Covariates in population pharmacokinetic studies of critically ill adults receiving ß-lactam antimicrobials: a systematic review and narrative synthesis.

Introduction: Population pharmacokinetic studies of ß-lactam antimicrobials in critically ill patients derive models that inform their dosing. In non-linear mixed-effects modelling, covariates are often used to improve model fit and explain variability. We aimed to investigate which covariates are most commonly assessed and which are found to be significant, along with global patterns of publication. Methods: We conducted a systematic review, searching MEDLINE, Embase, CENTRAL and Web of Science on 01 March 2023, including studies of critically ill adults receiving ß-lactam antimicrobials who underwent blood sampling for population pharmacokinetic studies. We extracted and categorized all reported covariates and assessed reporting quality using the ClinPK checklist. Results: Our search identified 151 studies with 6018 participants. Most studies reported observational cohorts (120 studies, 80%), with the majority conducted in high-income settings (136 studies, 90%). Of the 1083 identified covariate instances, 237 were unique; the most common categories were patient characteristics (n = 404), biomarkers (n = 206) and physiological parameters (n = 163). Only seven distinct commonly reported covariates (CLCR, weight, glomerular filtration rate, diuresis, need for renal replacement, serum albumin and C-reactive protein) were significant more than 20% of the time. Conclusions: Covariates are most commonly chosen based on biological plausibility, with patient characteristics and biomarkers the most frequently investigated. We developed an openly accessible database of reported covariates to aid investigators with covariate selection when designing population pharmacokinetic studies. Novel covariates, such as sepsis subphenotypes, have not been explored yet, leaving a research gap for future work.

Number of CAG repeats and mortality in middle aged and older men.

DESIGN: The androgen receptor (AR) mediates peripheral effects of testosterone. Previous data suggests an association between the number of CAG repeats in exon-1 of the AR gene and AR transcriptional activity. The aim of this analysis was to determine the association between the number of AR CAG repeats and all-cause mortality in men and the influence of testosterone level on the association. PATIENTS AND MEASUREMENTS: Follow-up data to 27 January 2018 were available for men aged 40-79 years recruited across six countries of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios (HR)/95% confidence intervals (CI). RESULTS: One thousand nine hundred and seventy-seven men were followed up. Mean baseline age was 60 ± 11.1 years. Mean duration of follow-up was 12.2 years. At follow up 25.1% of men had died. CAG repeat length ranged from 6 to 39, with the highest proportion of CAG repeat number at 21 repeats (16.4%). In a multivariable model, compared to men with 22-23 AR CAG repeats: for men with <22 and >23 AR CAG HR, 95% CI for mortality were, <22 CAG repeats 1.17 (0.93-1.49) and >23 CAG repeats 1.14 (0.88-1.47). In a post-hoc analysis, the association was significant for men in the lowest tertile of baseline testosterone (<14.2 nmol/L) with >23 CAG repeats: in the adjusted model for <22 and >23 CAG repeats, respectively, 1.49 (0.97-2.27) and 1.68 (1.06-2.67) versus 22-23 repeats. CONCLUSIONS: Our European-wide cohort data overall found no association of androgen receptor CAG repeat number and mortality in men. However, post hoc analysis suggested that an association might be present in men with lower baseline testosterone concentrations, which merits further investigation.

Failure to control conventional cardiovascular risk factors in women with type 2 diabetes might explain worse mortality.

INTRODUCTION: The standardised mortality rate (SMR) for people with diabetes in England is 1.5-1.7, with differences in outcomes between sexes. There has been little work examining the factors that could have an impact on this or on what may determine sex differences in outcome. METHODS: Data were extracted for patients with type 2 diabetes (T2D) in Salford (England) in 2010 for the years up to 2020, including any deaths recorded. Expected deaths were calculated from annual Office of National Statistics mortality rate and life expectancy by age and gender, adjusted for the local Index of Multiple Deprivation (IMD). This provided the SMR deprivation (SMRd), and life expectancy years lost per death (LEYLD). The effects of treatment type, and clinical features on SMRd relative to sex were examined by univariable and multivariable analysis. RESULTS: Data from n = 11,806 (F = 5184; M = 6622) patients were included. Of these, n = 5540 were newly diagnosed and n = 3921 died (F = 1841; M = 2080). In total, n = 78,930 patient years. The expected deaths numbered n = 2596 (adjusted for age, sex, and IMD). Excess deaths were n = 1325 (F = 689; M = 636). Life expectancy years lost (LEYL) 18,989 (F = 9714; M = 9275). SMRd 1.51 (F = 1.60; M = 1.44) and LEYLD 4.84 years (F = 5.28; M = 4.46). The impact of risk factors was not different by sex. However, women had higher prevalence of % diagnosed >65 years of age; % last eGFR <60 mLs/min/1.73 m2 , and lower prevalence of % prescribed ACE-inhibitor/ARB, DPP4-inhibitor and SGLT2-inhibitor. Applying the male prevalence rate to the female population and expected mortality suggested n = 437 (55%) of excess T2D female deaths were attributed to sex difference in the prevalence of these risk and protective factors. CONCLUSIONS: Outcomes in women with T2DM are worse than in men, contributed to by greater prevalence of adverse factors and less prescribing of cardioprotective medication.

Impact of QRS Duration on Non-ST-Segment Elevation Myocardial Infarction (from a National Registry).

QRS duration (QRSd) is ill-defined and under-researched as a prognosticator in patients with non-ST-segment myocardial infarction (NSTEMI). We analyzed 240,866 adult (≥18 years) hospitalizations with non-ST-segment elevation myocardial infarction using data from the United Kingdom Myocardial Infarction National Audit Project. Clinical characteristics and all-cause in-hospital mortality were analyzed according to QRSd, with 38,023 patients presenting with a QRSd >120 ms and 202,842 patients with a QRSd <120 ms. Patients with a QRSd >120 ms were more frequently older (median age of 79 years vs 71 years, p <0.001), and of white ethnicity (93% vs 91%, p <0.001). Patients with a QRSd <120 ms had higher frequency of use of aspirin (97% vs 95%, p <0.001), P2Y12 inhibitor (93% vs 89%, p <0.001), angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (82% vs 81%, p <0.001) and ß blockers (83% vs 78%, p <0.001). Invasive management strategies were more likely to be used in patients with QRSd <120 ms including invasive coronary angiography (72% vs 54%, p <0.001), percutaneous coronary intervention (46% vs 33%, p <0.001) and coronary artery bypass graft surgery (8% vs 6%, p <0.001). In a propensity score matching analysis, there were no differences between the 2 groups in the adjusted rates of in-hospital all-cause mortality (odds ratio 0.94, 95% confidence interval 0.86 to 1.01) or major adverse cardiac events (odds ratio 0.94, 95% confidence interval 0.85 to 1.02) during the index admission. In conclusion, prolonged QRSd >120 ms in the context of non-ST-segment myocardial infarction is not associated with worse in-hospital mortality or the outcomes of major adverse cardiac events.

Investigating the utility of COVID-19 antibody testing in end-stage renal disease patients receiving haemodialysis: a cohort study in the United Kingdom.

BACKGROUND: End-stage renal disease (ESRD) patients receiving haemodialysis (HD) are a vulnerable group of patients with increased mortality from COVID-19. Despite improved understanding, the duration of host immunity following COVID-19 infection and role of serological testing alone or in addition to real-time reverse transcription polymerase chain reaction (rRT-PCR) testing in the HD population is not fully understood, which this study aimed to investigate. METHODS: There were two parts to this study. Between 15th March 2020 to 15th July 2020, patients receiving HD who tested positive on rRT-PCR for SARS-CoV-2 were recruited into the COVID-19 arm, whilst asymptomatic patients without a previous diagnosis of COVID-19 were recruited to the epidemiological arm of the Salford Kidney Study (SKS). All patients underwent monthly testing for anti-SARS-CoV-2 antibodies as per routine clinical practice since August 2020. The aims were twofold: firstly, to determine seroprevalence and COVID-19 exposure in the epidemiological arm; secondly, to assess duration of the antibody response in the COVID-19 arm. Baseline characteristics were reviewed between groups. Statistical analysis was performed using SPSS. Mann-Whitney U and Chi-squared tests were used for testing significance of difference between groups. RESULTS: In our total HD population of 411 patients, 32 were PCR-positive for COVID-19. Of the remaining patients, 237 were recruited into the SKS study, of whom 12 (5.1%) had detectable anti-SARS-CoV-2 antibodies. Of the 32 PCR-positive patients, 27 (84.4%) were symptomatic and 25 patients admitted to hospital due to their symptoms. Of the 22 patients in COVID-19 arm that underwent testing for anti-SARS-CoV-2 IgG antibodies beyond 7 months, all had detectable antibodies. A higher proportion of the patients with COVID-19 were frail compared to patients without a diagnosis of COVID-19 (64.3% vs 34.1%, p = 0.003). Other characteristics were similar between the groups. Over a median follow up of 7 months, a higher number of deaths were recorded in patients with a diagnosis of COVID-19 compared to those without (18.7% vs 5.9%, p = 0.003). CONCLUSIONS: Serological testing in the HD population is a valuable tool to determine seroprevalence, monitor exposure, and guide improvements for infection prevention and control (IPC) measures to help prevent local outbreaks. This study revealed HD patients mount a humoral response detectable until at least 7 months after COVID-19 infection and provides hope of similar protection with the vaccines recently approved.

Transient Musical Hallucinations in a Young Adult Male Associated with Alcohol Withdrawal.

We present the case of a 25-year-old male who presented to A&E with isolated musical hallucinations, in the absence of audiological or neurological disease. The patient had a history of recreational drug use and a family history of psychosis. Hallucinations, which were preceded by discontinuation of alcohol and reinitiation of citalopram for depression, resolved spontaneously after three days. Aetiological factors are discussed alongside the existing literature. Whilst the underlying mechanisms underpinning musical hallucinations remain elusive, the case illustrates the potential role of alcohol withdrawal, serotonin toxicity, recreational drug use, and genetic vulnerability.

Outputs and Growth of Primary Care Databases in the United Kingdom: Bibliometric Analysis.

BACKGROUND: Electronic health database (EHD) data is increasingly used by researchers. The major United Kingdom EHDs are the 'Clinical Practice Research Datalink' (CPRD), 'The Health Improvement Network' (THIN) and 'QResearch'. Over time, outputs from these databases have increased, but have not been evaluated. OBJECTIVE: This study compares research outputs from CPRD, THIN and QResearch assessing growth and publication outputs over a 10-year period (2004-2013). CPRD was also reviewed separately over 20 years as a case study. METHODS:  Publications from CPRD and QResearch were extracted using the Science Citation Index (SCI) of the Thomson Scientific Institute for Scientific Information (Web of Science). THIN data was obtained from University College London and validated in Web of Science. All databases were analysed for growth in publications, the speciality areas and the journals in which their data have been published. RESULTS: These databases collectively produced 1,296 publications over a ten-year period, with CPRD representing 63.6% (n=825 papers), THIN 30.4% (n=394) and QResearch 5.9% (n=77). Pharmacoepidemiology and General Medicine were the most common specialities featured. Over the 9-year period (2004-2013), publications for THIN and QResearch have slowly increased over time, whereas CPRD publications have increased substantially in last 4 years with almost 75% of CPRD publications published in the past 9 years. CONCLUSION: These databases are enhancing scientific research and are growing yearly, however display variability in their growth. They could become more powerful research tools if the National Health Service and general practitioners can provide accurate and comprehensive data for inclusion in these databases.

Research Outputs of England's Hospital Episode Statistics (HES) Database: Bibliometric Analysis.

BACKGROUND: Hospital administrative data, such as those provided by the Hospital Episode Statistics (HES) database in England, are increasingly being used for research and quality improvement. To date, no study has tried to quantify and examine trends in the use of HES for research purposes. OBJECTIVE: To examine trends in the use of HES data for research. METHODS: Publications generated from the use of HES data were extracted from PubMed and analysed. Publications from 1996 to 2014 were then examined further in the Science Citation Index (SCI) of the Thompson Scientific Institute for Science Information (Web of Science) for details of research specialty area. RESULTS: 520 studies, categorised into 44 specialty areas, were extracted from PubMed. The review showed an increase in publications over the 18-year period with an average of 27 publications per year, however with the majority of output observed in the latter part of the study period. The highest number of publications was in the Health Statistics specialty area. CONCLUSION: The use of HES data for research is becoming more common. Increase in publications over time shows that researchers are beginning to take advantage of the potential of HES data. Although HES is a valuable database, concerns exist over the accuracy and completeness of the data entered. Clinicians need to be more engaged with HES for the full potential of this database to be harnessed.

Quality of care in university hospitals in Saudi Arabia: a systematic review.

OBJECTIVES: To identify the key issues, problems, barriers and challenges particularly in relation to the quality of care in university hospitals in the Kingdom of Saudi Arabia (KSA), and to provide recommendations for improvement. METHODS: A systematic search was carried out using five electronic databases, for articles published between January 2004 and January 2015. We included studies conducted in university hospitals in KSA that focused on the quality of healthcare. Three independent reviewers verified that the studies met the inclusion criteria, assessed the quality of the studies and extracted their relevant characteristics. All studies were assessed using the Institute of Medicine indicators of quality of care. RESULTS: Of the 1430 references identified in the initial search, eight studies were identified that met the inclusion criteria. The included studies clearly highlight a need to improve the quality of healthcare delivery, specifically in areas of patient safety, clinical effectiveness and patient-centredness, at university hospitals in KSA. Problems with quality of care could be due to failures of leadership, a requirement for better management and a need to establish a culture of safety alongside leadership reform in university hospitals. Lack of instructions given to patients and language communication were key factors impeding optimum delivery of patient-centred care. Decision-makers in KSA university hospitals should consider programmes and assessment tools to reveal problems and issues related to language as a barrier to quality of care. CONCLUSIONS: This review exemplifies the need for further improvement in the quality of healthcare in university hospitals in KSA. Many of the problems identified in this review could be addressed by establishing an independent body in KSA, which could monitor healthcare services and push for improvements in efficiency and quality of care.