The impact of changing risk thresholds on the number of people in England eligible for urgent investigation for possible cancer: an observational cross-sectional study.

BACKGROUND: Expediting cancer diagnosis may be achieved by targeted decreases in referral thresholds to increase numbers of patients referred for urgent investigation. METHODS: Clinical Practice Research Datalink data from England for 150,921 adults aged ≥40 were used to identify participants with features of possible cancer equating to risk thresholds ≥1%, ≥2% or ≥3% for breast, lung, colorectal, oesophago-gastric, pancreatic, renal, bladder, prostatic, ovarian, endometrial and laryngeal cancers. RESULTS: The mean age of participants was 60 (SD 13) years, with 73,643 males (49%). In 2016, 8576 consultation records contained coded features having a positive predictive value (PPV) of ≥3% for any of the 11 cancers. This equates to a rate of 5682/100,000 patients compared with 4601/100,000 Suspected Cancer NHS referrals for these cancers from April 2016-March 2017. Nine thousands two hundred ninety-one patient-consultation records had coded features equating to a ≥2% PPV, 8% more than met PPV ≥ 3%. Similarly, 19,517 had features with a PPV ≥ 1%, 136% higher than for PPV ≥ 3%. CONCLUSIONS: This study estimated the number of primary-care patients presenting at lower thresholds of cancer risk. The resource implications of liberalising this threshold to 2% are modest and manageable. The details across individual cancer sites should assist planning of English cancer services.

Cerebrospinal Fluid Cytokines and Neurodegeneration-Associated Proteins in Parkinson's Disease.

INTRODUCTION: Immune markers are altered in Parkinson's disease (PD), but relationships between cerebrospinal fluid (CSF) and plasma cytokines and associations with neurodegeneration-associated proteins remain unclear. METHODS: CSF and plasma samples and demographic/clinical measures were obtained from 35 PD patients. CSF samples were analyzed for cytokines (together with plasma) and for α-synuclein, amyloid ß(1-42) peptide, total tau, and phospho(Thr231)-tau. RESULTS: There were no CSF-plasma cytokine correlations. Interleukin (IL)-8 was higher and interferon-γ, IL-10, and tumor necrosis factor-α were lower in CSF versus plasma. In CSF, total tau correlated positively with IL-8 and IL-1ß, whereas α-synuclein correlated positively with amyloid ß(1-42) and negatively with semantic fluency (a known marker of PD dementia risk). DISCUSSION: CSF and peripheral cytokine profiles in PD are not closely related. Associations between CSF IL-8 and IL-1ß and tau suggest that CSF inflammatory changes may relate to tau pathology within PD. CSF α-synuclein/amyloid ß may reflect the risk of developing PD dementia. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Stroke and dementia risk: A systematic review and meta-analysis.

INTRODUCTION: Stroke is an established risk factor for all-cause dementia, though meta-analyses are needed to quantify this risk. METHODS: We searched Medline, PsycINFO, and Embase for studies assessing prevalent or incident stroke versus a no-stroke comparison group and the risk of all-cause dementia. Random effects meta-analysis was used to pool adjusted estimates across studies, and meta-regression was used to investigate potential effect modifiers. RESULTS: We identified 36 studies of prevalent stroke (1.9 million participants) and 12 studies of incident stroke (1.3 million participants). For prevalent stroke, the pooled hazard ratio for all-cause dementia was 1.69 (95% confidence interval: 1.49-1.92; P < .00001; I2 = 87%). For incident stroke, the pooled risk ratio was 2.18 (95% confidence interval: 1.90-2.50; P < .00001; I2 = 88%). Study characteristics did not modify these associations, with the exception of sex which explained 50.2% of between-study heterogeneity for prevalent stroke. DISCUSSION: Stroke is a strong, independent, and potentially modifiable risk factor for all-cause dementia.

Incidence of 'Low-Risk but Not No-Risk' Features of Cancer Prior to High-Risk Feature Occurrence: An Observational Cohort Study in Primary Care.

Diagnosing cancer may be expedited by decreasing referral risk threshold. Clinical Practice Research Datalink participants (≥40 years) had a positive predictive value (PPV) ≥3% feature for breast, lung, colorectal, oesophagogastric, pancreatic, renal, bladder, prostatic, ovarian, endometrial or laryngeal cancer in 2016. The numbers of participants with features representing a 1-1.99% or 2-2.99% PPV for same cancer in the previous year were reported, alongside the time difference between meeting the ≥3% criteria and the lower threshold criteria. A total of 8616 participants had a PPV ≥3% feature, of whom 365 (4.2%) and 1147 (13.3%), respectively, met 2-2.99% and 1-1.99% criteria in the preceding year. The median time difference was 131 days (Interquartile Range (IQR) 27 to 256) for the 2-2.99% band and 179 days (IQR 58 to 289) for the 1-1.99% band. Results were heterogeneous across cancer sites. For some cancers, participants may progress from presenting lower- to higher-risk features before meeting urgent referral criteria; however, this was not usually the case. The details of specific features across multiple cancer sites will allow for a tailored approach to future reductions in referral thresholds, potentially improving the efficiency of urgent cancer referrals for the benefit both of individuals and the National Health Service (NHS).

Pre-Referral Primary Care Blood Tests and Symptom Presentation before Cancer Diagnosis: National Cancer Diagnosis Audit Data.

BACKGROUND: Blood tests can support the diagnostic process in primary care. Understanding how symptomatic presentations are associated with blood test use in patients subsequently diagnosed with cancer can help to benchmark current practices and guide interventions. METHODS: English National Cancer Diagnosis Audit data on 39,751 patients with incident cancer in 2018 were analysed. The frequency of four generic (full blood count, urea and electrolytes, liver function tests, and inflammatory markers) and five organ-specific (cancer biomarkers (PSA or CA125), serum protein electrophoresis, ferritin, bone profile, and amylase) blood tests was described for a total of 83 presenting symptoms. The adjusted analysis explored variation in blood test use by the symptom-positive predictive value (PPV) group. RESULTS: There was a large variation in generic blood test use by presenting symptoms, being higher in patients subsequently diagnosed with cancer who presented with nonspecific symptoms (e.g., fatigue 81% or loss of appetite 79%), and lower in those who presented with alarm symptoms (e.g., breast lump 3% or skin lesion 1%). Serum protein electrophoresis (reflecting suspicion of multiple myeloma) was most frequently used in cancer patients who presented with back pain (18%), and amylase measurement (reflecting suspicion of pancreatic cancer) was used in those who presented with upper abdominal pain (14%). Prostate-specific antigen (PSA) use was greatest in men with cancer who presented with lower urinary tract symptoms (88%), and CA125 in women with cancer who presented with abdominal distention (53%). Symptoms with PPV values between 2.00-2.99% were associated with greater test use (64%) compared with 52% and 51% in symptoms with PPVs in the 0.01-0.99 or 1.00-1.99% range and compared with 42% and 31% in symptoms with PPVs in either the 3.00-4.99 or ≥5% range (p < 0.001). CONCLUSIONS: Generic blood test use reflects the PPV of presenting symptoms, and the use of organ-specific tests is greater in patients with symptomatic presentations with known associations with certain cancer sites. There are opportunities for greater blood test use in patients presenting with symptoms that do not meet referral thresholds (i.e., <3% PPV for cancer) where information gain to support referral decisions is likely greatest. The findings benchmark blood test use in cancer patients, highlighting opportunities for increasing use.

Association of Multimorbidity, Disease Clusters, and Modification by Genetic Factors With Risk of Dementia.

Importance: Individual conditions have been identified as risk factors for dementia; however, it is important to consider the role of multimorbidity, as conditions often co-occur. Objective: To investigate whether multimorbidity is associated with incident dementia and whether associations vary by different clusters of disease and genetic risk for dementia. Design, Setting, and Participants: This population-based prospective cohort study used data from the UK Biobank cohort, with baseline data collected between 2006 and 2010 and with up to 15 years of follow-up. Participants included women and men without dementia and aged at least 60 years at baseline. Medical conditions were captured as part of nurse-led verbal interviews conducted at baseline assessment centers. Data were analyzed from October 2020 to July 2022. Exposures: The presence of at least 2 long-term conditions from a preselected list of 42 conditions was used to define multimorbidity. High genetic risk for dementia was based on presence of 1 or 2 apolipoprotein (APOE) ε4 alleles. Main Outcomes and Measures: The main outcome, incident dementia, was derived from hospital inpatient and death registry records. Associations of multimorbidity with dementia were assessed with Cox proportional hazards models. Results: A total of 206 960 participants (mean [SD] age, 64.1 [2.9] years, 108 982 [52.7%] women) were included in the final sample, of whom 89 201 participants (43.1%) had multimorbidity. Over a mean (SD) of 11.8 (2.2) years of follow-up, 6182 participants (3.0%) developed dementia. The incidence rate was 1.87 (95% CI, 1.80-1.94) per 1000 person-years for those without multimorbidity and 3.41 (95% CI, 3.30-3.53) per 1000 person-years for those with multimorbidity. In Cox proportional hazards models adjusted for age, sex, ethnicity, education, socioeconomic status, and APOE-ε4 carrier status, multimorbidity was associated with an increased risk of incident dementia (hazard ratio [HR], 1.63 [95% CI, 1.55-1.71]). The highest dementia risk was observed for the hypertension, diabetes, and coronary heart disease cluster (HR, 2.20 [95% CI, 1.98-2.46]) and pain, osteoporosis, and dyspepsia cluster (HR, 2.00 [95% CI, 1.68-2.37]) in women and in the diabetes and hypertension cluster (HR, 2.24 [95% CI, 1.97-2.55]) and coronary heart disease, hypertension, and stroke cluster (HR, 1.94 [95% CI, 1.71-2.20]) in men, compared with no multimorbidity. The associations between multimorbidity and dementia were greater in those with a lower genetic risk of dementia (HR, 1.96 [95% CI, 1.81-2.11]) than in those with a higher genetic risk of dementia (HR, 1.39 [95% CI, 1.30-1.49]). Similar findings were observed when stratifying diseases clusters by genetic risk for dementia. Conclusions and Relevance: These findings suggest that multimorbidity was associated with an increased risk of dementia. The associations varied by clusters of disease and genetic risk for dementia. These findings could help with the identification of individuals at high risk of dementia as well as the development of targeted interventions to reduce or delay dementia incidence.

Higher Arm Versus Lower Arm Systolic Blood Pressure and Cardiovascular Outcomes: a Meta-Analysis of Individual Participant Data From the INTERPRESS-IPD Collaboration.

BACKGROUND: Guidelines recommend measuring blood pressure (BP) in both arms, adopting the higher arm readings for diagnosis and management. Data to support this recommendation are lacking. We evaluated associations of higher and lower arm systolic BPs with diagnostic and treatment thresholds, and prognosis in hypertension, using data from the Inter-arm Blood Pressure Difference-Individual Participant Data Collaboration. METHODS: One-stage multivariable Cox regression models, stratified by study, were used to examine associations of higher or lower reading arm BPs with cardiovascular mortality, all-cause mortality, and cardiovascular events, in individual participant data meta-analyses pooled from 23 cohorts. Cardiovascular events were modelled for Framingham and atherosclerotic cardiovascular disease risk scores. Model fit was compared throughout using Akaike information criteria. Proportions reclassified across guideline recommended intervention thresholds were also compared. RESULTS: We analyzed 53 172 participants: mean age 60 years; 48% female. Higher arm BP, compared with lower arm, reclassified 12% of participants at either 130 or 140 mm Hg systolic BP thresholds (both P<0.001). Higher arm BP models fitted better for all-cause mortality, cardiovascular mortality, and cardiovascular events (all P<0.001). Higher arm BP models better predicted cardiovascular events with Framingham and atherosclerotic cardiovascular disease risk scores (both P<0.001) and reclassified 4.6% and 3.5% of participants respectively to higher risk categories compared with lower arm BPs). CONCLUSIONS: Using BP from higher instead of lower reading arms reclassified 12% of people over thresholds used to diagnose hypertension. All prediction models performed better when using the higher arm BP. Both arms should be measured for accurate diagnosis and management of hypertension. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: CRD42015031227.

The Cerebrospinal Fluid Profile of Cholesterol Metabolites in Parkinson's Disease and Their Association With Disease State and Clinical Features.

Disordered cholesterol metabolism is linked to neurodegeneration. In this study we investigated the profile of cholesterol metabolites found in the cerebrospinal fluid (CSF) of Parkinson's disease (PD) patients. When adjustments were made for confounding variables of age and sex, 7α,(25R)26-dihydroxycholesterol and a second oxysterol 7α,x,y-trihydroxycholest-4-en-3-one (7α,x,y-triHCO), whose exact structure is unknown, were found to be significantly elevated in PD CSF. The likely location of the additional hydroxy groups on the second oxysterol are on the sterol side-chain. We found that CSF 7α-hydroxycholesterol levels correlated positively with depression in PD patients, while two presumptively identified cholestenoic acids correlated negatively with depression.

Associations Between Systolic Interarm Differences in Blood Pressure and Cardiovascular Disease Outcomes and Mortality: Individual Participant Data Meta-Analysis, Development and Validation of a Prognostic Algorithm: The INTERPRESS-IPD Collaboration.

Systolic interarm differences in blood pressure have been associated with all-cause mortality and cardiovascular disease. We undertook individual participant data meta-analyses to (1) quantify independent associations of systolic interarm difference with mortality and cardiovascular events; (2) develop and validate prognostic models incorporating interarm difference, and (3) determine whether interarm difference remains associated with risk after adjustment for common cardiovascular risk scores. We searched for studies recording bilateral blood pressure and outcomes, established agreements with collaborating authors, and created a single international dataset: the Inter-arm Blood Pressure Difference - Individual Participant Data (INTERPRESS-IPD) Collaboration. Data were merged from 24 studies (53 827 participants). Systolic interarm difference was associated with all-cause and cardiovascular mortality: continuous hazard ratios 1.05 (95% CI, 1.02-1.08) and 1.06 (95% CI, 1.02-1.11), respectively, per 5 mm Hg systolic interarm difference. Hazard ratios for all-cause mortality increased with interarm difference magnitude from a ≥5 mm Hg threshold (hazard ratio, 1.07 [95% CI, 1.01-1.14]). Systolic interarm differences per 5 mm Hg were associated with cardiovascular events in people without preexisting disease, after adjustment for Atherosclerotic Cardiovascular Disease (hazard ratio, 1.04 [95% CI, 1.00-1.08]), Framingham (hazard ratio, 1.04 [95% CI, 1.01-1.08]), or QRISK cardiovascular disease risk algorithm version 2 (QRISK2) (hazard ratio, 1.12 [95% CI, 1.06-1.18]) cardiovascular risk scores. Our findings confirm that systolic interarm difference is associated with increased all-cause mortality, cardiovascular mortality, and cardiovascular events. Blood pressure should be measured in both arms during cardiovascular assessment. A systolic interarm difference of 10 mm Hg is proposed as the upper limit of normal. Registration: URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42015031227.

Predictors of Parkinson's disease dementia: towards targeted therapies for a heterogeneous disease.

Parkinson's disease dementia (PDD) has become an increasing area of research as treatments for the motor features of Parkinson's disease (PD) have improved and the population of patients with PD grows and ages. If predictors could be used to identify a sub-population of patients at risk of developing an early PDD then research into its neuropathological basis and treatment could be more effectively targeted to specific individuals. At present the predictors with the most evidence have arisen from longitudinal studies tracking the development of dementia in populations of incident, newly diagnosed patients with PD. Evidence exists for predictors across multiple domains: clinical, biological, neuroimaging and genetic. Some of the most robust of these suggest that PDD may develop as the result of an age and tau dependent, posterior cortically based process driven in some cases by mutations in the gene for glucocerebrosidase (GBA). It is clear, though, that more research needs to be undertaken into finding reliable predictors of PDD. At present the best approach may be to combine a set of predictors already identified in order to provide a basis for understanding why and how it occurs. Through this, new therapeutic strategies may emerge.

Which patients with Parkinson's disease participate in clinical trials? One centre's experiences with a new cell based therapy trial (TRANSEURO).

BACKGROUND: There is currently little evidence regarding the selection of patients for clinical trials in Parkinson's Disease (PD), especially those involving experimental therapies delivered using invasive techniques. OBJECTIVE: Understanding which patients are recruited will increase awareness of issues regarding parity of access to clinical trials and have an impact on the wider applicability of results, as well as provoking discussion regarding future improvements in the enrolment process. METHODS: TRANSEURO is an open label multi-centre surgical transplant trial which seeks to investigate the feasibility and efficacy of grafts of human foetal ventral mesencephalic tissue in patients with PD. The Cambridge based cohort of TRANSEURO participants (n = 26) was compared with a population representative sample of patients with PD eligible for, but not enrolled in, TRANSEURO (n = 33). Measurements were available in both populations for demographics, neuropsychological tests, tests of motor and non-motor function and quality of life. RESULTS: Patients enrolled in TRANSEURO were younger and had significantly more years of education with higher scores on the revised Addenbrooke's Cognitive Examination. This difference was accounted for by memory, fluency and visuospatial subscores. There were significant differences in the Movement Disorder Society Unified PD Rating Scale scores with better motor function but more motor complications in the enrolled group. Those enrolled were also more likely to be under the care of the principal investigator of the study. CONCLUSIONS: In this trial our population was younger and more educated with higher cognitive scores and better motor function than eligible PD patients not enrolled. This raises interesting questions about the parity of access to clinical trials of this nature amongst patients with PD.