GABAA/benzodiazepine receptor distribution and subunit mRNA expression in human temporal lobe epilepsy

The GABAA/central benzodiazepine receptor (cBZR) complex is a major inhibitory receptor in the vertebrate CNS. A functional impairment of GABAergic inhibition has been proposed as one mechanism which may underlie increased seizure susceptibility in human temporal lobe epilepsy (TLE). The objective of this study was to characterise abnormalities of the GABAA/cBZR in TLE with a correlative autoradiography, in-situ hybridisation, immunohistochemistry and quantitative neuropathology study. Hippocampal tissue was obtained at surgery from patients with intractable TLE due to hippocampal sclerosis (HS) and autopsies of neurologically normal controls. Neuronal densities were obtained using a 3-D counting method in paraffin-embedded sections. Saturation autoradiographic studies were performed on cryostat sections using [3H]-flumazenil and expression of mRNA encoding the α1-α6, β3 and γ2 subunits of the GABAA receptor was assessed using in-situ hybridisation histochemistry. Distribution of the receptor protein was also determined using immunohistochemistry with antibodies to the GABAA α1 and β2/3 subunits. A significant decrease in central benzodiazepine binding sites was demonstrated in all subfields of the human hippocampus in HS. This loss of cBZR binding sites would appear to be due primarily to changes in neuronal density characteristic of this pathology. However, in the CA 1 subfield, a reduced BZ receptor concentration was evident on surviving neurones in the HS group (p<0.05). Expression of mRNA encoding GABAA receptor subunits α1, α2, α4, α5, and γ2, was upregulated in surviving neurones of the granule cell layer of the dentate gyrus in HS. In addition, epilepsy-associated increases in the expression of mRNA encoding the α1 subunit were observed in the hilus and CA2 and α2 mRNA in the hilus and CA1. In contrast, an apparent decrease in expression of β3 mRNA per neurone was detected in CA1 in HS (p<0.07) and of γ2 in the CA2 in HS (p<0.10). These findings imply a functional abnormality of the GABAA/CBZR complex that may have a role in the pathophysiology of epileptogenicity in HS

Electronic prescribing system design priorities for antimicrobial stewardship: a cross-sectional survey of 142 UK infection specialists.

The implementation of electronic prescribing and medication administration (EPMA) systems is a priority for hospitals and a potential component of antimicrobial stewardship (AMS).Accepted manuscript, 12 month embarg

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

An evidence-based surveillance tool to identify and report catheter/cannula bloodstream infection in patients receiving parenteral nutrition.

OBJECTIVE Catheter/cannula-bloodstream infection (CBI) has been proposed as a marker of the quality of care provided to patients receiving parenteral nutrition (PN). However, surveillance criteria for CBI are variable, inconsistent, and sometimes confusing and impractical. Surveillance criteria were developed to simply and accurately demonstrate the presence or absence of CBI. The aim of this study was to establish a simple and valid surveillance tool, with consideration of changes in vital signs, to identify CBI in patients receiving PN. METHODS Adult (≥18 y) inpatients prescribed PN at a single large teaching hospital were recruited between October 11, 2017 and November 16, 2018. Common clinical and laboratory criteria, including blood culture, associated with 100 consecutive PN episodes associated with suspected CBI were examined for potential predictive markers of CBI. Using binary logistic regression, criteria were incorporated into an instrument that was validated against a reference classification of CBI established by an expert multidisciplinary group. RESULTS The reference classification comprised 12 PN episodes with CBI and 88 without. Abnormal vital signs did not significantly predict CBI, but resolution of fever (≥38°C) and low systolic blood pressure (<100 mm Hg) in response to a specific treatment for CBI (line removal/antibiotics) did. Two other criteria were also significant predictors: positive blood culture; and absence of an alternative source that could explain the septic episode other than the catheter/cannula supplying PN. These two criteria together with a positive response to treatment (temperature and/or blood pressure, incorporated into a single binary variable), resulted in 100% correct CBI classification (100% sensitivity, 100% specificity, and 1.000 area under the curve in receiver operating characteristic analysis). All criteria could be retrospectively extracted from the medical records of all PN episodes. CONCLUSION A CBI tool shows promise as a surveillance instrument for benchmarking and interinstitutional comparisons of the care received by hospitalized patients given PN