Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.

BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minutes, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03855332.

A feasibility study using motivational interviewing and a smartphone application to promote physical activity (+Stay-Active) for women with gestational diabetes.

BACKGROUND: Physical activity (PA) interventions have an encouraging role in gestational diabetes mellitus (GDM) management. Digital technologies can potentially be used at scale to support PA. The aim of this study was to assess the feasibility and acceptability of + Stay-Active: a complex intervention which combines motivational interviewing with a smartphone application to promote PA levels in women with GDM. METHODS: This non-randomised feasibility study used a mixed methods approach. Participants were recruited from the GDM antenatal clinic at Oxford University Hospitals. Following baseline assessments (visit 1) including self-reported and device determined PA measurements (wrist worn accelerometer), women participated in an online motivational interview, and then downloaded (visit 2) and used the Stay-Active app (Android or iOS). Women had access to Stay-Active until 36 weeks' gestation, when acceptability and PA levels were reassessed (visit 3). The primary outcome measures were recruitment and retention rates, participant engagement, and acceptability and fidelity of the intervention. Secondary outcome measures included PA levels, app usage, blood glucose and perinatal outcomes. Descriptive statistics were performed for assessments at study visits. Statistics software package Stata 14 and R were used. RESULTS: Over the recruitment period (46 weeks), 114 of 285 women met inclusion criteria and 67 (58%) enrolled in the study. Mean recruitment rate of 1.5 participants/clinic with 2.5 women/clinic meeting inclusion criteria. Fifty-six (83%) received the intervention at visit 2 and 53 (79%) completed the study. Compliance to accelerometer measurement protocols were sufficient in 78% of participants (52/67); wearing the device for more than 10 h on 5 or more days at baseline and 61% (41/67) at 36 weeks. There was high engagement with Stay-Active; 82% (55/67) of participants set goals on Stay-Active. Sustained engagement was evident, participants regularly accessed and logged multiples activities on Stay-Active. The intervention was deemed acceptable; 85% of women rated their care was satisfactory or above, supported by written feedback. CONCLUSIONS: This combined intervention was feasible and accepted. Recruitment rates were lower than expected. However, retention rates remained satisfactory and participant compliance with PA measurements and engagement was a high. Future work will explore the intervention's efficacy to increase PA and impact on clinical outcomes. TRIAL REGISTRATION: The study has received a favourable opinion from South Central-Hampshire B Research Ethics Committee; REC reference: 20/SC/0342. ISRCTN11366562.

Artificial Intelligence-Based Quality Assessment of Histopathology Whole-Slide Images within a Clinical Workflow: Assessment of 'PathProfiler' in a Diagnostic Pathology Setting.

Digital pathology continues to gain momentum, with the promise of artificial intelligence to aid diagnosis and for assessment of features which may impact prognosis and clinical management. Successful adoption of these technologies depends upon the quality of digitised whole-slide images (WSI); however, current quality control largely depends upon manual assessment, which is inefficient and subjective. We previously developed PathProfiler, an automated image quality assessment tool, and in this feasibility study we investigate its potential for incorporation into a diagnostic clinical pathology setting in real-time. A total of 1254 genitourinary WSI were analysed by PathProfiler. PathProfiler was developed and trained on prostate tissue and, of the prostate biopsy WSI, representing 46% of the WSI analysed, 4.5% were flagged as potentially being of suboptimal quality for diagnosis. All had concordant subjective issues, mainly focus-related, 54% severe enough to warrant remedial action which resulted in improved image quality. PathProfiler was less reliable in assessment of non-prostate surgical resection-type cases, on which it had not been trained. PathProfiler shows potential for incorporation into a digitised clinical pathology workflow, with opportunity for image quality improvement. Whilst its reliability in the current form appears greatest for assessment of prostate specimens, other specimen types, particularly biopsies, also showed benefit.

Transdermal Blood Sampling for C-Peptide Is a Minimally Invasive, Reliable Alternative to Venous Sampling in Children and Adults With Type 1 Diabetes.

OBJECTIVE: C-peptide and islet autoantibodies are key type 1 diabetes biomarkers, typically requiring venous sampling, which limits their utility. We assessed transdermal capillary blood (TCB) collection as a practical alternative. RESEARCH DESIGN AND METHODS: Ninety-one individuals (71 with type 1 diabetes, 20 control; individuals with type 1 diabetes: aged median 14.8 years [interquartile range (IQR) 9.1-17.1], diabetes duration 4.0 years [1.5-7.7]; control individuals: 42.2 years [38.0-52.1]) underwent contemporaneous venous and TCB sampling for measurement of plasma C-peptide. Participants with type 1 diabetes also provided venous serum and plasma, and TCB plasma for measurement of autoantibodies to glutamate decarboxylase, islet antigen-2, and zinc transporter 8. The ability of TCB plasma to detect significant endogenous insulin secretion (venous C-peptide ≥200 pmol/L) was compared along with agreement in levels, using Bland-Altman. Venous serum was compared with venous and TCB plasma for detection of autoantibodies, using established thresholds. Acceptability was assessed by age-appropriate questionnaire. RESULTS: Transdermal sampling took a mean of 2.35 min (SD 1.49). Median sample volume was 50 µL (IQR 40-50) with 3 of 91 (3.3%) failures, and 13 of 88 (14.7%) <35 µL. TCB C-peptide showed good agreement with venous plasma (mean venous ln[C-peptide] - TCB ln[C-peptide] = 0.008, 95% CI [-0.23, 0.29], with 100% [36 of 36] sensitivity/100% [50 of 50] specificity to detect venous C-peptide ≥200 pmol/L). Where venous serum in multiple autoantibody positive TCB plasma agreed in 22 of 32 (sensitivity 69%), comparative specificity was 35 of 36 (97%). TCB was preferred to venous sampling (type 1 diabetes: 63% vs. 7%; 30% undecided). CONCLUSIONS: Transdermal capillary testing for C-peptide is a sensitive, specific, and acceptable alternative to venous sampling; TCB sampling for islet autoantibodies needs further assessment.

The association between acetylsalicylic acid and subarachnoid haemorrhage: the Framingham Heart Study.

Studies investigating the association between acetylsalicylic acid (ASA) use and spontaneous subarachnoid haemorrhage (SAH) in the general population have produced conflicting results. The aim of this study is to clarify the relationship between SAH and ASA. We included all participants who reported on ASA use during interim examinations of the Framingham Heart Study Cohorts. Using Cox proportional-hazards regression modelling, we estimated the hazard ratio (HR) associated with ASA use. 7692 participants were included in this study. There were 30 cases of SAH during follow up, with an estimated incidence of 10.0 per 100,000 person- years (CI 6.90-14.15). Univariate analysis showed no association between regular ASA use and SAH (HR, 0.33 [0.08-1.41]; p = 0.14). This was similar when accounting for smoking (HR, 0.35 [0.08-1.51]; p = 0.16). Using a large longitudinal dataset from the Framingham Heart Study, we observed some evidence suggesting fewer SAH in those participants taking regular ASA. However, multivariate statistical analysis showed no significant association between ASA use and SAH. Due to the low incidence of SAH in the general population, the absolute number of SAH events was low and it remains uncertain if a significant effect would become apparent with more follow up.

Risk of Aneurysm Rupture (ROAR) study: protocol for a long-term, longitudinal, UK multicentre study of unruptured intracranial aneurysms.

INTRODUCTION: Unruptured intracranial aneurysms (UIA) are common in the adult population, but only a relatively small proportion will rupture. It is therefore essential to have accurate estimates of rupture risk to target treatment towards those who stand to benefit and avoid exposing patients to the risks of unnecessary treatment. The best available UIA natural history data are the PHASES study. However, this has never been validated and given the known heterogeneity in the populations, methods and biases of the constituent studies, there is a need to do so. There are also many potential predictors not considered in PHASES that require evaluation, and the estimated rupture risk is largely based on short-term follow-up (mostly 1 year). The aims of this study are to: (1) test the accuracy of PHASES in a UK population, (2) evaluate additional predictors of rupture and (3) assess long-term UIA rupture rates. METHODS AND ANALYSIS: The Risk of Aneurysm Rupture study is a longitudinal multicentre study that will identify patients with known UIA seen in neurosurgery units. Patients will have baseline demographics and aneurysm characteristics collected by their neurosurgery unit and then a single aggregated national cohort will be linked to databases of hospital admissions and deaths to identify all patients who may have subsequently suffered a subarachnoid haemorrhage. All matched admissions and deaths will be checked against medical records to confirm the diagnosis of aneurysmal subarachnoid haemorrhage. The target sample size is 20 000 patients. The primary outcome will be aneurysm rupture resulting in hospital admission or death. Cox regression models will be built to test each of the study's aims. ETHICS AND DISSEMINATION: Ethical approval has been given by South Central Hampshire A Research Ethics Committee (21SC0064) and Confidentiality Advisory Group support (21CAG0033) provided under Section 251 of the NHS Act 2006. The results will be disseminated in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN17658526.

BLOod Test Trend for cancEr Detection (BLOTTED): protocol for an observational and prediction model development study using English primary care electronic health record data.

BACKGROUND: Simple blood tests can play an important role in identifying patients for cancer investigation. The current evidence base is limited almost entirely to tests used in isolation. However, recent evidence suggests combining multiple types of blood tests and investigating trends in blood test results over time could be more useful to select patients for further cancer investigation. Such trends could increase cancer yield and reduce unnecessary referrals. We aim to explore whether trends in blood test results are more useful than symptoms or single blood test results in selecting primary care patients for cancer investigation. We aim to develop clinical prediction models that incorporate trends in blood tests to identify the risk of cancer. METHODS: Primary care electronic health record data from the English Clinical Practice Research Datalink Aurum primary care database will be accessed and linked to cancer registrations and secondary care datasets. Using a cohort study design, we will describe patterns in blood testing (aim 1) and explore associations between covariates and trends in blood tests with cancer using mixed-effects, Cox, and dynamic models (aim 2). To build the predictive models for the risk of cancer, we will use dynamic risk modelling (such as multivariate joint modelling) and machine learning, incorporating simultaneous trends in multiple blood tests, together with other covariates (aim 3). Model performance will be assessed using various performance measures, including c-statistic and calibration plots. DISCUSSION: These models will form decision rules to help general practitioners find patients who need a referral for further investigation of cancer. This could increase cancer yield, reduce unnecessary referrals, and give more patients the opportunity for treatment and improved outcomes.

Aspirin and Subarachnoid Haemorrhage in the UK Biobank.

Previous studies investigating the relationship between aspirin use and subarachnoid haemorrhage (SAH) have yielded conflicting results. In this study, we aimed to clarify the association between aspirin and SAH in the general population. The UK Biobank is a prospective population-based cohort study. Sex, age, smoking, alcohol, medication use, hypertension, blood pressure, ischaemic heart disease and stroke were recorded at baseline assessments. Follow-up is conducted through linkages to National Health Service data including electronic, coded death certificate, hospital and primary care data. Cox proportional hazards modelling was used to analyse the association between aspirin use and SAH. Of the 501,060 participants included in the analysis, a total of 579 suffered from spontaneous SAH after their baseline assessment. There was no relationship between aspirin and SAH of all causes (HR, 1.16 [0.92-1.46]), aneurysmal SAH (HR, 1.15 [0.91-1.47]) or non-aneurysmal SAH (HR, 1.29 [0.54-3.09]). Aspirin use was associated with SAH resulting in death (HR, 1.69 [1.14-2.51]), especially out of hospital death (HR, 2.10 [1.13-3.91]). Despite reports of a protective association between aspirin and SAH in patients with known unruptured aneurysms, this study has not demonstrated the same effect in the general population. However, aspirin users were more likely to suffer SAH resulting in death, especially out of hospital.

Full Blood Count Trends for Colorectal Cancer Detection in Primary Care: Development and Validation of a Dynamic Prediction Model.

Colorectal cancer has low survival rates when late-stage, so earlier detection is important. The full blood count (FBC) is a common blood test performed in primary care. Relevant trends in repeated FBCs are related to colorectal cancer presence. We developed and internally validated dynamic prediction models utilising trends for early detection. We performed a cohort study. Sex-stratified multivariate joint models included age at baseline (most recent FBC) and simultaneous trends over historical haemoglobin, mean corpuscular volume (MCV), and platelet measurements up to baseline FBC for two-year risk of diagnosis. Performance measures included the c-statistic and calibration slope. We analysed 250,716 males and 246,695 females in the development cohort and 312,444 males and 462,900 females in the validation cohort, with 0.4% of males and 0.3% of females diagnosed two years after baseline FBC. Compared to average population trends, patient-level declines in haemoglobin and MCV and rise in platelets up to baseline FBC increased risk of diagnosis in two years. C-statistic: 0.751 (males) and 0.763 (females). Calibration slope: 1.06 (males) and 1.05 (females). Our models perform well, with low miscalibration. Utilising trends could bring forward diagnoses to earlier stages and improve survival rates. External validation is now required.

Study protocol: use of a smartphone application to support the implementation of a complex physical activity intervention (+Stay Active) in women with gestational diabetes mellitus-protocol for a non-randomised feasibility study.

INTRODUCTION: Physical activity (PA) interventions have a promising role in the management of gestational diabetes mellitus (GDM). Digital technologies can support PA at scale and remotely. The protocol describes a study designed to determine the feasibility and acceptability of a complex intervention; known as +Stay Active. +Stay Active combines motivational interviewing with a bespoke behaviour change informed smartphone application (Stay-Active) to augment PA levels in women with GDM. METHODS AND ANALYSIS: This is a non-randomised feasibility study using a mixed methods approach. Participants will be recruited from the GDM antenatal clinic at the Women Centre, John Radcliffe Hospital, Oxford. Following baseline assessments (visit 1) including self-reported and device determined PA assessment (wearing a wrist accelerometer), women will be invited to participate in an online motivational interview, then download and use the Stay-Active app (Android or iOS) (visit 2). Women will have access to Stay-Active until 36 weeks gestation, when engagement and PA levels will be reassessed (visit 3). The target sample size is 60 women. Primary outcomes are recruitment and retention rates, compliance and assessment of participant engagement and acceptability with the intervention. Secondary outcomes are assessment of blood glucose control, self-reported and device determined assessment of PA, usage and structured feedback of participant's attitudes to +Stay Active, assessment of health costs and description of maternal and neonatal outcomes. This study will provide key insights into this complex intervention regarding engagement in smartphone technology and the wearing of accelerometers. These data will inform the development of a randomised controlled trial with refinements to intervention implementation. ETHICS AND DISSEMINATION: The study has received a favourable opinion from South Central-Hampshire B Research Ethics Committee; REC reference: 20/SC/0342. Written informed consent will be obtained from all participants. Findings will be disseminated through peer-reviewed journals, conferences and seminar presentations. TRIAL REGISTRATION NUMBER: ISRCTN11366562.

Trends in the full blood count blood test and colorectal cancer detection: a longitudinal, case-control study of UK primary care patient data.

Background: The full blood count (FBC) is a common blood test performed in general practice. It consists of many individual parameters that may change over time due to colorectal cancer. Such changes are likely missed in practice. We identified trends in these FBC parameters to facilitate early detection of colorectal cancer. Methods: We performed a retrospective, case-control, longitudinal analysis of UK primary care patient data. LOWESS smoothing and mixed effects models were derived to compare trends in each FBC parameter between patients diagnosed and not diagnosed over a prior 10-year period. Results: There were 399,405 males (2.3%, n = 9,255 diagnosed) and 540,544 females (1.5%, n = 8,153 diagnosed) in the study. There was no difference between cases and controls in FBC trends between 10 and four years before diagnosis. Within four years of diagnosis, trends in many FBC levels statistically significantly differed between cases and controls, including red blood cell count, haemoglobin, white blood cell count, and platelets (interaction between time and colorectal cancer presence: p <0.05). FBC trends were similar between Duke's Stage A and D colorectal tumours, but started around one year earlier in Stage D diagnoses. Conclusions: Trends in FBC parameters are different between patients with and without colorectal cancer for up to four years prior to diagnosis. Such trends could help earlier identification.

Colorectal cancer is a common type of cancer in the UK. It is the second most common cause of cancer-related death in the UK. Chances of surviving depend heavily on the tumour stage at diagnosis, which represents how much the tumour has developed. If diagnosed and treated at the earliest stage, where the tumour is confined to the colon, nine in 10 patients are expected to be alive five years later. If diagnosed at the latest stage, when the cancer has spread outside the colon, this drops to one in 10 surviving. The majority of UK patients with colorectal cancer are diagnosed with late-stage tumours, so are likely to die. Detecting and treating the cancer earlier can save lives. There is a blood test called the Full Blood Count, which is commonly ordered by doctors for many reasons. This test includes many blood levels, such as haemoglobin, which carries oxygen around the body. Growing tumours cause subtle changes in the blood levels over time, but it is unclear what these changes are and if they could help find cancer in the early stages. In our study, we looked at blood tests from almost one million patients in the UK, including around 17,000 with colorectal cancer. We checked how blood levels change over 10 years before diagnosis. We found that in the few years before patients are diagnosed, patients usually had blood levels that rapidly started increasing or declining (depending on the blood level) and this was often not seen in patients without colorectal cancer. Our study highlights that using trends over time in blood test results may be useful to identify colorectal cancer. Such trends could facilitate earlier detection because they were present for years before diagnosis. That would improve the chances of successful treatment and chances of survival.

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

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 (p < 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.

Postpartum-Specific Vital Sign Reference Ranges.

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.

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

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.

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

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.

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

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; P<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.

Gestation-Specific Vital Sign Reference Ranges in Pregnancy.

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.

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

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.

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

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 (I2 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.