.13), pulmonary hemorrhage (OR: 3.07; 95% CI: 1.82, 5.18), death (OR: 3.32; 95% CI: 2.13, 5.17), and postnatal corticosteroid requirement (OR: 2.09; 95% CI: 1.35, 3.23). After adjustment for infant and respiratory morbidity risk factors, a lower mean birth weight z-score was associated with a higher prevalence of respiratory admissions (OR: 1.40; 95% CI: 1.03, 1.88 for 1 SD change in z-score), cough (OR: 1.28; 95% CI: 1.00, 1.65), and use of chest medicines (OR: 1.32; 95% CI: 1.01, 1.73). CONCLUSION: SGA infants who were born very prematurely, despite routine use of antenatal corticosteroids and postnatal surfactant, had increased respiratory morbidity at follow-up, which was not due to poor neonatal outcome.