Fluid balance, intradialytic hypotension, and outcomes in critically ill patients undergoing renal replacement therapy: a cohort study

Introduction: In this cohort study, we explored the relationship between fluid balance, intradialytic hypotension and outcomes in critically ill patients with acute kidney injury (AKI) who received renal replacement therapy (RRT).

Methods: We analysed prospectively collected registry data on patients older than 16 years who received RRT for at least two days in an intensive care unit at two university-affiliated hospitals. We used multivariable logistic regression to determine the relationship between mean daily fluid balance and intradialytic hypotension, both over seven days following RRT initiation, and the outcomes of hospital mortality and RRT dependence in survivors.

Results: In total, 492 patients were included (299 male (60.8%), mean (standard deviation (SD)) age 62.9 (16.3) years); 251 (51.0%) died in hospital. Independent risk factors for mortality were mean daily fluid balance (odds ratio (OR) 1.36 per 1000 mL positive (95% confidence interval (CI) 1.18 to 1.57), intradialytic hypotension (OR 1.14 per 10% increase in days with intradialytic hypotension (95% CI 1.06 to 1.23)), age (OR 1.15 per five-year increase (95% CI 1.07 to 1.25)), maximum sequential organ failure assessment score on days 1 to 7 (OR 1.21 (95% CI 1.13 to 1.29)), and Charlson comorbidity index (OR 1.28 (95% CI 1.14 to 1.44)); higher baseline creatinine (OR 0.98 per 10 mu mol/L (95% CI 0.97 to 0.996)) was associated with lower risk of death. Of 241 hospital survivors, 61 (25.3%) were RRT dependent at discharge. The only independent risk factor for RRT dependence was pre-existing heart failure (OR 3.13 (95% CI 1.46 to 6.74)). Neither mean daily fluid balance nor intradialytic hypotension was associated with RRT dependence in survivors. Associations between these exposures and mortality were similar in sensitivity analyses accounting for immortal time bias and dichotomising mean daily fluid balance as positive or negative. In the subgroup of patients with data on pre-RRT fluid balance, fluid overload at RRT initiation did not modify the association of mean daily fluid balance with mortality.

Conclusions: In this cohort of patients with AKI requiring RRT, a more positive mean daily fluid balance and intradialytic hypotension were associated with hospital mortality but not with RRT dependence at hospital discharge in survivors.

Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium

OBJECTIVE: To investigate the impact of smoking and smoking cessation on cardiovascular mortality, acute coronary events, and stroke events in people aged 60 and older, and to calculate and report risk advancement periods for cardiovascular mortality in addition to traditional epidemiological relative risk measures.

DESIGN: Individual participant meta-analysis using data from 25 cohorts participating in the CHANCES consortium. Data were harmonised, analysed separately employing Cox proportional hazard regression models, and combined by meta-analysis.

RESULTS: Overall, 503,905 participants aged 60 and older were included in this study, of whom 37,952 died from cardiovascular disease. Random effects meta-analysis of the association of smoking status with cardiovascular mortality yielded a summary hazard ratio of 2.07 (95% CI 1.82 to 2.36) for current smokers and 1.37 (1.25 to 1.49) for former smokers compared with never smokers. Corresponding summary estimates for risk advancement periods were 5.50 years (4.25 to 6.75) for current smokers and 2.16 years (1.38 to 2.39) for former smokers. The excess risk in smokers increased with cigarette consumption in a dose-response manner, and decreased continuously with time since smoking cessation in former smokers. Relative risk estimates for acute coronary events and for stroke events were somewhat lower than for cardiovascular mortality, but patterns were similar.

CONCLUSIONS: Our study corroborates and expands evidence from previous studies in showing that smoking is a strong independent risk factor of cardiovascular events and mortality even at older age, advancing cardiovascular mortality by more than five years, and demonstrating that smoking cessation in these age groups is still beneficial in reducing the excess risk.

Core Outcomes in Ventilation Trials (COVenT): protocol for a core outcome set using a Delphi survey with a nested randomised trial and observational cohort study

Background
Among clinical trials of interventions that aim to modify time spent on mechanical ventilation for critically ill patients there is considerable inconsistency in chosen outcomes and how they are measured. The Core Outcomes in Ventilation Trials (COVenT) study aims to develop a set of core outcomes for use in future ventilation trials in mechanically ventilated adults and children.

Methods/design
We will use a mixed methods approach that incorporates a randomised trial nested within a Delphi study and a consensus meeting. Additionally, we will conduct an observational cohort study to evaluate uptake of the core outcome set in published studies at 5 and 10 years following core outcome set publication. The three-round online Delphi study will use a list of outcomes that have been reported previously in a review of ventilation trials. The Delphi panel will include a range of stakeholder groups including patient support groups. The panel will be randomised to one of three feedback methods to assess the impact of the feedback mechanism on subsequent ranking of outcomes. A final consensus meeting will be held with stakeholder representatives to review outcomes.

Discussion
The COVenT study aims to develop a core outcome set for ventilation trials in critical care, explore the best Delphi feedback mechanism for achieving consensus and determine if participation increases use of the core outcome set in the long term.

Cataract extraction and patient vision-related quality of life: a cohort study

Aims: Cataract surgery is one of the most common surgeries performed, but its overuse has been reported. The threshold for cataract surgery has become increasingly lenient; therefore, the selection process and surgical need has been questioned. The aim of this study was to evaluate the changes associated with cataract surgery in patient-reported vision-related quality of life (VR-QoL).

Methods: A prospective cohort study was conducted. Consecutive patients referred to cataract clinics in an NHS unit in Scotland were identified. Those listed for surgery were invited to complete a validated questionnaire (TyPE) to measure VR-QoL pre- and post-operatively. TyPE has five different domains (near vision, distance vision, daytime driving, night-time driving, and glare) and a global score of vision. The influence of pre-operative visual acuity (VA) levels, vision, and lens status of the fellow eye on changes in VR-QoL were explored. 

Results: A total of 320 listed patients were approached, of whom 36 were excluded. Among the 284 enrolled patients, 229 (81%) returned the questionnaire after surgery. Results revealed that the mean overall vision improved, as reported by patients. Improvements were also seen in all sub-domains of the questionnaire.

Conclusion: The majority of patients appear to have improvement in patient-reported VR-QoL, including those with good pre-operative VA and previous surgery to the fellow eye. VA thresholds may not capture the effects of the quality of life on patients. This information can assist clinicians to make more informed decisions when debating over the benefits of listing a patient for cataract extraction.

β-Blocker usage and colorectal cancer mortality:a nested case-control study in the UK Clinical Practice Research Datalink cohort

BACKGROUND: Epidemiological and laboratory studies suggest that β-blockers may reduce cancer progression in various cancer sites. The aim of this study was to conduct the first epidemiological investigation of the effect of post-diagnostic β-blocker usage on colorectal cancer-specific mortality in a large population-based colorectal cancer patient cohort.

PATIENTS AND METHODS: A nested case-control analysis was conducted within a cohort of 4794 colorectal cancer patients diagnosed between 1998 and 2007. Patients were identified from the UK Clinical Practice Research Datalink and confirmed using cancer registry data. Patients with a colorectal cancer- specific death (data from the Office of National Statistics death registration system) were matched to five controls. Conditional logistic regression was applied to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) according to β-blocker usage (data from GP-prescribing records).

RESULTS: Post-diagnostic β-blocker use was identified in 21.4% of 1559 colorectal cancer-specific deaths and 23.7% of their 7531 matched controls, with little evidence of an association (OR = 0.89 95% CI 0.78-1.02). Similar associations were found when analysing drug frequency, β-blocker type or specific drugs such as propranolol. There was some evidence of a weak reduction in all-cause mortality in β-blocker users (adjusted OR = 0.88; 95% CI 0.77-1.00; P = 0.04) which was in part due to the marked effect of atenolol on cardiovascular mortality (adjusted OR = 0.62; 95% CI 0.40-0.97; P = 0.04).

CONCLUSIONS: In this novel, large UK population-based cohort of colorectal cancer patients, there was no evidence of an association between post-diagnostic β-blocker use and colorectal cancer-specific mortality.

CLINICAL TRIALS NUMBER: NCT00888797.

Statin use after colorectal cancer diagnosis and survival: a population-based cohort study

PURPOSE: To investigate whether statins used after colorectal cancer diagnosis reduce the risk of colorectal cancer-specific mortality in a cohort of patients with colorectal cancer.

PATIENTS AND METHODS: A cohort of 7,657 patients with newly diagnosed stage I to III colorectal cancer were identified from 1998 to 2009 from the National Cancer Data Repository (comprising English cancer registry data). This cohort was linked to the United Kingdom Clinical Practice Research Datalink, which provided prescription records, and to mortality data from the Office of National Statistics (up to 2012) to identify 1,647 colorectal cancer-specific deaths. Time-dependent Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% CIs by postdiagnostic statin use and to adjust these HRs for potential confounders.

RESULTS: Overall, statin use after a diagnosis of colorectal cancer was associated with reduced colorectal cancer-specific mortality (fully adjusted HR, 0.71; 95% CI, 0.61 to 0.84). A dose-response association was apparent; for example, a more marked reduction was apparent in colorectal cancer patients using statins for more than 1 year (adjusted HR, 0.64; 95% CI, 0.53 to 0.79). A reduction in all-cause mortality was also apparent in statin users after colorectal cancer diagnosis (fully adjusted HR, 0.75; 95% CI, 0.66 to 0.84).

CONCLUSION: In this large population-based cohort, statin use after diagnosis of colorectal cancer was associated with longer rates of survival.

Gleason Upgrading with Time in a Large Prostate Cancer Active Surveillance Cohort

PURPOSE: We report the percentage of patients on active surveillance who had disease pathologically upgraded and factors that predict for upgrading on surveillance biopsies.

MATERIALS AND METHODS: Patients in our active surveillance database with at least 1 repeat prostate biopsy were included. Histological upgrading was defined as any increase in primary or secondary Gleason grade on repeat biopsy. Multivariate analysis was used to determine baseline and dynamic factors associated with Gleason upgrading. This information was used to develop a nomogram to predict for upgrading or treatment in patients electing for active surveillance.

RESULTS: Of 862 patients in our cohort 592 had 2 or more biopsies. Median followup was 6.4 years. Of the patients 20% were intermediate risk, 0.3% were high risk and all others were low risk. During active surveillance 31.3% of cases were upgraded. On multivariate analysis clinical stage T2, higher prostate specific antigen and higher percentage of cores involved with disease at the time of diagnosis predicted for upgrading. A total of 27 cases (15% of those upgraded) were Gleason 8 or higher at upgrading, and 62% of all 114 upgraded cases went on to have active treatment. The nomogram incorporated clinical stage, age, prostate specific antigen, core positivity and Gleason score. The concordance index was 0.61.

CONCLUSIONS: In this large re-biopsy cohort with medium-term followup, most cases have not been pathologically upgraded to date. A model predicting for upgrading or radical treatment was developed which could be useful in counseling patients considering active surveillance for prostate cancer.

Long-Term Follow-Up of a Large Active Surveillance Cohort of Patients With Prostate Cancer

PURPOSE: Active surveillance is increasingly accepted as a treatment option for favorable-risk prostate cancer. Long-term follow-up has been lacking. In this study, we report the long-term outcome of a large active surveillance protocol in men with favorable-risk prostate cancer.

PATIENTS AND METHODS: In a prospective single-arm cohort study carried out at a single academic health sciences center, 993 men with favorable- or intermediate-risk prostate cancer were managed with an initial expectant approach. Intervention was offered for a prostate-specific antigen (PSA) doubling time of less than 3 years, Gleason score progression, or unequivocal clinical progression. Main outcome measures were overall and disease-specific survival, rate of treatment, and PSA failure rate in the treated patients.

RESULTS: Among the 819 survivors, the median follow-up time from the first biopsy is 6.4 years (range, 0.2 to 19.8 years). One hundred forty-nine (15%) of 993 patients died, and 844 patients are alive (censored rate, 85.0%). There were 15 deaths (1.5%) from prostate cancer. The 10- and 15-year actuarial cause-specific survival rates were 98.1% and 94.3%, respectively. An additional 13 patients (1.3%) developed metastatic disease and are alive with confirmed metastases (n = 9) or have died of other causes (n = 4). At 5, 10, and 15 years, 75.7%, 63.5%, and 55.0% of patients remained untreated and on surveillance. The cumulative hazard ratio for nonprostate-to-prostate cancer mortality was 9.2:1.

CONCLUSION: Active surveillance for favorable-risk prostate cancer is feasible and seems safe in the 15-year time frame. In our cohort, 2.8% of patients have developed metastatic disease, and 1.5% have died of prostate cancer. This mortality rate is consistent with expected mortality in favorable-risk patients managed with initial definitive intervention.

Inappropriate prescribing of combination inhalers in Northern Ireland: retrospective cross-sectional cohort study of prescribing practice in primary care

BACKGROUND: Asthma management guidelines advocate a stepwise approach to asthma therapy, including the addition of a long-acting bronchodilator to inhaled steroid therapy at step 3. This is almost exclusively prescribed as inhaled combination therapy.

AIMS: To examine whether asthma prescribing practice for inhaled combination therapy (inhaled corticosteroid/long-acting β2-agonist (ICS/LABA)) in primary care in Northern Ireland is in line with national asthma management guidelines.

METHODS: Using data from the Northern Ireland Enhanced Prescribing Database, we examined initiation of ICS/LABA in subjects aged 5-35 years in 2010.

RESULTS: A total of 2,640 subjects (67%) had no inhaled corticosteroid monotherapy (ICS) in the study year or six months of the preceding year (lead-in period) and, extending this to a 12-month lead-in period, 52% had no prior ICS. 41% of first prescriptions for ICS/LABA were dispensed in January to March. Prior to ICS/LABA prescription, in the previous six months only 17% had a short-acting β2-agonist (SABA) dispensed, 5% received oral steroids, and 17% received an antibiotic.

CONCLUSIONS: ICS/LABA therapy was initiated in the majority of young subjects with asthma without prior inhaled steroid therapy. Most prescriptions were initiated in the January to March period. However, the prescribing of ICS/LABA did not appear to be driven by asthma symptoms (17% received SABA in the previous 6 months) or severe asthma exacerbation (only 5% received oral steroids). Significant reductions in ICS/LABA, with associated cost savings, would occur if the asthma prescribing guidelines were followed in primary care.

Dimensions of Suicide Research: Substance misuse in life and death in a 2-year cohort of suicides

Background
While substance misuse is a key risk factor in suicide relatively little is known about the relationship between lifetime misuse and misuse in suicide.

Aim
To examine the relationship between a history of substance misuse and misuse at the time of a suicide.

Method
Linkage of Coroner reports of 403 suicides occurring over two years with associated primary care records. History of substance misuse was defined as alcohol misuse and/or prescription or illicit drug misuse, for which medical help was sought.

Results
With alcohol misuse: 65% of the cohort had previously sought help and 42% were intoxicated at the suicide (with 30% of these seeing their GP in the previous year). With misuse of other substances: 54% of the cohort were tested for blood toxicology (37% of these tested positive) - with positive toxicology defined as an excess of prescription drugs over the therapeutic minima and/or detection of illicit substances. Those tested were more likely to be young and have a history of drug abuse.

Conclusion
Understanding the links between substance misuse and the use of substances in conjunction with the act of suicide is discussed in light of the study results and current pathology and coroner practices.

Lead concentrations in bones and feathers of the globally threatened Spanish imperial eagle

Raptors that consume game species may ingest lead fragments or shot embedded in their prey's flesh. Threatened Spanish imperial eagles Aquila adalberti feed on greylag geese in southern Spain in winter, and often ingest lead shot. We analysed bone and feather samples from 65 Spanish imperial eagle museum specimens collected between 1980 and 1999, to investigate the prevalence of elevated lead concentrations. Four of 34 birds (12%) had very elevated bone lead concentrations. All four birds were young and the concentrations were outliers to the distribution, suggesting probable exposure to lead gunshot. Excluding these elevated lead outliers, bone lead concentrations were correlated with the bird's age at death. Three of 41 feathers (7%) had elevated lead concentrations, indicative of high exposure during feather formation. When these outliers were omitted, feather lead concentration was correlated with the age of museum specimens, suggesting that a high proportion of feather lead was exogenous, deposited after specimen collection. Therefore, careful interpretation of feather lead concentrations is required to separate endogenous and exogenous lead. We discuss the potential significance of lead poisoning in Spanish imperial eagles and other raptors, and recommend measures for its reduction. © 2004 Elsevier Ltd. All rights reserved.

Metformin use and survival after colorectal cancer: A population-based cohort study.

Preclinical evidence suggests that metformin could delay cancer progression. Previous epidemiological studies however have been limited by small sample sizes and certain time-related biases. This study aimed to investigate whether colorectal cancer patients with type 2 diabetes who were exposed to metformin had reduced cancer-specific mortality. We conducted a retrospective cohort study of 1,197 colorectal cancer patients newly diagnosed from 1998 to 2009 (identified from English cancer registries) with type 2 diabetes (based upon Clinical Practice Research Datalink, CPRD, prescription and diagnosis records). In this cohort 382 colorectal cancer-specific deaths occurred up to 2012 from the Office of National Statistics (ONS) mortality data. Metformin use was identified from CPRD prescription records. Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% CIs were calculated for the association between post-diagnostic exposure to metformin and colorectal cancer-specific mortality. Overall, there was no evidence of an association between metformin use and cancer-specific death before or after adjustment for potential confounders (adjusted HR 1.06, 95% CI 0.80, 1.40). In addition, after adjustment for confounders, there was also no evidence of associations between other diabetic medications and cancer-specific mortality including sulfonylureas (HR 1.14, 95% CI 0.86, 1.51), insulin use (HR 1.35, 95% CI 0.95, 1.93) or other anti-diabetic medications including thiazolidinediones (HR 0.73, 95% CI 0.46, 1.14). Similar associations were observed by duration of use and for all-cause mortality. This population-based study, the largest to date, does not support a protective association between metformin and survival in colorectal cancer patients.

The stability of alcohol consumption between age 16 and 26: Evidence from a National Birth Cohort Study

This study examined the association between moderate drinking at age 16 (adolescence) and alcohol consumption at age 26 (young adulthood), whilst controlling for possible confounding effects at the individual and family level (assessed at birth and age 10). Using the British Cohort Study (BCS70), 6515 respondents provided data on their adolescent alcohol consumption and other behaviours. Of these, 4392 also completed the survey at age 26. Consumption patterns established in adolescence persisted, to a large degree, into early adulthood. Those adolescents who drank moderately in adolescence drank significantly less in adulthood than those adolescents who drank to heavy or hazardous levels. Implications for health promotion strategies and guidance are discussed.