scholarly journals Adverse effects of Z-drugs for sleep disturbance in people living with dementia: a population-based cohort study

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Kathryn Richardson ◽  
Yoon K. Loke ◽  
Chris Fox ◽  
Ian Maidment ◽  
Robert Howard ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Adverse Events ◽  
Confidence Interval ◽  
Ischaemic Stroke ◽  
Sleep Disturbance ◽  
Cox Regression ◽  
Population Based ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Health Related

Abstract Background Sleep disturbance is common in dementia and often treated with Z-drugs (zopiclone, zaleplon, and zolpidem). While some observational studies suggest that Z-drugs are associated with adverse events such as falls and fracture risks in older people, this has not been studied in dementia. Methods We used data from 27,090 patients diagnosed with dementia between January 2000 and March 2016 from the Clinical Practice Research Datalink linked to Hospital Episodes Statistics data in England. We compared adverse events for 3532 patients newly prescribed Z-drugs by time-varying dosage to (1) 1833 non-sedative-users with sleep disturbance; (2) 10,214 non-sedative-users with proximal GP consultation matched on age, sex, and antipsychotic use; and (3) 5172 patients newly prescribed benzodiazepines. We defined higher dose Z-drugs and benzodiazepines as prescriptions equivalent to ≥ 7.5 mg zopiclone or > 5 mg diazepam daily. Cox regression was used to estimate hazard ratios (HRs) for incident fracture, hip fracture, fall, mortality, acute bacterial infection, ischaemic stroke/transient ischaemic attack, and venous thromboembolism over a 2-year follow-up, adjusted for demographic- and health-related covariates. Results The mean (SD) age of patients was 83 (7.7) years, and 16,802 (62%) were women. Of 3532 patients prescribed Z-drugs, 584 (17%) were initiated at higher doses. For patients prescribed higher dose Z-drugs relative to non-users with sleep disturbance, the HRs (95% confidence interval) for fractures, hip fractures, falls, and ischaemic stroke were 1.67 (1.13–2.46), 1.96 (1.16–3.31), 1.33 (1.06–1.66), and 1.88 (1.14–3.10), respectively. We observed similar associations when compared to non-sedative-users with proximal GP consultation. Minimal or inconsistent excess risks were observed at ≤ 3.75 mg zopiclone or equivalent daily, and for mortality, infection, and venous thromboembolism. We observed no differences in adverse events for Z-drugs compared to benzodiazepines, except lower mortality rates with Z-drugs (HR [95% confidence interval] of 0.73 [0.64–0.83]). Conclusions Higher dose Z-drug use in dementia is associated with increased fracture and stroke risks, similar or greater to that for higher dose benzodiazepines. Higher dose Z-drugs should be avoided, if possible, in people living with dementia, and non-pharmacological alternatives preferentially considered. Prescriptions for higher dose Z-drugs in dementia should be regularly reviewed. Trial registration ENCePP e-register of studies, EUPAS18006

scholarly journals Long-term effectiveness and safety of varenicline and nicotine replacement therapy in people with neurodevelopmental disorders: A prospective cohort study

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Taha Itani ◽  
Dheeraj Rai ◽  
Tim Jones ◽  
Gemma M. J. Taylor ◽  
Kyla H. Thomas ◽  
...  
Keyword(s):  
Mental Health ◽  
Smoking Cessation ◽  
Adverse Events ◽  
Confidence Interval ◽  
Neurodevelopmental Disorders ◽  
Instrumental Variable ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Instrumental Variable Analysis ◽  
Health Related

AbstractThis study aimed to determine the effectiveness and safety of varenicline versus NRT for smoking cessation in people with neurodevelopmental disorders, compared to those without, at up to four years after exposure. We analysed electronic medical records from the Clinical Practice Research Datalink using three different statistical approaches: multivariable logistic regression, propensity score matching (PSM), and instrumental variable analysis. Exposure was prescription of varenicline versus NRT and the primary outcome was smoking cessation at 2-years. We included 235,314 people aged 18 and above with eligible smoking cessation prescriptions in the effectiveness analysis. Smokers with neurodevelopmental disorders were 48% less likely (95% confidence interval: 42%, 54%) to be prescribed varenicline than NRT, compared to smokers without neurodevelopmental disorders. At 2-year follow-up, smokers with neurodevelopmental disorders prescribed varenicline were 38% more likely to quit smoking (95% confidence interval: 6%, 78%). Similar results were obtained using PSM and instrumental variable analyses. There was little evidence showing that varenicline increased the likelihood of mental health related adverse events in people with neurodevelopmental disorders. Varenicline is less likely to be prescribed to people with neurodevelopmental disorders despite results suggesting it is more effective than NRT and little evidence of increased likelihood of mental health related adverse events.

Epidemiology of first and recurrent venous thromboembolism: A population-based cohort study in patients without active cancer

2014 ◽  
Vol 112 (08) ◽  
pp. 255-263 ◽  
Author(s):  
Alexander T. Cohen ◽  
Luke Bamber ◽  
Stephan Rietbrock ◽  
Carlos Martinez
Keyword(s):  
Cohort Study ◽  
Venous Thromboembolism ◽  
The Elderly ◽  
Population Based ◽  
Incidence Rates ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Recurrence Rates ◽  
Recurrent Vte ◽  
Active Cancer

SummaryContemporary data from population studies on the incidence and complications of venous thromboembolism (VTE) are limited. An observational cohort study was undertaken to estimate the incidence of first and recurrent VTE. The cohort was identified from all patients in the UK Clinical Practice Research Datalink (CPRD) with additional linked information on hospitalisation and cause of death. Between 2001 and 2011, patients with first VTE were identified and the subset without active cancer-related VTE observed for up to 10 years for recurrent VTE. The 10-year cumulative incidence rates (CIR) were derived with adjustment for mortality as a competing risk event. A total of 35,373 first VTE events (12,073 provoked, 16,708 unprovoked and 6592 active cancer-associated VTE) among 26.9 million person-years of observation were identified. The overall incidence rate (IR) of VTE was 131.5 (95% CI, 130.2–132.9) per 100,000 person-years and 107.0 (95% CI, 105.8–108.2) after excluding cancer-associated VTE. DVT was more common in the young and PE was more common in the elderly. VTE recurrence occurred in 3671 (CIR 25.2%). The IR for recurrence peaked in the first six months at around 11 per 100 person years. It levelled out after three years and then remained at around 2 per 100 person years from year 4–10 of follow-up. The IRs for recurrences were particularly high in young men. In conclusion, VTE is common and associated with high recurrence rates. Effort is required to prevent VTE and to reduce recurrences.

scholarly journals Effect of Timing and Duration of Statin Exposure on Risk of Hip or Knee Revision Arthroplasty: A Population-based Cohort Study

2019 ◽  
Vol 47 (3) ◽  
pp. 441-448 ◽  
Author(s):  
Michael J. Cook ◽  
Antony K. Sorial ◽  
Mark Lunt ◽  
Tim N. Board ◽  
Terence W. O’Neill
Keyword(s):  
Propensity Score ◽  
Statin Therapy ◽  
Cox Regression ◽  
Large Population ◽  
Revision Arthroplasty ◽  
Population Based ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Adjusted Model ◽  
Reduced Risk

Objectives.To determine whether the timing and duration of statin exposure following total hip/knee arthroplasty (THA/TKA) influence the risk of revision arthroplasty.Methods.Subjects from the Clinical Practice Research Datalink, a large population-based clinical database, who had THA/TKA from 1988 to 2016, were included. Propensity score adjusted Cox regression models were used to determine the association between statin exposure and the risk of revision THA/TKA, (1) at any time, and (2) if first exposed 0–1, 1–5, or > 5 years following THA/TKA. We also investigated the effect of duration of statin exposure (< 1, 1–2, 2–3, 3–4, 4–5, > 5 yrs).Results.The study included 151,305 participants. There were 65,032 (43%) exposed to statins during followup and 3500 (2.3%) had revision arthroplasty. In a propensity score adjusted model, exposure to statins was associated with a reduced risk of revision arthroplasty (HR 0.82, 95% CI 0.75–0.90). Participants first exposed within 1 year and between 1 and 5 years following THA/TKA (vs unexposed) had a reduced risk of revision arthroplasty (HR 0.82, 95% CI 0.74–0.91 and HR 0.76, 95% CI 0.65–0.90, respectively). In relation to duration of statin therapy, participants exposed for more than 5 years in total (vs < 1 yr) had a reduced risk of revision (HR 0.74, 95% CI 0.62–0.88).Conclusion.Statin therapy initiated up to 5 years following THA/TKA may reduce the risk of revision arthroplasty.

scholarly journals Duration and Magnitude of Postoperative Risk of Venous Thromboembolism after Cholecystectomy: A Population-Based Cohort Study

2019 ◽  
Vol 37 (1) ◽  
pp. 32-38 ◽  
Author(s):  
Mei-Ling Henry ◽  
Alyshah Abdul-Sultan ◽  
Alex J. Walker ◽  
Joe West ◽  
David J. Humes
Keyword(s):  
Cohort Study ◽  
Venous Thromboembolism ◽  
Cox Regression ◽  
Absolute Risk ◽  
Fold Increase ◽  
Risk Groups ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Historical Cohort ◽  
Increase In Risk

Background: This study aimed to identify the burden and risk of venous thromboembolism (VTE) associated with cholecystectomy in England. Methods: An historical cohort study of cholecystectomy patients from 2001 to 2011 was undertaken using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care data. Crude rates and adjusted hazard ratios (HRs) were calculated for risk of VTE following cholecystectomy using Cox regression. Results: 24,677 patients were identified with a rate of VTE in the first year following cholecystectomy of 2.80 per 1,000 person years (95% CI 2.18–3.59). Patients aged ≥70 vs. aged < 50 had 8.3-fold increase in risk of VTE (HR 8.27, 95% CI 3.72–18.35); patients with body mass index (BMI) > 30 vs. BMI < 30 had 2.4-fold increase in risk (HR 2.42, 95% CI 1.40–4.18); open vs. laparoscopic operation had 3-fold increase in risk (HR 2.94, 95% CI 1.55–5.55). Compared to general population, VTE risk was the highest in the first 30 days post-operatively with 9.9-fold risk following emergency cholecystectomy and 4.5-fold risk after inpatient cholecystectomy (HR 9.90, 95% CI 4.42–22.21; HR 4.54, 95% CI 2.85–7.21). Conclusions: Cholecystectomy is associated with a low absolute risk of VTE and we have identified high risk groups including the elderly, obese and those having open surgery.

Epidemiology of first and recurrent venous thromboembolism in patients with active cancer

2017 ◽  
Vol 117 (01) ◽  
pp. 57-65 ◽  
Author(s):  
Anja Katholing ◽  
Stephan Rietbrock ◽  
Luke Bamber ◽  
Carlos Martinez ◽  
Alexander T. Cohen
Keyword(s):  
Venous Thromboembolism ◽  
Confidence Interval ◽  
Incidence Rate ◽  
Incidence Rates ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Source Population ◽  
Recurrence Rates ◽  
Recurrent Vte ◽  
Active Cancer

SummaryPopulation studies on the incidence of venous thromboembolism (VTE) in patients with active cancer are limited. An observational cohort study was undertaken to estimate the incidence of first and recurrent VTE. The source population consisted of all patients in the UK Clinical Practice Research Datalink, with additional information on hospitalisation and cause of death, between 2001 and 2011. A cancer-related clinical diagnosis or therapy within the 90 days before or after a VTE constituted an active-cancer-associated VTE. Incidence rates of first VTE among patients with active cancer and incidence rates of recurrent VTE during the 10-year observational period after a first VTE event were estimated. Incidence rates of all-cause mortality and age- and gender-specific mortality were also calculated. There were 6,592 active-cancer-associated VTEs with a total of 112,738 cancer-associated person-years of observation. The incidence rate of first VTE in patients with active cancer was 5.8 (95 % confidence interval 5.7–6.0) per 100 person-years. A first VTE recurrence was observed in 591 patients. The overall incidence rate for recurrence was 9.6 (95 % confidence interval 8.8–10.4) per 100 person-years, with a peak at 22.1 in the first six months. Recurrence rates were similar after initial pulmonary embolism and after initial deep-vein thrombosis. The mortality risk after VTE was considerable, with 64.5 % mortality after one year and 88.1 % after 10 years. VTE in patients with active cancer is common and associated with high recurrence and mortality rates. Efforts are needed to prevent VTE and reduce recurrence, especially in the first year after VTE diagnosis.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Risk of venous thromboembolism in people with lung cancer: a cohort study using linked UK healthcare data

2016 ◽  
Vol 115 (1) ◽  
pp. 115-121 ◽  
Author(s):  
Alex J Walker ◽  
David R Baldwin ◽  
Tim R Card ◽  
Helen A Powell ◽  
Richard B Hubbard ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cohort Study ◽  
Venous Thromboembolism ◽  
High Risk ◽  
Cox Regression ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Related Factors ◽  
Cox Regression Analysis ◽  
Healthcare Data

Abstract Background: Venous thromboembolism (VTE) is a potentially preventable cause of death in people with lung cancer. Identification of those most at risk and high-risk periods may provide the opportunity for better targeted intervention. Methods: We conducted a cohort study using the Clinical Practice Research Datalink linked to Hospital Episode Statistics and Cancer Registry data. Our cohort comprises 10 598 people with lung cancer diagnosed between 1997 and 2006 with follow-up continuing to the end of 2010. Cox regression analysis was performed to determine which demographic, tumour and treatment-related factors (time-varying effects of chemotherapy and surgery) independently affected VTE risk. We also determined the effect of a VTE diagnosis on the survival of people with lung cancer. Results: People with lung cancer had an overall VTE incidence of 39.2 per 1000 person-years (95% confidence interval (CI), 35.4–43.5), though rates varied depending on the patient group and treatment course. Independent factors associated with increased VTE risk were metastatic disease (hazard ratio (HR)=1.9, CI 1.2–3.0 vs local disease); adenocarcinoma subtype (HR=2.0, CI 1.5–2.7, vs squamous cell; chemotherapy administration (HR=2.1, CI 1.4–3.0 vs outside chemotherapy courses); and diagnosis via emergency hospital admission (HR=1.7, CI 1.2–2.3 vs other routes to diagnosis). Patients with VTE had an approximately 50% higher risk of mortality than those without VTE. Conclusions: People with lung cancer have especially high risk of VTE if they have advanced disease, adenocarcinoma or are undergoing chemotherapy. The presence of VTE is an independent risk factor for death.

scholarly journals Validity of an algorithm to identify cardiovascular deaths from administrative health records: a multi-database population-based cohort study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Lisa M. Lix ◽  
Shamsia Sobhan ◽  
Audray St-Jean ◽  
Jean-Marc Daigle ◽  
Anat Fisher ◽  
...  
Keyword(s):  
Cohort Study ◽  
Cardiovascular Mortality ◽  
Population Based ◽  
Vital Statistics ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Health Records ◽  
Predictive Values ◽  
Site Specific ◽  
Hospital Deaths

Abstract Background Cardiovascular death is a common outcome in population-based studies about new healthcare interventions or treatments, such as new prescription medications. Vital statistics registration systems are often the preferred source of information about cause-specific mortality because they capture verified information about the deceased, but they may not always be accessible for linkage with other sources of population-based data. We assessed the validity of an algorithm applied to administrative health records for identifying cardiovascular deaths in population-based data. Methods Administrative health records were from an existing multi-database cohort study about sodium-glucose cotransporter-2 (SGLT2) inhibitors, a new class of antidiabetic medications. Data were from 2013 to 2018 for five Canadian provinces (Alberta, British Columbia, Manitoba, Ontario, Quebec) and the United Kingdom (UK) Clinical Practice Research Datalink (CPRD). The cardiovascular mortality algorithm was based on in-hospital cardiovascular deaths identified from diagnosis codes and select out-of-hospital deaths. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for the cardiovascular mortality algorithm using vital statistics registrations as the reference standard. Overall and stratified estimates and 95% confidence intervals (CIs) were computed; the latter were produced by site, location of death, sex, and age. Results The cohort included 20,607 individuals (58.3% male; 77.2% ≥70 years). When compared to vital statistics registrations, the cardiovascular mortality algorithm had overall sensitivity of 64.8% (95% CI 63.6, 66.0); site-specific estimates ranged from 54.8 to 87.3%. Overall specificity was 74.9% (95% CI 74.1, 75.6) and overall PPV was 54.5% (95% CI 53.7, 55.3), while site-specific PPV ranged from 33.9 to 72.8%. The cardiovascular mortality algorithm had sensitivity of 57.1% (95% CI 55.4, 58.8) for in-hospital deaths and 72.3% (95% CI 70.8, 73.9) for out-of-hospital deaths; specificity was 88.8% (95% CI 88.1, 89.5) for in-hospital deaths and 58.5% (95% CI 57.3, 59.7) for out-of-hospital deaths. Conclusions A cardiovascular mortality algorithm applied to administrative health records had moderate validity when compared to vital statistics data. Substantial variation existed across study sites representing different geographic locations and two healthcare systems. These variations may reflect different diagnostic coding practices and healthcare utilization patterns.

scholarly journals Primary Care Consultations after Hospitalisation for Pneumonia: A Large Population-based Cohort Study

2020 ◽  
pp. BJGP.2020.0890
Author(s):  
Vadsala Baskaran ◽  
Fiona Pearce ◽  
Rowan H Harwood ◽  
Tricia McKeever ◽  
Wei Shen Lim
Keyword(s):  
Primary Care ◽  
Cohort Study ◽  
Large Population ◽  
Significant Proportion ◽  
Antibiotic Use ◽  
Population Based ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Respiratory Disorder ◽  
The Impact

Background: Up to 70% of patients report ongoing symptoms four weeks after hospitalisation for pneumonia, and the impact on primary care is poorly understood. Aim: To investigate the frequency of primary care consultations after hospitalisation for pneumonia, and the reasons for consultation. Design: Population-based cohort study. Setting: UK primary care database of anonymised medical records (Clinical Practice Research Datalink, CPRD) linked to Hospital Episode Statistics (HES), England. Methods: Adults with the first ICD-10 code for pneumonia (J12-J18) recorded in HES between July 2002-June 2017 were included. Primary care consultation within 30 days of discharge was identified as the recording of any medical Read code (excluding administration-related codes) in CPRD. Competing-risks regression analyses were conducted to determine the predictors of consultation and antibiotic use at consultation; death and readmission were competing events. Reasons for consultation were examined. Results: Of 56,396 adults, 55.9% (n=31,542) consulted primary care within 30 days of discharge. The rate of consultation was highest within 7 days (4.7 per 100 person-days). The strongest predictor for consultation was a higher number of primary care consultations in the year prior to index admission (adjusted sHR 8.98, 95% CI 6.42-12.55). The commonest reason for consultation was for a respiratory disorder (40.7%, n=12,840), 12% for pneumonia specifically. At consultation, 31.1% (n=9,823) received further antibiotics. Penicillins (41.6%, n=5,753) and macrolides (21.9%, n=3,029) were the commonest antibiotics prescribed. Conclusion: Following hospitalisation for pneumonia, a significant proportion of patients consulted primary care within 30 days, highlighting the morbidity experienced by patients during recovery from pneumonia.

scholarly journals Relative toxicity of benzodiazepines and hypnotics commonly used for self-poisoning: An epidemiological study of fatal toxicity and case fatality

2018 ◽  
Vol 32 (6) ◽  
pp. 654-662 ◽  
Author(s):  
Galit Geulayov ◽  
Anne Ferrey ◽  
Deborah Casey ◽  
Claudia Wells ◽  
Alice Fuller ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Case Fatality ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Relative Toxicity ◽  
Reference Drug ◽  
Alcohol Involvement ◽  
Self Harm ◽  
Hypnotic Drugs ◽  
Using Data

The relative toxicity of anxiolytic and hypnotic drugs commonly used for self-poisoning was assessed using data on suicides, prescriptions and non-fatal self-poisonings in England, 2005–2012. Data on suicide by self-poisoning were obtained from the Office for National Statistics, information on intentional non-fatal self-poisoning was derived from the Multicentre Study of Self-harm in England and data on prescriptions in general practice from the Clinical Practice Research Datalink. We used two indices of relative toxicity: fatal toxicity (the number of fatal self-poisonings relative to the number of individuals prescribed each drug) and case fatality (the number of fatal relative to non-fatal self-poisonings). Diazepam was the reference drug in all analyses. Temazepam was 10 times (95% confidence interval 5.48–18.99) and zopiclone/zolpidem nine times (95% confidence interval 5.01–16.65) more toxic in overdose than diazepam (fatal-toxicity index). Temazepam and zopiclone/zolpidem were 13 (95% confidence interval 6.97–24.41) and 12 (95% confidence interval 6.62–22.17) times more toxic than diazepam, respectively (case-fatality index). Differences in alcohol involvement between the drugs were unlikely to account for the findings. Overdoses of temazepam and zopiclone/zolpidem are considerably more likely to result in death than overdoses of diazepam. Practitioners need to exercise caution when prescribing these drugs, especially for individuals who may be at risk of self-harm, and also consider non-pharmacological options.

Abstract MP23: Urinary Magnesium Excretion and Risk of Incident Hypertension

Circulation ◽  
2013 ◽  
Vol 127 (suppl_12) ◽  
Author(s):  
Michel M Joosten ◽  
Ron T Gansevoort ◽  
Kenneth J Mukamal ◽  
Johanna M Geleijnse ◽  
Edith J Feskens ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Urinary Excretion ◽  
Cox Regression ◽  
Smoking Status ◽  
Population Based ◽  
Incident Hypertension ◽  
Adjusted Risk ◽  
Magnesium Uptake ◽  
Magnesium Excretion ◽  
Log Linear

Background: Observational studies on dietary magnesium and risk of hypertension have reported mixed findings, but have lacked direct measures of magnesium uptake. Urinary excretion of magnesium, an indicator of dietary uptake, may clarify these discrepant findings. Methods: We examined 4,070 participants aged 28-75 years free of hypertension, kidney disease, and cardiovascular disease in the PREVEND Study, a prospective population-based cohort study. Urinary magnesium excretion was measured in two 24-hour urine collections at baseline. Incident hypertension was defined as blood pressure ≥140/90 mm Hg or initiation of antihypertensive medication. Results: During a median follow-up of 7.5 years (interquartile range: 5.5-9.2 years), 1,001 participants developed incident hypertension. Mean 24-hour urinary magnesium excretion was 4.35 ± 1.61 mmol for men and 3.65 ± 1.35 mmol for women. Urinary magnesium excretion was associated with risk of hypertension in a log-linear fashion (Figure) after adjustment for age, body mass index, sex, smoking status, alcohol intake, family history of hypertension, and urinary excretion of sodium, potassium, and calcium. Each 1-unit increment in ln-transformed urinary magnesium excretion was associated with a 26% lower risk of incident hypertension after multivariable adjustment (adjusted hazard ratio, 0.74; 95% confidence interval, 0.65-0.84). Conclusion: Urinary magnesium excretion is inversely and independently associated with risk of incident hypertension. Increasing dietary intake of magnesium could reduce the risk of hypertension. Figure legend: Natural log-transformed urinary magnesium concentrations and adjusted risk of hypertension. Magnesium levels were back-transformed to original values for ease of interpretation. Association estimated by Cox regression based on restricted splines with three knots. Dashed lines represent the 95% confidence interval. The spline curve is truncated at the 0.5 percentile and 99.5 percentile of the distribution curve.

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