The effect of cartilage dehydration and rehydration on quantitative ultrashort echo time biomarkers.

Background: The effect of dehydration of ex vivo cartilage samples and rehydration with native synovial fluid or normal saline on quantitative ultrashort echo time (UTE) biomarkers are unknown. We aimed to investigate the effect of cartilage dehydration-rehydration on UTE biomarkers and to compare the rehydration capabilities of native synovial fluid and normal saline. Methods: A total of 37 cartilage samples were harvested from patients (n=5) who underwent total knee replacement. Fresh cartilage samples were exposed to air to dehydrate for 2 hours after baseline magnetic resonance (MR) scanning, then randomly divided into two groups: one soaking in native synovial fluid (n=17) and the other in normal saline (n=20) to rehydrate for 4 hours. UTE-based biomarkers [T1, adiabatic T1r (AdiabT1r), macromolecular fraction (MMF), magnetization transfer ratio (MTR), and T2*] and sample weights were evaluated for fresh, dehydrated, and rehydrated cartilage samples. Differences and agreements between groups were assessed using the values of fresh cartilage samples as reference standard. Results: Dehydrating in air for 2 hours resulted in significant weight loss (P=0.000). T1, AdiabT1r, and T2* decreased significantly while MMF and MTR increased significantly (all P<0.02). Non-significant differences were observed in cartilage weights after rehydrating in both synovial fluid and normal saline, with P values being 0.204 and 0.769, respectively. There were no significant differences in T1, AdiabT1r, MMF, and MTR after rehydrating in synovial fluid (P>0.0167, with Bonferroni correction) while T2* (P=0.001) still had significant differences compared with fresh samples. However, no significant differences were detected for any of the evaluated UTE biomarkers after rehydrating in normal saline (all P>0.05). No differences were detected in the agreement of UTE biomarker measurements between fresh samples and samples rehydrated with synovial fluid and normal saline. Conclusions: Cartilage dehydration resulted in significant changes in UTE biomarkers. Rehydrating with synovial fluid or normal saline had non-significant effect on all the evaluated UTE biomarkers except T2* values, which still had significant differences compared with fresh samples after rehydrating with synovial fluid. No significant difference was observed in the rehydration capabilities of native synovial fluid and normal saline.

Predicting Oral Beta-lactam susceptibilities against Streptococcus pneumoniae.

BACKGROUND: Oral beta-lactam antimicrobials are not routinely tested against Streptococcus pneumoniae due to presumed susceptibility based upon penicillin minimum inhibitory concentration (MIC) testing. Currently, Clinical and Laboratory Standards Institute provides comments to use penicillin MIC ≤0.06 to predict oral cephalosporin susceptibility. However, no guidance is provided when cefotaxime MIC is known, leading to uncertainty with interpretation. The purpose of this study was to evaluate cefotaxime and penicillin MICs and their respective correlation to oral beta-lactam categorical susceptibility patterns. METHODS: 249 S. pneumoniae isolates were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-ToF) and then tested by broth microdilution method to penicillin, cefotaxime, amoxicillin, cefdinir, cefpodoxime, and cefuroxime. RESULTS: Using Clinical and Laboratory Standards Institute (CLSI) non-meningitis breakpoints for cefotaxime, 240/249 isolates were classified as susceptible. Of the cefotaxime susceptible isolates, 23% of the isolates are misrepresented as cefdinir susceptible. Amoxicillin correlated well with penicillin MIC breakpoints with only 1 discordant isolate out of 249. CONCLUSION: The correlation between amoxicillin and penicillin creates a very reliable predictor to determine categorical susceptibility. However oral cephalosporins were not well predicted by either penicillin or cefotaxime leading to the possible risk of treatment failures. Caution should be used when transitioning to oral cephalosporins in cefotaxime susceptible isolates, especially with higher cefotaxime MICs.

Precision dosing of vancomycin: in defence of AUC-guided therapy in children.

In 2020, new vancomycin guidelines were released, recommending the transition from trough-based to AUC24 monitoring for adult and paediatric patients. Given the resources required to achieve this transition, there has been debate about the costs and benefits of AUC24-based monitoring. A recent narrative review of vancomycin therapeutic drug monitoring in paediatrics claims to have uncovered the methodological weaknesses of the data that informed the guidelines and advises against premature adoption of AUC24-guided monitoring. In this article, we present supporting arguments for AUC24-guided monitoring in children, which include that: (i) troughs alone are inadequate surrogates for AUC24; (ii) vancomycin-associated nephrotoxicity has significant consequences that warrant optimization of dosing; (iii) a substantial portion of children receiving vancomycin are at high risk for poor outcomes and deserve targeted monitoring; and (iv) limited efficacy data in support of AUC24 is not a justification to revert to a less supported monitoring approach.

How many medications do doctors in primary care use? An observational study of the DU90% indicator in primary care in England.

AIM: To apply the drug utilisation 90% (DU90%) indicator (the number of unique drugs which makes up 90% of a doctor's prescribing) to general practitioner (GP) practices prescribing in England to examine time trends, practice-level variation, and relationships with practice characteristics, prescribing costs and low-value prescribing. STUDY DESIGN: Retrospective cohort study. SETTING: Primary care in England, using publicly available prescribing data available from the National Health Service (NHS) digital platform for 2013-2017. PARTICIPANTS: All general practices in England (n=7620). PRIMARY AND SECONDARY OUTCOME MEASURES: The DU90% was calculated on an annual basis for each practice based on medication British National Formulary codes. Low-value prescribing was defined using NHS 2017 guidance (including lidocaine plasters, liothyronine, omega-3 supplements). Descriptive statistics were generated per year on time trends and practice-level variation in the DU90%. Multilevel linear regression was used to examine the practice characteristics (relating to staff, patients and deprivation of the practice area). RESULTS: Among 7620 practices, mean DU90% ranged from 130.0 to 131.0 across study years, and regarding variation between practices, there was a 1.4-fold difference between the lowest and highest 5% of practices. A range of medications were included in the DU90% of virtually all practices, including atorvastatin, levothyroxine, omeprazole, ramipril, amlodipine, simvastatin and aspirin. A higher volume of prescribing was associated with a lower DU90%, while having more patients, higher proportions of patients who are women or aged ≥45 years, higher number of GPs working in the practice and being in a more deprived area were associated with a higher DU90%. Practices in higher quintiles of DU90% had higher levels of low-priority prescribing and prescribing costs. CONCLUSION: GP practices typically use 130 different medications in the bulk of their prescribing. Higher DU90% was associated with higher levels of low-priority prescribing and prescribing costs. Increasing use of personal formularies may enhance prescribing quality and reduce costs.

Acute severe respiratory syndrome coronavirus-2 treatment overview for pediatrics.

PURPOSE OF REVIEW: The novel severe respiratory syndrome coronavirus-2 (SARS-CoV-2) virus has caused a world-wide pandemic with devastating effects. Fortunately, most children display only mild-to-moderate symptoms, but there are a subset that will have severe symptoms warranting treatment. This review evaluates the current evidence for antiviral and anti-inflammatory treatment of acute SARS-COV-2 infections, including coronavirus disease 2019 in pediatrics. RECENT FINDINGS: Treatment recommendations continue to evolve with emerging results from clinical trials. Initial therapies were tailored to repurposed medications, and have now transitioned toward more specific antiviral therapy. In addition to specific antiviral therapy, there is also support to modulate the immune system and reduce inflammatory damage seen in coronavirus disease 2019. Much of the data result from adult studies with subsequent extrapolation to pediatrics. SUMMARY: Recommended therapy will continue to adapt as results return from clinical trials. A continued commitment from the National Institutes of Health and research community to assist in determining optimal therapies for pediatric patients is essential. Until then, most recommendations will likely be informed from the results seen in adult populations.

Demonstrating Feasibility of an Opportunistic Sampling Approach for Pharmacokinetic Studies of ß-Lactam Antibiotics in Critically Ill Children.

There has been increasing interest in incorporating ß-lactam precision dosing into routine clinical care, but robust population pharmacokinetic models in critically ill children are needed for these purposes. The objective of this study was to demonstrate the feasibility of an opportunistic sampling approach that utilizes scavenged residual blood for future pharmacokinetic studies of cefepime, meropenem, and piperacillin. We aimed to show that opportunistic samples would cover the full concentration-versus-time profiles and to evaluate stability of the antibiotics in whole blood and plasma to optimize future use of the opportunistic sampling approach. A prospective observational study was conducted in a single-center pediatric intensive care unit, where pediatric patients administered at least 1 dose of cefepime, meropenem, or piperacillin/tazobactam and who had residual blood scavenged from samples obtained for routine clinical care were enrolled. A total of 138 samples from 22 pediatric patients were collected in a 2-week period. For all 3 antibiotics, the samples collected covered the entire dosing intervals and were not clustered around specific times. There was high variability in the free concentrations and in the percentage of drug bound to protein. There was less than 15% degradation for meropenem or piperacillin when stored in whole blood or plasma at 4°C after 6 days. Cefepime degraded by more than 15% after 3 days. The opportunistic sampling approach is a powerful and feasible method to obtain sufficient samples to study the variability of drug concentrations and protein binding for future pharmacokinetic studies in the pediatric critical care population.

An updated and more efficient search strategy to identify primary care-relevant clinical prediction rules.

OBJECTIVES: The aim of the study was to develop an improved search strategy for clinical prediction rules. STUDY DESIGN AND SETTING: We first refined a list of 30 primary care-relevant journals and improved the efficiency of the Haynes Narrow Filter/Teljour/Murphy Inclusion Filter with 26 items by removing one term (Modified Haynes 26 filter). We then developed the "Royal College of Surgeons in Ireland (RCSI) filter" and compared it with the modified HNF/TMIF26 for its ability to detect prediction rules in the primary care literature. All abstracts and, if necessary, full text were reviewed independently in parallel by primary care physicians. The key outcomes were the percentage of prediction rules identified out of the total identified by both search strategies (sensitivity) and the number of articles that had to be reviewed to identify them (efficiency). RESULTS: The Modified Haynes 26 filter returned 1,701 abstracts vs. 1,062 for the RCSI filter. The RCSI filter identified 105 of 111 of all prediction rules identified by either filter, compared with 107 of 111 by the Modified Haynes 26 filter (94.6% vs. 96.4%; P = 0.52). In addition, 9.9% of abstracts found using the RCSI filter were prediction rules, compared with only 6.3% using the Modified Haynes 25 filter (P = 0.001). CONCLUSION: We have developed a novel "RCSI filter" that more efficiently identifies prediction rules in the medical literature.

Supporting care for suboptimally controlled type 2 diabetes mellitus in general practice with a clinical decision support system: a mixed methods pilot cluster randomised trial.

OBJECTIVES: We developed a complex intervention called DECIDE (ComputeriseD dECisIonal support for suboptimally controlleD typE 2 Diabetes mellitus in Irish General Practice) which used a clinical decision support system to address clinical inertia and support general practitioner (GP) intensification of treatment for adults with suboptimally controlled type2 diabetes mellitus (T2DM). The current study explored the feasibility and potential impact of DECIDE. DESIGN: A pilot cluster randomised controlled trial. SETTING: Conducted in 14 practices in Irish General Practice. PARTICIPANTS: The DECIDE intervention was targeted at GPs. They applied DECIDE to patients with suboptimally controlled T2DM, defined as a glycated haemoglobin (HbA1c) ≥70 mmol/mol and/or blood pressure ≥150/95 mmHg. INTERVENTION: The intervention incorporated training and a web-based clinical decision support system which supported; (i) medication intensification actions; and (ii) non-pharmacological actions to support care. Control practices delivered usual care. PRIMARY AND SECONDARY OUTCOME MEASURES: Feasibility and acceptability was determined using thematic analysis of semi-structured interviews with GPs, combined with data from the DECIDE website. Clinical outcomes included HbA1c, medication intensification, blood pressure and lipids. RESULTS: We recruited 14 practices and 134 patients. At 4-month follow-up, all practices and 114 patients were followed up. GPs reported finding decision support helpful navigating increasingly complex medication algorithms. However, the majority of GPs believed that the target patient group had poor engagement with GP and hospital services for a range of reasons. At follow-up, there was no difference in glycaemic control (-3.6 mmol/mol (95% CI -11.2 to 4.0)) between intervention and control groups or in secondary outcomes including, blood pressure, total cholesterol, medication intensification or utilisation of services. Continuation criteria supported proceeding to a definitive randomised trial with some modifications. CONCLUSION: The DECIDE study was feasible and acceptable to GPs but wider impacts on glycaemic and blood pressure control need to be considered for this patient population going forward. TRIAL REGISTRATION NUMBER: ISRCTN69498919.

Water proton density in human cortical bone obtained from ultrashort echo time (UTE) MRI predicts bone microstructural properties.

PURPOSE: To investigate the correlations between cortical bone microstructural properties and total water proton density (TWPD) obtained from three-dimensional ultrashort echo time Cones (3D-UTE-Cones) magnetic resonance imaging techniques. MATERIALS AND METHODS: 135 cortical bone samples were harvested from human tibial and femoral midshafts of 37 donors (61 ± 24 years old). Samples were scanned using 3D-UTE-Cones sequences on a clinical 3T MRI and on a high-resolution micro-computed tomography (µCT) scanner. TWPD was measured using 3D-UTE-Cones MR images. Average bone porosity, pore size, and bone mineral density (BMD) were measured from µCT images at 9 µm voxel size. Pearson's correlation coefficients between TWPD and µCT-based measures were calculated. RESULTS: TWPD showed significant moderate correlation with both average bone porosity (R = 0.66, p < 0.01) and pore size (R = 0.57, p < 0.01). TWPD also showed significant strong correction with BMD (R = 0.71, p < 0.01). CONCLUSIONS: The presented 3D-UTE-Cones imaging technique allows assessment of TWPD in human cortical bone. This quick UTE-MRI-based technique was capable of predicting bone microstructure differences with significant correlations. Such correlations highlight the potential of UTE-MRI-based measurement of bone water proton density to assess bone microstructure.

In vivo assessment of extracellular pH of joint tissues using acidoCEST-UTE MRI.

BACKGROUND: Degradation of cartilage and meniscus may be mediated by changes in extracellular pH. The purpose of this study was to optimize saturation powers used with the acidoCEST magnetic resonance imaging (MRI) technique with a 3D ultrashort echo time readout (acidoCEST-UTE) and to demonstrate feasibility of the method for measuring pH in cartilage and meniscus in vivo. METHODS: Magnetization transfer ratio asymmetry and ratio of radiofrequency (RF) power mismatch at different powers were evaluated in cartilage and meniscus tissue phantoms for iopamidol and iohexol. Using optimized RF powers, the acidoCEST-UTE MRI sequence was used to assess pH of joint fluid and tissues in four patients after direct intra-articular administration of iodinated contrast. RESULTS: In the phantoms, the ratio of powers 0.54/1.10 µT showed the strongest correlation with pH. In vivo acidoCEST-UTE pH measurements of intra-articular fluid were similar to electrode measurements of the contrast agent (7.22 vs. 7.1 for iopamidol, respectively; 7.65 vs. 7.5 for iohexol, respectively). As measured with the acidoCEST-UTE technique, overall mean cartilage pH was significantly lower than overall mean meniscus pH (6.60 vs. 6.72, respectively; P=0.043). CONCLUSIONS: AcidoCEST-UTE MRI after direct intra-articular administration of either iopamidol or iohexol can be used to measure cartilage and meniscus pH in vivo.

Supporting general practitioner-based care for poorly controlled type 2 diabetes mellitus (the DECIDE study): feasibility study and protocol for a pilot cluster randomised controlled trial.

BACKGROUND: Poorly controlled type 2 diabetes mellitus (T2DM) is associated with significant morbidity, mortality and healthcare costs. Control of T2DM can be challenging for healthcare professionals for a number of reasons, including poor concordance with medications, difficulties modifying lifestyle behaviour and also clinical inertia, which is defined as a reluctance among health professionals to intensify medications. A complex intervention, called ComputeriseD dECisIonal support for poorly controlleD typE 2 Diabetes mellitus in Irish General Practice (DECIDE), was developed, identifying T2DM patients with poor glycaemic and blood pressure control and aiming to target clinical inertia, by supporting therapeutic action, including GP-led medication intensification where appropriate. A small-scale, uncontrolled, non-randomised feasibility study highlighted the acceptability of the DECIDE intervention within Irish General Practice. This paper presents a protocol for a pilot cluster randomised controlled trial (RCT) of the DECIDE intervention. METHODS/DESIGN: The pilot cluster RCT will involve 14 practices and 140 patients in Irish General Practice. Intervention GPs will participate in the DECIDE intervention, comprising (a) a training programme for the practices and (b) a web-based clinical decision support system supporting treatment escalation, tailored to specific patient information. Only patients who have poorly controlled T2DM (defined as HbA1c > 70 mmol/mol and/or BP > 150/95) will be included. The primary outcomes will include measures of feasibility such as recruitment and retention of practices and acceptability of the intervention and also HbA1c. Secondary outcomes will include medication intensification, blood pressure and lipids. Control GPs will continue to provide usual care. A process evaluation will be performed to determine whether the intervention is delivered as intended and treatment fidelity assessed to monitor and enhance the reliability and validity of interventions. An exploratory health economic analysis will examine the potential costs and cost effectiveness of the intervention relative to the control. DISCUSSION: A pilot cluster RCT will establish the feasibility of a complex intervention which aims to support primary care for patients with poorly controlled T2DM in Irish General Practice. TRIAL REGISTRATION: The protocol for the pilot cluster RCT is registered on the ISRCTN Registry at: ISRCTN69498919.

Epistemic lenses and virtues, beyond evidence-based medicine.

This editorial is based on the keynote by Dr Mark Murphy, Department of General Practice, Royal College of Surgeons, Ireland, at the Health Libraries Group conference, Keele University on 13-15 June 2018. https://bit.ly/2rubsIR#HLG2018.

Development of a complex intervention to promote appropriate prescribing and medication intensification in poorly controlled type 2 diabetes mellitus in Irish general practice.

BACKGROUND: Poorly controlled type 2 diabetes mellitus (T2DM) can be seen as failure to meet recommended targets for management of key risk factors including glycaemic control, blood pressure and lipids. Poor control of risk factors is associated with significant morbidity, mortality and healthcare costs. Failure to intensify medications for patients with poor control of T2DM when indicated is called clinical inertia and is one contributory factor to poor control of T2DM. We aimed to develop a theory and evidence-based complex intervention to improve appropriate prescribing and medication intensification in poorly controlled T2DM in Irish general practice. METHODS: The first stage of the Medical Research Council Framework for developing and evaluating complex interventions was utilised. To identify current evidence, we performed a systematic review to examine the effectiveness of interventions targeting patients with poorly controlled T2DM in community settings. The Behaviour Change Wheel theoretical approach was used to identify suitable intervention functions. Workshops, simulation, collaborations with academic partners and observation of physicians were utilised to operationalise the intervention functions and design the elements of the complex intervention. RESULTS: Our systematic review highlighted that professional-based interventions, potentially through clinical decision support systems, could address poorly controlled T2DM. Appropriate intensification of anti-glycaemic and cardiovascular medications, by general practitioners (GPs), for adults with poorly controlled T2DM was identified as the key behaviour to address clinical inertia. Psychological capability was the key driver of the behaviour, which needed to change, suggesting five key intervention functions (education, training, enablement, environmental restructuring and incentivisation) and nine key behaviour change techniques, which were operationalised into a complex intervention. The intervention has three components: (a) a training program/academic detailing of target GPs, (b) a remote finder tool to help GPs identify patients with poor control of T2DM in their practice and (c) A web-based clinical decision support system. CONCLUSIONS: This paper describes a multifaceted process including an exploration of current evidence and a thorough theoretical understanding of the predictors of the behaviour resulting in the design of a complex intervention to promote the implementation of evidence-based guidelines, through appropriate prescribing and medication intensification in poorly controlled T2DM.

Improving risk factor management for patients with poorly controlled type 2 diabetes: a systematic review of healthcare interventions in primary care and community settings.

OBJECTIVES: Poorly controlled type 2 diabetes mellitus (T2DM) is a major international health problem. Our aim was to assess the effectiveness of healthcare interventions, specifically targeting patients with poorly controlled T2DM, which seek to improve glycaemic control and cardiovascular risk in primary care settings. DESIGN: Systematic review. SETTING: Primary care and community settings. INCLUDED STUDIES: Randomised controlled trials (RCTs) targeting patients with poor glycaemic control were identified from Pubmed, Embase, Web of Science, Cochrane Library and SCOPUS. Poor glycaemic control was defined as HbA1c over 59 mmol/mol (7.5%). INTERVENTIONS: Interventions were classified as organisational, patient-oriented, professional, financial or regulatory. OUTCOMES: Primary outcomes were HbA1c, blood pressure and lipid control. Two reviewers independently assessed studies for eligibility, extracted data and assessed study quality. Meta-analyses were undertaken where appropriate using random-effects models. Subgroup analysis explored the effects of intervention type, baseline HbA1c, study quality and study duration. Meta-regression analyses were undertaken to investigate identified heterogeneity. RESULTS: Forty-two RCTs were identified, including 11 250 patients, with most undertaken in USA. In general, studies had low risk of bias. The main intervention types were patient-directed (48%) and organisational (48%). Overall, interventions reduced HbA1c by -0.34% (95% CI -0.46% to -0.22%), but meta-analyses had high statistical heterogeneity. Subgroup analyses suggested that organisational interventions and interventions on those with baseline HbA1c over 9.5% had better improvements in HbA1c. Meta-regression analyses suggested that only interventions on those with population HbA1c over 9.5% were more effective. Interventions had a modest improvement of blood pressure and lipids, although baseline levels of control were generally good. CONCLUSIONS: This review suggests that interventions for T2DM, in primary care, are better targeted at individuals with very poor glycaemic control and that organisational interventions may be more effective.

Geographical variation in anti-diabetic prescribing in Ireland in 2013 and 2014: a cross-sectional analysis.

Background: Several new medications for type 2 diabetes (T2DM) have been introduced, including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor (GLP-1) agonists. Variation in the prescribing of these agents has implications for quality, safety and costs. We aimed to investigate geographical variation in the prescribing of anti-diabetic medications in Ireland. Methods: Cross-sectional analyses were undertaken on the two main national pharmacy claims databases in Ireland in 2013 and 2014. Direct standardized rates of individual anti-diabetic medication prescribing per 100 000 population were calculated by geographical area. Variation in prescribing was assessed using the systematic component of variation (SCV) and classified as very high (>10), high (5.4-10), moderate (3-5.4) or low (<3). Estimated total costs of prescribing were calculated per geographical area using medication wholesale costs. Results: Very high levels of geographical variation of GLP-1 agonists (SCV 11.4 and 10.3 in 2013 and 2014) and moderate variation of DPP-4 inhibitors (SCV 3.8 and 4.1) were found. There was low/moderate variation in the prescribing of sulphonylureas (SVC 2.8 and 3.6) and low variation in prescribing of metformin (SVC 1.7 and 2.0). Geographical variation in Ireland leads to an estimated total wholesale cost differential of €500 000 for GLP-1 agonists, per 100 000 population, between the highest and lowest prescribing areas. Conclusions: There is substantial geographical variation in the prescribing of new T2DM medicines, particularly GLP-1 agonists. The prescribing variation which was identified may not only represent differences in the application of clinical guidelines, but also variation in professional opinion or patient preference.

The opinions and experiences of Irish obstetric and gynaecology trainee doctors in relation to abortion services in Ireland.

INTRODUCTION: The provision of abortion services in the Republic of Ireland is legally restricted. Recent legislation that has been implemented allows for abortion if there is a real and substantial risk to the woman's life, but in general Irish women must travel abroad for abortion services. The aims of this study were to investigate the clinical experiences of Irish obstetric non-consultant hospital doctors (NCHDs) that work in this environment and to assess their attitudes towards termination of pregnancy (ToP). METHODS: We conducted an online cross-sectional descriptive survey of 184 Irish obstetric NCHDs. Quantitate and qualitative analysis was performed. RESULTS: There was a 28% response rate. 88% of respondents thought that ToP should be permitted for fatal fetal abnormality if the parents choose, 96% if the woman's health is severely affected and 86% in cases of rape and incest. Over 90% of respondents believed a woman's health suffers because of the need to travel abroad to undergo a ToP. Physical, psychological and social reasons were explored. The research also highlights that obstetric trainees are actively involved in the provision of preabortion and postabortion care. CONCLUSIONS: The clinical experiences and opinions of the respondents suggest that the current legal availability of abortion in Ireland is insufficient to guide best clinical practice and does not represent the views of those that provide obstetric care.