An international review of the characteristics of viral nucleic acid-amplification testing (NAT) reveals a trend towards the use of smaller pool sizes and individual donation NAT.

BACKGROUND AND OBJECTIVES: Nucleic acid-amplification testing (NAT) is used for screening blood donations/donors for blood-borne viruses. We reviewed global viral NAT characteristics and NAT-yield confirmatory testing used by blood operators. MATERIALS AND METHODS: NAT characteristics and NAT-yield confirmatory testing used during 2019 was surveyed internationally by the International Society of Blood Transfusion Working Party Transfusion-Transmitted Infectious Diseases. Reported characteristics are presented herein. RESULTS: NAT was mainly performed under government mandate. Human immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B virus (HBV) NAT was performed on all donors and donation types, while selective testing was reported for West Nile virus, hepatitis E virus (HEV), and Zika virus. Individual donation NAT was used for HIV, HCV and HBV by ~50% of responders, while HEV was screened in mini-pools by 83% of responders performing HEV NAT. Confirmatory testing for NAT-yield samples was generally performed by NAT on a sample from the same donation or by NAT and serology on samples from the same donation and a follow-up sample. CONCLUSION: In the last decade, there has been a trend towards use of smaller pool sizes or individual donation NAT. We captured characteristics of NAT internationally in 2019 and provide insights into confirmatory testing approaches used for NAT-yields, potentially benefitting blood operators seeking to implement NAT.

International review of blood donation nucleic acid amplification testing.

BACKGROUND AND OBJECTIVES: Nucleic acid amplification testing (NAT), in blood services context, is used for the detection of viral and parasite nucleic acids to reduce transfusion-transmitted infections. This project reviewed NAT for screening blood donations globally. MATERIALS AND METHODS: A survey on NAT usage, developed by the International Society of Blood Transfusion Working Party on Transfusion-transmitted Infectious Diseases (ISBT WP-TTID), was distributed through ISBT WP-TTID members. Data were analysed using descriptive statistics. RESULTS: Forty-three responses were received from 32 countries. Increased adoption of blood donation viral screening by NAT was observed over the past decade. NAT-positive donations were detected for all viruses tested in 2019 (proportion of donations positive by NAT were 0.0099% for human immunodeficiency virus [HIV], 0.0063% for hepatitis C virus [HCV], 0.0247% for hepatitis B virus [HBV], 0.0323% for hepatitis E virus [HEV], 0.0014% for West Nile virus [WNV] and 0.00005% for Zika virus [ZIKV]). Globally, over 3100 NAT-positive donations were identified as NAT yield or solely by NAT in 2019 and over 22,000 since the introduction of NAT, with HBV accounting for over half. NAT-positivity rate was higher in first-time donors for all viruses tested except WNV. During 2019, a small number of participants performed NAT for parasites (Trypanosoma cruzi, Babesia spp., Plasmodium spp.). CONCLUSION: This survey captures current use of blood donation NAT globally. There has been increased NAT usage over the last decade. It is clear that NAT contributes to improving blood transfusion safety globally; however, there is a need to overcome economic barriers for regions/countries not performing NAT.

Population pharmacokinetics of fluconazole in critically ill patients receiving extracorporeal membrane oxygenation and continuous renal replacement therapy: an ASAP ECMO study.

This multicenter study describes the population pharmacokinetics (PK) of fluconazole in critically ill patients receiving concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and includes an evaluation of different fluconazole dosing regimens for achievement of target exposure associated with maximal efficacy. Serial blood samples were obtained from critically ill patients on ECMO and CRRT receiving fluconazole. Total fluconazole concentrations were measured in plasma using a validated chromatographic assay. A population PK model was developed and Monte Carlo dosing simulations were performed using Pmetrics in R. The probability of target attainment (PTA) of various dosing regimens to achieve fluconazole area under the curve to minimal inhibitory concentration ratio (AUC0-24/MIC) >100 was estimated. Eight critically ill patients receiving concomitant ECMO and CRRT were included. A two-compartment model including total body weight as a covariate on clearance adequately described the data. The mean (±standard deviation, SD) clearance and volume of distribution were 2.87 ± 0.63 L/h and 15.90 ± 13.29 L, respectively. Dosing simulations showed that current guidelines (initial loading dose of 12 mg/kg then 6 mg/kg q24h) achieved >90% of PTA for a MIC up to 1 mg/L. None of the tested dosing regimens achieved 90% of PTA for MIC above 2 mg/L. Current fluconazole dosing regimen guidelines achieved >90% PTA only for Candida species with MIC <1 mg/L and thus should be only used for Candida-documented infections in critically ill patients receiving concomitant ECMO and CRRT. Total body weight should be considered for fluconazole dose.

Evaluation of glutamic acid decarboxylase (GAD) 65 antibody detection methods for neurological and diabetic investigation in an Australian diagnostic laboratory.

The role of anti-glutamic acid decarboxylase (GAD) 65 autoantibodies in autoimmune neurological conditions is evolving, but testing recommendations remain unchanged in Australia with GAD enzyme-linked immunosorbent assay (ELISA) and immunoblot as the only two Therapeutic Goods Administration approved testing methods available in Australia. Common practice is for use of ELISA in diagnosis of type 1 diabetes mellitus (T1DM) and use of immunoblot for diagnosis of GAD65-associated neurological disease. We observed a cohort of patients with negative immunoblot results and positive ELISA in the context of GAD-associated neurological disease without T1DM. In the absence of robust consensus guidelines on preferred testing modalities, we sought to determine if ELISA could have a superior role in the diagnosis of GAD-associated neurological disease when compared to immunoblot in this paper. We tested for anti-GAD65 autoantibodies on 55 patient samples, 40 samples requested for neurological disease and 15 type 1 diabetes samples with detectable anti-GAD65, using two testing platforms: Euroimmun anti-GAD enzyme-linked immunosorbent assay (ELISA) and. Euroimmun EuroLine immunoblot for paraneoplastic neurologic syndromes. These results were correlated against the clinical scenario. Positive ELISA results had a sensitivity of 100% and specificity of 91% for GAD65-related neurological disease. Immunoblot showed sensitivity of 43% and specificity of 76% for GAD65-related neurological disease. ELISA proved more sensitive and specific for GAD65-related neurological disease compared to immunoblot, raising questions about the role of this testing modality in neurological disease. We propose that ELISA should be used as a sole diagnostic method for all GAD65 antibody-related neurological disease over immunoblot. The presence of anti-GAD65 antibody on immunoblot is of doubtful clinical significance.

Undeclared pre-exposure or post-exposure prophylaxis (PrEP/PEP) use among syphilis-positive blood donors, England, 2020 to 2021.

An individualised blood donor selection policy was implemented in the United Kingdom from summer 2021. We have investigated the impact of this policy by comparing the extent of undeclared use of HIV pre-exposure or post-exposure prophylaxis (PrEP/PEP) before and after this change. The rate of PrEP usage in syphilis-positive male blood donors has not changed since individualised donor assessment was implemented but provides continuing evidence of undisclosed PrEP use which may be associated with current or past higher-risk sexual behaviours.

Absence of detectable monkeypox virus DNA in 11,000 English blood donations during the 2022 outbreak.

BACKGROUND: A large, worldwide outbreak of mpox (formerly referred to as monkeypox) involving mainly men who have sex with men commenced in May 2022. We evaluated the frequency of positivity for the causative agent, monkeypox virus (MPXV), in blood donations collected in August 2022, during the outbreak period in Southern England. METHODS/MATERIALS: The sensitivity and specificity of an MPXV-specific PCR and a generic non-variola orthopoxvirus (NVO) PCR were evaluated using samples from mpox cases and synthetic DNA standards. Residual minipools from nucleic acid testing were obtained from 10,896 blood donors in Southern England, with 21% from London. RESULTS: MPXV and NVO PCRs were both capable of detection of single copies of target sequence with calculated limits of detection (LOD)90 s of 2.3 and 2.1 DNA copies and analytical sample sensitivities of 46 and 42 MPXV DNA copies/ml, respectively. 454 minipools produced from 10,896 unique donors were assayed for MPXV DNA by both methods. No positive minipools were detected by either PCR. CONCLUSIONS: Although blood donors are unrepresentative of the UK population in terms of MPXV infection risk, the uniformly negative MPXV DNA testing results provide reassurance that MPXV viraemia and potential transmission risk were rare or absent in donors during the outbreak period. Minipools from blood donors allow rapid implementation of large-scale population-based screening for emerging pathogens and represent an important resource for pandemic preparedness.

Blood donor notification of variant Creutzfeldt-Jakob disease risk: Lessons in communicating donor deferral and risk.

BACKGROUND: In 2005, the blood service in England notified 101 donors by letter that they may be at risk of variant Creutzfeldt-Jakob disease (vCJD) because a recipient of their blood later developed vCJD. Donor experience of the notification was studied in a 2009 survey. METHODS: Fifteen questions focused on satisfaction, emotional response and understanding of the notification letter. An average Likert score was calculated: 1 and 2 = dissatisfied, 3 = equivocal and 4 and 5 = satisfied; the per cent satisfied and dissatisfied were calculated and characteristics compared using the Fisher and Chi-squared tests. RESULTS: The questionnaire was completed by 56 of 90 notified donors, mostly repeat, U.K.-born donors over 45 years of age. Four years after notification, many individuals still felt surprise (44%), upset (44%) or worry (50%) about the letter, with 10 feeling depressed. Thirty per cent were uncertain if they had vCJD or not. For future notifications, 57% would still favour a detailed letter and 36% would prefer a discussion in person. DISCUSSION: It was notable how many individuals, 4 years later, still felt continuing anxiety about the vCJD notification letter, not noted in earlier interviews. This highlights a need for on-going support required in donor notifications where outcome for the individual is highly uncertain.

Antimicrobial Exposures in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation.

Rationale: Data suggest that altered antimicrobial concentrations are likely during extracorporeal membrane oxygenation (ECMO). Objectives: The primary aim of this analysis was to describe the pharmacokinetics (PKs) of antimicrobials in critically ill adult patients receiving ECMO. Our secondary aim was to determine whether current antimicrobial dosing regimens achieve effective and safe exposure. Methods: This study was a prospective, open-labeled, PK study in six ICUs in Australia, New Zealand, South Korea, and Switzerland. Serial blood samples were collected over a single dosing interval during ECMO for 11 antimicrobials. PK parameters were estimated using noncompartmental methods. Adequacy of antimicrobial dosing regimens were evaluated using predefined concentration exposures associated with maximal clinical outcomes and minimal toxicity risks. Measurements and Main Results: We included 993 blood samples from 85 patients. The mean age was 44.7 ± 14.4 years, and 61.2% were male. Thirty-eight patients (44.7%) were receiving renal replacement therapy during the first PK sampling. Large variations (coefficient of variation of ⩾30%) in antimicrobial concentrations were seen leading to more than fivefold variations in all PK parameters across all study antimicrobials. Overall, 70 (56.5%) concentration profiles achieved the predefined target concentration and exposure range. Target attainment rates were not significantly different between modes of ECMO and renal replacement therapy. Poor target attainment was observed across the most frequently used antimicrobials for ECMO recipients, including for oseltamivir (33.3%), piperacillin (44.4%), and vancomycin (27.3%). Conclusions: Antimicrobial PKs were highly variable in critically ill patients receiving ECMO, leading to poor target attainment rates. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000559819).

Communicating the move to individualized donor selection policy: Framing messages focused on recipients and safety.

BACKGROUND: Men-who-have-sex-with-men (MSM) have been deferred from donating blood. However, recent evidence supports the adoption of donor screening based on individuals' sexual behavior over population-based criteria. We explore how best to frame communications about adopting this change to minimize any potential negative consequences (e.g., reduced donor numbers). We examine the effectiveness of risk (emphasizing safety vs. emphasizing low risk), and focus (donor vs. recipient) frames on intentions to donate blood (approach) or feeling deterred from donating (avoid), and mechanisms linked to under-reporting sexual behavior. STUDY DESIGN AND METHODS: We conducted a 2 (risk frame: risk vs. safety) by 3 (focus: donor vs. recipient vs. both) between-subjects online experiment (n = 2677). The main outcomes were intentions to donate and feelings of being put-off/deterred from donating (both for self and others). We also assessed the extent that forgetting, embarrassment/shame, and question irrelevance were perceived to be associated with under-reporting sexual behavior. RESULTS: Frames that focused on safety or a recipient resulted in people reporting being less deterred from donating. Regardless of frame, people from ethnic minorities were more likely to feel deterred. Embarrassment/shame followed by forgetting and perceived irrelevance were the main reasons for under-reporting sexual behaviors, especially in ethnic minorities, and smartphones were perceived as an acceptable memory aid for sexual behavior. DISCUSSION: Blood services moving to an individualized policy should frame donor selection in terms of safety and/or a recipient focus, explore sensitivities in ethnic minority communities, consider ways to normalize reporting sexual behavior, and use smartphones as a memory aid.

Fulminant Transfusion-Associated Hepatitis E Virus Infection Despite Screening, England, 2016-2020.

In England, all blood donations are screened in pools of 24 by nucleic acid test (NAT) for hepatitis E virus (HEV) RNA. During 2016-2020, this screening successfully identified and intercepted 1,727 RNA-positive donations. However, review of previous donations from infected platelet donors identified 9 donations in which HEV RNA detection was missed, of which 2 resulted in confirmed transmission: 1 infection resolved with ribavirin treatment, and 1 proceeded to fatal multiorgan failure within a month from infection. Residual risk calculations predict that over the 5-year study period, HEV RNA detection was missed by minipool NAT in 12-23 platelet and 177-354 whole-blood donations, but transmission risk remains undetermined. Although screening has been able to largely eliminate infectious HEV from the blood supply in England, missed detection of low levels of HEV RNA in donated blood can lead to a severe, even fulminant, infection in recipients and could be prevented by more sensitive screening.

People in intensive care with COVID-19: demographic and clinical features during the first, second, and third pandemic waves in Australia.

OBJECTIVE: To compare the demographic and clinical features, management, and outcomes for patients admitted with COVID-19 to intensive care units (ICUs) during the first, second, and third waves of the pandemic in Australia. DESIGN, SETTING, AND PARTICIPANTS: People aged 16 years or more admitted with polymerase chain reaction-confirmed COVID-19 to the 78 Australian ICUs participating in the Short Period Incidence Study of Severe Acute Respiratory Infection (SPRINT-SARI) Australia project during the first (27 February - 30 June 2020), second (1 July 2020 - 25 June 2021), and third COVID-19 waves (26 June - 1 November 2021). MAIN OUTCOME MEASURES: Primary outcome: in-hospital mortality. SECONDARY OUTCOMES: ICU mortality; ICU and hospital lengths of stay; supportive and disease-specific therapies. RESULTS: 2493 people (1535 men, 62%) were admitted to 59 ICUs: 214 during the first (9%), 296 during the second (12%), and 1983 during the third wave (80%). The median age was 64 (IQR, 54-72) years during the first wave, 58 (IQR, 49-68) years during the second, and 54 (IQR, 41-65) years during the third. The proportion without co-existing illnesses was largest during the third wave (41%; first wave, 32%; second wave, 29%). The proportion of ICU beds occupied by patients with COVID-19 was 2.8% (95% CI, 2.7-2.9%) during the first, 4.6% (95% CI, 4.3-5.1%) during the second, and 19.1% (95% CI, 17.9-20.2%) during the third wave. Non-invasive (42% v 15%) and prone ventilation strategies (63% v 15%) were used more frequently during the third wave than during the first two waves. Thirty patients (14%) died in hospital during the first wave, 35 (12%) during the second, and 281 (17%) during the third. After adjusting for age, illness severity, and other covariates, the risk of in-hospital mortality was similar for the first and second waves, but 9.60 (95% CI, 3.52-16.7) percentage points higher during the third than the first wave. CONCLUSION: The demographic characteristics of patients in intensive care with COVID-19 and the treatments they received during the third pandemic wave differed from those of the first two waves. Adjusted in-hospital mortality was highest during the third wave.

The effect of a structured ECPR protocol aided by specific simulation training in a quaternary ECMO centre: A retrospective pre-post study.

Background: There is limited literature exploring the relationship between simulation training and extracorporeal cardiopulmonary resuscitation (ECPR) outcomes. We examined whether there was an association between the implementation of an in situ simulation training program and ECPR utilisation, time to extracorporeal membrane oxygenation (ECMO), and neurologically intact survival. Methods: In this retrospective pre-post study of in-hospital cardiac arrests (IHCA) and out-of-hospital cardiac arrests (OHCA), we analysed data for all patients recorded as receiving ECPR from September 2009 to December 2020 at our institution, relative to the implementation of an in situ ECPR simulation training program and a standardised procedure for high-quality ECPR. The primary outcome was Cerebral Performance Category (CPC) 1 or 2 at hospital discharge. Results: There were 27 patients in the pre-intervention period and 39 patients in the post-intervention period. The median ECPR rate per year was 2 pre-intervention and 7 post-intervention (p = 0.073). There was an association between the implementation of the program and decreased median time from OHCA to ECMO flow, from 87 (IQR 78-95) minutes pre-intervention to 70 (IQR 69-72) minutes post-intervention (p = 0.002). Median time from IHCA to ECMO flow was 40 (IQR 20-75) minutes pre-intervention and 28 (IQR 16-41) minutes post-intervention (p = 0.134). Survival with CPC 1 or 2 was 7/27 (25.9%) pre-intervention and 15/39 (38.5%) post-intervention (p = 0.288). Conclusion: We observed an association between the implementation of an ECPR-specific simulation program and decreased time from OHCA to ECMO flow. There was no association between the implementation of the program and neurologically intact survival at hospital discharge.

Trust and distrust: Identifying recruitment targets for ethnic minority blood donors.

BACKGROUND: We explore the role of trust, distrust, and the prevailing socio-political context to better understand why people from ethnic minority communities are less likely to be blood donors compared to people from White communities. Recruiting more ethnic minority donors will enhance representativeness, reduce inequality, and help meet the clinical need to increase the proportion of blood with Ro Kell antigen to treat Sickle Cell Disease (SCD). STUDY DESIGN AND METHODS: A 2 (donor-status: current donor; non-donors) by 4 (ethnicity: People from Asian, Black, Mixed and White ethnic backgrounds) quasi-experiment (N = 981) was conducted to examine perceptions of trust/distrust and their influence on willingness to donate blood, within the socio-political context of the Windrush scandal and Brexit. RESULTS: We identified five domains of trust ('National Health Service [NHS] and staff,' 'NHS Blood and Transplant,' 'outgroups,' 'individuals' and 'politics'), and a single domain of conditional distrust domain. Trust across all the domains was lower, and 'conditional distrust' higher for ethnic minorities. Trust in 'individuals' and 'NHSBT' predicted willingness to donate in non-donors from ethnic minorities and White non-donors, respectively. Concerns about the Windrush scandal were related to lower political trust. Viewing Brexit as 'positive for the UK' was related to lower trust across domains and reduced willingness to donate in White non-donors through its influence on reduced trust in NHSBT. CONCLUSION: Distinct domains of trust and distrust are identified, and targeting 'trust in others' through conditional cooperation is recommended as a strategy to increase donor numbers from ethnic minority communities.

Population pharmacokinetics of ciprofloxacin in critically ill patients receiving extracorporeal membrane oxygenation (an ASAP ECMO study).

INTRODUCTION: This study aimed to describe the pharmacokinetics (PK) of ciprofloxacin in critically ill patients receiving ECMO and recommend a dosing regimen that provides adequate drug exposure. METHODS: Serial blood samples were taken from ECMO patients receiving ciprofloxacin. Total ciprofloxacin concentrations were measured by chromatographic assay and analysed using a population PK approach with Pmetrics®. Dosing simulations were performed to ascertain the probability of target attainment (PTA) represented by the area under the curve to minimum inhibitory concentration ratio (AUC0-24/MIC) ≥ 125. RESULTS: Eight patients were enrolled, of which three received concurrent continuous venovenous haemodiafiltration (CVVHDF). Ciprofloxacin was best described in a two-compartment model with total body weight and creatinine clearance (CrCL) included as significant predictors of PK. Patients not requiring renal replacement therapy generated a mean clearance of 11.08 L/h while patients receiving CVVHDF had a mean clearance of 1.51 L/h. Central and peripheral volume of distribution was 77.31 L and 90.71 L, respectively. ECMO variables were not found to be significant predictors of ciprofloxacin PK. Dosing simulations reported that a 400 mg 8 -hly regimen achieved > 72% PTA in all simulated patients with CrCL of 30 mL/min, 50 mL/min and 100 mL/min and total body weights of 60 kg and 100 kg at a MIC of 0.5 mg/L. CONCLUSION: Our study reports that established dosing recommendations for critically ill patients not on ECMO provides sufficient drug exposure for maximal ciprofloxacin activity for ECMO patients. In line with non-ECMO critically ill adult PK studies, higher doses and therapeutic drug monitoring may be required for critically ill adult patients on ECMO.

Population Pharmacokinetics and Dosing Simulations of Ceftriaxone in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (An ASAP ECMO Study).

BACKGROUND: Despite the surge in use of extracorporeal membrane oxygenation (ECMO) in the adult intensive care unit, little guidance is available on the appropriate dosing of antimicrobials in this setting. Ceftriaxone is an antimicrobial with a high affinity to plasma protein, a property identified in the literature as susceptible to sequestration into extracorporeal circuits and hypothesised to require dosage adjustments in this setting. OBJECTIVE: The aim of this study was to describe the pharmacokinetics of ceftriaxone and identify the best dosing regimen for critically ill adult patients receiving ECMO. METHODS: Serial blood samples were taken from patients receiving both ECMO and ceftriaxone. Total and unbound drug concentrations were measured in plasma by chromatographic assay and analysed using a population pharmacokinetic approach with Pmetrics®. Dosing simulations were performed to identify the optimal dosing strategy: 60 and 100% of time with free (unbound) drug concentration exceeding the minimum inhibitory concentration (fT>MIC). RESULTS: In total, 14 patients were enrolled, of which three were receiving renal replacement therapy (RRT). Total and unbound ceftriaxone was best described in a two-compartment model with total body weight, serum albumin concentrations, creatinine clearance (CrCL), and the presence of RRT included as significant predictors of pharmacokinetics. Patients not on RRT generated a mean renal clearance of 0.90 L/h, non-renal clearance of 0.33 L/h, and central volume of distribution of 7.94 L. Patients on RRT exhibited a mean total clearance of 1.18 L/h. ECMO variables were not significant predictors of ceftriaxone pharmacokinetics. Steady-state dosing simulations found that dosages of 1 g every 12 h and 2 g every 24 h achieved >90% probabilities of target attainment in patients with CrCL of 0 mL/min with RRT and 30 and 100 mL/min and various serum albumin concentrations (17 and 26 g/L). CONCLUSIONS: Dosing recommendations for critically ill adult patients not on ECMO appear to be sufficient for patients on ECMO. Patients exhibiting augmented renal clearance (> 130 mL/min) or treatment of less susceptible pathogens may require higher doses, which requires further investigation.

Differential ER stress as a driver of cell fate following ricin toxin exposure.

Inhalation of trace amounts of ricin toxin, a plant-derived ribosome-inactivating protein, results in ablation of alveolar macrophages, widespread epithelial damage, and the onset of acute respiratory distress syndrome (ARDS). While ricin's receptors are ubiquitous, certain cell types are more sensitive to ricin-induced cell death than others for reasons that remain unclear. For example, we demonstrate in side-by-side studies that macrophage-like differentiated THP-1 (dTHP-1) cells are hyper-sensitive to ricin, while lung epithelium-derived A549 cells are relatively insensitive, even though both cell types experience similar degrees of translational inhibition and p38 MAPK activation in response to ricin. Using a variety of small molecule inhibitors, we provide evidence that ER stress contributes to ricin-mediated cytotoxicity of dTHP-1 cells, but not A549 cells. On the other hand, the insensitivity of A549 cells to ricin was overcome by the addition of (TNF)-related apoptosis-inducing ligand (TRAIL; CD253), a known stimulator of extrinsic programmed cell death. These results have implications for understanding the complex pathophysiology of ricin-induced ARDS in that they demonstrate that intrinsic (e.g., ER stress) and extrinsic (e.g., TRAIL) factors may ultimately determine the fate of specific cell types following ricin intoxication.

Population Pharmacokinetics of Vancomycin in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation (an ASAP ECMO Study).

Our study aimed to describe the population pharmacokinetics (PK) of vancomycin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO), including those receiving concomitant renal replacement therapy (RRT). Dosing simulations were used to recommend maximally effective and safe dosing regimens. Serial vancomycin plasma concentrations were measured and analyzed using a population PK approach on Pmetrics. The final model was used to identify dosing regimens that achieved target exposures of area under the curve (AUC0-24) of 400-700 mg · h/liter at steady state. Twenty-two patients were enrolled, of which 11 patients received concomitant RRT. In the non-RRT patients, the median creatinine clearance (CrCL) was 75 ml/min and the mean daily dose of vancomycin was 25.5 mg/kg. Vancomycin was well described in a two-compartment model with CrCL, the presence of RRT, and total body weight found as significant predictors of clearance and central volume of distribution (Vc). The mean vancomycin renal clearance and Vc were 3.20 liters/h and 29.7 liters respectively, while the clearance for patients on RRT was 0.15 liters/h. ECMO variables did not improve the final covariate model. We found that recommended dosing regimens for critically ill adult patients not on ECMO can be safely and effectively used in those on ECMO. Loading doses of at least 25 mg/kg followed by maintenance doses of 12.5-20 mg/kg every 12 h are associated with a 97-98% probability of efficacy and 11-12% probability of toxicity, in patients with normal renal function. Therapeutic drug monitoring along with reductions in dosing are warranted for patients with renal impairment and those with concomitant RRT. (This study is registered with the Australian New Zealand Clinical Trials Registry [ANZCTR] under number ACTRN12612000559819.).

Lessons learnt from syphilis-infected blood donors: a timely reminder of missed opportunities.

OBJECTIVE: Due to the increased number of syphilis infections diagnosed in the UK and beyond, we reviewed our data on blood donors infected with syphilis in the UK and Ireland between 2016 and 2019. METHODS: Data were extracted from the surveillance database for all blood donors confirmed positive for syphilis in the UK and Ireland between 2016 and 2019, together with the total number of donations tested during that period. Data on positive cases included gender, age group, reported treatment, symptoms and confirmatory results. All cases were divided into recently acquired within 24 months and past syphilis infection. We also reviewed the information on symptoms characteristic of syphilis reported by blood donors with an untreated syphilis infection during the postdonation discussions. RESULTS: Screening of 8 246 600 blood donations for treponemal antibodies identified 316 blood donors with confirmed syphilis infection in the UK and Ireland between 2016 and 2019 (1.6 per 100 000 donations). 42% of them (133 of 316) were classed as a recent infection based on their donation testing results, previous donation date and clinical history provided, and they were hence considered potentially infectious. Most of these blood donors (202 of 316, 64%) had not been previously diagnosed or treated for syphilis, although 50 of them reported symptoms consistent with syphilis infection and 19 had been misdiagnosed despite seeking medical help. CONCLUSIONS: This observational study shows that syphilis infection remains undiagnosed, especially among heterosexual men, and that infectious syphilis is often missed as a differential diagnosis even when donors have presented with genital or oral ulceration, rashes in the genital area and lymphadenopathy. Considering the recent resurgence of syphilis infections in the UK and beyond and our generally expanding sexual networks, it is important to consider syphilis in differential diagnosis even if specific risk factors have not been identified.

Evidence of HIV pre-exposure or post-exposure prophylaxis (PrEP/PEP) among blood donors: a pilot study, England June 2018 to July 2019.

OBJECTIVE: Due to increased use of pre-exposure prohylaxis (PrEP) and its potential to affect HIV screening of blood donors, we undertook antiretroviral residual testing among HIV-negative male donors in England. METHODS: Residual plasma samples were obtainnd from 46 male donors confirmed positive for syphilis and 96 donors who were repeat reactive for HIV antibodies in screening but confirmed as HIV-negative by reference testing. These were tested for concentrations of tenofovir and emtricitabine by high-performance liquid chromatograhpy coupled with mass spectrometry. RESULTS: We found evidence of pre-exposure or post-exposure prophylaxis (PrEP/PEP) use in three male blood donors confirmed positive for syphilis (3 out of 46 screened, 6.5%). Two were estimated to have taken PrEP/PEP within a day of donating, and the third within 2 days. Two were new donors, whereas one had donated previously but acquired syphilis infection after his last donation. CONCLUSIONS: Our findings indicate that a small proportion of blood donors have not been disclosing PrEP/PEP use and therefore donating in non-compliance to donor eligibility criteria.

Neurological involvement in children with hemolytic uremic syndrome.

Our objective was to establish the rate of neurological involvement in Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS) and describe the clinical presentation, management and outcome. A retrospective chart review of children aged ≤ 16 years with STEC-HUS in Children's Health Ireland from 2005 to 2018 was conducted. Laboratory confirmation of STEC infection was required for inclusion. Neurological involvement was defined as encephalopathy, focal neurological deficit, and/or seizure activity. Data on clinical presentation, management, and outcome were collected. We identified 240 children with HUS; 202 had confirmed STEC infection. Neurological involvement occurred in 22 (11%). The most common presentation was seizures (73%). In the neurological group, 19 (86%) were treated with plasma exchange and/or eculizumab. Of the 21 surviving children with neurological involvement, 19 (91%) achieved a complete neurological recovery. A higher proportion of children in the neurological group had renal sequelae (27% vs. 12%, P = .031). One patient died from multi-organ failure.Conclusion: We have identified the rate of neurological involvement in a large cohort of children with STEC-HUS as 11%. Neurological involvement in STEC-HUS is associated with good long-term outcome (complete neurological recovery in 91%) and a low case-fatality rate (4.5%) in our cohort. What is Known: • HUS is associated with neurological involvement in up to 30% of cases. • Neurological involvement has been reported as predictor of poor outcome, with associated increased morbidity and mortality. What is New: • The incidence of neurological involvement in STEC-HUS is 11%. • Neurological involvement is associated with predominantly good long-term outcome (90%) and a reduced case-fatality rate (4.5%) compared to older reports.