Impact of antibiotic timing on mortality from Gram-negative bacteraemia in an English district general hospital: the importance of getting it right every time.

OBJECTIVES: There is limited evidence that empirical antimicrobials affect patient-oriented outcomes in Gram-negative bacteraemia. We aimed to establish the impact of effective antibiotics at four consecutive timepoints on 30 day all-cause mortality and length of stay in hospital. METHODS: We performed a multivariable survival analysis on 789 patients with Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa bacteraemias. Antibiotic choices at the time of the blood culture (BC), the time of medical clerking and 24 and 48 h post-BC were reviewed. RESULTS: Patients that received ineffective empirical antibiotics at the time of the BC had higher risk of mortality before 30 days (HR = 1.68, 95% CI = 1.19-2.38, P = 0.004). Mortality was higher if an ineffective antimicrobial was continued by the clerking doctor (HR = 2.73, 95% CI = 1.58-4.73, P < 0.001) or at 24 h from the BC (HR = 1.83, 95% CI = 1.05-3.20, P = 0.033) when compared with patients who received effective therapy throughout. Hospital-onset infections, 'high inoculum' infections and elevated C-reactive protein, lactate and Charlson comorbidity index were independent predictors of mortality. Effective initial antibiotics did not statistically significantly reduce length of stay in hospital (-2.98 days, 95% CI = -6.08-0.11, P = 0.058). The primary reasons for incorrect treatment were in vitro antimicrobial resistance (48.6%), initial misdiagnosis of infection source (22.7%) and non-adherence to hospital guidelines (15.7%). CONCLUSIONS: Consecutive prescribing decisions affect mortality from Gram-negative bacteraemia.

A systematic review of adherence to oral pre-exposure prophylaxis for HIV - how can we improve uptake and adherence?

INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) is an effective strategy to reduce the risk of HIV transmission in high risk individuals. However, the effectiveness of oral pre-exposure prophylaxis is highly dependent on user adherence, which some previous trials have struggled to optimise particularly in low and middle income settings. This systematic review aims to ascertain the reasons for non-adherence to pre-exposure prophylaxis to guide future implementation. METHODS: We performed structured literature searches of online databases and conference archives between August 8, 2016 and September 16, 2017. In total, 18 prospective randomized control trials and implementation studies investigating oral pre-exposure prophylaxis were reviewed. A structured form was used for data extraction and findings summarized regarding efficacy, effectiveness, adherence and possible reasons for non-adherence. RESULTS: Adherence varied between differing populations both geographically and socioeconomically. Common reasons for non-adherence reported over multiple studies were; social factors such as stigma, low risk perception, low decision making power, an unacceptable dosing regimen, side effects, and the logistics of daily life. Oral pre-exposure prophylaxis with included antiviral regimens was not associated with a high risk of antiviral resistance development in the reviewed studies. CONCLUSION: Our findings indicate that oral pre-exposure prophylaxis should be delivered within a holistic intervention, acknowledging the other needs of the targeted demographic in order to maximise acceptability. Socioeconomic factors and poor governmental policy remain major barriers to widespread implementation of pre-exposure prophylaxis.

Comment on "A model for phosphate glass topology considering the modifying ion sub-network" [J. Chem. Phys. 140, 154501 (2014)].

In a recent paper, Hermansen, Mauro, and Yue [J. Chem. Phys. 140, 154501 (2014)] applied the temperature-dependent constraint theory to model both the glass transition temperature, Tg, and fragility, m, of a series of binary alkali phosphate glasses of the form R2OxP2O5 1-x, where R represents an alkali species. Key to their success seems to be the retention of linear constraints between the alkali ion (R(+)) and the non-bridging oxygens near Tg, which allows the model to mimic a supposed minimum for both Tg(x) and m(x) located near x = 0.2. However, the authors have overlooked several recent studies that clearly show there is no minimum in m(x). We argue that the retention of the alkali ion constraints at these temperatures is unjustified and question whether the model calculations can be revised to meet the actual experimental data. We also discuss alternative interpretations for the fragility based on two-state thermodynamics that can accurately account for its compositional dependence.

Antithrombotic drugs for cardiovascular risk reduction in patients with lower limb peripheral arterial disease: protocol for a systematic review and network meta-analysis of randomised controlled trials.

INTRODUCTION: The optimal antithrombotic regimen to reduce the risk of vascular events in patients with peripheral arterial disease (PAD) is contentious. This systematic review and network meta-analysis (NMA) aims to define the relative efficacy and risks of previously investigated antithrombotic medication regimens in preventing major cardiovascular events, vascular limb events and mortality in patients with PAD. METHODS AND ANALYSIS: A peer-reviewed, systematic search will be executed in English on Medline, Embase, Cochrane (CENTRAL), Web of Science and Google Scholar databases in late 2022. The WHO International Clinical Trials Registry platform will also be searched for ongoing trials. Abstracts will be screened independently by two researchers for randomised controlled trials meeting the review criteria. All associated publications including the study protocol will be sought and evaluated together against prespecified inclusion/exclusion criteria. Two researchers will extract the data into a prepiloted extraction form. Risk-of-bias assessments will be performed using the Cochrane 'Risk-of-Bias V.2' criteria by individuals with domain expertise. All differences will be resolved by consensus or a third individual for ties.Included trials will be summarised. An NMA will be performed, subject to checks of assumptions. Both primary and secondary outcomes will be analysed on a whole network basis. Pairwise comparisons and league tables will be produced. Prespecified subgroup analyses will include sex, ethnicity, disease status, conservative versus interventional management and key comorbidities. The findings will be evaluated using the Grading of Recommendation Assessment, Development and Evaluation, informed by patient and public involvement work. ETHICS AND DISSEMINATION: This is a systematic review of data in the public domain and does not require ethical approval. Dissemination will include presentations to key vascular and patient organisations, publication in a peer-reviewed journal and an open-access repository of the study data. PROSPERO REGISTRATION NUMBER: CRD42023389262.

Long-term outcome and risk factors for late mortality in Gram-negative bacteraemia: a retrospective cohort study.

OBJECTIVES: The long-term outcomes of patients following Gram-negative bacteraemia (GNB) are poorly understood. Here we describe a cohort of patients with GNB over a 2-year period and determine factors associated with late mortality (death between Days 31 and 365 after detection of bacteraemia). METHODS: This was a single-centre, retrospective, observational cohort study of 789 patients with confirmed Escherichia coli, Klebsiella spp. or Pseudomonas aeruginosa bacteraemia with a follow-up of 1 year. Multivariable survival analysis was used to determine risk factors for late mortality in patients who survived the initial 30-day period of infection. RESULTS: Overall, 1-year all-cause mortality was 36.2%, with 18.1% of patients dying within 30 days and 18.1% of patients suffering late mortality. An adverse antimicrobial resistance profile [hazard ratio (HR) = 1.095 per any additional antimicrobial category, 95% confidence interval (CI) 1.018-1.178; P = 0.014] and infection with P. aeruginosa (HR = 2.08, 95% CI 1.11-3.88; P = 0.022) were independent predictors of late mortality. Other significant factors included Charlson comorbidity index and length of hospitalisation after the index blood culture. CONCLUSION: Patients with GNB have a poor long-term prognosis. Risk factors for greater mortality at 1 year include co-morbidity, length of hospitalisation, and infecting organism and its resistance profile.

Can rescuers accurately deliver subtle changes to chest compression depth if recommended by future guidelines?

BACKGROUND: A recent study reported that a compression depth of 4.56 cm optimised survival following cardiac arrest, which is at variance with the current guidelines of 5.0-6.0 cm. A reduction in recommended compression depth is only likely to improve survival if healthcare professionals can accurately deliver a relatively small change in target depth. This study aimed to determine if healthcare professionals could accurately judge their delivered compression depth by 0.5 cm increments. METHOD: This randomised interventional trial asked BLS-trained healthcare professionals to complete two minutes of continuous chest compressions on an adult manikin, randomised (without any feedback device), to compress to one of three target depth ranges of 4.0-5.0 cm, 4.5-5.5 cm or 5.0-6.0 cm, at the recommended rate of 100-120 compressions min-1. Basic demographic data, compression rate, and compression depth were recorded. RESULTS: One hundred and one participants were recruited, of whom one withdrew. Median depths of 3.66 cm (IQR: 3.37-4.16 cm), 4.13 cm (IQR: 3.65-4.36 cm) and 4.76 cm (IQR: 4.16-5.24 cm) were found for the target depths of 4.0-5.0 cm (n = 30), 4.5-5.5 cm (n = 35) and 5.0-6.0 cm (n = 35) respectively (P < 0.001). Overall, 18 participants successfully compressed to their target depth. CONCLUSIONS: Rescuers are able to judge 0.5 cm differences in compression depth with precision, but remain unable to accurately judge overall target depth. Reducing the current recommended compression depth to 4.56 cm is likely to result in delivered compressions significantly below the optimal depth.

Saving lives with public access defibrillation: A deadly game of hide and seek.

BACKGROUND: Early defibrillation is a critical link in the chain of survival. Public access defibrillation (PAD) programmes utilising automated external defibrillators (AEDs) aim to decrease the time-to-first-shock, and improve survival from out-of-hospital cardiac arrest. Effective use of PADs requires rapid location of the device, facilitated by adequate signage. We aimed to therefore assess the quality of signage for PADs in the community. METHOD: From April 2017 to January 2018 we surveyed community PADs available for public use on the 'Save a Life' AED locator mobile application in and around Southampton, UK. Location and signage characteristics were collected, and the distance from the furthest sign to the AED was measured. RESULTS: Researchers evaluated 201 separate PADs. All devices visited were included in the final analysis. No signage at all was present for 135 (67.2%) devices. Only 15/201 (7.5%) AEDs had signage at a distance from AED itself. In only 5 of these cases (2.5%) was signage mounted more than 5.0 m from the AED. When signage was present, 46 used 2008 ILCOR signage and 15 used 2006 Resuscitation Council (UK) signage. Signage visibility was partially or severely obstructed at 27/66 (40.9%) sites. None of the 45 GP surgeries surveyed used exterior signage or an exterior 24/7 access box. CONCLUSIONS: Current signage of PADs is poor and limits the device effectiveness by impeding public awareness and location of AEDs. Recommendations should promote visible signage within the operational radius of each AED.

Possession of human leucocyte antigen DQ6 alleles and the rate of CD4 T-cell decline in human immunodeficiency virus-1 infection.

Polymorphism amongst the human leucocyte antigen (HLA) class II genes could influence antigen presentation and the ability to control human immunodeficiency virus (HIV)-1 by modulating the virus specific CD4 immune response. To examine the effect of such polymorphisms on disease progression, we studied a cohort of 46 HIV-1 infected long-term non-progressors (LTNPs), 87 intermediate progressors (IPs) and 26 rapid progressors. Kaplan-Meier survival analysis of all patients in the cohort on time to a CD4 count less than 350 cells/ micro l, showed a trend for a slower rate of CD4 decline in patients with, compared to those without, the DRB1*15-DQB1*06 haplotype (hazard ratio (HR) 0.69, 95% CI 0.46-1.01, P = 0.06). A similar effect was not observed with the DRB1*13-DQB1*06 haplotype (HR 1.18, 95% CI 0.75-1.88, P = 0.46), but was observed when DQB1*06 alleles were considered irrespective of their DR association (HR 0.74, 95% CI 0.52-1.05, P = 0.06). Major HLA-DQ6 alleles encode aspartate (Asp) at position 57 on the DQbeta chain, a phenotype associated with protection from other immune disorders. We therefore examined the frequency of all DQbeta57 Asp+ alleles, but could not detect a significant effect on the rate of CD4 decline. To examine whether the genotype associated with slower CD4 decline was over-represented in patients with a slow rate of disease progression, we conducted a categorical analysis of a subset of patients with an extended follow-up of 14+years. We found a higher proportion of LTNPs at 14+ years possessed the DRB1*15-DQB1*06 haplotype compared to IPs at 14+ years (38.46 versus 18.18%), though this difference did not reach statistical significance. When DQB1*06 alleles irrespective of their DR association were considered, the protective effect was greater (76.9% LTNPs versus 18.18% IPs, P = 0.04). Our results highlight the potential protective effect of HLA DQB1*06 alleles on the course of HIV disease.