Vertical structure of conventionally neutral atmospheric boundary layers.

SignificanceThe presented model describes the vertical structure of conventionally neutral atmospheric boundary layers. Due to the complicated interplay between buoyancy, shear, and Coriolis effects, analytical descriptions have been limited to the mean wind speed. We introduce an analytical approach based on the Ekman equations and the basis function of the universal potential temperature flux profile that allows one to describe the wind and turbulent shear stress profiles and hence capture features like the wind veer profile. The analytical profiles are validated against high-fidelity large-eddy simulations and atmospheric measurements. Our findings contribute to the scientific community's fundamental understanding of atmospheric turbulence with direct relevance for weather forecasting, climate modeling, and wind energy applications.

Aspect Ratio Dependence of Heat Transfer in a Cylindrical Rayleigh-Bénard Cell.

While the heat transfer and the flow dynamics in a cylindrical Rayleigh-Bénard (RB) cell are rather independent of the aspect ratio Γ (diameter/height) for large Γ, a small-Γ cell considerably stabilizes the flow and thus affects the heat transfer. Here, we first theoretically and numerically show that the critical Rayleigh number for the onset of convection at given Γ follows Ra_{c,Γ}∼Ra_{c,∞}(1+CΓ^{-2})^{2}, with C≲1.49 for Oberbeck-Boussinesq (OB) conditions. We then show that, in a broad aspect ratio range (1/32)≤Γ≤32, the rescaling Ra→Ra_{ℓ}≡Ra[Γ^{2}/(C+Γ^{2})]^{3/2} collapses various OB numerical and almost-OB experimental heat transport data Nu(Ra,Γ). Our findings predict the Γ dependence of the onset of the ultimate regime Ra_{u,Γ}∼[Γ^{2}/(C+Γ^{2})]^{-3/2} in the OB case. This prediction is consistent with almost-OB experimental results (which only exist for Γ=1, 1/2, and 1/3) for the transition in OB RB convection and explains why, in small-Γ cells, much larger Ra (namely, by a factor Γ^{-3}) must be achieved to observe the ultimate regime.

Spontaneous Reporting to Regulatory Authorities of Suspected Adverse Drug Reactions to COVID-19 Vaccines Over Time: The Effect of Publicity.

INTRODUCTION: The UK Medicines and Healthcare products Regulatory Agency (MHRA) has published frequent summaries of spontaneous reports of suspected adverse drug reactions (ADRs) (Yellow Cards) to vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The EudraVigilance database has provided similar data for the European Economic Area. OBJECTIVE: Our objective was to characterize the evolution over time of spontaneous reports of suspected ADRs to coronavirus disease 2019 (COVID-19) vaccines and to observe the effect of a publicized reaction (cerebral venous and sinus thrombosis [CVST]) on reporting rates. METHODS: We used publicly available data on reports of suspected ADRs and doses of vaccine administered, published by the MHRA, EudraVigilance, and the European Centre for Disease Prevention and Control to calculate reporting rates. RESULTS: Approximately 4814 Yellow Card reports (23 fatal) per million doses of ChAdOx1 nCoV-19 (AstraZeneca) and 2890 (13 fatal) per million doses of tozinameran (Pfizer/BioNTech) have been lodged. Between 15 March and 31 October 2021, cumulative European reports of CVST rose from 0 to 443 (183 with thrombocytopenia, 72 fatal) with ChAdOx1 nCoV-19 and from 2 to 315 (9 with thrombocytopenia, 28 fatal) with tozinameran. European cases of retinal vein occlusion and thrombosis rose from 0 to 168 with ChAdOx1 nCoV-19 and from 1 to 220 with tozinameran; four of the ChAdOx1 nCoV-19 cases were associated with thrombocytopenia. CONCLUSION: Reports of fatal adverse reactions to coronavirus vaccines are very rare. Reports of CVST have been made in relation to both vaccines. Most were submitted after the reaction had been publicized. Thrombocytopenia occurred in a minority of cases. Reports linked both vaccines to cases of retinal vein thrombosis, just four cases with thrombocytopenia. This suggests two different mechanisms of thrombosis associated with the vaccines.

Associations between statins and adverse events in primary prevention of cardiovascular disease: systematic review with pairwise, network, and dose-response meta-analyses.

OBJECTIVE: To assess the associations between statins and adverse events in primary prevention of cardiovascular disease and to examine how the associations vary by type and dosage of statins. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Studies were identified from previous systematic reviews and searched in Medline, Embase, and the Cochrane Central Register of Controlled Trials, up to August 2020. REVIEW METHODS: Randomised controlled trials in adults without a history of cardiovascular disease that compared statins with non-statin controls or compared different types or dosages of statins were included. MAIN OUTCOME MEASURES: Primary outcomes were common adverse events: self-reported muscle symptoms, clinically confirmed muscle disorders, liver dysfunction, renal insufficiency, diabetes, and eye conditions. Secondary outcomes included myocardial infarction, stroke, and death from cardiovascular disease as measures of efficacy. DATA SYNTHESIS: A pairwise meta-analysis was conducted to calculate odds ratios and 95% confidence intervals for each outcome between statins and non-statin controls, and the absolute risk difference in the number of events per 10 000 patients treated for a year was estimated. A network meta-analysis was performed to compare the adverse effects of different types of statins. An Emax model based meta-analysis was used to examine the dose-response relationships of the adverse effects of each statin. RESULTS: 62 trials were included, with 120 456 participants followed up for an average of 3.9 years. Statins were associated with an increased risk of self-reported muscle symptoms (21 trials, odds ratio 1.06 (95% confidence interval 1.01 to 1.13); absolute risk difference 15 (95% confidence interval 1 to 29)), liver dysfunction (21 trials, odds ratio 1.33 (1.12 to 1.58); absolute risk difference 8 (3 to 14)), renal insufficiency (eight trials, odds ratio 1.14 (1.01 to 1.28); absolute risk difference 12 (1 to 24)), and eye conditions (six trials, odds ratio 1.23 (1.04 to 1.47); absolute risk difference 14 (2 to 29)) but were not associated with clinically confirmed muscle disorders or diabetes. The increased risks did not outweigh the reduction in the risk of major cardiovascular events. Atorvastatin, lovastatin, and rosuvastatin were individually associated with some adverse events, but few significant differences were found between types of statins. An Emax dose-response relationship was identified for the effect of atorvastatin on liver dysfunction, but the dose-response relationships for the other statins and adverse effects were inconclusive. CONCLUSIONS: For primary prevention of cardiovascular disease, the risk of adverse events attributable to statins was low and did not outweigh their efficacy in preventing cardiovascular disease, suggesting that the benefit-to-harm balance of statins is generally favourable. Evidence to support tailoring the type or dosage of statins to account for safety concerns before starting treatment was limited. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020169955.

Universal Wind Profile for Conventionally Neutral Atmospheric Boundary Layers.

Conventionally neutral atmospheric boundary layers (CNBLs), which are characterized with zero surface potential temperature flux and capped by an inversion of potential temperature, are frequently encountered in nature. Therefore, predicting the wind speed profiles of CNBLs is relevant for weather forecasting, climate modeling, and wind energy applications. However, previous attempts to predict the velocity profiles in CNBLs have had limited success due to the complicated interplay between buoyancy, shear, and Coriolis effects. Here, we utilize ideas from the classical Monin-Obukhov similarity theory in combination with a local scaling hypothesis to derive an analytic expression for the stability correction function ψ=-c_{ψ}(z/L)^{1/2}, where c_{ψ}=4.2 is an empirical constant, z is the height above ground, and L is the local Obukhov length based on potential temperature flux at that height, for CNBLs. An analytic expression for this flux is also derived using dimensional analysis and a perturbation method approach. We find that the derived profile agrees excellently with the velocity profile in the entire boundary layer obtained from high-fidelity large eddy simulations of typical CNBLs.

Impact of changes to national guidelines on hypertension-related workload: an interrupted time series analysis in English primary care.

BACKGROUND: In 2011, National Institute for Health and Care Excellence (NICE) guidelines recommended the routine use of out-of-office blood pressure (BP) monitoring for the diagnosis of hypertension. These changes were predicted to reduce unnecessary treatment costs and workload associated with misdiagnosis. AIM: To assess the impact of guideline change on rates of hypertension-related consultation in general practice. DESIGN AND SETTING: A retrospective open cohort study in adults registered with English general practices contributing to the Clinical Practice Research Datalink between 1 April 2006 and 31 March 2017. METHOD: The primary outcome was the rate of face-to-face, telephone, and home visit consultations related to hypertension with a GP or nurse. Age- and sex-standardised rates were analysed using interrupted time-series analysis. RESULTS: In 3 937 191 adults (median follow-up 4.2 years) there were 12 253 836 hypertension-related consultations. The rate of hypertension-related consultation was 71.0 per 100 person-years (95% confidence interval [CI] = 67.8 to 74.2) in April 2006, which remained flat before 2011. The introduction of the NICE hypertension guideline in 2011 was associated with a change in yearly trend (change in trend -3.60 per 100 person-years, 95% CI = -5.12 to -2.09). The rate of consultation subsequently decreased to 59.2 per 100 person-years (95% CI = 56.5 to 61.8) in March 2017. These changes occurred around the time of diagnosis, and persisted when accounting for wider trends in all consultations. CONCLUSION: Hypertension-related workload has declined in the last decade, in association with guideline changes. This is due to changes in workload at the time of diagnosis, rather than reductions in misdiagnosis.

Diffusion-Free Scaling in Rotating Spherical Rayleigh-Bénard Convection.

Direct numerical simulations are employed to reveal three distinctly different flow regions in rotating spherical Rayleigh-Bénard convection. In the high-latitude region I vertical (parallel to the axis of rotation) convective columns are generated between the hot inner and the cold outer sphere. The mid-latitude region I I is dominated by vertically aligned convective columns formed between the Northern and Southern hemispheres of the outer sphere. The diffusion-free scaling, which indicates bulk-dominated convection, originates from this mid-latitude region. In the equator region I I I , the vortices are affected by the outer spherical boundary and are much shorter than in region I I .

Long-term health outcomes of people with reduced kidney function in the UK: A modelling study using population health data.

BACKGROUND: People with reduced kidney function have increased cardiovascular disease (CVD) risk. We present a policy model that simulates individuals' long-term health outcomes and costs to inform strategies to reduce risks of kidney and CVDs in this population. METHODS AND FINDINGS: We used a United Kingdom primary healthcare database, the Clinical Practice Research Datalink (CPRD), linked with secondary healthcare and mortality data, to derive an open 2005-2013 cohort of adults (≥18 years of age) with reduced kidney function (≥2 measures of estimated glomerular filtration rate [eGFR] <90 mL/min/1.73 m2 ≥90 days apart). Data on individuals' sociodemographic and clinical characteristics at entry and outcomes (first occurrences of stroke, myocardial infarction (MI), and hospitalisation for heart failure; annual kidney disease stages; and cardiovascular and nonvascular deaths) during follow-up were extracted. The cohort was used to estimate risk equations for outcomes and develop a chronic kidney disease-cardiovascular disease (CKD-CVD) health outcomes model, a Markov state transition model simulating individuals' long-term outcomes, healthcare costs, and quality of life based on their characteristics at entry. Model-simulated cumulative risks of outcomes were compared with respective observed risks using a split-sample approach. To illustrate model value, we assess the benefits of partial (i.e., at 2013 levels) and optimal (i.e., fully compliant with clinical guidelines in 2019) use of cardioprotective medications. The cohort included 1.1 million individuals with reduced kidney function (median follow-up 4.9 years, 45% men, 19% with CVD, and 74% with only mildly decreased eGFR of 60-89 mL/min/1.73 m2 at entry). Age, kidney function status, and CVD events were the key determinants of subsequent morbidity and mortality. The model-simulated cumulative disease risks corresponded well to observed risks in participant categories by eGFR level. Without the use of cardioprotective medications, for 60- to 69-year-old individuals with mildly decreased eGFR (60-89 mL/min/1.73 m2), the model projected a further 22.1 (95% confidence interval [CI] 21.8-22.3) years of life if without previous CVD and 18.6 (18.2-18.9) years if with CVD. Cardioprotective medication use at 2013 levels (29%-44% of indicated individuals without CVD; 64%-76% of those with CVD) was projected to increase their life expectancy by 0.19 (0.14-0.23) and 0.90 (0.50-1.21) years, respectively. At optimal cardioprotective medication use, the projected health gains in these individuals increased by further 0.33 (0.25-0.40) and 0.37 (0.20-0.50) years, respectively. Limitations include risk factor measurements from the UK routine primary care database and limited albuminuria measurements. CONCLUSIONS: The CKD-CVD policy model is a novel resource for projecting long-term health outcomes and assessing treatment strategies in people with reduced kidney function. The model indicates clear survival benefits with cardioprotective treatments in this population and scope for further benefits if use of these treatments is optimised.

Impact of Changes to National Hypertension Guidelines on Hypertension Management and Outcomes in the United Kingdom.

In recent years, national and international guidelines have recommended the use of out-of-office blood pressure monitoring for diagnosing hypertension. Despite evidence of cost-effectiveness, critics expressed concerns this would increase cardiovascular morbidity. We assessed the impact of these changes on the incidence of hypertension, out-of-office monitoring and cardiovascular morbidity using routine clinical data from English general practices, linked to inpatient hospital, mortality, and socio-economic status data. We studied 3 937 191 adults with median follow-up of 4.2 years (49% men, mean age=39.7 years) between April 1, 2006 and March 31, 2017. Interrupted time series analysis was used to examine the impact of changes to English hypertension guidelines in 2011 on incidence of hypertension (primary outcome). Secondary outcomes included rate of out-of-office monitoring and cardiovascular events. Across the study period, incidence of hypertension fell from 2.1 to 1.4 per 100 person-years. The change in guidance in 2011 was not associated with an immediate change in incidence (change in rate=0.01 [95% CI, -0.18-0.20]) but did result in a leveling out of the downward trend (change in yearly trend =0.09 [95% CI, 0.04-0.15]). Ambulatory monitoring increased significantly in 2011/2012 (change in rate =0.52 [95% CI, 0.43-0.60]). The rate of cardiovascular events remained unchanged (change in rate =-0.02 [95% CI, -0.05-0.02]). In summary, changes to hypertension guidelines in 2011 were associated with a stabilisation in incidence and no increase in cardiovascular events. Guidelines should continue to recommend out-of-office monitoring for diagnosis of hypertension.

Validation of clinical prediction models: what does the "calibration slope" really measure?

BACKGROUND AND OBJECTIVES: Definitions of calibration, an aspect of model validation, have evolved over time. We examine use and interpretation of the statistic currently referred to as the calibration slope. METHODS: The history of the term "calibration slope", and usage in papers published in 2016 and 2017, were reviewed. The behaviour of the slope in illustrative hypothetical examples and in two examples in the clinical literature was demonstrated. RESULTS: The paper in which the statistic was proposed described it as a measure of "spread" and did not use the term "calibration". In illustrative examples, slope of 1 can be associated with good or bad calibration, and this holds true across different definitions of calibration. In data extracted from a previous study, the slope was correlated with discrimination, not overall calibration. Many authors of recent papers interpret the slope as a measure of calibration; a minority interpret it as a measure of discrimination or do not explicitly categorise it as either. Seventeen of thirty-three papers used the slope as the sole measure of calibration. CONCLUSION: Misunderstanding about this statistic has led to many papers in which it is the sole measure of calibration, which should be discouraged.

The Impact of Using Emotionally Arousing Stimuli on Muscle Response Testing Accuracy.

INTRODUCTION: Muscle response testing (MRT) is an assessment method used by 1 million practitioners worldwide, yet its usefulness remains uncertain. The aim of this study, one in a series assessing the accuracy of MRT, was to determine whether emotionally arousing stimuli influence its accuracy compared to neutral stimuli. METHODS: To assess diagnostic test accuracy 20 MRT practitioners were paired with 20 test patients (TPs). Forty MRTs were performed as TPs made true and false statements about emotionally arousing and neutral pictures. Blocks of MRT alternated with blocks of intuitive guessing (IG). RESULTS: MRT accuracy using emotionally arousing stimuli was different than when using neutral stimuli. However, MRT accuracy was found to be significantly better than IG and chance. Similar to previous studies in this series, this study failed to detect any characteristic that consistently influenced MRT accuracy. CONCLUSION: Using emotionally arousing stimuli had no effect on MRT accuracy compared to using neutral stimuli. This study would have been strengthened by adding personally relevant lies instead of impersonal stimuli. A limitation of this study is its lack of generalizability to other applications of MRT. This study shows that a simple yet robust methodology for assessing MRT as a diagnostic tool can be implemented effectively.

Statistical models for the deterioration of kidney function in a primary care population: A retrospective database analysis.

Background: Evidence for kidney function monitoring intervals in primary care is weak, and based mainly on expert opinion. In the absence of trials of monitoring strategies, an approach combining a model for the natural history of kidney function over time combined with a cost-effectiveness analysis offers the most feasible approach for comparing the effects of monitoring under a variety of policies. This study aimed to create a model for kidney disease progression using routinely collected measures of kidney function. Methods: This is an open cohort study of patients aged ≥18 years, registered at 643 UK general practices contributing to the Clinical Practice Research Datalink between 1 April 2005 and 31 March 2014. At study entry, no patients were kidney transplant donors or recipients, pregnant or on dialysis. Hidden Markov models for estimated glomerular filtration rate (eGFR) stage progression were fitted to four patient cohorts defined by baseline albuminuria stage; adjusted for sex, history of heart failure, cancer, hypertension and diabetes, annually updated for age. Results: Of 1,973,068 patients, 1,921,949 had no recorded urine albumin at baseline, 37,947 had normoalbuminuria (<3mg/mmol), 10,248 had microalbuminuria (3-30mg/mmol), and 2,924 had macroalbuminuria (>30mg/mmol). Estimated annual transition probabilities were 0.75-1.3%, 1.5-2.5%, 3.4-5.4% and 3.1-11.9% for each cohort, respectively. Misclassification of eGFR stage was estimated to occur in 12.1% (95%CI: 11.9-12.2%) to 14.7% (95%CI: 14.1-15.3%) of tests. Male gender, cancer, heart failure and age were independently associated with declining renal function, whereas the impact of raised blood pressure and glucose on renal function was entirely predicted by albuminuria. Conclusions: True kidney function deteriorates slowly over time, declining more sharply with elevated urine albumin, increasing age, heart failure, cancer and male gender. Consecutive eGFR measurements should be interpreted with caution as observed improvement or deterioration may be due to misclassification.

The utility of long-term blood pressure variability for cardiovascular risk prediction in primary care.

OBJECTIVES: Blood pressure (BP) is a long-established risk factor for cardiovascular disease (CVD). SBP is used in all widely used cardiovascular risk scores for clinical decision-making. Recently, within-person BP variability has been shown to be a major predictor of CVD. We investigated whether cardiovascular risk scores could be improved by incorporating BP variability with standard risk factors. METHODS: We used cohort data on patients aged 40-74 on 1 January 2005, from English general practices contributing to the Clinical Practice Research Datalink, a research database derived from electronic health records. Data were linked to hospital episodes and mortality data. SBP variability independent of the mean was calculated across up to six clinic visits. We divided data geographically into derivation and validation data sets. In the derivation data set, we developed a reference model, incorporating risk factors used in previous scores and an index model, incorporating the same factors and BP variability. We calculated model validation statistics in the validation data set including calibration ratio and c-statistic. RESULTS: In the derivation data set, BP variability was associated with CVD, independently of other risk factors (P = 0.005). However, in the validation data set, both models had similar c-statistic (0.7415 and 0.7419, respectively), R (31.8 and 32.0, respectively) and calibration ratio (0.938 and 0.940, respectively). CONCLUSION: The association of BP variability with CVD is statistically significant in a large data set but does not substantially improve the performance of a cardiovascular risk score.

Quality of diabetes care in breast, colorectal, and prostate cancer.

PURPOSE: Overlooking other medical conditions during cancer treatment and follow-up could result in excess morbidity and mortality, thereby undermining gains associated with early detection and improved treatment of cancer. We compared the quality of care for diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer to matched, diabetic non-cancer controls. METHODS: Longitudinal cohort study using primary care records from the Clinical Practice Research Datalink, United Kingdom. Patients with pre-existing diabetes were followed for up to 5 years after cancer diagnosis, or after an assigned index date (non-cancer controls). Quality of diabetes care was estimated based on Quality and Outcomes Framework indicators. Mixed effects logistic regression analyses were used to compare the unadjusted and adjusted odds of meeting quality measures between cancer patients and controls, overall and stratified by type of cancer. RESULTS: 3382 cancer patients and 11,135 controls contributed 44,507 person-years of follow-up. In adjusted analyses, cancer patients were less likely to meet five of 14 quality measures, including: total cholesterol ≤ 5 mmol/L (odds ratio [OR] = 0.82; 95% confidence interval [CI], 0.75-0.90); glycosylated hemoglobin ≤ 59 mmol/mol (adjusted OR = 0.77; 95% CI, 0.70-0.85); and albumin creatinine ratio testing (adjusted OR = 0.83; 95% CI, 0.75-0.91). However, cancer patients were as likely as their matched controls to meet quality measures for other diabetes services, including retinal screening, foot examination, and dietary review. CONCLUSIONS: Although in the short-term, cancer patients were less likely to achieve target thresholds for cholesterol and HbA1c, they continued to receive high-quality diabetes primary care throughout 5 years post diagnosis. IMPLICATIONS FOR CANCER SURVIVORS: These findings are important for cancer survivors with pre-existing diabetes because they indicate that high-quality diabetes care is maintained throughout the continuum of cancer diagnosis, treatment, and follow-up.

Association of guideline and policy changes with incidence of lifestyle advice and treatment for uncomplicated mild hypertension in primary care: a longitudinal cohort study in the Clinical Practice Research Datalink.

OBJECTIVES: Evidence to support initiation of pharmacological treatment in patients with uncomplicated (low risk) mild hypertension is inconclusive. As such, clinical guidelines are contradictory and healthcare policy has changed regularly. The aim of this study was to determine the incidence of lifestyle advice and drug therapy in this population and whether secular trends were associated with policy changes. DESIGN: Longitudinal cohort study. SETTING: Primary care practices contributing to the Clinical Practice Research Datalink in England. PARTICIPANTS: Data were extracted from the linked electronic health records of patients aged 18-74 years, with stage 1 hypertension (blood pressure between 140/90 and 159/99 mm Hg), no cardiovascular disease (CVD) risk factors and no treatment, from 1998 to 2015. Patients exited if follow-up records became unavailable, they progressed to stage 2 hypertension, developed a CVD risk factor or received lifestyle advice/treatment. PRIMARY OUTCOME MEASURES: The association between policy changes and incidence of lifestyle advice or treatment, examined using an interrupted time-series analysis. RESULTS: A total of 108 843 patients were defined as having uncomplicated mild hypertension (mean age 51.9±12.9 years, 60.0% female). Patientsspent a median 2.6 years (IQR 0.9-5.5) in the study, after which 12.2% (95% CI 12.0% to 12.4%) were given lifestyle advice, 29.9% (95% CI 29.7% to 30.2%) were prescribed medication and 19.4% (95% CI 19.2% to 19.6%) were given both. The introduction of the quality outcomes framework (QOF) and subsequent changes to QOF indicators were followed by significant increases in the incidence of lifestyle advice. Treatment prescriptions decreased slightly over time, but were not associated with policy changes. CONCLUSIONS: Despite secular trends that accord with UK guidance, many patients are still prescribed treatment for mild hypertension. Adequately powered studies are needed to determine if this is appropriate.

Is "chronic kidney disease" a disease?

Several philosophers of medicine have attempted to answer the question "what is disease?" In current clinical practice, an umbrella term "chronic kidney disease" (CKD) encompasses a wide range of kidney health states from commonly prevalent subclinical, asymptomatic disease to rare end-stage renal disease requiring transplant or dialysis to support life. Differences in severity are currently expressed using a "stage" system, whereby stage 1 is the least severe, and stage 5 the most. Early stage CKD in older patients is normal, of little concern, and does not require treatment. However, studies have shown that many patients find being informed of their CKD distressing, even in its early stages. Using existing analyses of disease in the philosophy literature, we argue that the most prevalent diagnoses of CKD are not, in fact, diseases. We conclude that, in many diagnosed cases of CKD, diagnosing a patient with a "disease" is not only redundant, but unhelpful.