Performance of point-of-care HbA1c test devices: implications for use in clinical practice – a systematic review and meta-analysis

Regular monitoring of glycated hemoglobin subfraction A1c (HbA1c) in people with diabetes and treatment with glucose-lowering medications to improve glycaemic control can reduce the risk of developing complications [1]. In 2011, a World Health Organization consultation concluded that HbA1cat a threshold of 6.5% (48 mmol/mol) can be used as a diagnostic test for diabetes [2]. HbA1c monitoring often requires the patient to attend the health center twice: once to have blood taken and then returning to get test results and receive adjustments to medication. Point-of-care (POC) analysers are bench-top instruments that use a finger-prick blood sample and are designed for use in a treatment room or at the bed-side. They provide a test result within a few minutes allowing clinical decisions and medication changes to take place immediately. The suitability of many of these devices for the accurate measurement of HbA1c has been questioned, with some POC HbA1c test devices reported not to meet accepted accuracy and precision criteria [3]. Ideal imprecision goals for HbA1c should be coefficient of variation (CV) of <2% for HbA1c reported in % units (or <3% in SI units, mmol/mol) [4], [5], [6]. Most evaluations of POC HbA1c devices have taken place in laboratory settings [7], [8]; fewer studies have assessed device performance in a POC setting or with clinicians performing the tests [9], [10]. The only published review that has attempted to combine data from accuracy studies identified five studies covering three devices and compared correlation coefficients [11]. Systematically reporting and pooling data estimates of bias and precision between POC HbA1c devices and laboratory measurements would enable end users to assess which analysers best meet their analytical performance needs. This may be of particular importance for clinicians in primary care settings where much of the management of diabetes patients takes place. The comparison of accuracy between devices over the entire therapeutic range would need to be carried out by combining data on measurement error (bias) between POC and laboratory tests [12]. The aim of this study was to compare accuracy and precision of POC HbA1c devices with the local laboratory method based on data from published studies and discuss the clinical implications of the findings

Trends in kidney function testing in UK primary care since the introduction of the Quality and Outcomes Framework:a retrospective cohort study using CPRD

Objectives: To characterise serum creatinine and urinary protein testing in UK general practices from 2005 to 2013 and to examine how the frequency of testing varies across demographic factors, with the presence of chronic conditions and with the prescribing of drugs for which kidney function monitoring is recommended. Design: Retrospective open cohort study. Setting: Routinely collected data from 630 UK general practices contributing to the Clinical Practice Research Datalink. Participants: 4 573 275 patients aged over 18 years registered at up-to-standard practices between 1 April 2005 and 31 March 2013. At study entry, no patients were kidney transplant donors or recipients, pregnant or on dialysis. Primary outcome measures: The rate of serum creatinine and urinary protein testing per year and the percentage of patients with isolated and repeated testing per year. Results: The rate of serum creatinine testing increased linearly across all age groups. The rate of proteinuria testing increased sharply in the 2009–2010 financial year but only for patients aged 60 years or over. For patients with established chronic kidney disease (CKD), creatinine testing increased rapidly in 2006–2007 and 2007–2008, and proteinuria testing in 2009–2010, reflecting the introduction of Quality and Outcomes Framework indicators. In adjusted analyses, CKD Read codes were associated with up to a twofold increase in the rate of serum creatinine testing, while other chronic conditions and potentially nephrotoxic drugs were associated with up to a sixfold increase. Regional variation in serum creatinine testing reflected country boundaries. Conclusions: Over a nine-year period, there have been increases in the numbers of patients having kidney function tests annually and in the frequency of testing. Changes in the recommended management of CKD in primary care were the primary determinant, and increases persist even after controlling for demographic and patient-level factors. Future studies should address whether increased testing has led to better outcomes.</p

Standard and competing risk analysis of the effect of albuminuria on cardiovascular and cancer mortality in patients with type 2 diabetes mellitus

Abstract Background Competing risks occur when populations may experience outcomes that either preclude or alter the probability of experiencing the main study outcome(s). Many standard survival analysis methods do not account for competing risks. We used mortality risk in people with diabetes with and without albuminuria as a case study to investigate the impact of competing risks on measures of absolute and relative risk. Methods A population with type 2 diabetes was identified in Clinical Practice Research Datalink as part of a historical cohort study. Patients were followed for up to 9 years. To quantify differences in absolute risk estimates of cardiovascular and cancer, mortality standard (Kaplan-Meier) estimates were compared to competing-risks-adjusted (cumulative incidence competing risk) estimates. To quantify differences in measures of association, regression coefficients for the effect of albuminuria on the relative hazard of each outcome were compared between standard cause-specific hazard (CSH) models (Cox proportional hazards regression) and two competing risk models: the unstratified Lunn-McNeil model, which estimates CSH, and the Fine-Gray model, which estimates subdistribution hazard (SDH). Results In patients with normoalbuminuria, standard and competing-risks-adjusted estimates for cardiovascular mortality were 11.1% (95% confidence interval (CI) 10.8–11.5%) and 10.2% (95% CI 9.9–10.5%), respectively. For cancer mortality, these figures were 8.0% (95% CI 7.7–8.3%) and 7.2% (95% CI 6.9–7.5%). In patients with albuminuria, standard and competing-risks-adjusted estimates for cardiovascular mortality were 21.8% (95% CI 20.9–22.7%) and 18.5% (95% CI 17.8–19.3%), respectively. For cancer mortality, these figures were 10.7% (95% CI 10.0–11.5%) and 8.6% (8.1–9.2%). For the effect of albuminuria on cardiovascular mortality, regression coefficient values from multivariable standard CSH, competing risks CSH, and competing risks SDH models were 0.557 (95% CI 0.491–0.623), 0.561 (95% CI 0.494–0.628), and 0.456 (95% CI 0.389–0.523), respectively. For the effect of albuminuria on cancer mortality, these values were 0.237 (95% CI 0.148–0.326), 0.244 (95% CI 0.154–0.333), and 0.102 (95% CI 0.012–0.192), respectively. Conclusions Studies of absolute risk should use methods that adjust for competing risks to avoid over-stating risk, such as the CICR estimator. Studies of relative risk should consider carefully which measure of association is most appropriate for the research question

Placebo's invisible brother: a restricted scoping review of the biomedical literature on the nocebo effect

Placebos and their beneficial clinical and psychological effects are well-researched, but nocebo effects receive far less attention, despite being highly undesirable. The aim of this restricted scoping review was to examine how nocebo effects are represented in the biomedical literature and to identify the trends and gaps in existing knowledge. After searching 5 biomedical databases and 2 clinical trials registries (from their inception to December 23, 2020) for articles on nocebo effects or negative placebo effects, 1161 eligible publications were identified. The 2 main publication types were nonsystematic reviews (37.7%) and primary research studies (35.6%); only 85 publications (7.3%) were systematic reviews and meta-analyses. The nonsystematic reviews, many of them heavily opinion-based, may contribute to the amplification of narratives, attitudes, and beliefs about nocebo effects that do not objectively reflect the primary research. The primary research articles often used nocebo effects to explain results, rather than as the primary phenomenon under investigation. Most publications were concerned with both positive and negative placebo effects, rather than just nocebo effects. Over half of the abstracts were in the field of neurology, psychiatry, psychology, or neuroscience (52.8%). The nocebo effect was most frequently investigated in the context of pain. Studies were almost exclusively in adults and more often in healthy participants than in patients. In conclusion, in the biomedical literature, there is an overabundance of nonsystematic reviews and expert opinions and a lack of primary research and high-quality systematic reviews and meta-analyses specifically dealing with nocebo effects

Climate evolution through the onset and intensification of Northern Hemisphere glaciation

The Pliocene Epoch (∼5.3–2.6 million years ago, Ma) was characterized by a warmer than present climate with smaller Northern Hemisphere ice sheets, and offers an example of a climate system in long-term equilibrium with current or predicted near-future atmospheric CO2 concentrations (pCO2). A long-term trend of ice-sheet expansion led to more pronounced glacial (cold) stages by the end of the Pliocene (∼2.6 Ma), known as the “intensification of Northern Hemisphere Glaciation” (iNHG). We assessed the spatial and temporal variability of ocean temperatures and ice-volume indicators through the late Pliocene and early Pleistocene (from 3.3 to 2.4 Ma) to determine the character of this climate transition. We identified asynchronous shifts in long-term means and the pacing and amplitude of shorter-term climate variability, between regions and between climate proxies. Early changes in Antarctic glaciation and Southern Hemisphere ocean properties occurred even during the mid-Piacenzian warm period (∼3.264–3.025 Ma) which has been used as an analog for future warming. Increased climate variability subsequently developed alongside signatures of larger Northern Hemisphere ice sheets (iNHG). Yet, some regions of the ocean felt no impact of iNHG, particularly in lower latitudes. Our analysis has demonstrated the complex, non-uniform and globally asynchronous nature of climate changes associated with the iNHG. Shifting ocean gateways and ocean circulation changes may have pre-conditioned the later evolution of ice sheets with falling atmospheric pCO2. Further development of high-resolution, multi-proxy reconstructions of climate is required so that the full potential of the rich and detailed geological records can be realized