Publications by authors named "Jacqueline Birks"

53 Publications

A meta-analysis of aspirin and subarachnoid hemorrhage in patients with intracranial aneurysms yields different results to the general population.

Int J Stroke 2021 Apr 4:17474930211004888. Epub 2021 Apr 4.

▪, University Hospital Southampton, Southampton, UK.

Background: Some studies have shown a protective association between aspirin use and subarachnoid hemorrhage. Other studies have found no relationship or the reverse. These studies differ in their study populations and definitions of subarachnoid hemorrhage.

Aims: Our aim was to establish (1) if there is an association between aspirin and subarachnoid hemorrhage, (2) how this differs between the general population and those with intracranial aneurysms.

Summary Of Review: Studies reporting aspirin use and the occurrence of subarachnoid hemorrhage were included and grouped based on population (general population vs. aneurysm population). Odds ratios, hazard ratios, and confidence intervals were combined in random-effects models. Eleven studies were included. Overall, there was an association between aspirin and subarachnoid hemorrhage (OR 0.68 [0.48, 0.96]). However, populations were diverse and heterogeneity between studies high ( < 0.00001), questioning the validity of combining these studies and justifying analysis by population. In the general population, there was no difference in aspirin use between individuals with and without subarachnoid hemorrhage (OR 1.15 [0.96, 1.38]). In patients with intracranial aneurysms, aspirin use was greater in patients without subarachnoid hemorrhage (OR 0.37 [0.24, 0.58]), although these studies were at higher risk of bias.

Conclusions: There is an association between aspirin use and subarachnoid hemorrhage in patients with intracranial aneurysms. This apparent protective relationship is not seen in the general population. Prospective randomized studies are required to further investigate the effect of aspirin on unruptured intracranial aneurysms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/17474930211004888DOI Listing
April 2021

Postpartum-Specific Vital Sign Reference Ranges.

Obstet Gynecol 2021 02;137(2):295-304

Nuffield Department of Clinical Neurosciences, the Institute of Biomedical Engineering, Department of Engineering Science, the Nuffield Department of Women's & Reproductive Health, and the Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom; the Department of Anaesthesia, Wellington Hospital, Wellington, New Zealand; and Guy's and St Thomas' NHS Foundation Trust and the Department of Women and Children's Health, King's College, London, and the National Perinatal Epidemiology Unit and the Oxford National Institute for Health Research Biomedical Research Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Objective: To estimate normal ranges for postpartum maternal vital signs.

Methods: We conducted a multicenter prospective longitudinal cohort study in the United Kingdom. We recruited women before 20 weeks of gestation without significant comorbidities and with accurately dated singleton pregnancies. Women recorded their own blood pressure, heart rate, oxygen saturation and temperature daily for 2 weeks postpartum. Trained midwives measured participants' vital signs including respiratory rate around postpartum days 1, 7, and 14.

Results: From August 2012 to September 2016, we screened 4,279 pregnant women; 1,054 met eligibility criteria and chose to take part. Postpartum vital sign data were available for 909 women (86.2%). Median, or 50th centile (3rd-97th centile), systolic and diastolic blood pressures increased from the day of birth: 116 mm Hg (88-147) and 74 mm Hg (59-93) to a maximum median of 121 mm Hg (102-143) and 79 mm Hg (63-94) on days 5 and 6 postpartum, respectively, an increase of 5 mm Hg (95% CI 3-7) and 5 mm Hg (95% CI 4-6), respectively. Median (3rd-97th centile) systolic and diastolic blood pressure returned to 116 mm Hg (98-137) and 75 mm Hg (61-91) by day 14 postpartum. The median (3rd-97th centile) heart rate was highest on the day of birth, 84 beats per minute (bpm) (59-110) decreasing to a minimum of 75 bpm (55-101) 14 days postpartum. Oxygen saturation, respiratory rate, and temperature did not change in the 2 weeks postbirth. Median (3rd-97th centile) day-of-birth oxygen saturation was 96% (93-98). Median (3rd-97th centile) day-of-birth respiratory rate was 15 breaths per minute (10-22). Median (3rd-97th centile) day-of-birth temperature was 36.7°C (35.6-37.6).

Conclusion: We present widely relevant, postpartum, day-specific reference ranges which may facilitate early detection of abnormal blood pressure, heart rate, respiratory rate, oxygen saturation and temperature during the puerperium. Our findings could inform construction of an evidence-based modified obstetric early warning system to better identify unwell postpartum women.

Clinical Trial Registration: ISRCTN, 10838017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AOG.0000000000004239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813441PMC
February 2021

The Full Blood Count Blood Test for Colorectal Cancer Detection: A Systematic Review, Meta-Analysis, and Critical Appraisal.

Cancers (Basel) 2020 Aug 19;12(9). Epub 2020 Aug 19.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK.

Introduction: A full blood count (FBC) blood test includes 20 components. We systematically reviewed studies that assessed the association of the FBC and diagnosis of colorectal cancer to identify components as risk factors. We reviewed FBC-based prediction models for colorectal cancer risk.

Methods: MEDLINE, EMBASE, CINAHL, and Web of Science were searched until 3 September 2019. We meta-analysed the mean difference in FBC components between those with and without a diagnosis and critically appraised the development and validation of FBC-based prediction models.

Results: We included 53 eligible articles. Three of four meta-analysed components showed an association with diagnosis. In the remaining 16 with insufficient data for meta-analysis, three were associated with colorectal cancer. Thirteen FBC-based models were developed. Model performance was commonly assessed using the c-statistic (range 0.72-0.91) and calibration plots. Some models appeared to work well for early detection but good performance may be driven by early events.

Conclusion: Red blood cells, haemoglobin, mean corpuscular volume, red blood cell distribution width, white blood cell count, and platelets are associated with diagnosis and could be used for referral. Existing FBC-based prediction models might not perform as well as expected and need further critical testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12092348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564785PMC
August 2020

Early warning scores for detecting deterioration in adult hospital patients: systematic review and critical appraisal of methodology.

BMJ 2020 05 20;369:m1501. Epub 2020 May 20.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK.

Objective: To provide an overview and critical appraisal of early warning scores for adult hospital patients.

Design: Systematic review.

Data Sources: Medline, CINAHL, PsycInfo, and Embase until June 2019.

Eligibility Criteria For Study Selection: Studies describing the development or external validation of an early warning score for adult hospital inpatients.

Results: 13 171 references were screened and 95 articles were included in the review. 11 studies were development only, 23 were development and external validation, and 61 were external validation only. Most early warning scores were developed for use in the United States (n=13/34, 38%) and the United Kingdom (n=10/34, 29%). Death was the most frequent prediction outcome for development studies (n=10/23, 44%) and validation studies (n=66/84, 79%), with different time horizons (the most frequent was 24 hours). The most common predictors were respiratory rate (n=30/34, 88%), heart rate (n=28/34, 83%), oxygen saturation, temperature, and systolic blood pressure (all n=24/34, 71%). Age (n=13/34, 38%) and sex (n=3/34, 9%) were less frequently included. Key details of the analysis populations were often not reported in development studies (n=12/29, 41%) or validation studies (n=33/84, 39%). Small sample sizes and insufficient numbers of event patients were common in model development and external validation studies. Missing data were often discarded, with just one study using multiple imputation. Only nine of the early warning scores that were developed were presented in sufficient detail to allow individualised risk prediction. Internal validation was carried out in 19 studies, but recommended approaches such as bootstrapping or cross validation were rarely used (n=4/19, 22%). Model performance was frequently assessed using discrimination (development n=18/22, 82%; validation n=69/84, 82%), while calibration was seldom assessed (validation n=13/84, 15%). All included studies were rated at high risk of bias.

Conclusions: Early warning scores are widely used prediction models that are often mandated in daily clinical practice to identify early clinical deterioration in hospital patients. However, many early warning scores in clinical use were found to have methodological weaknesses. Early warning scores might not perform as well as expected and therefore they could have a detrimental effect on patient care. Future work should focus on following recommended approaches for developing and evaluating early warning scores, and investigating the impact and safety of using these scores in clinical practice.

Systematic Review Registration: PROSPERO CRD42017053324.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmj.m1501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238890PMC
May 2020

Impact of Treatment Delay on Outcome in the International Subarachnoid Aneurysm Trial.

Stroke 2020 05 25;51(5):1600-1603. Epub 2020 Mar 25.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford University Hospitals Foundation NHS Trust, United Kingdom (A.C., M.S., A.J.M.).

Background and Purpose- ISAT (International Subarachnoid Aneurysm Trial) demonstrated that 1 year after aneurysmal subarachnoid hemorrhage, coiling resulted in a significantly better clinical outcome than clipping. After 5 years, this difference did not reach statistical significance, but mortality was still higher in the clipping group. Here, we present additional analyses, reporting outcome after excluding pretreatment deaths. Methods- Outcome measures were death with or without dependency at 1 and 5 years after treatment, after exclusion of all pretreatment deaths. Treatment differences were assessed using relative risks (RRs). With sensitivity and exploratory analyses, the relation between treatment delay and outcome was analyzed. Results- After exclusion of pretreatment deaths, at 1-year follow-up coiling was favorable over clipping for death or dependency (RR, 0.77 [95% CI, 0.67-0.89]) but not for death alone (RR, 0.88 [95% CI, 0.66-1.19]). After 5 years, no significant differences were observed, neither for death or dependency (RR, 0.88 [95% CI, 0.77-1.02]) nor for death alone (RR, 0.82 [95% CI, 0.64-1.05]). Sensitivity analyses showed a similar picture. In good-grade patients, coiling remained favorable over clipping in the long-term. Time between randomization and treatment was significantly longer in the clipping arm (mean 1.7 versus 1.1 days; <0.0001), during which 17 patients died because of rebleeding versus 6 pretreatment deaths in the endovascular arm (RR, 2.81 [95% CI, 1.11-7.11]). Conclusions- These additional analyses support the conclusion of ISAT that at 1-year follow-up after aneurysmal subarachnoid hemorrhage coiling has a better outcome than clipping. After 5 years, with pretreatment mortality excluded, the difference between coiling and clipping is not significant. The high number of pretreatment deaths in the clipping group highlights the importance of urgent aneurysm treatment to prevent early rebleeding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.120.028993DOI Listing
May 2020

Gestation-Specific Vital Sign Reference Ranges in Pregnancy.

Obstet Gynecol 2020 03;135(3):653-664

Nuffield Department of Clinical Neurosciences, Nuffield Department of Women's & Reproductive Health, the Department of Engineering Science, and the Centre for Statistics in Medicine, University of Oxford, Oxford, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, Guy's and St Thomas' NHS Foundation Trust, London, the Department of Women and Children's Health, King's College, London, and the Oxford National Institute for Health Research Biomedical Research Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Objective: To estimate normal ranges for maternal vital signs throughout pregnancy, which have not been well defined in a large contemporary population.

Methods: We conducted a three-center, prospective, longitudinal cohort study in the United Kingdom from August 2012 to September 2017. We recruited women at less than 20 weeks of gestation without significant comorbidities with accurately dated singleton pregnancies. We measured participants' blood pressure (BP), heart rate, respiratory rate, oxygen saturation and temperature following standardized operating procedures at 4-6 weekly intervals throughout pregnancy.

Results: We screened 4,279 pregnant women, 1,041 met eligibility criteria and chose to take part. Systolic and diastolic BP decreased slightly from 12 weeks of gestation: median or 50th centile (3rd-97th centile) 114 (95-138); 70 (56-87) mm Hg to reach minimums of 113 (95-136); 69 (55-86) mm Hg at 18.6 and 19.2 weeks of gestation, respectively, a change (95% CI) of -1.0 (-2 to 0); -1 (-2 to -1) mm Hg. Systolic and diastolic BP then rose to a maximum median (3rd-97th centile) of 121 (102-144); 78 (62-95) mm Hg at 40 weeks of gestation, a difference (95% CI) of 7 (6-9) and9 (8-10) mm Hg, respectively. The median (3rd-97th centile) heart rate was lowest at 12 weeks of gestation: 82 (63-105) beats per minute (bpm), rising progressively to a maximum of 91 (68-115) bpm at 34.1 weeks. SpO2 decreased from 12 weeks of gestation: median (3-97 centile) 98% (94-99%) to 97% (93-99%) at 40 weeks. The median (3-97 centile) respiratory rate at 12 weeks of gestation was 15 (9-22), which did not change with gestation. The median (3-97 centile) temperature at 12 weeks of gestation was 36.7 (35.6-37.5)°C, decreasing to a minimum of 36.5 (35.3-37.3)°C at 33.4 weeks.

Conclusion: We present widely relevant, gestation-specific reference ranges for detecting abnormal BP, heart rate, respiratory rate, oxygen saturation and temperature during pregnancy. Our findings refute the existence of a clinically significant BP drop from 12 weeks of gestation.

Clinical Trial Registration: ISRCTN, ISRCTN10838017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AOG.0000000000003721DOI Listing
March 2020

Components of the full blood count as risk factors for colorectal cancer detection: a systematic review protocol.

BMJ Open 2019 12 16;9(12):e032759. Epub 2019 Dec 16.

Centre for Statistics in Medicine, University of Oxford, Oxford, UK.

Introduction: Colorectal cancer is the fourth most common type of cancer and the second most common cause of cancer-related deaths in the UK. The full blood count (FBC) is a blood test that may play a role in early detection of the disease. Previous studies have aimed to identify how levels of individual components, such as haemoglobin, can be used to assist the diagnosis. We aim to systematically review studies to identify whether components of the FBC are risk factors for diagnosis of colorectal cancer, critically appraise the methods used to assess the association and assess performance of the components.

Methods And Analysis: The MEDLINE (via OVID), EMBASE (via OVID), CINAHL (via EBSCOhost) and Web of Science databases will be searched to identify studies reporting the association between the levels of at least one FBC component and the risk of a future diagnosis of colorectal cancer in undiagnosed individuals. Clincialtrials.gov and the WHO registry will be searched to identify relevant ongoing research. Search terms will include relevant Medical Subject Headings and Emtree headings, and free-text terms relating to FBC, colorectal cancer and diagnosis. No date or language restrictions will be applied. Two reviewers will independently identify the studies for inclusion and perform data extraction. Time intervals between the blood tests and diagnosis will form the subgroups for analysis.

Ethics And Dissemination: There is no direct patient involvement and only published articles will be reviewed; no ethical approval is required. Results from this review will set a foundation for intended future work on developing a new risk score for early detection of colorectal cancer, derived using FBC data. This systematic review will also provide guidance on the analysis of time to diagnosis. The model will be freely available to UK primary care practices.

Prospero Registration Number: CRD42019134400.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2019-032759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937079PMC
December 2019

Trends of blood pressure and heart rate in normal pregnancies: a systematic review and meta-analysis.

BMC Med 2019 09 11;17(1):167. Epub 2019 Sep 11.

Kadoorie Centre for Critical Care Research and Education, Nuffield Department of Clinical Neurosciences, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 9DU, UK.

Background: Current reference ranges for blood pressure and heart rate throughout pregnancy have a poor evidence base.

Methods: This is a systematic review and meta-analysis. We included studies measuring blood pressure or heart rate from healthy pregnant women within defined gestational periods of 16 weeks or less. We analysed systolic blood pressure, diastolic blood pressure and heart rate by gestational age. We assessed effects of measurement year and method.

Results: We included 39 studies undertaken in 1967-2017, containing 124,349 systolic measurements from 36,239 women, 124,291 diastolic measurements from 36,181 women and 10,948 heart rate measurements from 8317 women. Mean (95% CI) systolic blood pressure was lowest at 10 weeks gestation, 110.4 (108.5, 112.3) mmHg, rising to 116.0 (113.6, 118.4) mmHg at 40 weeks, mean (95% CI) change 5.6 (4.0, 7.2) mmHg. Mean (95% CI) diastolic blood pressure was lowest at 21 weeks gestation, 65.9 (64.2, 67.7) mmHg; rising to 72.8 (71.0, 74.6) mmHg at 40 weeks, mean (95% CI) change 6.9 (6.2, 7.5) mmHg. Mean (95% CI) heart rate rose from 79.3 (75.5, 83.1) beats/min at 10 weeks to 86.9 (82.2, 91.6) beats/min at 40 weeks gestation, mean (95% CI) change 7.6 (1.8, 13.4) beats/min. Studies using manual measurement reported higher diastolic blood pressures than studies using automated measurement, mean (95 CI) difference 4.9 (0.8, 8.9) mmHg. Diastolic blood pressure increased by 0.26 (95% CI 0.10-0.43) mmHg/year. Including only higher-quality studies had little effect on findings, with heterogeneity remaining high (I statistic > 50%).

Conclusions: Significant gestational blood pressure and heart rate changes occur that should be taken into account when assessing pregnant women. Commonly taught substantial decreases in blood pressure mid-pregnancy were not seen and heart rate increases were lower than previously thought. Manual and automated blood pressure measurement cannot be used interchangeably. Increases in diastolic blood pressure over the last half-century and differences between published studies show contemporary data are required to define current normal ranges.

Study Registration: PROSPERO CRD42014009673.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12916-019-1399-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737610PMC
September 2019

Comparing different ways of calculating sample size for two independent means: A worked example.

Contemp Clin Trials Commun 2019 Mar 29;13:100309. Epub 2018 Nov 29.

Institute of Biomedical Engineering (IBME), Department of Engineering Science, University of Oxford, United Kingdom.

We discuss different methods of sample size calculation for two independent means, aiming to provide insight into the calculation of sample size at the design stage of a parallel two-arm randomised controlled trial (RCT). We compare different methods for sample size calculation, using published results from a previous RCT. We use variances and correlation coefficients to compare sample sizes using different methods, including 1. The choice of the primary outcome measure: post-intervention score vs. change from baseline score. 2. The choice of statistical methods: -test without using correlation coefficients vs. analysis of covariance (ANCOVA). We show that the required sample size will depend on whether the outcome measure is the post-intervention score, or the change from baseline score, with or without baseline score included as a covariate. We show that certain assumptions have to be met when using simplified sample size equations, and discuss their implications in sample size calculation when planning an RCT. We strongly recommend publishing the crucial result "mean change (SE, standard error)" in a study paper, because it allows (i) the calculation of the variance of the change score in each arm, and (ii) to pool the variances from both arms. It also enables us to calculate the correlation coefficient in each arm. This subsequently allows us to calculate sample size using change score as the outcome measure. We use simulation to demonstrate how sample sizes by different methods are influenced by the strength of the correlation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.conctc.2018.100309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297128PMC
March 2019

Impact of Electronic Versus Paper Vital Sign Observations on Length of Stay in Trauma Patients: Stepped-Wedge, Cluster Randomized Controlled Trial.

JMIR Med Inform 2018 Oct 31;6(4):e10221. Epub 2018 Oct 31.

Kadoorie Centre for Critical Care Research and Education, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Background: Electronic recording of vital sign observations (e-Obs) has become increasingly prevalent in hospital care. The evidence of clinical impact for these systems is mixed.

Objective: The objective of our study was to assess the effect of e-Obs versus paper documentation (paper) on length of stay (time between trauma unit admission and "fit to discharge") for trauma patients.

Methods: A single-center, randomized stepped-wedge study of e-Obs against paper was conducted in two 26-bed trauma wards at a medium-sized UK teaching hospital. Randomization of the phased intervention order to 12 study areas was computer generated. The primary outcome was length of stay.

Results: A total of 1232 patient episodes were randomized (paper: 628, e-Obs: 604). There were 37 deaths in hospital: 21 in the paper arm and 16 in the e-Obs arm. For discharged patients, the median length of stay was 5.4 (range: 0.2-79.0) days on the paper arm and 5.6 (range: 0.1-236.7) days on the e-Obs arm. Competing risks regression analysis for time to discharge showed no difference between the treatment arms (subhazard ratio: 1.05; 95% CI 0.82-1.35; P=.68). A greater proportion of patient episodes contained an Early Warning Score (EWS) ≥3 using the e-Obs system than using paper (subhazard ratio: 1.63; 95% CI 1.28-2.09; P<.001). However, there was no difference in the time to the subsequent observation, "escalation time" (hazard ratio 1.05; 95% CI 0.80-1.38; P=.70).

Conclusions: The phased introduction of an e-Obs documentation system was not associated with a change in length of stay. A greater proportion of patient episodes contained an EWS≥3 using the e-Obs system, but this was not associated with a change in "escalation time."

Trial Registration: ISRCTN Registry ISRCTN91040762; http://www.isrctn.com/ISRCTN91040762 (Archived by WebCite at http://www.webcitation.org/72prakGTU).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/10221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236204PMC
October 2018

Donepezil for dementia due to Alzheimer's disease.

Cochrane Database Syst Rev 2018 06 18;6:CD001190. Epub 2018 Jun 18.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford, UK, OX3 7LD.

Background: Alzheimer's disease is the most common cause of dementia in older people. One approach to symptomatic treatment of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by blocking the action of the enzyme responsible for the breakdown of the neurotransmitter acetylcholine. This can be done by a group of drugs known as cholinesterase inhibitors. Donepezil is a cholinesterase inhibitor.This review is an updated version of a review first published in 1998.

Objectives: To assess the clinical efficacy and safety of donepezil in people with mild, moderate or severe dementia due to Alzheimer's disease; to compare the efficacy and safety of different doses of donepezil; and to assess the effect of donepezil on healthcare resource use and costs.

Search Methods: We searched Cochrane Dementia and Cognitive Improvement's Specialized Register, MEDLINE, Embase, PsycINFO and a number of other sources on 20 May 2017 to ensure that the search was as comprehensive and up-to-date as possible. In addition, we contacted members of the Donepezil Study Group and Eisai Inc.

Selection Criteria: We included all double-blind, randomised controlled trials in which treatment with donepezil was administered to people with mild, moderate or severe dementia due to Alzheimer's disease for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two different doses of donepezil were compared.

Data Collection And Analysis: One reviewer (JSB) extracted data on cognitive function, activities of daily living, behavioural symptoms, global clinical state, quality of life, adverse events, deaths and healthcare resource costs. Where appropriate and possible, we estimated pooled treatment effects. We used GRADE methods to assess the quality of the evidence for each outcome.

Main Results: Thirty studies involving 8257 participants met the inclusion criteria of the review, of which 28 studies reported results in sufficient detail for the meta-analyses. Most studies were of six months' duration or less. Only one small trial lasted 52 weeks. The studies tested mainly donepezil capsules at a dose of 5 mg/day or 10 mg/day. Two studies tested a slow-release oral formulation that delivered 23 mg/day. Participants in 21 studies had mild to moderate disease, in five studies moderate to severe, and in four severe disease. Seventeen studies were industry funded or sponsored, four studies were funded independently of industry and for nine studies there was no information on source of funding.Our main analysis compared the safety and efficacy of donepezil 10 mg/day with placebo at 24 to 26 weeks of treatment. Thirteen studies contributed data from 3396 participants to this analysis. Eleven of these studies were multicentre studies. Seven studies recruited patients with mild to moderate Alzheimer's disease, two with moderate to severe, and four with severe Alzheimer's disease, with a mean age of about 75 years. Almost all evidence was of moderate quality, downgraded due to study limitations.After 26 weeks of treatment, donepezil compared with placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog, range 0 to 70) (mean difference (MD) -2.67, 95% confidence interval (CI) -3.31 to -2.02, 1130 participants, 5 studies), the Mini-Mental State Examination (MMSE) score (MD 1.05, 95% CI 0.73 to 1.37, 1757 participants, 7 studies) and the Severe Impairment Battery (SIB, range 0 to 100) (MD 5.92, 95% CI 4.53 to 7.31, 1348 participants, 5 studies). Donepezil was also associated with better function measured with the Alzheimer's Disease Cooperative Study activities of daily living score for severe Alzheimer's disease (ADCS-ADL-sev) (MD 1.03, 95% CI 0.21 to 1.85, 733 participants, 3 studies). A higher proportion of participants treated with donepezil experienced improvement on the clinician-rated global impression of change scale (odds ratio (OR) 1.92, 95% CI 1.54 to 2.39, 1674 participants, 6 studies). There was no difference between donepezil and placebo for behavioural symptoms measured by the Neuropsychiatric Inventory (NPI) (MD -1.62, 95% CI -3.43 to 0.19, 1035 participants, 4 studies) or by the Behavioural Pathology in Alzheimer's Disease (BEHAVE-AD) scale (MD 0.4, 95% CI -1.28 to 2.08, 194 participants, 1 study). There was also no difference between donepezil and placebo for Quality of Life (QoL) (MD -2.79, 95% CI -8.15 to 2.56, 815 participants, 2 studies).Participants receiving donepezil were more likely to withdraw from the studies before the end of treatment (24% versus 20%, OR 1.25, 95% CI 1.05 to 1.50, 2846 participants, 12 studies) or to experience an adverse event during the studies (72% vs 65%, OR 1.59, 95% 1.31 to 1.95, 2500 participants, 10 studies).There was no evidence of a difference between donepezil and placebo for patient total healthcare resource utilisation.Three studies compared donepezil 10 mg/day to donepezil 5 mg/day over 26 weeks. The 5 mg dose was associated with slightly worse cognitive function on the ADAS-Cog, but not on the MMSE or SIB, with slightly better QoL and with fewer adverse events and withdrawals from treatment. Two studies compared donepezil 10 mg/day to donepezil 23 mg/day. There were no differences on efficacy outcomes, but fewer participants on 10 mg/day experienced adverse events or withdrew from treatment.

Authors' Conclusions: There is moderate-quality evidence that people with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12 or 24 weeks with donepezil experience small benefits in cognitive function, activities of daily living and clinician-rated global clinical state. There is some evidence that use of donepezil is neither more nor less expensive compared with placebo when assessing total healthcare resource costs. Benefits on 23 mg/day were no greater than on 10 mg/day, and benefits on the 10 mg/day dose were marginally larger than on the 5 mg/day dose, but the rates of withdrawal and of adverse events before end of treatment were higher the higher the dose.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD001190.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513124PMC
June 2018

Methylene blue fluorescence of the ureter during colorectal surgery.

Surg Endosc 2018 09 21;32(9):4036-4043. Epub 2018 May 21.

Nuffield Department of Surgery, University of Oxford, Oxford, UK.

Background: Iatrogenic ureteric injury is a serious complication of colorectal surgery. Incidence is estimated to be between 0.3 and 1.5%. Of all ureteric injuries, 9% occur during colorectal procedures. Ureteric stents are utilised as a method to reduce the risk of injury; however, these are not without risk and do not guarantee prevention of injury. Fluorescence is a safe and effective alternative for intraoperative ureteric localisation. This proof of principle study aims to assess the use of methylene blue to fluoresce the ureter during colorectal surgery.

Method: Patients undergoing elective colorectal surgery were included in this open label, non-randomised study. Methylene blue was administered intravenously at varying doses (0.25-1 mg/kg) over 5 min, 10-15 min prior to entering 'ureteric territory.' Fluorescence was assessed using the PINPOINT Deep Red laparoscopic system at fixed time points by the surgeon and an independent observer.

Results: 42 patients received methylene blue; 2 patients were excluded from analysis. Of the 69 ureters assessed, 64 were seen under fluorescence. Of these, 14 were not visible under white light. 50 ureters were observed with both fluorescence and white light with 14 of these being seen earlier with fluorescence. In ten cases, fluorescence revealed the ureter to be in a different location than suspected.

Conclusion: Fluorescence is a promising method to allow visualisation of the ureter, where it is not identified easily under standard operative conditions, thereby improving safety and reducing operative time and difficulty.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00464-018-6219-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096537PMC
September 2018

Comparing the Efficacy of a Mobile Phone-Based Blood Glucose Management System With Standard Clinic Care in Women With Gestational Diabetes: Randomized Controlled Trial.

JMIR Mhealth Uhealth 2018 Mar 20;6(3):e71. Epub 2018 Mar 20.

Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom.

Background: Treatment of hyperglycemia in women with gestational diabetes mellitus (GDM) is associated with improved maternal and neonatal outcomes and requires intensive clinical input. This is currently achieved by hospital clinic attendance every 2 to 4 weeks with limited opportunity for intervention between these visits.

Objective: We conducted a randomized controlled trial to determine whether the use of a mobile phone-based real-time blood glucose management system to manage women with GDM remotely was as effective in controlling blood glucose as standard care through clinic attendance.

Methods: Women with an abnormal oral glucose tolerance test before 34 completed weeks of gestation were individually randomized to a mobile phone-based blood glucose management solution (GDm-health, the intervention) or routine clinic care. The primary outcome was change in mean blood glucose in each group from recruitment to delivery, calculated with adjustments made for number of blood glucose measurements, proportion of preprandial and postprandial readings, baseline characteristics, and length of time in the study.

Results: A total of 203 women were randomized. Blood glucose data were available for 98 intervention and 85 control women. There was no significant difference in rate of change of blood glucose (-0.16 mmol/L in the intervention and -0.14 mmol/L in the control group per 28 days, P=.78). Women using the intervention had higher satisfaction with care (P=.049). Preterm birth was less common in the intervention group (5/101, 5.0% vs 13/102, 12.7%; OR 0.36, 95% CI 0.12-1.01). There were fewer cesarean deliveries compared with vaginal deliveries in the intervention group (27/101, 26.7% vs 47/102, 46.1%, P=.005). Other glycemic, maternal, and neonatal outcomes were similar in both groups. The median time from recruitment to delivery was similar (intervention: 54 days; control: 49 days; P=.23). However, there were significantly more blood glucose readings in the intervention group (mean 3.80 [SD 1.80] and mean 2.63 [SD 1.71] readings per day in the intervention and control groups, respectively; P<.001). There was no significant difference in direct health care costs between the two groups, with a mean cost difference of the intervention group compared to control of -£1044 (95% CI -£2186 to £99). There were no unexpected adverse outcomes.

Conclusions: Remote blood glucocse monitoring in women with GDM is safe. We demonstrated superior data capture using GDm-health. Although glycemic control and maternal and neonatal outcomes were similar, women preferred this model of care. Further studies are required to explore whether digital health solutions can promote desired self-management lifestyle behaviors and dietetic adherence, and influence maternal and neonatal outcomes. Digital blood glucose monitoring may provide a scalable, practical method to address the growing burden of GDM around the world.

Trial Registration: ClinicalTrials.gov NCT01916694; https://clinicaltrials.gov/ct2/show/NCT01916694 (Archived by WebCite at http://www.webcitation.org/6y3lh2BOQ).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/mhealth.9512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883074PMC
March 2018

Early warning scores for detecting deterioration in adult hospital patients: a systematic review protocol.

BMJ Open 2017 Dec 3;7(12):e019268. Epub 2017 Dec 3.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Introduction: Early warning scores (EWSs) are used extensively to identify patients at risk of deterioration in hospital. Previous systematic reviews suggest that studies which develop EWSs suffer methodological shortcomings and consequently may fail to perform well. The reviews have also identified that few validation studies exist to test whether the scores work in other settings. We will aim to systematically review papers describing the development or validation of EWSs, focusing on methodology, generalisability and reporting.

Methods: We will identify studies that describe the development or validation of EWSs for adult hospital inpatients. Each study will be assessed for risk of bias using the Prediction model Risk of Bias ASsessment Tool (PROBAST). Two reviewers will independently extract information. A narrative synthesis and descriptive statistics will be used to answer the main aims of the study which are to assess and critically appraise the methodological quality of the EWS, to describe the predictors included in the EWSs and to describe the reported performance of EWSs in external validation.

Ethics And Dissemination: This systematic review will only investigate published studies and therefore will not directly involve patient data. The review will help to establish whether EWSs are fit for purpose and make recommendations to improve the quality of future research in this area.

Prospero Registration Number: CRD42017053324.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2017-019268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736035PMC
December 2017

Evaluation of a prediction model for colorectal cancer: retrospective analysis of 2.5 million patient records.

Cancer Med 2017 Oct 21;6(10):2453-2460. Epub 2017 Sep 21.

Cancer Epidemiology Unit, Nuffield Department of Population Health, Oxford University, Richard Doll Building, Old Road Campus, Oxford, OX3 7LF, United Kingdom.

Earlier detection of colorectal cancer greatly improves prognosis, largely through surgical excision of neoplastic polyps. These include benign adenomas which can transform over time to malignant adenocarcinomas. This progression may be associated with changes in full blood count indices. An existing risk algorithm derived in Israel stratifies individuals according to colorectal cancer risk using full blood count data, but has not been validated in the UK. We undertook a retrospective analysis using the Clinical Practice Research Datalink. Patients aged over 40 with full blood count data were risk-stratified and followed up for a diagnosis of colorectal cancer over a range of time intervals. The primary outcome was the area under the receiver operating characteristic curve for the 18-24-month interval. We also undertook a case-control analysis (matching for age, sex, and year of risk score), and a cohort study of patients undergoing full blood count testing during 2012, to estimate predictive values. We included 2,550,119 patients. The area under the curve for the 18-24-month interval was 0.776 [95% confidence interval (CI): 0.771, 0.781]. Performance improves as the time interval reduces. The area under the curve for the age-matched case-control analysis was 0.583 [0.574, 0.591]. For the population risk-scored in 2012, the positive predictive value at 99.5% specificity was 8.8% with negative predictive value 99.6%. The algorithm offers an additional means of identifying risk of colorectal cancer, and could support other approaches to early detection, including screening and active case finding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.1183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633543PMC
October 2017

Interobserver Variability in Histologic Evaluation of Liver Fibrosis Using Categorical and Quantitative Scores.

Am J Clin Pathol 2017 04;147(4):364-369

Department of Histopathology, Oxford University Hospitals, Oxford, UK.

Objectives: The aim of the study was to investigate the interobserver agreement for categorical and quantitative scores of liver fibrosis.

Methods: Sixty-five consecutive biopsy specimens from patients with mixed liver disease etiologies were assessed by three pathologists using the Ishak and nonalcoholic steatohepatitis Clinical Research Network (NASH CRN) scoring systems, and the fibrosis area (collagen proportionate area [CPA]) was estimated by visual inspection (visual-CPA). A subset of 20 biopsy specimens was analyzed using digital imaging analysis (DIA) for the measurement of CPA (DIA-CPA).

Results: The bivariate weighted κ between any two pathologists ranged from 0.57 to 0.67 for Ishak staging and from 0.47 to 0.57 for the NASH CRN staging. Bland-Altman analysis showed poor agreement between all possible pathologist pairings for visual-CPA but good agreement between all pathologist pairings for DIA-CPA. There was good agreement between the two pathologists who assessed biopsy specimens by visual-CPA and DIA-CPA. The intraclass correlation coefficient, which is equivalent to the κ statistic for continuous variables, was 0.78 for visual-CPA and 0.97 for DIA-CPA.

Conclusions: These results suggest that DIA-CPA is the most robust method for assessing liver fibrosis followed by visual-CPA. Categorical scores perform less well than both the quantitative CPA scores assessed here.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcp/aqx011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848246PMC
April 2017

Arterial Effects of Canakinumab in Patients With Atherosclerosis and Type 2 Diabetes or Glucose Intolerance.

J Am Coll Cardiol 2016 10;68(16):1769-1780

Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background: Evidence suggests that interleukin (IL)-1β is important in the pathogenesis of atherosclerosis and its complications and that inhibiting IL-1β may favorably affect vascular disease progression.

Objectives: The goal of this study was to evaluate the effects of IL-1β inhibition with canakinumab versus placebo on arterial structure and function, determined by magnetic resonance imaging.

Methods: Patients (N = 189) with atherosclerotic disease and either type 2 diabetes mellitus or impaired glucose tolerance were randomized to receive placebo (n = 94) or canakinumab 150 mg monthly (n = 95) for 12 months. They underwent magnetic resonance imaging of the carotid arteries and aorta.

Results: There were no statistically significant differences between canakinumab compared with placebo in the primary efficacy and safety endpoints. There was no statistically significant change in mean carotid wall area and no effect on aortic distensibility, measured at 3 separate anatomic sites. The change in mean carotid artery wall area was -3.37 mm after 12 months with canakinumab versus placebo. High-sensitivity C-reactive protein was significantly reduced by canakinumab compared with placebo at 3 months (geometric mean ratio [GMR]: 0.568; 95% confidence interval [CI]: 0.436 to 0.740; p < 0.0001) and 12 months (GMR: 0.56; 95% CI: 0.414 to 0.758; p = 0.0002). Lipoprotein(a) levels were reduced by canakinumab compared with placebo (-4.30 mg/dl [range: -8.5 to -0.55 mg/dl]; p = 0.025] at 12 months), but triglyceride levels increased (GMR: 1.20; 95% CI: 1.046 to 1.380; p = 0.01). In these patients with type 2 diabetes mellitus or impaired glucose tolerance, canakinumab had no effect compared with placebo on any of the measures assessed by using a standard oral glucose tolerance test.

Conclusions: There were no statistically significant effects of canakinumab on measures of vascular structure or function. Canakinumab reduced markers of inflammation (high-sensitivity C-reactive protein and interleukin-6), and there were modest increases in levels of total cholesterol and triglycerides. (Safety & Effectiveness on Vascular Structure and Function of ACZ885 in Atherosclerosis and Either T2DM or IGT Patients; NCT00995930).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2016.07.768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064025PMC
October 2016

Large-scale community echocardiographic screening reveals a major burden of undiagnosed valvular heart disease in older people: the OxVALVE Population Cohort Study.

Eur Heart J 2016 Dec 26;37(47):3515-3522. Epub 2016 Jun 26.

National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

Background: Valvular heart disease (VHD) is expected to become more common as the population ages. However, current estimates of its natural history and prevalence are based on historical studies with potential sources of bias. We conducted a cross-sectional analysis of the clinical and epidemiological characteristics of VHD identified at recruitment of a large cohort of older people.

Methods And Results: We enrolled 2500 individuals aged ≥65 years from a primary care population and screened for undiagnosed VHD using transthoracic echocardiography. Newly identified (predominantly mild) VHD was detected in 51% of participants. The most common abnormalities were aortic sclerosis (34%), mitral regurgitation (22%), and aortic regurgitation (15%). Aortic stenosis was present in 1.3%. The likelihood of undiagnosed VHD was two-fold higher in the two most deprived socioeconomic quintiles than in the most affluent quintile, and three-fold higher in individuals with atrial fibrillation. Clinically significant (moderate or severe) undiagnosed VHD was identified in 6.4%. In addition, 4.9% of the cohort had pre-existing VHD (a total prevalence of 11.3%). Projecting these findings using population data, we estimate that the prevalence of clinically significant VHD will double before 2050.

Conclusions: Previously undetected VHD affects 1 in 2 of the elderly population and is more common in lower socioeconomic classes. These unique data demonstrate the contemporary clinical and epidemiological characteristics of VHD in a large population-based cohort of older people and confirm the scale of the emerging epidemic of VHD, with widespread implications for clinicians and healthcare resources.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehw229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216199PMC
December 2016

Trial protocol to compare the efficacy of a smartphone-based blood glucose management system with standard clinic care in the gestational diabetic population.

BMJ Open 2016 Mar 17;6(3):e009702. Epub 2016 Mar 17.

Nuffield Department of Obstetrics & Gynaecology, Oxford University Hospitals NHS Trust, Oxford, UK.

Introduction: The prevalence of gestational diabetes mellitus (GDM) is rising in the UK. Good glycaemic control improves maternal and neonatal outcomes. Frequent clinical review of patients with GDM by healthcare professionals is required owing to the rapidly changing physiology of pregnancy and its unpredictable course. Novel technologies that allow home blood glucose (BG) monitoring with results transmitted in real time to a healthcare professional have the potential to deliver good-quality healthcare to women more conveniently and at a lower cost to the patient and the healthcare provider compared to the conventional face-to-face or telephone-based consultation. We have developed an integrated GDm-health management system and aim to test the impact of using this system on maternal glycaemic control, costs, patient satisfaction and maternal and neonatal outcomes compared to standard clinic care in a single large publicly funded (National Health Service (NHS)) maternity unit.

Methods And Analysis: Women with confirmed gestational diabetes in a current pregnancy are individually randomised to either the GDm-health system and half the normal clinic visits or normal clinic care. Primary outcome is mean BG in each group from recruitment to delivery calculated, with adjustments made for number of BG measurements, proportion of preprandial and postprandial readings and length of time in study, and compared between the groups. The secondary objective will be to compare the two groups for compliance to the allocated BG monitoring regime, maternal and neonatal outcomes, glycaemic control using glycated haemoglobin (HbA1c) and other BG metrics, and patient attitudes to care assessed using a questionnaire and resource use.

Ethics And Dissemination: Thresholds for treatment, dietary advice and clinical management are the same in both groups. The results of the study will be published in a peer-reviewed journal and disseminated electronically and in print.

Trial Registration Number: NCT01916694; Pre-results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2015-009702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800121PMC
March 2016

Implementing an electronic observation and early warning score chart in the emergency department: a feasibility study.

Eur J Emerg Med 2017 Dec;24(6):e11-e16

aEmergency Department, John Radcliffe Hospital bDepartment of Engineering Science, Institute of Biomedical Engineering cCentre for Statistics in Medicine, Botnar Research Centre, Oxford University, Oxford dEmergency Department, Wexham Park Hospital, Slough, UK.

Background: Use of automated systems to aid identification of patient deterioration in routine hospital practice is limited and their impact on patient outcomes remains unclear. This study was designed to evaluate the feasibility of implementing an electronic observation chart with automated early warning score (EWS) calculation in the high-acuity area of an emergency department.

Methods: This study enrolled 3219 participants before and 3352 after implementation of an automated system, using bedside vital-sign entry on networked mobile devices. The primary outcome measure was the percentage of participants for whom an EWS was accurately recorded at each stage.

Results: Of the participants, 52.7% before and 92.9% after implementation of the electronic system had an accurate EWS recorded on charts available to the study team. Participant groups were well balanced for baseline characteristics and acuity.

Conclusion: In this study, the feasibility and limitations of implementing an electronic observation chart in the ED were demonstrated. Accurate EWS documentation was more frequent after implementation of the electronic observation chart. Retrospective analysis suggests that the use of an electronic observation system may lead to a greater percentage of observations being taken from those patients with a higher EWS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MEJ.0000000000000371DOI Listing
December 2017

Trends of vital signs with gestational age in normal pregnancies: a systematic review protocol.

BMJ Open 2016 Jan 5;6(1):e008769. Epub 2016 Jan 5.

Nuffield Department of Clinical Neurosciences, Oxford University Hospitals NHS Trust, Oxford, UK.

Introduction: Vital signs (blood pressure, heart rate, temperature, oxygen saturation and respiratory rate) are thought to undergo changes during and immediately after pregnancy. However, these physiological changes are not taken into account in the normal ranges, which themselves are not evidence-based, used in routine and acute care monitoring. We aim to synthesise the existing evidence base for changes in vital signs during pregnancy, in order to derive new centile charts for each stage of pregnancy and the immediate postpartum period.

Methods And Analysis: We will search the MEDLINE, EMBASE and CINAHL databases from their inception to April 2015 for vital signs from pregnant, intrapartum or postpartum women who were recruited as 'healthy'. Assessment of bias will be conducted using a predefined set of independently agreed methodological criteria, which assigns an overall quality score to each study. We will record whether the vital sign measurements were made with measurement devices validated for use in pregnancy and in a standard posture. We will use regression methods to construct centile charts of vital signs across pregnancy and the immediate postpartum period for each vital sign. We will compare existing reference ranges to those derived from our centile charts.

Dissemination: The systematic review will be published in a peer-reviewed journal and disseminated electronically and in print.

Prospero Reference: CRD42014009673.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2015-008769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716207PMC
January 2016

Rivastigmine for Alzheimer's disease.

Cochrane Database Syst Rev 2015 Sep 22;9:CD001191. Epub 2015 Sep 22.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford, UK, OX3 7LD.

Background: Alzheimer's disease is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and lower risk of adverse effects have since been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA.

Objectives: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type.

Search Methods: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 2 March 2015 using the terms: Rivastigmine OR  exelon OR ENA OR "SDZ ENA 713". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries and grey literature sources.

Selection Criteria: We included all unconfounded, double-blind, randomised, controlled trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two formulations of rivastigmine were compared.

Data Collection And Analysis: One review author (JSB) applied the study selection criteria, assessed the quality of studies and extracted data.

Main Results: A total of 13 trials met the inclusion criteria of the review. The trials had a duration of between 12 and 52 weeks. The older trials tested a capsule form with a dose of up to 12 mg/day. Trials reported since 2007 have tested continuous dose transdermal patch formulations delivering 4.6, 9.5 and 17.7 mg/day.Our main analysis compared the safety and efficacy of rivastigmine 6 to 12 mg/day orally or 9.5 mg/day transdermally with placebo.Seven trials contributed data from 3450 patients to this analysis. Data from another two studies were not included because of a lack of information and methodological concerns. All the included trials were multicentre trials and recruited patients with mild to moderate Alzheimer's disease with a mean age of about 75 years. All had low risk of bias for randomisation and allocation but the risk of bias due to attrition was unclear in four studies, low in one study and high in two studies.After 26 weeks of treatment rivastigmine compared to placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score (mean difference (MD) -1.79; 95% confidence interval (CI) -2.21 to -1.37, n = 3232, 6 studies) and the Mini-Mental State Examination (MMSE) score (MD 0.74; 95% CI 0.52 to 0.97, n = 3205, 6 studies), activities of daily living (SMD 0.20; 95% CI 0.13 to 0.27, n = 3230, 6 studies) and clinician rated global impression of changes, with a smaller proportion of patients treated with rivastigmine experiencing no change or a deterioration (OR 0.68; 95% CI 0.58 to 0.80, n = 3338, 7 studies).Three studies reported behavioural change, and there were no differences compared to placebo (standardised mean difference (SMD) -0.04; 95% CI -0.14 to 0.06, n = 1529, 3 studies). Only one study measured the impact on caregivers using the Neuropsychiatric Inventory-Caregiver Distress (NPI-D) scale and this found no difference between the groups (MD 0.10; 95% CI -0.91 to 1.11, n = 529, 1 study). Overall, participants who received rivastigmine were about twice as likely to withdraw from the trials (odds ratio (OR) 2.01, 95% CI 1.71 to 2.37, n = 3569, 7 studies) or to experience an adverse event during the trials (OR 2.16, 95% CI 1.82 to 2.57, n = 3587, 7 studies).

Authors' Conclusions: Rivastigmine (6 to 12 mg daily orally or 9.5 mg daily transdermally) appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, better outcomes were observed for rate of decline of cognitive function and activities of daily living, although the effects were small and of uncertain clinical importance. There was also a benefit from rivastigmine on the outcome of clinician's global assessment. There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers. At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy. The quality of evidence is only moderate for all of the outcomes reviewed because of a risk of bias due to dropouts. All the studies with usable data were industry funded or sponsored. This review has not examined economic data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD001191.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050299PMC
September 2015

Functional Defects in Color Vision in Patients With Choroideremia.

Am J Ophthalmol 2015 Oct 29;160(4):822-31.e3. Epub 2015 Jun 29.

Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom; Oxford Biomedical Research Centre and Moorfields Eye Hospital-UCL Institute of Ophthalmology NIHR Biomedical Research Centre, London, United Kingdom.

Purpose: To characterize defects in color vision in patients with choroideremia.

Design: Prospective cohort study.

Methods: Thirty patients with choroideremia (41 eyes) and 10 age-matched male controls (19 eyes) with visual acuity of ≥6/36 attending outpatient clinics in Oxford Eye Hospital underwent color vision testing with the Farnsworth-Munsell 100 hue test, visual acuity testing, and autofluorescence imaging. To exclude changes caused by degeneration of the fovea, a subgroup of 14 patients with a visual acuity ≥6/6 was analyzed. Calculated color vision total error scores were compared between the groups and related to a range of factors using a random-effects model.

Results: Mean color vision total error scores were 120 (95% confidence interval [CI] 92, 156) in the ≥6/6 choroideremia group, 206 (95% CI 161, 266) in the <6/6 visual acuity choroideremia group, and 47 (95% CI 32, 69) in the control group. Covariate analysis showed a significant difference in color vision total error score between the groups (P < .001 between each group).

Conclusions: Patients with choroideremia have a functional defect in color vision compared with age-matched controls. The color vision defect deteriorates as the degeneration encroaches on the fovea. The presence of an early functional defect in color vision provides a useful biomarker against which to assess successful gene transfer in gene therapy trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajo.2015.06.018DOI Listing
October 2015

ISAT: end of the debate on coiling versus clipping? - Authors' reply.

Lancet 2015 Jun;385(9984):2252

Department of Neurosurgery, John Radcliffe Hospital, Oxford, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(15)61061-3DOI Listing
June 2015

The relationship between symptoms and blood pressure during maintenance hemodialysis.

Hemodial Int 2015 Oct 7;19(4):543-52. Epub 2015 May 7.

Medical Statistics, Centre for Statistics in Medicine, Oxford, UK.

Intradialytic hypotension (IDH) is a detrimental complication of maintenance hemodialysis, but how it is defined and reported varies widely in the literature. European Best Practice Guideline and Kidney Disease Outcomes Quality Initiative guidelines require symptoms and a mitigating intervention to fulfill the diagnosis, but morbidity and mortality outcomes are largely based on blood pressure alone. Furthermore, little is known about the incidence of asymptomatic hypotension, which may be an important cause of hypoperfusion injury and impaired outcome. Seventy-seven patients were studied over 456 dialysis sessions. Blood pressure was measured at 15-minute intervals throughout the session and compared with post-dialysis symptom questionnaire results using mixed modeling to adjust for repeated measures in the same patient. The frequency of asymptomatic hypotension was estimated by logistic regression using a variety of commonly cited blood pressure metrics that describe IDH. In 113 sessions (25%) where symptoms were recorded on the questionnaire, these appear not to have been reported to dialysis staff. When symptoms were reported (293 sessions [64%]), an intervention invariably followed. Dizziness and cramp were strongly associated with changes in systolic blood pressure (SBP), but not diastolic blood pressure. Nausea occurred more frequently in younger patients but was not associated with falls in blood pressure. Thresholds that maximized the probability of an intervention rather than a session remaining asymptomatic were SBP <100 mmHg or a 20% reduction in SBP from baseline. The probability of SBP falling to <100 mmHg in an asymptomatic session was 0.23. Symptoms are frequently not reported by patients who are hypotensive during hemodialysis, which leads to an underestimation of IDH if symptom-based definitions are used. A revised definition of IDH excluding patient-reported symptoms would be in line with literature reporting morbidity and mortality outcomes and include sessions in which potentially detrimental asymptomatic hypotension occurs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hdi.12306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682453PMC
October 2015

Rivastigmine for Alzheimer's disease.

Cochrane Database Syst Rev 2015 Apr 10(4):CD001191. Epub 2015 Apr 10.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford, UK, OX3 7LD.

Background: Alzheimer's disease is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and lower risk of adverse effects have since been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA.

Objectives: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type.

Search Methods: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 2 March 2015 using the terms: Rivastigmine OR  exelon OR ENA OR "SDZ ENA 713". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries and grey literature sources.

Selection Criteria: We included all unconfounded, double-blind, randomised, controlled trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two formulations of rivastigmine were compared.

Data Collection And Analysis: One review author (JSB) applied the study selection criteria, assessed the quality of studies and extracted data.

Main Results: A total of 13 trials met the inclusion criteria of the review. The trials had a duration of between 12 and 52 weeks. The older trials tested a capsule form with a dose of up to 12 mg/day. Trials reported since 2007 have tested continuous dose transdermal patch formulations delivering 4.6, 9.5 and 17.7 mg/day.Our main analysis compared the safety and efficacy of rivastigmine 6 to 12 mg/day orally or 9.5 mg/day transdermally with placebo.Seven trials contributed data from 3450 patients to this analysis. Data from another two studies were not included because of a lack of information and methodological concerns. All the included trials were multicentre trials and recruited patients with mild to moderate Alzheimer's disease with a mean age of about 75 years. All had low risk of bias for randomisation and allocation but the risk of bias due to attrition was unclear in four studies, low in one study and high in two studies.After 26 weeks of treatment rivastigmine compared to placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score (mean difference (MD) -1.79; 95% confidence interval (CI) -2.21 to -1.37, n = 3232, 6 studies) and the Mini-Mental State Examination (MMSE) score (MD 0.74; 95% CI 0.52 to 0.97, n = 3205, 6 studies), activities of daily living (SMD 0.20; 95% CI 0.13 to 0.27, n = 3230, 6 studies) and clinician rated global impression of changes, with a smaller proportion of patients treated with rivastigmine experiencing no change or a deterioration (OR 0.68; 95% CI 0.58 to 0.80, n = 3338, 7 studies).Three studies reported behavioural change, and there were no differences compared to placebo (standardised mean difference (SMD) -0.04; 95% CI -0.14 to 0.06, n = 1529, 3 studies). Only one study measured the impact on caregivers using the Neuropsychiatric Inventory-Caregiver Distress (NPI-D) scale and this found no difference between the groups (MD 0.10; 95% CI -0.91 to 1.11, n = 529, 1 study). Overall, participants who received rivastigmine were about twice as likely to withdraw from the trials (odds ratio (OR) 2.01, 95% CI 1.71 to 2.37, n = 3569, 7 studies) or to experience an adverse event during the trials (OR 2.16, 95% CI 1.82 to 2.57, n = 3587, 7 studies).

Authors' Conclusions: Rivastigmine (6 to 12 mg daily orally or 9.5 mg daily transdermally) appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, better outcomes were observed for rate of decline of cognitive function and activities of daily living, although the effects were small and of uncertain clinical importance. There was also a benefit from rivastigmine on the outcome of clinician's global assessment. There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers. At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy. The quality of evidence is only moderate for all of the outcomes reviewed because of a risk of bias due to dropouts. All the studies with usable data were industry funded or sponsored. This review has not examined economic data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD001191.pub3DOI Listing
April 2015

Immunogenicity of reduced dose priming schedules of serogroup C meningococcal conjugate vaccine followed by booster at 12 months in infants: open label randomised controlled trial.

BMJ 2015 Apr 1;350:h1554. Epub 2015 Apr 1.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK.

Objective: To determine whether the immunogenicity of a single dose infant priming schedule of serogroup C meningococcal (MenC) conjugate vaccine is non-inferior to a two dose priming schedule when followed by a booster dose at age 12 months.

Design: Phase IV open label randomised controlled trial carried out from July 2010 until August 2013 SETTING: Four centres in the United Kingdom and one centre in Malta.

Participants: Healthy infants aged 6-12 weeks followed up until age 24 months.

Interventions: In the priming phase of the trial 509 infants were randomised in a 10:10:7:4 ratio into four groups to receive either a single MenC-cross reacting material 197 (CRM) dose at 3 months; two doses of MenC-CRM at 3 and 4 months; a single MenC-polysaccharide-tetanus toxoid (TT) dose at 3 months; or no MenC doses, respectively. Haemophilus influenzae type b (Hib)-MenC-TT vaccine was administered to all infants at 12 months of age. All infants also received the nationally routinely recommended vaccines. Blood samples were taken at age 5, 12, 13, and 24 months.

Main Outcome Measure: MenC serum bactericidal antibody assay with rabbit complement (rSBA) one month after the Hib-MenC-TT vaccine. Non-inferiority was met if the lower 95% confidence limit of the difference in the mean log10 MenC rSBA between the single dose MenC-CRM and the two dose MenC-CRM groups was >-0.35.

Results: The primary objective was met: after a Hib-MenC-TT booster dose at 12 months of age the MenC rSBA geometric mean titres induced in infants primed with a single MenC-CRM dose were not inferior to those induced in participants primed with two MenC-CRM doses in infancy (660 (95% confidence interval 498 to 876) v 295 (220 to 398)) with a corresponding difference in the mean log10 MenC rSBA of 0.35 (0.17 to 0.53) that showed superiority of the single over the two dose schedule). Exploration of differences between the priming schedules showed that one month after Hib-MenC-TT vaccination, MenC rSBA ≥ 1:8 was observed in >96% of participants previously primed with any of the MenC vaccine schedules in infancy and in 83% of those who were not vaccinated against MenC in infancy. The MenC rSBA geometric mean titres induced by the Hib-MenC-TT boost were significantly higher in children who were primed with one rather than two MenC-CRM doses in infancy. Only priming with MenC-TT, however, induced robust MenC bactericidal antibody after the Hib-MenC-TT booster that persisted until 24 months of age.

Conclusions: MenC vaccination programmes with two MenC infant priming doses could be reduced to a single priming dose without reducing post-boost antibody titres. When followed by a Hib-MenC-TT booster dose, infant priming with a single MenC-TT vaccine dose induces a more robust antibody response than one or two infant doses of MenC-CRM. Bactericidal antibody induced by a single Hib-MenC-TT conjugate vaccine dose at 12 months of age (that is, a toddler only schedule), without infant priming, is not well sustained at 24 months. Because of rapid waning of MenC antibody, programmes using toddler only schedules will still need to rely on herd protection to protect infants and young children.Trial registration Eudract No: 2009-016579-31; NCT01129518; study ID: 2008_06 (http://clinicaltrials.gov).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382115PMC
http://dx.doi.org/10.1136/bmj.h1554DOI Listing
April 2015

The durability of endovascular coiling versus neurosurgical clipping of ruptured cerebral aneurysms: 18 year follow-up of the UK cohort of the International Subarachnoid Aneurysm Trial (ISAT).

Lancet 2015 Feb 28;385(9969):691-7. Epub 2014 Oct 28.

Department of Neurosurgery, John Radcliffe Hospital, Oxford, UK.

Background: Previous analyses of the International Subarachnoid Aneurysm Trial (ISAT) cohort have reported on the risks of recurrent subarachnoid haemorrhage and death or dependency for a minimum of 5 years and up to a maximum of 14 years after treatment of a ruptured intracranial aneurysm with either neurosurgical clipping or endovascular coiling. At 1 year there was a 7% absolute and a 24% relative risk reduction of death and dependency in the coiling group compared with the clipping group, but the medium-term results showed the increased need for re-treatment of the target aneurysm in the patients given coiling. We report the long-term follow-up of patients in this UK cohort.

Methods: In ISAT, patients were randomly allocated to either neurosurgical clipping or endovascular coiling after a subarachnoid haemorrhage, assuming treatment equipoise, between Sept 12, 1994, and May 1, 2002. We followed up 1644 patients in 22 UK neurosurgical centres for death and clinical outcomes for 10·0-18·5 years. We assessed dependency as self-reported modified Rankin scale score obtained through yearly questionnaires. Data for recurrent aneurysms and rebleeding events were collected from questionnaires and from hospital and general practitioner records. The Office for National Statistics supplied data on deaths. This study is registered, number ISRCTN49866681.

Findings: At 10 years, 674 (83%) of 809 patients allocated endovascular coiling and 657 (79%) of 835 patients allocated neurosurgical clipping were alive (odds ratio [OR] 1·35, 95% CI 1·06-1·73). Of 1003 individuals who returned a questionnaire at 10 years, 435 (82%) patients treated with endovascular coiling and 370 (78%) patients treated with neurosurgical clipping were independent (modified Rankin scale score 0-2; OR 1·25; 95% CI 0·92-1·71). Patients in the endovascular treatment group were more likely to be alive and independent at 10 years than were patients in the neurosurgery group (OR 1·34, 95% CI 1·07-1·67). 33 patients had a recurrent subarachnoid haemorrhage more than 1 year after their initial haemorrhage (17 from the target aneurysm).

Interpretation: Although rates of increased dependency alone did not differ between groups, the probability of death or dependency was significantly greater in the neurosurgical group than in the endovascular group. Rebleeding was more likely after endovascular coiling than after neurosurgical clipping, but the risk was small and the probability of disability-free survival was significantly greater in the endovascular group than in the neurosurgical group at 10 years.

Funding: UK Medical Research Council.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(14)60975-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356153PMC
February 2015

Evaluation of the induction of immune memory following infant immunisation with serogroup C Neisseria meningitidis conjugate vaccines--exploratory analyses within a randomised controlled trial.

PLoS One 2014 14;9(7):e101672. Epub 2014 Jul 14.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.

Aim: We measured meningococcal serogroup C (MenC)-specific memory B-cell responses in infants by Enzyme-Linked Immunospot (ELISpot) following different MenC conjugate vaccine schedules to investigate the impact of priming on immune memory.

Methods: Infants aged 2 months were randomised to receive 1 or 2 doses of MenC-CRM197 at 3 or 3 and 4 months, 1 dose of MenC-TT at 3 months, or no primary MenC doses. All children received a Haemophilus influenzae type b (Hib)-MenC booster at 12 months. Blood was drawn at 5, 12, 12 months +6 days and 13 months of age.

Results: Results were available for 110, 103, 76 and 44 children from each group respectively. Following primary immunisations, and prior to the 12-month booster, there were no significant differences between 1- or 2-dose primed children in the number of MenC memory B-cells detected. One month following the booster, children primed with 1 dose MenC-TT had more memory B-cells than children primed with either 1-dose (p = 0.001) or 2-dose (p<0.0001) MenC-CRM197. There were no differences in MenC memory B-cells detected in children who received 1 or 2 doses of MenC-CRM197 in infancy and un-primed children.

Conclusions: MenC-specific memory B-cell production may be more dependent on the type of primary vaccine used than the number of doses administered. Although the mechanistic differences between MenC-CRM197 and MenC-TT priming are unclear, it is possible that structural differences, including the carrier proteins, may underlie differential interactions with B- and T-cell populations, and thus different effects on various memory B-cell subsets. A MenC-TT/Hib-MenC-TT combination for priming/boosting may offer an advantage in inducing more persistent antibody.

Trial Registration: EU Clinical Trials Register 2009-016579-31 ClinicalTrials.gov NCT01129518.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0101672PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096514PMC
April 2016